To complete this series on CD38, here are some outstanding questions and answers.
Why do the numbers of CD38-expressing cells in a CLL clone predict clinical course?
A definite answer to this question is not available at this point; the following is the view of the authors on this issue. CD38 expression is dynamic and indicates the proliferative activity of members of the leukemic clone at the time of analysis. Therefore, it is a “real-time” indicator of the level of leukemic proliferation and thereby actual or potential clonal evolution, which ultimately determines the clinical course and outcome for an individual patient. This evolutionary change can be affected by many parameters; in particular, it can be influenced by stimulation through cell surface receptors for antigens, cytokines, chemokines, etc, within the microenvironment. Simplistically viewed, the more CD38+ cells in a clone, the greater the number of dividing cells and hence the greater the chance for occurrence of new DNA lesions, enhanced clonal aggressiveness, and worse clinical outcome.
Why and how do the numbers of CD38-expressing cells and IGHV mutation status of a CLL clone interrelate and herald clinical course?
IGHV mutation status is a more static marker, indicative of the cell of origin and the maturational events that occurred in the life of the B cell before its leukemic transformation. In particular, the absence or presence of IGHV mutations could report the ability and type of antigen binding that the BCR can accomplish (eg, polyreactive vs oligoreactive vs monoreactive). Antigen binding specificity correlates with outcome because it indicates the breadth of antigenic epitopes that the BCR can engage, the affinity of these engagements, and therefore the likelihood that survival/proliferation signals will be delivered to the CLL cell. It is for these reasons that CD38 expression, which is a reflection of the existing level of cellular activation within a leukemic clone, often correlates with a lack of IGHV somatic mutations, which is more likely to lead to polyspecific binding, cell signaling, and eventual cellular proliferation. Thus, both prognostic indicators can be linked by the common thread of leukemic cell proliferation: IGHV mutations indicating the likelihood of binding multiple antigens and of cellular stimulation and CD38 expression representing the consequence of such binding and stimulation.
What are the advantages of using CD38 clonal percentages as a prognostic marker?
As mentioned, the number of CD38-expressing cells can be considered a real-time indicator of the proliferative activity of a patient's CLL clone. As such, it is a reflection or harbinger of new genomic lesions, which require DNA replication and subsequently of clonal evolution to a more dangerous leukemic variant.
What are the disadvantages of using CD38 clonal percentages as a prognostic marker?
It has been documented that CD38 levels can change over time. Although this change is usually not large (∼ 10%) and more often than not does not overstep the boundaries that mark “better” or “worse” clinical outcome, it can occur. However, when it does, the suggested downside can be actually viewed as a positive feature of this prognostic indicator as an upward trend in CD38-expressing cells may signal clonal evolution to a more aggressive state. Therefore, serial analyses of the percentage of CD38+ cells, real-time indicators of leukemic cell proliferation, can have an additional advantage of indicating a change in clonal behavior.
Is there a role for CD38 SNP analysis?
The C > G SNP identified in the regulatory region is localized within an E-box and conditions the affinity of E2A binding. The consequence is that G carriers up-regulate CD38 in response to environmental signals with a higher efficiency than CC homozygotes. It would be of interest to test, in a retrospective cohort, whether the C > G SNP affects the stability of CD38 expression over time. The prediction based on in vitro observations would be that G carriers up-regulate CD38 more readily in response to specific external signals and then become CD38+. CC homozygotes, on the other hand, would be less prone to do so. If confirmed, this observation would support the clinical usefulness of identifying the CD38 SNP at diagnosis, with closer monitoring of CD38 expression over time selectively in G carriers. In addition, clinical testing for the G allele, one of the few risk factors for RS transformation, may highlight patients more susceptible to this dangerous event.
How can CD38 expression be best used as a prognostic indicator?
The current National Cancer Institute guidelines recommend that treatment be initiated at disease progression (ie, in patients at Binet stage C or Rai stage III or IV). This strategy is suggested because patients are heterogeneous in clinical course and certain patients never progress, often dying of a different disease, whereas others do progress, at times quite rapidly. Thus, to prevent unnecessary treatment of a large segment of affected persons, a watch-and-wait attitude is chosen and treatment is generally delayed until patients become symptomatic. The disadvantage of this understandably prudent approach is that treatment may come too late for those persons requiring it, when a number of unfavorable cytogenetic lesions have already accumulated in CLL subclones. Therefore, the option of early treatment should be carefully considered if markers were available to precisely predict clinical course and progression to select patients based on real treatment requirement. So far, none of the available predictors alone is sufficiently precise to mandate a change in the present therapeutic strategy. In addition, most of the available studies with marker combinations have been carried out retrospectively and in studies where the precise assessment of the value of CD38 can be hampered by the time of marker determination during the clinical course, perhaps because of change that can occur longitudinally.
Despite these limitations, scoring systems involving a multiplicity of markers (eg, IGHV mutations), CD38 and/or ZAP-70 levels, chromosomal abnormalities, p53 mutations, and serum molecules such as β2-microglobulin, can be effective risk assessors and group stratifiers. The issue of markers is covered by a wide literature. These approaches may require further prospective testing to refine and simplify the methods. At this point, the watch-and-wait strategy should be compared with that of early, potentially aggressive treatments in patients randomized into a formal clinical trial and selected for expression of unfavorable prognostic markers.
Is there a role for CD38 as a therapeutic target?
Targeted immunotherapy with mAbs has become critical for the successful treatment of many forms of cancer. This is exemplified by rituximab, a chimeric anti-CD20 mAb, which has revolutionized the treatment of several B-cell malignancies. The main concern about in vivo use of anti-CD38 mAbs is its widespread expression in multiple cell types and differentiation stages, such as early committed BM precursors, activated T cells, and cells of the innate immune response. Another serious drawback is the presence of CD38 in the brain, pancreas, and retina, although the earliest hematopoietic stem cells do not appear to express CD38. Another potentially useful approach could rely on the use of inhibitors of the enzymatic activities of CD38, even if experience is so far limited.
These intrinsic limits, however, have not prevented the design of models for in vivo applications. In the past, several Abs to human CD38 have been generated that induce killing of neoplastic B-cell lines. Two CD38 mAbs are currently in clinical development: a humanized mAb (SAR650984, http://clinicaltrialsfeeds.org/clinical-trials/show/NCT01084252) and a human mAb (daratumumab). Ongoing clinical trials will determine whether these reagents are effective (alone or in combination) and at the same time safe.
Wednesday, October 19, 2011
Italian Guidelines
In its mandate to promote the best hematological care, the Italian Society of Hematology (SIE) and the affiliate societies SIES (Società Italiana di Ematologia Sperimentale) and GITMO (Gruppo Italiano Trapianto di Midollo Osseo) issued guidelines for the management of patients with CLL in 2006. They have now updated these guidelines in Leukemia Research.
Recommendations
In order to plan an optimal clinical management, they recommended that the following information should be obtained at the time of CLL diagnosis: serum lactate dehydrogenase and β2-microglobulin level; imaging of adenomegalies as assessed either by total body computed tomography or by the combination of chest X-ray and abdomen ultrasound; direct Coombs’ test in patients with anemia.
Del [11q], del [17p] and the IgVH mutational profile should be investigated, especially in patients who are eligible for more intensive treatments. In patients with no del [17p], testing of p53 deletions or mutations is recommended.
The indication for treatment initiation includes the presence of at least one of the following features: B symptoms (i.e. fever, sweats, fatigue or weight loss), rapid lymphocyte doubling time, progressive enlargement of lymph nodes or hepatosplenomegaly, obstructive adenopathy, development or worsening of thrombocytopenia or anemia, immune hemolysis or thrombocytopenia not responsive to steroids.
In the clinical practice, the presence of an unfavourable biologic profile is not a reason to start treatment when the disease is in an early stage and clinically stable.
In patients with no treatment indication, a disease monitoring should be made at least every 6 months and should include: physical examination, hematologic evaluation and biochemistry, including serum lactate dehydrogenasis and β2-microglobulin. Patients with a poor prognostic biologic profile or clinical signs of a more aggressive disease should be evaluated more frequently, at least every 3 months. An abdominal ultrasound should be monitored every 6–12 months. Chest X-ray should be evaluated when informative at diagnosis.
Before starting treatment, the following information should be obtained in order to evaluate the more appropriate treatment approach: physical examination, performance status, co-morbidity assessment, peripheral blood count with morphologic examination, when required, bone marrow evaluation, serum biochemistry including serum lactate dehydrogenasis and β2-microglobulin, Coombs’ test, imaging of adenomegalies, assessed either by CT scan or by the combination of chest X-ray and abdomen ultrasound.
Treatment Recommendations
In summary, even though superior CR and OR rates were observed across all trials comparing fludarabine with chlorambucil, no advantage in terms of PFS and OS were demonstrated in 2 out of 3 analyzed trials. The panel, concluded that first-line therapy with fludarabine given as a single agent had better benefit/risk profile compared with chlorambucil in younger patients but not in elderly patients where fludarabine was associated with a higher myelotoxicity and no advantage in terms of PFS and OS.
Should fludarabine monotherapy or fludarabine plus cyclophosphamide combination therapy be preferred to chlorambucil monotherapy in first- line therapy for previously untreated CLL patients? Recommendation - Use it, weak positive evidence.
Bendamustine and chlorambucil given as single agents were compared in a RCT including 319 patients with B or C Binet stage. Bendamustine arm yielded a higher OR rate (68% vs. 31%) and CR rate (31% vs. 3%) than chlorambucil arm. Furthermore, the median PFS was superior for bendamustine than chlorambucil arm (21.6 vs. 8.3 months). However, severe infections were more frequently observed in bendamustine than in chlorambucil-treated patients (8% vs. 3%). The strength of evidence was judged weak due to the fact that a single trial could not make consistency of the results possible (weak positive). The EP judged that the benefit of using bendamustine instead of chlorambucil as first line treatment of patients with CLL results in a better clinical benefit/risk ratio.
Should bendamustine be preferred to chlorambucil in first-line therapy for previously untreated CLL patients? Recommendation Use it, weak positive evidence.
Alemtuzumab was compared with chlorambucil in a RCT (CAM307. Patients treated with alemtuzumab obtained a significantly higher CR rate (24.2% vs. 2%) and median PFS (14.6 vs. 11.7 months) than patients treated with chlorambucil. However, serious drug-related AEs were more common in patients treated with alemtuzumab (26.5% vs. 6.8%). The EP deemed a higher activity of alemtuzumab as compared to chlorambucil. However, the EP judged that the benefit of alemtuzumab was offset by an increase in the toxicity.
Should alemtuzumab monotherapy be preferred to chlorambucil in first-line therapy for previously untreated CLL patients? Recommendation Probably don’t use it, weak negative evidence.
Since the publication of the last SIE guidelines in 2006, the results of two RCTs comparing FC combination to fludarabine as single agent have been published. Both studies demonstrated the superiority of FC in terms of CR rate and PFS. Moreover, a meta-analysis performed by Catovsky et al. focused on the published RCTs comparing FC combination versus fludarabine monotherapy confirmed the superiority of FC schedule in terms of PFS. On this basis, the panel judged that the benefit/risk ratio of using FC combination was higher than that proved by fludarabine given as single agent.
Non RCTs evaluated alternative FC schedules and were also discussed by the EP, even though they were not considered for the strength of evidence. Two trials proved the efficacy and safety of the oral FC schedule. In a Spanish study the addition of mitoxantrone to the FC combination resulted in a high response rate (90%).
Should fludarabine-cyclophosphamide combination be preferred to fludarabine monotherapy in first- line therapy for previously untreated CLL patients? Recommendation Probably use it, weak positive evidence.
The efficacy of cladribine as single agent or in combination with other drugs has been investigated by the Polish Adult Leukemia Group. Front-line cladribine-cyclophosphamide-mitoxantrone (CCM) combination was associated with a higher CR rate as compared to cladribine-cyclophosphamide (CC) or cladribine (C) monotherapy. However CCM regimen showed no advantage in terms of PFS and OS and was associated with a higher myelotoxicity. In a more recent RCT including previously untreated patients, no significant differences in the CR rates, PFS, OS and severe AEs were observed between patients treated with CC or FC. Both combinations proved unsatisfactory activity in patients with deletion 17p-. Due to the patient sample size and the short follow-up, the evidence provided by these studies was judged too weak by the EP to formulate a recommendation.
In a open-label randomized trial by the GCLLSG, the activity and safety of FC regimen (409 patients) was compared to that of FC plus rituximab (FCR; 408 patients). The primary end-point of the study was PFS. FCR was more effective than FC in terms of CR rate (44% vs. 22%), PFS (at 3 years: 65% vs. 45%) and OS (at 3 years: 87% vs. 83%). Despite the higher rate of grade 3–4 granulocytopenia, FCR was not associated with a significant increase in the infection rate. In addition, no differences in the health related quality of life were noted between the 2 arms. The presence of deletion 17p- was the strongest unfavourable prognostic variable for both PFS and OS. The evidence derived from this trial was judged of good quality and on this basis, the EP produced a strong positive recommendation in favour of front-line FCR for CLL patients with good physical fitness.
Should Rituximab be added to FC in first- line therapy for previously untreated CLL patients? Recommendation Use it, strong positive evidence.
Treatment options for patients with deletion 17p- and/or p53 mutations were separately discussed. In the study by Hillmen et al., previously untreated patients with deletion 17p- showed a better OR rate with alemtuzumab than with chlorambucil (64 vs. 20%). In a study by Stilgenbauer et al. presented in an abstract form at the 2010 ASH meeting, 25 previously untreated patients with del [17p] showed a very high OR rate (96%) with 24% CR rate after a front-line treatment including alemtuzumab and dexamethasone. In a study by the GIMEMA group presented in an abstract form at the same meeting, fludarabine and alemtuzumab combination (FluCam) was investigated in 43 younger patients with an adverse biologic profile. The CR rate for the 9 patients with del [17p] included in this study was 46%.
Recommendation
Younger CLL patients and selected older patients with a good performance status, no clinically significant co-morbidities and with no deletion 17p-and/or p53 mutations, should receive FCR regimen.
Patients not eligible for FCR regimen should be treated with a less toxic regimen in order to pursue a control of the diseases and a good quality of life, while preserving overall survival. Chlorambucil, bendamustine, fludarabine, cladribine, as single agents, fludarabine or cladribine associated with cyclophosphamide have been tested in RCTs and there is evidence of the efficacy and safety of use. The lack of RCTs, the small sample size or the poor directness of the existing evidence, do not allow to grade alternative treatment options that have demonstrated efficacy and safety such as fludarabine and rituximab schedule, modified FCR regimens (FCR lite, FCR according to Sloan Kettering), pentostatin including regimen (PCR), chlorambucil or bendamustine combined with rituximab.
In patients with del [17p] and/or p53 mutations and active disease the EP agreed that the use of alemtuzumab-based treatments should be preferred. In younger patients with del [17p] and/or p53 mutations, adequate fitness status and no significant co-morbidities, the strategy approach should include an allogeneic SCT.
Monitoring
Patients in clinical CR or PR after therapy should have the following parameters assessed during follow-up: physical examination (every 3–6 months), peripheral blood count (every 3–6 months), imaging of abdomen every 6–12 months.
Minimal residual disease (MRD) assessment performed by any method on bone marrow is not recommended since the eradication of MRD cannot be considered a therapeutic goal for all patients outside clinical trials.
Consolidation
Only one randomized controlled trial tackled the key question of appropriateness of a consolidation therapy in CLL. Patients in CR or PR after fludarabine or FC first-line treatment were randomized to receive alemtuzumab or only clinical observation. The primary endpoint was the PFS. The trial was prematurely stopped after the enrolment of the first 21 patients because of a severe infection rate in the alemtuzumab group. However, the PFS at month 36 after randomization was 81.8% for patients in the alemtuzumab arm vs. 20.6% in the observation arm. On the basis of these results and data derived from a non RCT the EP deemed that at present there was no evidence that patients in CR or PR may benefit from a consolidation treatment and provided the following recommendations: The panel agreed that at present a consolidation/maintenance treatment approach in CLL patients should be undertaken only in the setting of controlled clinical trials.
Relapsed and refractory patients
Robak et al. randomized 552 patients (≤70 years: 83% of patients) who had received one prior line of therapy. Eligible patients were required to be sensitive (55% of patients) or refractory (27% of patients) to prior alkylating agents but had to be sensitive to fludarabine (prior responses ≥6 months; 17% of patients). A prior treatment with interferon, rituximab, other monoclonal antibodies, alkylators/nucleoside analogues combinations or transplantation was not allowed. Patients treated with FCR showed a significantly higher PFS than patients treated with FC (median PFS, FCR vs. FC: 30.6 vs. 20.6 months). The CR rate was also in favour of the FCR group. Of note, both Binet stage B and C patients benefited from FCR, as did patients with high lymphocyte count, poor renal function, poor prognostic factors such as del [11q], unmutated IgVH, positive ZAP-70 while no benefit emerged for patients with del [17p]. Univariate and multivariate Cox regression analyses for PFS confirmed the advantage of FCR over FC. The AEs rate leading to dose modification or treatment interruption were 39% for the FCR group and 51% for the FC group. The evidence was graded as strong and the EP decided that the benefit of using FCR rather than FC in patients relapsed or refractory after single agent therapy overcome the risks.
In order to analyze the effect of the prior therapy on the response to FCR, Badoux et al. explored the efficacy of FCR given to 284 patients beyond first relapse. The overall RR in patients who were previously exposed to a single agent such as rituximab, fludarabine, alkylating agents were 92%, 90%, 78%, respectively, while the response rate of patients previously exposed to fludarabine combined with an alkylating agent was 73%. Patients refractory to fludarabine and those who had received more than three prior therapies, experienced short PFS. Del [17p] was also an adverse factor for PFS. Moreover, elderly patients were less likely to complete more than three courses of FCR, had a lower CR rate and experienced more infectious complications. Taken together these data suggest that FCR is an effective treatment option in relapsed and fit patients without del [17p].
Engert et al. presented at the 2010 ASH meeting the results of a multicentre randomized study including 335 relapsed or refractory patients after one prior regimen that included fludarabine in only 15% of the cases. Patients were randomized to receive fludarabine as single agent or fludarabine and alemtuzumab (FluCam) combination. Patients treated with FluCam showed a better outcome in terms of CR rate (12.5% vs. 4%) and PFS (24 vs. 18 months) with a similar infection rate.
Should R-FC be preferred to FC in previously treated CLL patients? Recommendation Use it, weak positive evidence
Oblimerson
In a RCT including 241 patients with relapsed or refractory CLL after one prior first line fludarabine, patients were randomized to receive FC or FC plus oblimersen. Patients treated with FC-oblimersen showed a better response rate (17% vs. 7%). However, the OS between the 2 groups was not significantly different. The evidence was graded as weak.
Should oblimersen plus fludarabine and cyclophosphamide be preferred to fludarabine and cyclophosphamide in previously treated CLL patients? Recommendation Probably don’t use it, weak negative evidence
Allogeneic stem cell transplantation (SCT)
No prospective RCTs comparing allogeneic SCT to conventional chemotherapy or immunochemotherapy have been carried out in the setting of CLL patients. Phase II studies with a follow-up longer than 2 years were considered by the EP. Among these, the study by Dreger et al. including 90 poor risk CLL patients, ≤65 years, who underwent allogeneic SCT. The CR and overall response rates were 73% and 94%, respectively. The OS, relapse rate and EFS at 4 years were 65%, 40% and 42%, respectively.
Sorror et al. treated 82 patients (median age, 56 years) with fludarabine-refractory CLL with a conditioning regimen including 2 Gy TBI alone or combined with fludarabine followed by an allogeneic SCT from a related (52 patients) or unrelated (30 patients) donor. A CR and a PR were observed in 55% and 15% of patients respectively. After a median follow-up of 5 years, the non transplant related mortality (NTRM), the OS and the PFS were 23%, 50% and 39%, respectively.
A retrospective analysis of the European Blood and Marrow Transplantation Group (EBMTR) included 44 patients (median age, 54 years) with deletion 17 p-. Patients received an allogeneic SCT after a median number of 3 prior treatments. The OS, PFS, and NTRM at 3 years were 44%, 37% and 32%, respectively.
Treatment options for patients refractory to a prior fludarabine-based treatment, patients with early relapse and patients with del [17p] and/or p53 mutations.
In an analysis from the GCLLSG CLL8 trial comparing FC and FCR regimens an inverse relationship between response duration and survival probability has been observed. The median OS of patients with a PFS lower than 12 months (47 patients), between 12 and 24 months (45 patients) or higher than 24 months from the time point of a second-line treatment, were 13.1, 20.3 and 44.6 months, respectively (p< 0.01). These findings indicate that the small subgroup of patients who relapse within 24 months after a fludarabine based treatment is characterized by a very poor prognosis.
Second-line treatment options for this subgroup of patients have been separately discussed. The evidence derived from subgroup analysis of comparative trials carried on relapsed or refractory patients was integrated by the EP with the results of phase II non RCTs. Stilgenbauer et al. reported an OR rate of 34% with a median PFS of 8 months in 103 fludarabine-refractory patients treated with alemtuzumab given as single agent. The OR rate of the 31 patients with del [17p] included in this study was 39% with a median PFS of 6 months. In a study presented in an abstract form at the 2010 ASH meeting by the same Author, alemtuzumab and dexamethasone combination was given to 23 fludarabine-refractory patients and to 12 patients with del [17p] treated in first relapse. The OR rate was 56% for the fludarabine-refractory patients and 75% for the relapsed patients with del [17p].
Recently, a new anti-CD20 monoclonal antibody, ofatumumab has been investigated by Wierda et al. in a non RCT including patients with CLL refractory to both fludarabine and alemtuzumab or refractory to fludarabine with bulky lymphadenopathy. The OR rates in the two groups were 58% and 47%, respectively. The median PFS and OS were 5.7 months and 13.7 months, respectively, for the first group, 5.9 and 15.4 months, respectively, for the second group. Survival parameters seemed to be higher than those reported from a historical assessment of other salvage therapies in a corresponding group of patients.
Recommendations
In patients requiring a second-line treatment, del [17p] and/or p53 mutations should be checked. In patients with no del [17p] and/or p53 mutations and relapsed after 24 months, the same front-line therapy including rituximab can be considered.
In patients with del [17p] and/or p53 mutations, in patients refractory or relapsed within 24 months from a fludarabine-based treatment, alemtuzumab containing regimens, or experimental treatment approaches within controlled trials should be given.
Furthermore, in poor prognosis younger patients with adequate fitness status and no significant co-morbidities, a treatment approach including an allogeneic SCT, from either a sibling or well-matched unrelated donor, should be offered after an appropriate cytoreductive treatment.
Recommendations
In order to plan an optimal clinical management, they recommended that the following information should be obtained at the time of CLL diagnosis: serum lactate dehydrogenase and β2-microglobulin level; imaging of adenomegalies as assessed either by total body computed tomography or by the combination of chest X-ray and abdomen ultrasound; direct Coombs’ test in patients with anemia.
Del [11q], del [17p] and the IgVH mutational profile should be investigated, especially in patients who are eligible for more intensive treatments. In patients with no del [17p], testing of p53 deletions or mutations is recommended.
The indication for treatment initiation includes the presence of at least one of the following features: B symptoms (i.e. fever, sweats, fatigue or weight loss), rapid lymphocyte doubling time, progressive enlargement of lymph nodes or hepatosplenomegaly, obstructive adenopathy, development or worsening of thrombocytopenia or anemia, immune hemolysis or thrombocytopenia not responsive to steroids.
In the clinical practice, the presence of an unfavourable biologic profile is not a reason to start treatment when the disease is in an early stage and clinically stable.
In patients with no treatment indication, a disease monitoring should be made at least every 6 months and should include: physical examination, hematologic evaluation and biochemistry, including serum lactate dehydrogenasis and β2-microglobulin. Patients with a poor prognostic biologic profile or clinical signs of a more aggressive disease should be evaluated more frequently, at least every 3 months. An abdominal ultrasound should be monitored every 6–12 months. Chest X-ray should be evaluated when informative at diagnosis.
Before starting treatment, the following information should be obtained in order to evaluate the more appropriate treatment approach: physical examination, performance status, co-morbidity assessment, peripheral blood count with morphologic examination, when required, bone marrow evaluation, serum biochemistry including serum lactate dehydrogenasis and β2-microglobulin, Coombs’ test, imaging of adenomegalies, assessed either by CT scan or by the combination of chest X-ray and abdomen ultrasound.
Treatment Recommendations
In summary, even though superior CR and OR rates were observed across all trials comparing fludarabine with chlorambucil, no advantage in terms of PFS and OS were demonstrated in 2 out of 3 analyzed trials. The panel, concluded that first-line therapy with fludarabine given as a single agent had better benefit/risk profile compared with chlorambucil in younger patients but not in elderly patients where fludarabine was associated with a higher myelotoxicity and no advantage in terms of PFS and OS.
Should fludarabine monotherapy or fludarabine plus cyclophosphamide combination therapy be preferred to chlorambucil monotherapy in first- line therapy for previously untreated CLL patients? Recommendation - Use it, weak positive evidence.
Bendamustine and chlorambucil given as single agents were compared in a RCT including 319 patients with B or C Binet stage. Bendamustine arm yielded a higher OR rate (68% vs. 31%) and CR rate (31% vs. 3%) than chlorambucil arm. Furthermore, the median PFS was superior for bendamustine than chlorambucil arm (21.6 vs. 8.3 months). However, severe infections were more frequently observed in bendamustine than in chlorambucil-treated patients (8% vs. 3%). The strength of evidence was judged weak due to the fact that a single trial could not make consistency of the results possible (weak positive). The EP judged that the benefit of using bendamustine instead of chlorambucil as first line treatment of patients with CLL results in a better clinical benefit/risk ratio.
Should bendamustine be preferred to chlorambucil in first-line therapy for previously untreated CLL patients? Recommendation Use it, weak positive evidence.
Alemtuzumab was compared with chlorambucil in a RCT (CAM307. Patients treated with alemtuzumab obtained a significantly higher CR rate (24.2% vs. 2%) and median PFS (14.6 vs. 11.7 months) than patients treated with chlorambucil. However, serious drug-related AEs were more common in patients treated with alemtuzumab (26.5% vs. 6.8%). The EP deemed a higher activity of alemtuzumab as compared to chlorambucil. However, the EP judged that the benefit of alemtuzumab was offset by an increase in the toxicity.
Should alemtuzumab monotherapy be preferred to chlorambucil in first-line therapy for previously untreated CLL patients? Recommendation Probably don’t use it, weak negative evidence.
Since the publication of the last SIE guidelines in 2006, the results of two RCTs comparing FC combination to fludarabine as single agent have been published. Both studies demonstrated the superiority of FC in terms of CR rate and PFS. Moreover, a meta-analysis performed by Catovsky et al. focused on the published RCTs comparing FC combination versus fludarabine monotherapy confirmed the superiority of FC schedule in terms of PFS. On this basis, the panel judged that the benefit/risk ratio of using FC combination was higher than that proved by fludarabine given as single agent.
Non RCTs evaluated alternative FC schedules and were also discussed by the EP, even though they were not considered for the strength of evidence. Two trials proved the efficacy and safety of the oral FC schedule. In a Spanish study the addition of mitoxantrone to the FC combination resulted in a high response rate (90%).
Should fludarabine-cyclophosphamide combination be preferred to fludarabine monotherapy in first- line therapy for previously untreated CLL patients? Recommendation Probably use it, weak positive evidence.
The efficacy of cladribine as single agent or in combination with other drugs has been investigated by the Polish Adult Leukemia Group. Front-line cladribine-cyclophosphamide-mitoxantrone (CCM) combination was associated with a higher CR rate as compared to cladribine-cyclophosphamide (CC) or cladribine (C) monotherapy. However CCM regimen showed no advantage in terms of PFS and OS and was associated with a higher myelotoxicity. In a more recent RCT including previously untreated patients, no significant differences in the CR rates, PFS, OS and severe AEs were observed between patients treated with CC or FC. Both combinations proved unsatisfactory activity in patients with deletion 17p-. Due to the patient sample size and the short follow-up, the evidence provided by these studies was judged too weak by the EP to formulate a recommendation.
In a open-label randomized trial by the GCLLSG, the activity and safety of FC regimen (409 patients) was compared to that of FC plus rituximab (FCR; 408 patients). The primary end-point of the study was PFS. FCR was more effective than FC in terms of CR rate (44% vs. 22%), PFS (at 3 years: 65% vs. 45%) and OS (at 3 years: 87% vs. 83%). Despite the higher rate of grade 3–4 granulocytopenia, FCR was not associated with a significant increase in the infection rate. In addition, no differences in the health related quality of life were noted between the 2 arms. The presence of deletion 17p- was the strongest unfavourable prognostic variable for both PFS and OS. The evidence derived from this trial was judged of good quality and on this basis, the EP produced a strong positive recommendation in favour of front-line FCR for CLL patients with good physical fitness.
Should Rituximab be added to FC in first- line therapy for previously untreated CLL patients? Recommendation Use it, strong positive evidence.
Treatment options for patients with deletion 17p- and/or p53 mutations were separately discussed. In the study by Hillmen et al., previously untreated patients with deletion 17p- showed a better OR rate with alemtuzumab than with chlorambucil (64 vs. 20%). In a study by Stilgenbauer et al. presented in an abstract form at the 2010 ASH meeting, 25 previously untreated patients with del [17p] showed a very high OR rate (96%) with 24% CR rate after a front-line treatment including alemtuzumab and dexamethasone. In a study by the GIMEMA group presented in an abstract form at the same meeting, fludarabine and alemtuzumab combination (FluCam) was investigated in 43 younger patients with an adverse biologic profile. The CR rate for the 9 patients with del [17p] included in this study was 46%.
Recommendation
Younger CLL patients and selected older patients with a good performance status, no clinically significant co-morbidities and with no deletion 17p-and/or p53 mutations, should receive FCR regimen.
Patients not eligible for FCR regimen should be treated with a less toxic regimen in order to pursue a control of the diseases and a good quality of life, while preserving overall survival. Chlorambucil, bendamustine, fludarabine, cladribine, as single agents, fludarabine or cladribine associated with cyclophosphamide have been tested in RCTs and there is evidence of the efficacy and safety of use. The lack of RCTs, the small sample size or the poor directness of the existing evidence, do not allow to grade alternative treatment options that have demonstrated efficacy and safety such as fludarabine and rituximab schedule, modified FCR regimens (FCR lite, FCR according to Sloan Kettering), pentostatin including regimen (PCR), chlorambucil or bendamustine combined with rituximab.
In patients with del [17p] and/or p53 mutations and active disease the EP agreed that the use of alemtuzumab-based treatments should be preferred. In younger patients with del [17p] and/or p53 mutations, adequate fitness status and no significant co-morbidities, the strategy approach should include an allogeneic SCT.
Monitoring
Patients in clinical CR or PR after therapy should have the following parameters assessed during follow-up: physical examination (every 3–6 months), peripheral blood count (every 3–6 months), imaging of abdomen every 6–12 months.
Minimal residual disease (MRD) assessment performed by any method on bone marrow is not recommended since the eradication of MRD cannot be considered a therapeutic goal for all patients outside clinical trials.
Consolidation
Only one randomized controlled trial tackled the key question of appropriateness of a consolidation therapy in CLL. Patients in CR or PR after fludarabine or FC first-line treatment were randomized to receive alemtuzumab or only clinical observation. The primary endpoint was the PFS. The trial was prematurely stopped after the enrolment of the first 21 patients because of a severe infection rate in the alemtuzumab group. However, the PFS at month 36 after randomization was 81.8% for patients in the alemtuzumab arm vs. 20.6% in the observation arm. On the basis of these results and data derived from a non RCT the EP deemed that at present there was no evidence that patients in CR or PR may benefit from a consolidation treatment and provided the following recommendations: The panel agreed that at present a consolidation/maintenance treatment approach in CLL patients should be undertaken only in the setting of controlled clinical trials.
Relapsed and refractory patients
Robak et al. randomized 552 patients (≤70 years: 83% of patients) who had received one prior line of therapy. Eligible patients were required to be sensitive (55% of patients) or refractory (27% of patients) to prior alkylating agents but had to be sensitive to fludarabine (prior responses ≥6 months; 17% of patients). A prior treatment with interferon, rituximab, other monoclonal antibodies, alkylators/nucleoside analogues combinations or transplantation was not allowed. Patients treated with FCR showed a significantly higher PFS than patients treated with FC (median PFS, FCR vs. FC: 30.6 vs. 20.6 months). The CR rate was also in favour of the FCR group. Of note, both Binet stage B and C patients benefited from FCR, as did patients with high lymphocyte count, poor renal function, poor prognostic factors such as del [11q], unmutated IgVH, positive ZAP-70 while no benefit emerged for patients with del [17p]. Univariate and multivariate Cox regression analyses for PFS confirmed the advantage of FCR over FC. The AEs rate leading to dose modification or treatment interruption were 39% for the FCR group and 51% for the FC group. The evidence was graded as strong and the EP decided that the benefit of using FCR rather than FC in patients relapsed or refractory after single agent therapy overcome the risks.
In order to analyze the effect of the prior therapy on the response to FCR, Badoux et al. explored the efficacy of FCR given to 284 patients beyond first relapse. The overall RR in patients who were previously exposed to a single agent such as rituximab, fludarabine, alkylating agents were 92%, 90%, 78%, respectively, while the response rate of patients previously exposed to fludarabine combined with an alkylating agent was 73%. Patients refractory to fludarabine and those who had received more than three prior therapies, experienced short PFS. Del [17p] was also an adverse factor for PFS. Moreover, elderly patients were less likely to complete more than three courses of FCR, had a lower CR rate and experienced more infectious complications. Taken together these data suggest that FCR is an effective treatment option in relapsed and fit patients without del [17p].
Engert et al. presented at the 2010 ASH meeting the results of a multicentre randomized study including 335 relapsed or refractory patients after one prior regimen that included fludarabine in only 15% of the cases. Patients were randomized to receive fludarabine as single agent or fludarabine and alemtuzumab (FluCam) combination. Patients treated with FluCam showed a better outcome in terms of CR rate (12.5% vs. 4%) and PFS (24 vs. 18 months) with a similar infection rate.
Should R-FC be preferred to FC in previously treated CLL patients? Recommendation Use it, weak positive evidence
Oblimerson
In a RCT including 241 patients with relapsed or refractory CLL after one prior first line fludarabine, patients were randomized to receive FC or FC plus oblimersen. Patients treated with FC-oblimersen showed a better response rate (17% vs. 7%). However, the OS between the 2 groups was not significantly different. The evidence was graded as weak.
Should oblimersen plus fludarabine and cyclophosphamide be preferred to fludarabine and cyclophosphamide in previously treated CLL patients? Recommendation Probably don’t use it, weak negative evidence
Allogeneic stem cell transplantation (SCT)
No prospective RCTs comparing allogeneic SCT to conventional chemotherapy or immunochemotherapy have been carried out in the setting of CLL patients. Phase II studies with a follow-up longer than 2 years were considered by the EP. Among these, the study by Dreger et al. including 90 poor risk CLL patients, ≤65 years, who underwent allogeneic SCT. The CR and overall response rates were 73% and 94%, respectively. The OS, relapse rate and EFS at 4 years were 65%, 40% and 42%, respectively.
Sorror et al. treated 82 patients (median age, 56 years) with fludarabine-refractory CLL with a conditioning regimen including 2 Gy TBI alone or combined with fludarabine followed by an allogeneic SCT from a related (52 patients) or unrelated (30 patients) donor. A CR and a PR were observed in 55% and 15% of patients respectively. After a median follow-up of 5 years, the non transplant related mortality (NTRM), the OS and the PFS were 23%, 50% and 39%, respectively.
A retrospective analysis of the European Blood and Marrow Transplantation Group (EBMTR) included 44 patients (median age, 54 years) with deletion 17 p-. Patients received an allogeneic SCT after a median number of 3 prior treatments. The OS, PFS, and NTRM at 3 years were 44%, 37% and 32%, respectively.
Treatment options for patients refractory to a prior fludarabine-based treatment, patients with early relapse and patients with del [17p] and/or p53 mutations.
In an analysis from the GCLLSG CLL8 trial comparing FC and FCR regimens an inverse relationship between response duration and survival probability has been observed. The median OS of patients with a PFS lower than 12 months (47 patients), between 12 and 24 months (45 patients) or higher than 24 months from the time point of a second-line treatment, were 13.1, 20.3 and 44.6 months, respectively (p< 0.01). These findings indicate that the small subgroup of patients who relapse within 24 months after a fludarabine based treatment is characterized by a very poor prognosis.
Second-line treatment options for this subgroup of patients have been separately discussed. The evidence derived from subgroup analysis of comparative trials carried on relapsed or refractory patients was integrated by the EP with the results of phase II non RCTs. Stilgenbauer et al. reported an OR rate of 34% with a median PFS of 8 months in 103 fludarabine-refractory patients treated with alemtuzumab given as single agent. The OR rate of the 31 patients with del [17p] included in this study was 39% with a median PFS of 6 months. In a study presented in an abstract form at the 2010 ASH meeting by the same Author, alemtuzumab and dexamethasone combination was given to 23 fludarabine-refractory patients and to 12 patients with del [17p] treated in first relapse. The OR rate was 56% for the fludarabine-refractory patients and 75% for the relapsed patients with del [17p].
Recently, a new anti-CD20 monoclonal antibody, ofatumumab has been investigated by Wierda et al. in a non RCT including patients with CLL refractory to both fludarabine and alemtuzumab or refractory to fludarabine with bulky lymphadenopathy. The OR rates in the two groups were 58% and 47%, respectively. The median PFS and OS were 5.7 months and 13.7 months, respectively, for the first group, 5.9 and 15.4 months, respectively, for the second group. Survival parameters seemed to be higher than those reported from a historical assessment of other salvage therapies in a corresponding group of patients.
Recommendations
In patients requiring a second-line treatment, del [17p] and/or p53 mutations should be checked. In patients with no del [17p] and/or p53 mutations and relapsed after 24 months, the same front-line therapy including rituximab can be considered.
In patients with del [17p] and/or p53 mutations, in patients refractory or relapsed within 24 months from a fludarabine-based treatment, alemtuzumab containing regimens, or experimental treatment approaches within controlled trials should be given.
Furthermore, in poor prognosis younger patients with adequate fitness status and no significant co-morbidities, a treatment approach including an allogeneic SCT, from either a sibling or well-matched unrelated donor, should be offered after an appropriate cytoreductive treatment.
John 7:21-24. Set in their ways
Jesus said to them, “I did one miracle, and you are all amazed. Yet, because Moses gave you circumcision (though actually it did not come from Moses, but from the patriarchs), you circumcise a boy on the Sabbath. Now if a boy can be circumcised on the Sabbath so that the law of Moses may not be broken, why are you angry with me for healing a man’s whole body on the Sabbath? Stop judging by mere appearances, but instead judge correctly.”
We are very prone to judge by appearances rather than thinking things through. In this case the Jews were too set upon following a protocol rather than thinking for themselves. We too can become set in our ways. We do things in a particular way because they have always been done that way. We need to open our minds to what the Spirit has to say ti us.
We are very prone to judge by appearances rather than thinking things through. In this case the Jews were too set upon following a protocol rather than thinking for themselves. We too can become set in our ways. We do things in a particular way because they have always been done that way. We need to open our minds to what the Spirit has to say ti us.
Tuesday, October 18, 2011
The genetics of CD38
Human CD38, located on the short arm of chromosome 4 (4p15), exhibits a number of unique features. First, the gene is relatively large, with > 98% of the genetic material consisting of introns. The promoter region is atypical, lacking a canonical TATA box, but containing a CpG island, pointing to epigenetic regulatory mechanisms, yet to be demonstrated.
CD38 expression by peripheral blood mononuclear cells behaves as a polymorphic trait in the general population, in keeping with the notion that the gene is under the pressure of constant and intense regulatory activity. Retinoids, vitamin D, and a variety of cytokines are the most known inducers.
(Now you see my reticence in endorsing megadoses of vitamin D for the general CLL population. It could theoretically increase CD38 expression.)
Besides being variable among CLL patients, CD38 expression can change at anatomic sites, being higher in BM and in areas of intense CLL/T lymphocyte contact. Accordingly, during CLL cell activation in vitro, CD38 expression can be up-regulated by a number of different signals, such as IL-2, CD40L plus IL-4, CpG oligonucleotides, and coculture with mesenchymal stem cells.
A single nucleotide polymorphism (C > G, rs6449182) is located at the 5′ end of intron 1 of CD38, and allelic frequencies of the polymorphism in healthy Italian, Spanish, Irish, and Polish populations have been defined. The frequency of the G allele is significantly higher in a subset of CLL patients exhibiting clinical and molecular markers of poor prognosis. The highest frequency is found in patients with Richter syndrome (RS), with the G allele representing an independent risk factor for RS. The same G allele is a susceptibility factor for CLL development in the Polish population. Furthermore, there are no significant differences in the percentage of CD38+ cells or intensity of expression in circulating CLL lymphocytes of G carriers and CC homozygotes in these populations, whereas environmental signals lead to greater increases in CD38 expression selectively in G carriers. The latter suggests involvement of the single nucleotide polymorphism (SNP) in transcription, possibly because the C > G SNP is located within a binding site for E47, the predominantly active isoform of E2A in human B lymphocytes that binds canonical E-box elements and activates gene transcription. These events are essential in the programs regulating B-cell differentiation by controlling Ig gene transcription and recombination as well as expression of other B-lineage genes. E47 is effectively recruited to the regulatory region of CD38 and the CD38 genotype in the E-box conditions the strength of the binding. E2A shows a comparatively higher affinity for the G allele, linking CD38 genotype to the dynamic regulation of surface expression of the molecule. The finding that E2A directly drives transcription of AICDA, in turn responsible for class switch recombination and somatic hypermutation, opens the possibility that the interplay between E47 and CD38 may lead to increased susceptibility to the insurgence of RS.
In line with the presence of a CpG island, the CD38 promoter can be methylated and methylation negatively correlates with surface expression. In a study of 168 CLL patients and using a cut-off of 7% for surface CD38 expression, 96% of CD38− persons exhibited methylation, whereas only 25% of CD38+ samples were methylated.
Methylation was not observed in peripheral blood mononuclear cells of healthy controls. Given that the defect appears to be site-specific and not a global event in CLL patients, it is foreseeable that it will become a useful predictor of outcome.
CD38 expression by peripheral blood mononuclear cells behaves as a polymorphic trait in the general population, in keeping with the notion that the gene is under the pressure of constant and intense regulatory activity. Retinoids, vitamin D, and a variety of cytokines are the most known inducers.
(Now you see my reticence in endorsing megadoses of vitamin D for the general CLL population. It could theoretically increase CD38 expression.)
Besides being variable among CLL patients, CD38 expression can change at anatomic sites, being higher in BM and in areas of intense CLL/T lymphocyte contact. Accordingly, during CLL cell activation in vitro, CD38 expression can be up-regulated by a number of different signals, such as IL-2, CD40L plus IL-4, CpG oligonucleotides, and coculture with mesenchymal stem cells.
A single nucleotide polymorphism (C > G, rs6449182) is located at the 5′ end of intron 1 of CD38, and allelic frequencies of the polymorphism in healthy Italian, Spanish, Irish, and Polish populations have been defined. The frequency of the G allele is significantly higher in a subset of CLL patients exhibiting clinical and molecular markers of poor prognosis. The highest frequency is found in patients with Richter syndrome (RS), with the G allele representing an independent risk factor for RS. The same G allele is a susceptibility factor for CLL development in the Polish population. Furthermore, there are no significant differences in the percentage of CD38+ cells or intensity of expression in circulating CLL lymphocytes of G carriers and CC homozygotes in these populations, whereas environmental signals lead to greater increases in CD38 expression selectively in G carriers. The latter suggests involvement of the single nucleotide polymorphism (SNP) in transcription, possibly because the C > G SNP is located within a binding site for E47, the predominantly active isoform of E2A in human B lymphocytes that binds canonical E-box elements and activates gene transcription. These events are essential in the programs regulating B-cell differentiation by controlling Ig gene transcription and recombination as well as expression of other B-lineage genes. E47 is effectively recruited to the regulatory region of CD38 and the CD38 genotype in the E-box conditions the strength of the binding. E2A shows a comparatively higher affinity for the G allele, linking CD38 genotype to the dynamic regulation of surface expression of the molecule. The finding that E2A directly drives transcription of AICDA, in turn responsible for class switch recombination and somatic hypermutation, opens the possibility that the interplay between E47 and CD38 may lead to increased susceptibility to the insurgence of RS.
In line with the presence of a CpG island, the CD38 promoter can be methylated and methylation negatively correlates with surface expression. In a study of 168 CLL patients and using a cut-off of 7% for surface CD38 expression, 96% of CD38− persons exhibited methylation, whereas only 25% of CD38+ samples were methylated.
Methylation was not observed in peripheral blood mononuclear cells of healthy controls. Given that the defect appears to be site-specific and not a global event in CLL patients, it is foreseeable that it will become a useful predictor of outcome.
Cutaneous Richter Syndrome
A paper in the Journal of the American Academy of Dermatology reports three cases of what they call cutaneous Richter syndrome.
Case 1
A 74-year-old woman with a 10-year history of CLL/small lymphocytic lymphoma presented to our dermatology clinic in 1999 with a nodule on her nose, which was clinically diagnosed as rhinophyma and treated with doxycycline. Five months later, a skin biopsy specimen of this lesion was taken and showed a dense monotonous infiltrate of small lymphocytes in the dermis and subcutis. The majority of the infiltrating cells were CD79a+ and CD20+ B cells that coexpressed CD5 and CD43. A diagnosis of cutaneous CLL was made. The patient’s white blood cell count was 19,500/μL at the time. The lesion gradually resolved after local radiation. In 2002, she developed multiple 2- to 3-mm red-blue papules on her face and on the pinnae of both ears. Skin biopsy specimens showed a dermal nodular infiltrate of large B cells expressing CD20, CD79a, CD43, and weak CD5. In the context of her history of CLL, cutaneous RS was diagnosed. Physical examination and computed tomography scans failed to reveal any lymphadenopathy or splenomegaly. Her white blood cell count was 18,500/μL with an absolute lymphocyte differential count of 13,900/μL (normal range: 1.2-4.0 × 103/μL). A bone-marrow biopsy specimen and aspiration also demonstrated CLL with large-cell transformation. Bone-marrow flow cytometry revealed a monoclonal B-cell population with an immunophenotype of CD19+, CD20+ (dim), CD5+, CD10–, CD11c+ (dim), CD23+, CD38+, and serum immunoglobulin lambda light chain (dim). A trisomy 12 abnormality was detected by fluorescence in situ hybridization on her bone marrow. The patient subsequently received chemotherapy with Cytoxan, Adriamycin, Oncovin, prednisone, and Rituxan. She achieved complete remission of her skin lesions. Repeated biopsy specimens of the nasal area in 2003 and 2004 did not show residual/recurrent lymphoma. The patient has remained asymptomatic with a follow-up of 8 years from the time of Richter transformation to last clinical visit.
Case 2
A 63-year-old man presented with an erythematous rash on the right side of his back in 2002. His medical history was significant for CLL involving a right axillary lymph node diagnosed in 1995. A skin biopsy specimen showed a dermal nodular infiltrate of mainly large lymphocytes expressing CD20, CD79a, and CD43, with scattered small T lymphocytes in the background. The findings were consistent with cutaneous RS. His rash and lymphadenopathy resolved after two cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone. In 2006, the patient developed hepatomegaly and recurrent lymphadenopathy. Subsequent chemotherapy was stopped because of severe herpes zoster. Chromosome 11q and 13q deletions were detected in the peripheral blood by fluorescence in situ hybridization in 2007. He died of septicemia in 2007 after 5 years of follow-up.
Case 3
A 61-year-old man presented with large bruises on his right wrist and forearm in 2000 associated with an elevated white blood cell count of 32,600/μL with 91% lymphocytes. Peripheral blood flow cytometry identified an abnormal monoclonal B-cell population expressing CD5, dim CD11c, CD19, dim CD20, CD23, CD45, and dim kappa light chain, consistent with CLL. The patient was treated with 6 cycles of fludarabine in 2002 and 2005 because of worsening lymphocytosis, anemia, adenopathy, and splenomegaly, and had an excellent response. In 2007, his peripheral blood and bone marrow showed recurrent CLL. No cytogenetic abnormality was found. Despite continued chemotherapy, he experienced worsening lymphadenopathy, thrombocytopenia, and anemia. Nodular opacities concerning for involvement by lymphoma were seen in his lungs. A cervical lymph node biopsy specimen showed CLL. In 2008, he developed multiple erythematous nodules and plaques on the chest. A skin biopsy specimen revealed a perivascular infiltrate of large atypical lymphocytes that labeled positive for CD20, CD43, and CD30, consistent with cutaneous RS. The patient decided to pursue palliative care and died 20 days after the diagnosis.
From these reports it is clear that this is a much more benign condition than true Richter syndrome and probably the appearance of large 'blast-like' cells in the skin does not carry the same importance as their occurrence elsewhere.
Case 1
A 74-year-old woman with a 10-year history of CLL/small lymphocytic lymphoma presented to our dermatology clinic in 1999 with a nodule on her nose, which was clinically diagnosed as rhinophyma and treated with doxycycline. Five months later, a skin biopsy specimen of this lesion was taken and showed a dense monotonous infiltrate of small lymphocytes in the dermis and subcutis. The majority of the infiltrating cells were CD79a+ and CD20+ B cells that coexpressed CD5 and CD43. A diagnosis of cutaneous CLL was made. The patient’s white blood cell count was 19,500/μL at the time. The lesion gradually resolved after local radiation. In 2002, she developed multiple 2- to 3-mm red-blue papules on her face and on the pinnae of both ears. Skin biopsy specimens showed a dermal nodular infiltrate of large B cells expressing CD20, CD79a, CD43, and weak CD5. In the context of her history of CLL, cutaneous RS was diagnosed. Physical examination and computed tomography scans failed to reveal any lymphadenopathy or splenomegaly. Her white blood cell count was 18,500/μL with an absolute lymphocyte differential count of 13,900/μL (normal range: 1.2-4.0 × 103/μL). A bone-marrow biopsy specimen and aspiration also demonstrated CLL with large-cell transformation. Bone-marrow flow cytometry revealed a monoclonal B-cell population with an immunophenotype of CD19+, CD20+ (dim), CD5+, CD10–, CD11c+ (dim), CD23+, CD38+, and serum immunoglobulin lambda light chain (dim). A trisomy 12 abnormality was detected by fluorescence in situ hybridization on her bone marrow. The patient subsequently received chemotherapy with Cytoxan, Adriamycin, Oncovin, prednisone, and Rituxan. She achieved complete remission of her skin lesions. Repeated biopsy specimens of the nasal area in 2003 and 2004 did not show residual/recurrent lymphoma. The patient has remained asymptomatic with a follow-up of 8 years from the time of Richter transformation to last clinical visit.
Case 2
A 63-year-old man presented with an erythematous rash on the right side of his back in 2002. His medical history was significant for CLL involving a right axillary lymph node diagnosed in 1995. A skin biopsy specimen showed a dermal nodular infiltrate of mainly large lymphocytes expressing CD20, CD79a, and CD43, with scattered small T lymphocytes in the background. The findings were consistent with cutaneous RS. His rash and lymphadenopathy resolved after two cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone. In 2006, the patient developed hepatomegaly and recurrent lymphadenopathy. Subsequent chemotherapy was stopped because of severe herpes zoster. Chromosome 11q and 13q deletions were detected in the peripheral blood by fluorescence in situ hybridization in 2007. He died of septicemia in 2007 after 5 years of follow-up.
Case 3
A 61-year-old man presented with large bruises on his right wrist and forearm in 2000 associated with an elevated white blood cell count of 32,600/μL with 91% lymphocytes. Peripheral blood flow cytometry identified an abnormal monoclonal B-cell population expressing CD5, dim CD11c, CD19, dim CD20, CD23, CD45, and dim kappa light chain, consistent with CLL. The patient was treated with 6 cycles of fludarabine in 2002 and 2005 because of worsening lymphocytosis, anemia, adenopathy, and splenomegaly, and had an excellent response. In 2007, his peripheral blood and bone marrow showed recurrent CLL. No cytogenetic abnormality was found. Despite continued chemotherapy, he experienced worsening lymphadenopathy, thrombocytopenia, and anemia. Nodular opacities concerning for involvement by lymphoma were seen in his lungs. A cervical lymph node biopsy specimen showed CLL. In 2008, he developed multiple erythematous nodules and plaques on the chest. A skin biopsy specimen revealed a perivascular infiltrate of large atypical lymphocytes that labeled positive for CD20, CD43, and CD30, consistent with cutaneous RS. The patient decided to pursue palliative care and died 20 days after the diagnosis.
From these reports it is clear that this is a much more benign condition than true Richter syndrome and probably the appearance of large 'blast-like' cells in the skin does not carry the same importance as their occurrence elsewhere.
John 7:20. The word not the wonder.
"You are demon-possessed," the crowd answered, " who is trying to kill you."
This was a common accusation of the Jews about Jesus who gives a sufficient answer elsewhere. But why invoke demons? Because they were seeing miracles yet unwilling to believe what they signified. They were clinging to their Sabbath-day observance as being greater than the word of God as given by his son. Let us resolve not to be influenced by signs and wonders, but to follow the word of God.
This was a common accusation of the Jews about Jesus who gives a sufficient answer elsewhere. But why invoke demons? Because they were seeing miracles yet unwilling to believe what they signified. They were clinging to their Sabbath-day observance as being greater than the word of God as given by his son. Let us resolve not to be influenced by signs and wonders, but to follow the word of God.
A randomized trial of FA v F.
The Lancet Oncology reports and randomized phase 3 trial comparing fludarabine plus alemtuzumab with fludarabine alone in relased or refractory patients with CLL who have had no more than one previous line of chemotherapy. They were allowed to have had either of the agents alone previously as long as the duration of response had been greater than 12 months, but they were not allowed to have previously received the combination. I have reported this trial in some detail since it differs from other FA combinations. There is little to recommend FA as first line therapy, but since we know that p53 abnormalities are so common after FCR and that alemtuzumab is useless in bulky disease, this report might have something important to say about second line disease. It also gives a lot of detail about what it is like to receive alemtuzumab.
The study was done in five centres in North America and 43 in Europe. Inclusion criteria were Binet stage A, B, or C or Rai stage I–IV disease; WHO performance status (PS) 0 or 1; life expectancy of 12 weeks or longer; age 18 years or older; anticancer treatment, major surgery, or radiation therapy more than 3 weeks before randomisation in the study; complete recovery from acute side-effects of previous therapy; and adequate renal and liver function.
Exclusion criteria were positive Coombs test and active haemolysis; absolute neutrophil count (ANC) of less than 1·5×109 cells per L or platelet count of less than 75×109 per L, unless due to bone-marrow involvement with CLL; disorders requiring chronic use of corticosteroids; history of anaphylaxis to monoclonal antibodies; HIV positivity; evidence of active infection or history of grade 4 infection within 3 months before randomisation in the study; active second malignancy; known CNS involvement with CLL; other severe concurrent disease; progression due to a more aggressive B-cell cancer (eg, Richter's syndrome); and a history of viral hepatitis or positive hepatitis B serology in the absence of immunisation.
During the first treatment cycle, patients in the combination group were given escalating doses of alemtuzumab. If grade 3 or 4 infusion-related adverse events occurred, the same dose was repeated daily until it was well tolerated (grade 2 or lower toxicity) with appropriate premedication. A maximum of 14 days were allowed for alemtuzumab escalation to 30 mg. After completion of the escalation, patients were given fludarabine 30 mg/m2 per day, intravenously over 30 min), followed immediately by alemtuzumab (30 mg/day, intravenously over 2 h); both were administered daily for 3 days. Cycles were repeated every 28 days. After cycle 1, alemtuzumab was infused over 4–6 h for the first day of each new cycle and over 2 h during days 2 and 3. Patients randomly assigned to the fludarabine monotherapy were treated with 25 mg/m2 per day for 5 days, intravenously, over 15–30 min, every 28 days. Patients in both groups were scheduled to receive a minimum of four cycles and a maximum of six treatment cycles, depending on response and toxicity. They were assessed for response every two cycles. Patients in the fludarabine plus alemtuzumab group were administered paracetamol 500–1000 mg orally 30 min before alemtuzumab infusion for control of infusion-related events (or equivalent) and an antihistamine 30 min before drug administration as prophylaxis for infusion-related events. Patients were premedicated with hydrocortisone (100 mg, intravenously, or equivalent steroid) just before alemtuzumab infusion during the dose escalation phase, on day 1 of each subsequent cycle, and if clinically indicated thereafter. All patients were given prophylaxis with co-trimoxazole (trimethoprim 160 mg plus sulfamethoxazole 800 mg twice a day, three times a week, orally) or equivalent and famciclovir (500 mg twice a day, orally), starting on the first day of the study treatment and continuing until CD4+ cell counts were at least 200 cells per μL.
Patients were monitored weekly with complete blood count and testing for cytomegalovirus (with quantitative PCR on peripheral blood) during cycles 1 and 2, and every 2 weeks thereafter. Monthly complete blood count, CD4+ cell count, and testing for cytomegalovirus continued after cycle 6 until blood counts recovered or stabilised and CD4+ cell counts rose to more than 200 cells per μL. Patients who were PCR-positive for cytomegalovirus without clinical symptoms of cytomegalovirus infection or had rising viral transcripts on subsequent weekly PCR testing were treated with valganciclovir while on study treatment. Those with clinical manifestations of cytomegalovirus infection (fever or end-organ symptoms) were treated with ganciclovir for at least 10 days. Interruption of study treatment was allowed for up to 28 days before necessitating discontinuation from study participation.
The primary endpoint was progression-free survival (PFS), defined as the time of randomisation to progression or death from any cause, whichever was earlier. The primary endpoint was changed from time to progression (TTP) to a more conservative definition of PFS before any of the planned interim analyses were undertaken to make the data more comparable with data from other randomised studies of patients with CLL.
The main secondary endpoints were ORR, CR rate, overall survival, and safety. Additional, secondary endpoints were TTP, duration of response, time to alternative treatment, incidence of MRD negativity, fludarabine pharmacokinetics, and health-related quality of life. The main analysis of efficacy was based on the assessments of response and disease progression for each patient by the independent response review panel, members of which were masked to treatment assignment. Response criteria and progression were assessed according to the National Cancer Institute Working Group's 1996 guidelines for CLL; criteria for disease progression were specified in the study protocol and were in accordance with these guidelines. The health-related quality-of-life instrument was a five-dimensional questionnaire about health status and a visual analogue scale thermometer for self-rating current health-related quality of life. The five dimensions were mobility, self-care, usual activities, pain or discomfort, and anxiety or depression, rated according to three possible levels (no problems, some problems, and extreme problems). Exploratory analyses to investigate the effect of prespecified prognostic factors on efficacy outcomes were also undertaken.
From July, 2004, to October, 2008, 335 patients were enrolled (18 in centres in North America and 317 in Europe) and randomly assigned to fludarabine alone or with alemtuzumab. More patients than planned were enrolled to enable an analysis of potential drug–drug interactions. Six patients were not given the study treatment and therefore were not included in the safety analysis. Baseline demographics and disease characteristics used for stratification were well balanced between the treatment groups.
Fludarabine plus alemtuzumab significantly prolonged PFS compared with fludarabine. The ORR was non-significantly higher in the combination treatment group than in the monotherapy group. The CR rate was significantly higher in the fludarabine plus alemtuzumab group than in the fludarabine alone group. The independent response review panel identified six patients in the combination treatment group and none in the monotherapy group as MRD negative (p=0·014).
With a median follow-up for all enrolled patients of 29·5 months (IQR 16·5 to 42·1 months), the median overall survival was significantly improved in the fludarabine plus alemtuzumab group, with 117 (70%) of 168 patients in the combination treatment group and 100 (60%) of 167 in the monotherapy group alive at the data cutoff or last follow-up date. After the predefined multiple testing adjustment, the comparisons between groups for CR rate and overall survival remained significant (p=0·018 and p=0·042, respectively). There was no apparent treatment difference in the quality-of-life indicators.
The significantly improved PFS in patients treated with combination treatment compared with monotherapy was consistent for all prespecified subgroups, including those judged to be high risk (advanced disease and older patients). Patients with advanced disease (Rai stage III or IV) who were given combination treatment had a longer median PFS than did those given fludarabine. The ORR and CR rate were also significantly higher. Notably, patients with Rai stage III or IV who were given fludarabine plus alemtuzumab also had significantly improved median overall survival compared with those treated with fludarabine alone, indicating survival benefit in favour of the combination treatment. Improvement in overall survival was not noted in patients with Rai stage I or II CLL (HR 1·07, 95% CI 0·62–1·84; p=0·82). There was evidence of differential treatment benefit in terms of overall survival with the combination treatment in the patients who were Rai stage III or IV compared with Rai stage I or II (p=0·011). In older patients (age ≥65 years), median PFS was significantly longer with the combination treatment than with fludarabine alone. Median overall survival for this older population was not reached in the group assigned to fludarabine plus alemtuzumab, whereas it was 40·9 months in the monotherapy group.
161 (98%) of 164 patients in the fludarabine plus alemtuzumab group and 149 (90%) of 165 in the fludarabine group had all-cause adverse events. In the combination treatment group, non-haematological all-cause adverse events occurring in more than 10% of patients were pyrexia, chills, rash, infusion-related reactions, urticaria, cytomegalovirus PCR positivity, and nausea. In the monotherapy group, none of the non-haematological all-cause adverse events arose in more than 10% of patients. The most common all-cause serious adverse events that arose in more than 2% of patients in the fludarabine plus alemtuzumab group were neutropenia, febrile neutropenia, pneumonia, pyrexia, thrombocytopenia, diarrhoea, and leucopenia. In the fludarabine group, these were febrile neutropenia and anaemia.
Ten patients in the fludarabine plus alemtuzumab group and 12 in the fludarabine group died as a result of adverse events (irrespective of cause). During the treatment period (date of first dose to 30 days after last dose), four patients in the combination treatment group and seven in the monotherapy group died as a result of an adverse event. The causes of these deaths were similar (acute respiratory and circulatory insufficiency [n=2], acute haemolysis [n=1], and cardiopulmonary insufficiency [n=1] in the fludarabine plus alemtuzumab group; disease related [n=2], acute respiratory and circulatory insufficiency [n=2], septic shock syndrome [n=1], acute myocardial infarction [n=1], and pulmonary oedema in the fludarabine group [n=1]). Of these, three fatal drug-related adverse events occurred in the combination treatment group (acute haemolysis [n=1] and acute respiratory and circulatory insufficiency [n=2]) and three in the fludarabine group (acute respiratory and circulatory insufficiency [n=2] and septic shock syndrome [n=1]).
The median time to recovery of CD4+ cell counts (>200 cells per μL) was 3·0 months (95% CI 2·7–4·7) in the fludarabine plus alemtuzumab group and 2·0 months (1·8–2·6) in the fludarabine group. All-cause infections occurred in 67 (41%) of 164 patients in the combination treatment group and in 58 (35%) of 165 in the monotherapy group. The types and severity of all infections were similar in the two groups with the exception of lower-respiratory-tract infections (26 [16%] vs eight [5%]) and viral infections (19 [12%] vs ten [6%]), which occurred more frequently in the fludarabine plus alemtuzumab group. Additionally, the incidences of infections that were greater than grade 3 were similar in both groups—19 patients in the combination treatment group (grade 3 [n=17], grade 4 [n=1, pneumonia], grade 5 (= death) [n=1, pneumonia]) versus 17 in the monotherapy group (grade 3 [n=10], grade 4 [n=3], grade 5 [n=4]). Grade 4 infections in the fludarabine group were Escherichia coli gastroenteritis (n=1) and sepsis (n=2), and grade 5 infections were pneumococcal sepsis (n=1), pyelonephritis (n=1), septic shock (n=1), and fungal infection (n=1).
Cytomegalovirus-PCR-positive tests were reported in 19 (12%) asymptomatic patients in the fludarabine plus alemtuzumab group and in one (<1%) asymptomatic patient in the fludarabine group. Study drug was not discontinued for any of the patients with asymptomatic cytomegalovirus PCR positivity. The median time to first occurrence of a PCR-positive test was 30 days (range 20–52) for patients in the fludarabine plus alemtuzumab group; only one patient in the fludarabine monotherapy group had cytomegalovirus PCR positivity (on day 69 after the start of treatment). Symptomatic cytomegalovirus infection was reported in four patients (2%) only in the fludarabine plus alemtuzumab group, and their symptoms were fever (n=2), hepatitis (n=1), and fever, fatigue, malaise, and leucopenia (n=1). One patient discontinued study treatment because of symptomatic cytomegalovirus infection. All patients with symptomatic cytomegalovirus infections were treated with ganciclovir and recovered without sequelae.
121 (74%) of 164 patients in the fludarabine plus alemtuzumab group had at least one potentially alemtuzumab infusion-related event (defined as having at least one drug-related adverse event out of the following preferred terms: chills, pyrexia, nausea, vomiting, rash, urticaria, hypotension, bronchospasm, cytokine release syndrome, or infusion-related reaction) during cycles 1–6 compared with 24 (15%) of 165 in the fludarabine group. Potentially alemtuzumab infusion-related adverse events were most common in the initial treatment cycles for the fludarabine plus alemtuzumab group (data not shown). For chills, pyrexia, nausea, and urticaria, the incidences were highest in cycle 1 and seemed to show a general reduction with progression from cycle 1 to cycle 6 for the fludarabine plus alemtuzumab group (data not shown). The incidences of bronchospasm, infusion-related reaction, vomiting, and cytokine release were also highest in cycle 1, but the total incidence was low, and therefore a pattern could not be discerned for the fludarabine plus alemtuzumab group (data not shown). The incidences of hypotension (two [1%]) and rash (21 [13%]) did not seem to be related to the cycle. Furthermore, most of the infusion-related events were mild in the combination and monotherapy groups (grade 1 and 2, 102 [62%] and 22 [13%], respectively), one patient in the fludarabine plus alemtuzumab group had a grade 4 event (pyrexia), and there were no fatal infusion-related events.
No clinically relevant differences in incidence of adverse events were noted between patients with Rai stage I or II versus III or IV, patients aged 65 years and older versus younger than 65 years, or male versus female patients. Furthermore, the safety profile of combination treatment in patients 65 years and older was similar to that of the overall patient population.
Comment
A search of the literature identified an earlier phase 2 trial in which excellent results were reported for three times weekly alemtuzumab used in combination with 4-weekly fludarabine, suggesting superadditive effects. At the time of initiation of this trial, results from another phase 2 trial by a German chronic lymphocytic leukaemia (CLL) study group were available, combining alemtuzumab with fludarabine in a 4-week schedule in patients with relapsed and refractory CLL; they also reported high response rates with tolerable toxicity. Since the monthly fludarabine plus alemtuzumab schedule had not been previously investigated in a large, randomised phase 3 study, the authors designed this study for further assessment of combination treatment.
The findings of this randomised phase 3 study suggest that the monthly administration of alemtuzumab plus fludarabine results in excellent response rates and prolonged progression-free survival and overall survival with a tolerable side-effect profile. Furthermore, the total dose of each drug is substantially reduced and is more convenient for patients. Noteworthy is that patients, especially those with advanced Rai stages, benefited from this treatment approach. Thus, this combination as an important treatment option for patients with relapsed or refractory CLL.
Additionally, at the time the protocol was initiated, no combination regimens were approved for use in previously treated patients with CLL and few randomised controlled studies have been undertaken in patients with relapsed or refractory CLL. O'Brien and colleagues reported an ORR of 65% with fludarabine plus cyclophosphamide and 80% with fludarabine plus cyclophosphamide plus oblimersen in patients with relapsed or refractory CLL. Robak and colleagues reported that in previously treated patients with CLL, compared with fludarabine plus cyclophosphamide, the three-drug combination of fludarabine plus cyclophosphamide plus rituximab extended median PFS (21·9 months vs 27·0 months), and increased ORR (49% vs 61%) and CR rates (3% vs 9%) as assessed by independent review. (I was one of those who participated in the Independent Review). The results presented in this report are comparable to those of Robak and colleagues' combination chemotherapy and immunochemotherapy regimens in previously treated patients with relapsed or refractory CLL. This comparability is important because fludarabine plus cyclophosphamide and fludarabine plus cyclophosphamide plus rituximab are increasingly used in the front-line setting; additional novel treatment regimens are needed for second-line therapy.
Treatment of CLL has been evolving over the period this study was undertaken. For patients with relapsed or refractory CLL, various guidelines provide options for treatment but no globally recognised standard of care exists. However, fludarabine-based combination regimens have been increasingly used as first-line or subsequent treatments. Although no conclusion can be drawn about the benefit of the combination treatment in the subset of patients with previous exposure to fludarabine because of the small sample size, the HR of 0·82 suggests that the combination treatment is beneficial. Additionally, the significant overall treatment benefit noted from all the enrolled patients suggests that the combination treatment provided benefit to all enrolled patients previously given different types of treatment. Also, cytogenetic testing was not required in the initial stages of the study and was added midway through the study. Therefore, cytogenetic data were available for 57% of 335 patients, restricting the statistical precision of analyses in subgroups defined on the basis of these data, and restricting the ability to make conclusions about any effect of cytogenetics on response.
For second-line therapy, the fludarabine plus alemtuzumab regimen has several potential advantages. First, unlike fludarabine plus cyclophosphamide and fludarabine plus cyclophosphamide plus rituximab, the fludarabine plus alemtuzumab regimen spares patients from additional exposure to alkylating drugs, which theoretically might be associated with serious early and late toxicities, such as leukaemia possibly associated with secondary therapy. Second, patients treated with fludarabine plus alemtuzumab had a lower exposure to each drug than with the commonly used dosing regimen when each drug is used alone. The combination regimen uses 50% less alemtuzumab and 30% less fludarabine than the dosing regimen approved by the US FDA for single drug use. Last, the dosing schedule for alemtuzumab of 3 days per month in the fludarabine plus alemtuzumab regimen improves patient convenience compared with the standard dosing regimen of three times per week for up to 12 weeks.
The fludarabine plus alemtuzumab combination provides clinical benefits with an acceptable safety profile in previously treated patients with CLL when compared with single-agent fludarabine. This combination might become an important additional treatment option for patients with relapsed or refractory CLL.
.
The study was done in five centres in North America and 43 in Europe. Inclusion criteria were Binet stage A, B, or C or Rai stage I–IV disease; WHO performance status (PS) 0 or 1; life expectancy of 12 weeks or longer; age 18 years or older; anticancer treatment, major surgery, or radiation therapy more than 3 weeks before randomisation in the study; complete recovery from acute side-effects of previous therapy; and adequate renal and liver function.
Exclusion criteria were positive Coombs test and active haemolysis; absolute neutrophil count (ANC) of less than 1·5×109 cells per L or platelet count of less than 75×109 per L, unless due to bone-marrow involvement with CLL; disorders requiring chronic use of corticosteroids; history of anaphylaxis to monoclonal antibodies; HIV positivity; evidence of active infection or history of grade 4 infection within 3 months before randomisation in the study; active second malignancy; known CNS involvement with CLL; other severe concurrent disease; progression due to a more aggressive B-cell cancer (eg, Richter's syndrome); and a history of viral hepatitis or positive hepatitis B serology in the absence of immunisation.
During the first treatment cycle, patients in the combination group were given escalating doses of alemtuzumab. If grade 3 or 4 infusion-related adverse events occurred, the same dose was repeated daily until it was well tolerated (grade 2 or lower toxicity) with appropriate premedication. A maximum of 14 days were allowed for alemtuzumab escalation to 30 mg. After completion of the escalation, patients were given fludarabine 30 mg/m2 per day, intravenously over 30 min), followed immediately by alemtuzumab (30 mg/day, intravenously over 2 h); both were administered daily for 3 days. Cycles were repeated every 28 days. After cycle 1, alemtuzumab was infused over 4–6 h for the first day of each new cycle and over 2 h during days 2 and 3. Patients randomly assigned to the fludarabine monotherapy were treated with 25 mg/m2 per day for 5 days, intravenously, over 15–30 min, every 28 days. Patients in both groups were scheduled to receive a minimum of four cycles and a maximum of six treatment cycles, depending on response and toxicity. They were assessed for response every two cycles. Patients in the fludarabine plus alemtuzumab group were administered paracetamol 500–1000 mg orally 30 min before alemtuzumab infusion for control of infusion-related events (or equivalent) and an antihistamine 30 min before drug administration as prophylaxis for infusion-related events. Patients were premedicated with hydrocortisone (100 mg, intravenously, or equivalent steroid) just before alemtuzumab infusion during the dose escalation phase, on day 1 of each subsequent cycle, and if clinically indicated thereafter. All patients were given prophylaxis with co-trimoxazole (trimethoprim 160 mg plus sulfamethoxazole 800 mg twice a day, three times a week, orally) or equivalent and famciclovir (500 mg twice a day, orally), starting on the first day of the study treatment and continuing until CD4+ cell counts were at least 200 cells per μL.
Patients were monitored weekly with complete blood count and testing for cytomegalovirus (with quantitative PCR on peripheral blood) during cycles 1 and 2, and every 2 weeks thereafter. Monthly complete blood count, CD4+ cell count, and testing for cytomegalovirus continued after cycle 6 until blood counts recovered or stabilised and CD4+ cell counts rose to more than 200 cells per μL. Patients who were PCR-positive for cytomegalovirus without clinical symptoms of cytomegalovirus infection or had rising viral transcripts on subsequent weekly PCR testing were treated with valganciclovir while on study treatment. Those with clinical manifestations of cytomegalovirus infection (fever or end-organ symptoms) were treated with ganciclovir for at least 10 days. Interruption of study treatment was allowed for up to 28 days before necessitating discontinuation from study participation.
The primary endpoint was progression-free survival (PFS), defined as the time of randomisation to progression or death from any cause, whichever was earlier. The primary endpoint was changed from time to progression (TTP) to a more conservative definition of PFS before any of the planned interim analyses were undertaken to make the data more comparable with data from other randomised studies of patients with CLL.
The main secondary endpoints were ORR, CR rate, overall survival, and safety. Additional, secondary endpoints were TTP, duration of response, time to alternative treatment, incidence of MRD negativity, fludarabine pharmacokinetics, and health-related quality of life. The main analysis of efficacy was based on the assessments of response and disease progression for each patient by the independent response review panel, members of which were masked to treatment assignment. Response criteria and progression were assessed according to the National Cancer Institute Working Group's 1996 guidelines for CLL; criteria for disease progression were specified in the study protocol and were in accordance with these guidelines. The health-related quality-of-life instrument was a five-dimensional questionnaire about health status and a visual analogue scale thermometer for self-rating current health-related quality of life. The five dimensions were mobility, self-care, usual activities, pain or discomfort, and anxiety or depression, rated according to three possible levels (no problems, some problems, and extreme problems). Exploratory analyses to investigate the effect of prespecified prognostic factors on efficacy outcomes were also undertaken.
From July, 2004, to October, 2008, 335 patients were enrolled (18 in centres in North America and 317 in Europe) and randomly assigned to fludarabine alone or with alemtuzumab. More patients than planned were enrolled to enable an analysis of potential drug–drug interactions. Six patients were not given the study treatment and therefore were not included in the safety analysis. Baseline demographics and disease characteristics used for stratification were well balanced between the treatment groups.
Fludarabine plus alemtuzumab significantly prolonged PFS compared with fludarabine. The ORR was non-significantly higher in the combination treatment group than in the monotherapy group. The CR rate was significantly higher in the fludarabine plus alemtuzumab group than in the fludarabine alone group. The independent response review panel identified six patients in the combination treatment group and none in the monotherapy group as MRD negative (p=0·014).
With a median follow-up for all enrolled patients of 29·5 months (IQR 16·5 to 42·1 months), the median overall survival was significantly improved in the fludarabine plus alemtuzumab group, with 117 (70%) of 168 patients in the combination treatment group and 100 (60%) of 167 in the monotherapy group alive at the data cutoff or last follow-up date. After the predefined multiple testing adjustment, the comparisons between groups for CR rate and overall survival remained significant (p=0·018 and p=0·042, respectively). There was no apparent treatment difference in the quality-of-life indicators.
The significantly improved PFS in patients treated with combination treatment compared with monotherapy was consistent for all prespecified subgroups, including those judged to be high risk (advanced disease and older patients). Patients with advanced disease (Rai stage III or IV) who were given combination treatment had a longer median PFS than did those given fludarabine. The ORR and CR rate were also significantly higher. Notably, patients with Rai stage III or IV who were given fludarabine plus alemtuzumab also had significantly improved median overall survival compared with those treated with fludarabine alone, indicating survival benefit in favour of the combination treatment. Improvement in overall survival was not noted in patients with Rai stage I or II CLL (HR 1·07, 95% CI 0·62–1·84; p=0·82). There was evidence of differential treatment benefit in terms of overall survival with the combination treatment in the patients who were Rai stage III or IV compared with Rai stage I or II (p=0·011). In older patients (age ≥65 years), median PFS was significantly longer with the combination treatment than with fludarabine alone. Median overall survival for this older population was not reached in the group assigned to fludarabine plus alemtuzumab, whereas it was 40·9 months in the monotherapy group.
161 (98%) of 164 patients in the fludarabine plus alemtuzumab group and 149 (90%) of 165 in the fludarabine group had all-cause adverse events. In the combination treatment group, non-haematological all-cause adverse events occurring in more than 10% of patients were pyrexia, chills, rash, infusion-related reactions, urticaria, cytomegalovirus PCR positivity, and nausea. In the monotherapy group, none of the non-haematological all-cause adverse events arose in more than 10% of patients. The most common all-cause serious adverse events that arose in more than 2% of patients in the fludarabine plus alemtuzumab group were neutropenia, febrile neutropenia, pneumonia, pyrexia, thrombocytopenia, diarrhoea, and leucopenia. In the fludarabine group, these were febrile neutropenia and anaemia.
Ten patients in the fludarabine plus alemtuzumab group and 12 in the fludarabine group died as a result of adverse events (irrespective of cause). During the treatment period (date of first dose to 30 days after last dose), four patients in the combination treatment group and seven in the monotherapy group died as a result of an adverse event. The causes of these deaths were similar (acute respiratory and circulatory insufficiency [n=2], acute haemolysis [n=1], and cardiopulmonary insufficiency [n=1] in the fludarabine plus alemtuzumab group; disease related [n=2], acute respiratory and circulatory insufficiency [n=2], septic shock syndrome [n=1], acute myocardial infarction [n=1], and pulmonary oedema in the fludarabine group [n=1]). Of these, three fatal drug-related adverse events occurred in the combination treatment group (acute haemolysis [n=1] and acute respiratory and circulatory insufficiency [n=2]) and three in the fludarabine group (acute respiratory and circulatory insufficiency [n=2] and septic shock syndrome [n=1]).
The median time to recovery of CD4+ cell counts (>200 cells per μL) was 3·0 months (95% CI 2·7–4·7) in the fludarabine plus alemtuzumab group and 2·0 months (1·8–2·6) in the fludarabine group. All-cause infections occurred in 67 (41%) of 164 patients in the combination treatment group and in 58 (35%) of 165 in the monotherapy group. The types and severity of all infections were similar in the two groups with the exception of lower-respiratory-tract infections (26 [16%] vs eight [5%]) and viral infections (19 [12%] vs ten [6%]), which occurred more frequently in the fludarabine plus alemtuzumab group. Additionally, the incidences of infections that were greater than grade 3 were similar in both groups—19 patients in the combination treatment group (grade 3 [n=17], grade 4 [n=1, pneumonia], grade 5 (= death) [n=1, pneumonia]) versus 17 in the monotherapy group (grade 3 [n=10], grade 4 [n=3], grade 5 [n=4]). Grade 4 infections in the fludarabine group were Escherichia coli gastroenteritis (n=1) and sepsis (n=2), and grade 5 infections were pneumococcal sepsis (n=1), pyelonephritis (n=1), septic shock (n=1), and fungal infection (n=1).
Cytomegalovirus-PCR-positive tests were reported in 19 (12%) asymptomatic patients in the fludarabine plus alemtuzumab group and in one (<1%) asymptomatic patient in the fludarabine group. Study drug was not discontinued for any of the patients with asymptomatic cytomegalovirus PCR positivity. The median time to first occurrence of a PCR-positive test was 30 days (range 20–52) for patients in the fludarabine plus alemtuzumab group; only one patient in the fludarabine monotherapy group had cytomegalovirus PCR positivity (on day 69 after the start of treatment). Symptomatic cytomegalovirus infection was reported in four patients (2%) only in the fludarabine plus alemtuzumab group, and their symptoms were fever (n=2), hepatitis (n=1), and fever, fatigue, malaise, and leucopenia (n=1). One patient discontinued study treatment because of symptomatic cytomegalovirus infection. All patients with symptomatic cytomegalovirus infections were treated with ganciclovir and recovered without sequelae.
121 (74%) of 164 patients in the fludarabine plus alemtuzumab group had at least one potentially alemtuzumab infusion-related event (defined as having at least one drug-related adverse event out of the following preferred terms: chills, pyrexia, nausea, vomiting, rash, urticaria, hypotension, bronchospasm, cytokine release syndrome, or infusion-related reaction) during cycles 1–6 compared with 24 (15%) of 165 in the fludarabine group. Potentially alemtuzumab infusion-related adverse events were most common in the initial treatment cycles for the fludarabine plus alemtuzumab group (data not shown). For chills, pyrexia, nausea, and urticaria, the incidences were highest in cycle 1 and seemed to show a general reduction with progression from cycle 1 to cycle 6 for the fludarabine plus alemtuzumab group (data not shown). The incidences of bronchospasm, infusion-related reaction, vomiting, and cytokine release were also highest in cycle 1, but the total incidence was low, and therefore a pattern could not be discerned for the fludarabine plus alemtuzumab group (data not shown). The incidences of hypotension (two [1%]) and rash (21 [13%]) did not seem to be related to the cycle. Furthermore, most of the infusion-related events were mild in the combination and monotherapy groups (grade 1 and 2, 102 [62%] and 22 [13%], respectively), one patient in the fludarabine plus alemtuzumab group had a grade 4 event (pyrexia), and there were no fatal infusion-related events.
No clinically relevant differences in incidence of adverse events were noted between patients with Rai stage I or II versus III or IV, patients aged 65 years and older versus younger than 65 years, or male versus female patients. Furthermore, the safety profile of combination treatment in patients 65 years and older was similar to that of the overall patient population.
Comment
A search of the literature identified an earlier phase 2 trial in which excellent results were reported for three times weekly alemtuzumab used in combination with 4-weekly fludarabine, suggesting superadditive effects. At the time of initiation of this trial, results from another phase 2 trial by a German chronic lymphocytic leukaemia (CLL) study group were available, combining alemtuzumab with fludarabine in a 4-week schedule in patients with relapsed and refractory CLL; they also reported high response rates with tolerable toxicity. Since the monthly fludarabine plus alemtuzumab schedule had not been previously investigated in a large, randomised phase 3 study, the authors designed this study for further assessment of combination treatment.
The findings of this randomised phase 3 study suggest that the monthly administration of alemtuzumab plus fludarabine results in excellent response rates and prolonged progression-free survival and overall survival with a tolerable side-effect profile. Furthermore, the total dose of each drug is substantially reduced and is more convenient for patients. Noteworthy is that patients, especially those with advanced Rai stages, benefited from this treatment approach. Thus, this combination as an important treatment option for patients with relapsed or refractory CLL.
Additionally, at the time the protocol was initiated, no combination regimens were approved for use in previously treated patients with CLL and few randomised controlled studies have been undertaken in patients with relapsed or refractory CLL. O'Brien and colleagues reported an ORR of 65% with fludarabine plus cyclophosphamide and 80% with fludarabine plus cyclophosphamide plus oblimersen in patients with relapsed or refractory CLL. Robak and colleagues reported that in previously treated patients with CLL, compared with fludarabine plus cyclophosphamide, the three-drug combination of fludarabine plus cyclophosphamide plus rituximab extended median PFS (21·9 months vs 27·0 months), and increased ORR (49% vs 61%) and CR rates (3% vs 9%) as assessed by independent review. (I was one of those who participated in the Independent Review). The results presented in this report are comparable to those of Robak and colleagues' combination chemotherapy and immunochemotherapy regimens in previously treated patients with relapsed or refractory CLL. This comparability is important because fludarabine plus cyclophosphamide and fludarabine plus cyclophosphamide plus rituximab are increasingly used in the front-line setting; additional novel treatment regimens are needed for second-line therapy.
Treatment of CLL has been evolving over the period this study was undertaken. For patients with relapsed or refractory CLL, various guidelines provide options for treatment but no globally recognised standard of care exists. However, fludarabine-based combination regimens have been increasingly used as first-line or subsequent treatments. Although no conclusion can be drawn about the benefit of the combination treatment in the subset of patients with previous exposure to fludarabine because of the small sample size, the HR of 0·82 suggests that the combination treatment is beneficial. Additionally, the significant overall treatment benefit noted from all the enrolled patients suggests that the combination treatment provided benefit to all enrolled patients previously given different types of treatment. Also, cytogenetic testing was not required in the initial stages of the study and was added midway through the study. Therefore, cytogenetic data were available for 57% of 335 patients, restricting the statistical precision of analyses in subgroups defined on the basis of these data, and restricting the ability to make conclusions about any effect of cytogenetics on response.
For second-line therapy, the fludarabine plus alemtuzumab regimen has several potential advantages. First, unlike fludarabine plus cyclophosphamide and fludarabine plus cyclophosphamide plus rituximab, the fludarabine plus alemtuzumab regimen spares patients from additional exposure to alkylating drugs, which theoretically might be associated with serious early and late toxicities, such as leukaemia possibly associated with secondary therapy. Second, patients treated with fludarabine plus alemtuzumab had a lower exposure to each drug than with the commonly used dosing regimen when each drug is used alone. The combination regimen uses 50% less alemtuzumab and 30% less fludarabine than the dosing regimen approved by the US FDA for single drug use. Last, the dosing schedule for alemtuzumab of 3 days per month in the fludarabine plus alemtuzumab regimen improves patient convenience compared with the standard dosing regimen of three times per week for up to 12 weeks.
The fludarabine plus alemtuzumab combination provides clinical benefits with an acceptable safety profile in previously treated patients with CLL when compared with single-agent fludarabine. This combination might become an important additional treatment option for patients with relapsed or refractory CLL.
.
Blowing our own trumpet
I had my first dose of my second course of my third line of chemotherapy this morning. Once again I was impressed by the set-up at the Royal Bournemouth Hospital. I learned today that it received the accolade of NHS Hospital of the Year in 2009. And in 2010 it was awarded Safe Hospital of the Year status. It is now 21 months since there has been a case of hospital acquired MRSA.
To continue blowing our own trumpet may I direct you to our new website set up by our new colleague, Dr Renata Walewska. http://www.rbch.nhs.uk/index.php?id=616 Please browse. You will see that we have had nearly 800 scientific publications over the past 30 years.
To continue blowing our own trumpet may I direct you to our new website set up by our new colleague, Dr Renata Walewska. http://www.rbch.nhs.uk/index.php?id=616 Please browse. You will see that we have had nearly 800 scientific publications over the past 30 years.
Monday, October 17, 2011
The role of CD38 in affecting CLL migration
In vitro activation of CD38 caused by stimulating mAbs induces a portion of the CLL clone (10%-30%) to proliferate, giving rise to an immunoblast-like component that does not secrete Igs; these effects are dependent on significant amounts of soluble IL-2, in keeping with the observation that T lymphocytes and accessory cells are needed in vivo. This was a first indication that CD38 transduces signals, leading or contributing to CLL cell growth, even in the absence of stimuli coming from the BCR.
First indications that CD38 acts as a molecular signpost that routes leukemic cells to specialized niches arose from in vivo findings that the number of CD38 molecules expressed in BM and LN is higher than in circulating lymphocytes. In addition, nurse-like cells, differentiated in vitro from circulating CD14+ cells and also presumably present in solid lymphoid tissues in vivo, express CD31, the CD38 ligand. Interactions between CD38 and CD31 in this system promote proliferation and survival through a molecular circuit that can be interrupted by blocking anti-CD31 or anti-CD38 mAbs. CD38/CD31 interaction results in a genetic signature that includes more than 1500 modulated sequences. Pathway analysis drastically reduces this complexity, with proliferation and migration emerging as the main elements characterizing this receptor/ligand system.
CD38 signaling may be influenced by the presence of ZAP-70. Patients with CD38+ZAP-70+ clones are more responsive to activation of intracellular proteins than CD38+ZAP-70− persons. This may explain why the simultaneous expression of the two molecules offers a more efficient identification of the high-risk patient subset. CD38+ZAP-70+ CLL cells also migrate better in response to the CXCL12 chemokine and exhibit a genetic signature primarily consisting of genes involved in cell locomotion. A functional cooperation between CD38 and CXCR4 was demonstrated by showing that binding of stimulating anti-CD38 mAbs and de novo expression of CD38 by lentiviral infection increases chemotaxis in response to CXCL12.
These effects on proliferation and chemotaxis are altered by blocking reagents, which interfere with CXCL12-mediated migration in vitro and block CLL homing in an NOD/SCID mouse model. A possible explanation is that CD38 and CXCR4 are associated on the same membrane patches; and hence, stimulating and blocking anti-CD38 mAbs have the potential to interfere positively or negatively with CXCL12 binding to the CXCR4 receptor, changing responses. Recent data indicate that this signaling platform of molecules is more complex and includes adhesion molecules, such as CD49d and matrix metalloproteases, such as MMP-9.
First indications that CD38 acts as a molecular signpost that routes leukemic cells to specialized niches arose from in vivo findings that the number of CD38 molecules expressed in BM and LN is higher than in circulating lymphocytes. In addition, nurse-like cells, differentiated in vitro from circulating CD14+ cells and also presumably present in solid lymphoid tissues in vivo, express CD31, the CD38 ligand. Interactions between CD38 and CD31 in this system promote proliferation and survival through a molecular circuit that can be interrupted by blocking anti-CD31 or anti-CD38 mAbs. CD38/CD31 interaction results in a genetic signature that includes more than 1500 modulated sequences. Pathway analysis drastically reduces this complexity, with proliferation and migration emerging as the main elements characterizing this receptor/ligand system.
CD38 signaling may be influenced by the presence of ZAP-70. Patients with CD38+ZAP-70+ clones are more responsive to activation of intracellular proteins than CD38+ZAP-70− persons. This may explain why the simultaneous expression of the two molecules offers a more efficient identification of the high-risk patient subset. CD38+ZAP-70+ CLL cells also migrate better in response to the CXCL12 chemokine and exhibit a genetic signature primarily consisting of genes involved in cell locomotion. A functional cooperation between CD38 and CXCR4 was demonstrated by showing that binding of stimulating anti-CD38 mAbs and de novo expression of CD38 by lentiviral infection increases chemotaxis in response to CXCL12.
These effects on proliferation and chemotaxis are altered by blocking reagents, which interfere with CXCL12-mediated migration in vitro and block CLL homing in an NOD/SCID mouse model. A possible explanation is that CD38 and CXCR4 are associated on the same membrane patches; and hence, stimulating and blocking anti-CD38 mAbs have the potential to interfere positively or negatively with CXCL12 binding to the CXCR4 receptor, changing responses. Recent data indicate that this signaling platform of molecules is more complex and includes adhesion molecules, such as CD49d and matrix metalloproteases, such as MMP-9.
Health update
I have a week off chemotherapy and I am feeling better. Last week we had some sunshine and I was able to go for a walk on the beach at respectively Bournemouth, Poole and Highcliffe, depending of where the cusp of the cold front encroaching on the British Isles was exactly situated; 15 minutes walking and 30 minutes sitting in the sun.
I saw the oncologist this morning and had the good news that my carcinoembrionic antigen had fallen. It had always been in the normal range until before the last lot of chemotherapy began, when it had risen to 32. After this course it has fallen to 24 which is obviously in the right direction. Enough anyway to encourage them to restart the same type of chemotherapy tomorrow.
I am due a CT scan this afternoon. I met a new registrar this morning; a very pleasant young woman from Bangalore.
I saw the oncologist this morning and had the good news that my carcinoembrionic antigen had fallen. It had always been in the normal range until before the last lot of chemotherapy began, when it had risen to 32. After this course it has fallen to 24 which is obviously in the right direction. Enough anyway to encourage them to restart the same type of chemotherapy tomorrow.
I am due a CT scan this afternoon. I met a new registrar this morning; a very pleasant young woman from Bangalore.
CD38 and the BCR
Clones with higher numbers of CD38+ cells are generally those more responsive to BCR signaling in vitro, whereas CD38− clones are generally anergic, although exceptions exist. The same phenomena are observed at the intraclonal level as CD38+ cells respond more readily to BCR stimulation than CD38− cells of the same clone. However, evidence for involvement of CD38 in the BCR signaling pathway is indirect and linked to lateral associations with CD19 and CD81 (in turn part of the BCR complex) and colocalization in the same lipid rafts as the BCR.
The most favorable conditions for expansion of CLL clones exist in discrete anatomic sites, such as Proliferation Centers (PC) in Lymph Nodes (LN) and in the Bone Marrow, where leukemic cells come into contact with accessory cells and the appropriate array of cytokines and chemokines. These sites contain more CD38+ CLL cells than detected in the blood, implying that CD38 is involved in the expansion process and/or results from it.
These findings may indicate that a trafficking fraction of CLL cells may enter PCs of peripheral LNs, become activated, and express (more) CD38 as well as ZAP-70 and other activation markers. Additional stimulatory signals may also be delivered directly via CD38. The degree of activation would influence a cell's capacity to up-regulate the number of markers per cell and the percentage of positive cells. On re-entry into the peripheral circulation, CLL cells may express more activation markers (CD38, ZAP-70, CD49d, and others), thereby representing important predictors of disease outcome. Besides the BCR, CD38+ cells also respond better to signals coming through chemokine and other receptors (eg Toll-like receptors). Therefore, signals emanating initially and subsequently from this pathway probably provide molecular bridges to the extended CLL microenvironment, thereby favoring survival/proliferation of CLL cells.
The most favorable conditions for expansion of CLL clones exist in discrete anatomic sites, such as Proliferation Centers (PC) in Lymph Nodes (LN) and in the Bone Marrow, where leukemic cells come into contact with accessory cells and the appropriate array of cytokines and chemokines. These sites contain more CD38+ CLL cells than detected in the blood, implying that CD38 is involved in the expansion process and/or results from it.
These findings may indicate that a trafficking fraction of CLL cells may enter PCs of peripheral LNs, become activated, and express (more) CD38 as well as ZAP-70 and other activation markers. Additional stimulatory signals may also be delivered directly via CD38. The degree of activation would influence a cell's capacity to up-regulate the number of markers per cell and the percentage of positive cells. On re-entry into the peripheral circulation, CLL cells may express more activation markers (CD38, ZAP-70, CD49d, and others), thereby representing important predictors of disease outcome. Besides the BCR, CD38+ cells also respond better to signals coming through chemokine and other receptors (eg Toll-like receptors). Therefore, signals emanating initially and subsequently from this pathway probably provide molecular bridges to the extended CLL microenvironment, thereby favoring survival/proliferation of CLL cells.
What do we have but the Bible?
There is an extreme view of the origin of the gospels contaminated by the German higher critics of the nineteenth century, that holds that the Gospels were late documents cobbled together by people in the second century who did not know Jesus.
Modern scholarship suggests that all 4 evangelists were contemporaries of Jesus and the three synoptic gospels were written within 20 years of the death of Jesus. The incident of the young man who lost his clothes puts John Mark at the arrest of Jesus, Matthew was himself a disciple, Luke was a confidant of both Mary the mother of Jesus and Peter and he was later a companion of Paul whose own writings predate the gospels, even though he never met Jesus in His earthy lifetime. John's gospel is later but he was a very old man when he wrote it and there is no reason to believe it was written by anyone other than John the beloved disciple.
As for Jesus' own sayings, he claims to have come not to negate the Law but to fulfill it. The Old Testament apparent anomalies were pictures of the Christ to come. This same Jesus speaks more about the Hell to come than any other person in either testament and will come to judge the world. He is not the milksop that liberal Christians claim him to be and though for now he offers salvation, that offer is not for all time. After we die there will be no second chance and then if not covered by his death and resurrection, our sins will surely find us out. It is then that he will confront us with, "I was hungry and you gave me nothing to eat, I was thirsty and you gave me nothing to drink, I needed clothes and you did not clothe me, I was sick and in prison and you did not look after me. ... I tell you the truth, whatever you did not do for one of the least of these you did not do it for me ... then they will go away to eternal punishment."
Modern scholarship suggests that all 4 evangelists were contemporaries of Jesus and the three synoptic gospels were written within 20 years of the death of Jesus. The incident of the young man who lost his clothes puts John Mark at the arrest of Jesus, Matthew was himself a disciple, Luke was a confidant of both Mary the mother of Jesus and Peter and he was later a companion of Paul whose own writings predate the gospels, even though he never met Jesus in His earthy lifetime. John's gospel is later but he was a very old man when he wrote it and there is no reason to believe it was written by anyone other than John the beloved disciple.
As for Jesus' own sayings, he claims to have come not to negate the Law but to fulfill it. The Old Testament apparent anomalies were pictures of the Christ to come. This same Jesus speaks more about the Hell to come than any other person in either testament and will come to judge the world. He is not the milksop that liberal Christians claim him to be and though for now he offers salvation, that offer is not for all time. After we die there will be no second chance and then if not covered by his death and resurrection, our sins will surely find us out. It is then that he will confront us with, "I was hungry and you gave me nothing to eat, I was thirsty and you gave me nothing to drink, I needed clothes and you did not clothe me, I was sick and in prison and you did not look after me. ... I tell you the truth, whatever you did not do for one of the least of these you did not do it for me ... then they will go away to eternal punishment."
John 7:19. Falling short.
"Has not Moses given you the law? Yet not one of you keeps the law. Why are you trying to kill me?”
The inadequacy of the Law; it points out our faults but it does nothing to help us to keep it. Truly, all have sinned and fallen short of the glory of God
The inadequacy of the Law; it points out our faults but it does nothing to help us to keep it. Truly, all have sinned and fallen short of the glory of God
Sunday, October 16, 2011
Royal Wooton Bassett
In a moving ceremony this afternoon the small town of Wooton Bassett received the Letters patent to be able to prefix the town's name with "Royal". This was only the third occasion that this has happened and the first time for over 100 years.
The other two towns are Royal Tunbridge Wells and Royal Leamingston Spa which are both watering holes favored by previous monarchs. For Tunbridge Wells the prefix "Royal" dates to 1909, when King Edward VII granted the town its official "Royal" title to celebrate its popularity over the years amongst members of the royal family. It is a Spa town, incorporated as a municipal borough in 1888. In 1909 Edward VII allowed the prefix "Royal" in recognition of the town's connections with the royal family since the Stuart dynasty. The Borough of Royal Tunbridge Wells was abolished in April 1974, and charter trustees were briefly appointed to preserve the mayoralty of the town. The trustees, who were themselves abolished in December 1974, obtained letters patent reauthorising the prefix "Royal" to the name of the town
Leamington was granted a "Royal" prefix in 1838 by Queen Victoria, who visited the town as a Princess in 1830 and as Queen in 1858. There are other Royal counties and boroughs recognized because there are Royal palaces in them. The following places have been explicitly granted or confirmed the use of the title "royal" by royal charter, letters patent or similar instrument issued by the monarch. Berkshire, Greenwich, Kensington and Chelsea, Kingston on Thames, Windsor. Since 1926 the entitlement to the title "royal borough" has been strictly enforced. Devizes in Wiltshire, which had previously used the title without sanction was forced to end the practice.
The title "regis" (of the king) has also been granted to one town - Bognor. Tourism gradually took off in Bognor during the 19th century, with the area being chosen as an ideal location for King George V to convalesce during 1929, the King and Queen actually staying at Craigwell House in Aldwick. As a result, the King was asked to bestow the suffix "Regis" ("of the King") on "Bognor". The petition was presented to Lord Stamfordham, the King's Private Secretary, who in turn delivered it to the King. King George supposedly replied, "Oh, bugger Bognor." Lord Stamfordham then went back to the petitioners and told them, "the King has been graciously pleased to grant your request. There are 13 other Regis-es in the UK, but it generally signifies nothing more than that the Crown originally owned the manor. Among them are Houghton Regis in Bedfordshire, Salcombe Regis in Devon, Bere Regis and Lyme Regis in Dorset, Milton Regis in Kent, Beeston Regis in Norfolk, Grafton Regis in Northamptonshire, Brompton Regis in Somerset, Newton Regis in Warwickshire and Rowley Regis in the West Midlands.
The prefix King---- signifies something similar and there are more of these: Kingham, Kingsclere, King's Heath, Kingskerswell, Kings Langley, King's Lynn, King's Norton, King's Sutton, Kings Tamerton, Kingstanding, Kingsteignton, Kingston by Ferring, Kingston upon Hull, Kingston upon Thames, Kingswinford Winterborne, Kingston, Kingsbridge, Kingsbury Episcopi, Kingsdon, Kingston Seymour, Kingston St Mary, Kingstone, Kingweston, Kingswood, Queen Adelaide, Cambridgeshire, Queen Camel, Queen Charlton, Queen's Park, Princes Risborough, and Princetown.
Royal Wooton Bassett is different. It is the closest town to the RAF base at Lyneham. In 2005 a Hercules aircraft from Lyneham was lost in Iraq with all its crew. As they were repatriated people from the town spontaneously lined the streets to honor the servicemen as their hearses drove through the town. After 2007 servicemen killed in Afghanistan were routinely repatriated through Lyneham and again the town stood in silence as the funeral corteges drove through. Eventually several thousand people lined the streets, distributing flowers on the funeral vehicles. This was a spontaneous gesture of respect and honor for our servicemen. They performed this ceremony for 365 soldiers, marines, sailors and airman. It is for this act of honor that they have been honored. In future repatriation flights will be through a different RAF base at Brize Norton.
The other two towns are Royal Tunbridge Wells and Royal Leamingston Spa which are both watering holes favored by previous monarchs. For Tunbridge Wells the prefix "Royal" dates to 1909, when King Edward VII granted the town its official "Royal" title to celebrate its popularity over the years amongst members of the royal family. It is a Spa town, incorporated as a municipal borough in 1888. In 1909 Edward VII allowed the prefix "Royal" in recognition of the town's connections with the royal family since the Stuart dynasty. The Borough of Royal Tunbridge Wells was abolished in April 1974, and charter trustees were briefly appointed to preserve the mayoralty of the town. The trustees, who were themselves abolished in December 1974, obtained letters patent reauthorising the prefix "Royal" to the name of the town
Leamington was granted a "Royal" prefix in 1838 by Queen Victoria, who visited the town as a Princess in 1830 and as Queen in 1858. There are other Royal counties and boroughs recognized because there are Royal palaces in them. The following places have been explicitly granted or confirmed the use of the title "royal" by royal charter, letters patent or similar instrument issued by the monarch. Berkshire, Greenwich, Kensington and Chelsea, Kingston on Thames, Windsor. Since 1926 the entitlement to the title "royal borough" has been strictly enforced. Devizes in Wiltshire, which had previously used the title without sanction was forced to end the practice.
The title "regis" (of the king) has also been granted to one town - Bognor. Tourism gradually took off in Bognor during the 19th century, with the area being chosen as an ideal location for King George V to convalesce during 1929, the King and Queen actually staying at Craigwell House in Aldwick. As a result, the King was asked to bestow the suffix "Regis" ("of the King") on "Bognor". The petition was presented to Lord Stamfordham, the King's Private Secretary, who in turn delivered it to the King. King George supposedly replied, "Oh, bugger Bognor." Lord Stamfordham then went back to the petitioners and told them, "the King has been graciously pleased to grant your request. There are 13 other Regis-es in the UK, but it generally signifies nothing more than that the Crown originally owned the manor. Among them are Houghton Regis in Bedfordshire, Salcombe Regis in Devon, Bere Regis and Lyme Regis in Dorset, Milton Regis in Kent, Beeston Regis in Norfolk, Grafton Regis in Northamptonshire, Brompton Regis in Somerset, Newton Regis in Warwickshire and Rowley Regis in the West Midlands.
The prefix King---- signifies something similar and there are more of these: Kingham, Kingsclere, King's Heath, Kingskerswell, Kings Langley, King's Lynn, King's Norton, King's Sutton, Kings Tamerton, Kingstanding, Kingsteignton, Kingston by Ferring, Kingston upon Hull, Kingston upon Thames, Kingswinford Winterborne, Kingston, Kingsbridge, Kingsbury Episcopi, Kingsdon, Kingston Seymour, Kingston St Mary, Kingstone, Kingweston, Kingswood, Queen Adelaide, Cambridgeshire, Queen Camel, Queen Charlton, Queen's Park, Princes Risborough, and Princetown.
Royal Wooton Bassett is different. It is the closest town to the RAF base at Lyneham. In 2005 a Hercules aircraft from Lyneham was lost in Iraq with all its crew. As they were repatriated people from the town spontaneously lined the streets to honor the servicemen as their hearses drove through the town. After 2007 servicemen killed in Afghanistan were routinely repatriated through Lyneham and again the town stood in silence as the funeral corteges drove through. Eventually several thousand people lined the streets, distributing flowers on the funeral vehicles. This was a spontaneous gesture of respect and honor for our servicemen. They performed this ceremony for 365 soldiers, marines, sailors and airman. It is for this act of honor that they have been honored. In future repatriation flights will be through a different RAF base at Brize Norton.
Model of role of CD38
CD38+ CLL cells are more sensitive to chemokine (CXCL12) signals, with a higher likelihood to home to lymphoid tissues than the CD38− cells. Once inside the Lymph Node Proliferation Centers, CLL lymphocytes come into contact with accessory cells, such as nurse-like (NLC), follicular dendritic (FDC), stromal, endothelial, mesenchymal (these may be different names for the same cells in some circumstances), and T cells. The presence of antigen and accessory signals leads to proliferation which runs the risk of causing the acquisition of novel genetic lesions (like del 11q or del 17p) that promote clonal evolution and disease progression. These events are more apparent in the CD38+ subsets.
Other characteristics of the CD38+ and CD38− CLL subgroups are variable telomere lengths, telomerase levels, expression of the COX-2 enzyme, and in vivo incorporation of heavy hydrogen into DNA of dividing leukemic cells. Lastly, they differ in high-risk genomic abnormalities, in the development of new DNA mutations and copy number changes over time.
These findings suggest that cellular proliferation might be at the root of the association between higher levels of CD38, aggressively growing CLL clones, and poor patient outcome. This suggestion is consistent with in vivo labeling experiments using 2H2O (“heavy water”) that demonstrated larger than anticipated rates of CLL birth, especially in patients with poor clinical course and outcome and a several-fold higher percentage of newly born cells in CD38+ fractions of CLL clones than in CD38− counterparts of the same clones.
Furthermore, preliminary results from a large clinical study suggest that the percentage of CD38+ CLL cells strongly correlates with the level of leukemic cell turnover observed in vivo. Finally, a recent study using improved cell surface phenotyping and sorting techniques that incorporate expression densities of CXCR4 and CD5 indicates that the percentage of newly born cells is ∼ 10 times higher in the CD38+ than the CD38− fraction. Thus, the combined kinetic and CXCR4 expression analyses highlight relationships between CD38 expression, in vivo kinetics, cell migration to solid tissues, and clinical outcome.
Therefore, CD38 expression is at least a quantitative reflection of in vivo CLL cell activation. However, the activation status acquired in the PCs of lymphoid tissues may wane over time, leading to the conversion of CD38+ cells to CD38− quiescent cells. The circuit may be restarted when the cells are recruited into lymphoid tissues, where they may be reactivated. The initiating event for this activation is unclear, although the association of higher numbers of CD38+ cells with IGHV unmutated CLL clones that often exhibit biased use and selection for specific IGHV/D/J rearrangements (stereotyped BCRs) suggests that one factor promoting cellular stimulation is BCR signaling.
Other characteristics of the CD38+ and CD38− CLL subgroups are variable telomere lengths, telomerase levels, expression of the COX-2 enzyme, and in vivo incorporation of heavy hydrogen into DNA of dividing leukemic cells. Lastly, they differ in high-risk genomic abnormalities, in the development of new DNA mutations and copy number changes over time.
These findings suggest that cellular proliferation might be at the root of the association between higher levels of CD38, aggressively growing CLL clones, and poor patient outcome. This suggestion is consistent with in vivo labeling experiments using 2H2O (“heavy water”) that demonstrated larger than anticipated rates of CLL birth, especially in patients with poor clinical course and outcome and a several-fold higher percentage of newly born cells in CD38+ fractions of CLL clones than in CD38− counterparts of the same clones.
Furthermore, preliminary results from a large clinical study suggest that the percentage of CD38+ CLL cells strongly correlates with the level of leukemic cell turnover observed in vivo. Finally, a recent study using improved cell surface phenotyping and sorting techniques that incorporate expression densities of CXCR4 and CD5 indicates that the percentage of newly born cells is ∼ 10 times higher in the CD38+ than the CD38− fraction. Thus, the combined kinetic and CXCR4 expression analyses highlight relationships between CD38 expression, in vivo kinetics, cell migration to solid tissues, and clinical outcome.
Therefore, CD38 expression is at least a quantitative reflection of in vivo CLL cell activation. However, the activation status acquired in the PCs of lymphoid tissues may wane over time, leading to the conversion of CD38+ cells to CD38− quiescent cells. The circuit may be restarted when the cells are recruited into lymphoid tissues, where they may be reactivated. The initiating event for this activation is unclear, although the association of higher numbers of CD38+ cells with IGHV unmutated CLL clones that often exhibit biased use and selection for specific IGHV/D/J rearrangements (stereotyped BCRs) suggests that one factor promoting cellular stimulation is BCR signaling.
John 7:18. Content to be second
Whoever speaks on their own does so to gain personal glory, but he who seeks the glory of the one who sent him is a man of truth; there is nothing false about him.
I don't suppose that this is a verse on everyone's lips, yet it is so true. It speaks of the absolute servanthood of Jesus. Despite being co-equal with the Father, he is subject to him. How rare is such an attitude in our human doings. Always trying to strive for the top position. Remember Paul's picture of the body - how we all have our designated roles.
I don't suppose that this is a verse on everyone's lips, yet it is so true. It speaks of the absolute servanthood of Jesus. Despite being co-equal with the Father, he is subject to him. How rare is such an attitude in our human doings. Always trying to strive for the top position. Remember Paul's picture of the body - how we all have our designated roles.
Saturday, October 15, 2011
CD38 as a marker in CLL
Like somatic mutations of IGHV, CD38 expression identifies two subgroups of CLL patients with different clinical outcomes; this distinction is based on the percentage of CD38+ leukemic cells within a CLL clone. In the majority of studies, the threshold is considered as ≥ 30% CD38+ clonal members. The 2 patient subgroups that result from this cut-off point differ clinically in several ways, including overall survival, time to first treatment, bias toward male gender, number of leukemic cells with atypical morphology, extent and level of adenopathy, lactate dehydrogenase and β2-microglobulin levels, and absolute lymphocyte counts. These subgroups also differ in responsiveness to various therapies.
Combining CD38 with other prognostic markers, such as ZAP-70 and CD49d, provides complementary prognostic information. Because these molecules are components of the same functional network, their interrelated biologic roles probably explain these observations.
The past decade has highlighted several molecular differences between CD38+ and CD38− members of the same clone, including expression of specific activation markers, which reflect quantitative and temporal differences in response to stimulation. CD38+ CLL cells express high levels of CD69 and HLA-DR, both indicative of recent activation. CD38 also marks a cellular subset enriched in Ki-67+ and ZAP-70+ cells, more efficiently responding to surface IgM cross-linking. Both features are apparently independent of the percentage of CD38-expressing cells within the original clone. In addition, CD38+ CLL clones display enhanced ability to migrate in response to CXCL12, to transduce BCR-mediated signals, and to respond to anti-IgM and anti-IgD antibody-mediated crosslinking. The genetic signature characterizing CD38+ and CD38− members of the same clone revealed higher VEGF and Mcl-1 levels in CD38+ cells, pointing to a survival advantage from microenvironmental interactions.
Combining CD38 with other prognostic markers, such as ZAP-70 and CD49d, provides complementary prognostic information. Because these molecules are components of the same functional network, their interrelated biologic roles probably explain these observations.
The past decade has highlighted several molecular differences between CD38+ and CD38− members of the same clone, including expression of specific activation markers, which reflect quantitative and temporal differences in response to stimulation. CD38+ CLL cells express high levels of CD69 and HLA-DR, both indicative of recent activation. CD38 also marks a cellular subset enriched in Ki-67+ and ZAP-70+ cells, more efficiently responding to surface IgM cross-linking. Both features are apparently independent of the percentage of CD38-expressing cells within the original clone. In addition, CD38+ CLL clones display enhanced ability to migrate in response to CXCL12, to transduce BCR-mediated signals, and to respond to anti-IgM and anti-IgD antibody-mediated crosslinking. The genetic signature characterizing CD38+ and CD38− members of the same clone revealed higher VEGF and Mcl-1 levels in CD38+ cells, pointing to a survival advantage from microenvironmental interactions.
Which is the best hospital in America?
Which are the best hospitals in America? Most people who make a judgement would pick on the famous ones like: MD Anderson, Duke, Mass General, Stanford, Mount Sinai, Cleveland Clinic, Vanderbilt, the Mayo, University of Michigan, Brigham and Womens, University of Washington, Johns Hopkins etc. There are 17 that make the US News and World Report. These hospitals publish the best research and are most in the news for their innovative work.
But there is another way of looking at things. The Joint Commision for accrediting hospitals in America has released a list of the 450 best performing hospitals in America and none of the 17 makes the cut. This is because the Joint Commission focuses on everyday diagnoses such as the routine care of surgical cases, and people with pneumonia or myocardial infarction. It uses only wellattested process measures such a giving aspirin to people with chest pain and prophylactic antibiotics to patients undergoing surgery. Hospitals had to score 95% or better on all the 22 tested process measures.
The 405 hospitals included many small community hospitals and very few major urban and famous institutions. Some hospitals use their complex case mix as an excuse though it is hard to see how this would make a difference to drawing blood cultures before giving iv antibiotics or giving chemotherapy on time according to the prescribed schedule.
I do not think this is a purely American problem. In my role of inspecting pathology departments in most of teh big teaching hospitals in teh UK, I noticed remarkable carelessness in attention to detail. In looking at the glamorous aspects of a research institution they often took their eye off the ball. My son at teh CQC and my daughter as a junior doctor would concur, and most of the medicao-legal cases that I have been involved with involve large teaching hospitals.
I think at Bournemouth we had the best of both worlds. We were undoubtedly the District General Hospital with the best record for research and innovation, but we were also consistantly one of the best in teh country interms of achieving the highest standards in patient care and financial management.
But there is another way of looking at things. The Joint Commision for accrediting hospitals in America has released a list of the 450 best performing hospitals in America and none of the 17 makes the cut. This is because the Joint Commission focuses on everyday diagnoses such as the routine care of surgical cases, and people with pneumonia or myocardial infarction. It uses only wellattested process measures such a giving aspirin to people with chest pain and prophylactic antibiotics to patients undergoing surgery. Hospitals had to score 95% or better on all the 22 tested process measures.
The 405 hospitals included many small community hospitals and very few major urban and famous institutions. Some hospitals use their complex case mix as an excuse though it is hard to see how this would make a difference to drawing blood cultures before giving iv antibiotics or giving chemotherapy on time according to the prescribed schedule.
I do not think this is a purely American problem. In my role of inspecting pathology departments in most of teh big teaching hospitals in teh UK, I noticed remarkable carelessness in attention to detail. In looking at the glamorous aspects of a research institution they often took their eye off the ball. My son at teh CQC and my daughter as a junior doctor would concur, and most of the medicao-legal cases that I have been involved with involve large teaching hospitals.
I think at Bournemouth we had the best of both worlds. We were undoubtedly the District General Hospital with the best record for research and innovation, but we were also consistantly one of the best in teh country interms of achieving the highest standards in patient care and financial management.
John 7:17 Doing God's will
Anyone who chooses to do the will of God will find out whether my teaching comes from God or whether I speak on my own.
Being a Christian is an experiential thing. Apologetics are all very well, but you can't argue someone into the Kingdom. People talk about a leap of faith and there is something in that. When I was a convinced as I could be that there was no other way, I decided that I would live Chist's way and Lo and behold, it worked.
Being a Christian is an experiential thing. Apologetics are all very well, but you can't argue someone into the Kingdom. People talk about a leap of faith and there is something in that. When I was a convinced as I could be that there was no other way, I decided that I would live Chist's way and Lo and behold, it worked.
Friday, October 14, 2011
Biology of CD38
Although originally defined as a T-cell activation molecule, CD38 expression is found on other cell lineages. Within the B-cell compartment, CD38 is expressed by B lineage blasts in bone marrow and by B lymphocytes in germinal centers, activated tonsils, and by plasma cells. Mature virgin and memory B cells express only low levels of the molecule. CD38 also has been found in pancreatic acinar cells, smooth muscle cells, osteoclasts, and in different areas of the brain, although in most of these instances, CD38 is found in the cytosol and/or in the nucleus and not on the cell membrane.
The protein encoded by CD38 is a single chain type II transmembrane molecule displaying a molecular weight of ∼ 45 kDa. The functional CD38 molecule is a dimer, with the central part between the two monomers hosting the catalytic site. The monomer to dimer transition controls the functions of the molecule. Additional control is made by how the CD38 is arranged in lipid microdomains of the plasma membrane where the molecule has a tendency to associate with other proteins, forming large supramolecular complexes. CD38-associated molecules in human B cells include the CD19/CD81 complex, the chemokine receptor CXCR4, and adhesion molecules such as CD49d. CD38 is also found in exosomes, membrane vesicles secreted by B cells, and is probably part of an intercellular communication network.
An initial function attributed to CD38 was the regulation of activation/ proliferation of human T lymphocytes. Stimulating monoclonal antibodies (mAbs) specific for CD38 induce rapid Ca2+ fluxes and trigger the phosphorylation of a cascade of intracellular substrates, leading to activation of the NF-κB complex. Protracted effects include initiation of genetic programs causing cytokine secretion and proliferation of T lymphocytes. CD31 (also known as PECAM-1) is a non-substrate CD38 ligand that can start the signaling cascade and recapitulate the biologic events observed in vitro using surrogate agonistic mAbs.
The functional properties of CD38 on human B cells appear to be strictly linked to the stage of maturation. Blocking mAbs in cultures of CD19+ B-cell precursors on stromal layers markedly suppresses B-cell lymphopoiesis by inducing apoptosis. Opposite effects are observed in mature circulating B lymphocytes and tonsillar germinal center B cells, where CD38 ligation is followed by activation, apoptosis inhibition, proliferation, and cytokine secretion. In both instances, the mechanisms are attributed to the activation of an intracellular signaling pathway ruled by CD38 and requiring an association with CD19. The ensuing phosphorylation cascade includes lyn and phosphatidylinositol 3-kinase, among other kinases.
CD38 has a striking similarity to the enzyme adenosine diphosphate (ADP) ribosyl cyclase. This enzyme has the unique characteristic of cyclizing NAD+ to generate cyclic ADP ribose (cADPR), a second messenger that releases Ca2+ from internal stores, independently of the IP3 pathway. cADPR is a ubiquitous second messenger in eukaryotic cells. A further enzymatic activity recently attributed to CD38 is the pH-dependent conversion of NADP+ to NAADP+. These products bind different receptors and channels involved in the regulation of Ca2+ and activating critical signaling pathways.
How these varied functional activities can be conducted by a single molecule is yet to be defined.
The protein encoded by CD38 is a single chain type II transmembrane molecule displaying a molecular weight of ∼ 45 kDa. The functional CD38 molecule is a dimer, with the central part between the two monomers hosting the catalytic site. The monomer to dimer transition controls the functions of the molecule. Additional control is made by how the CD38 is arranged in lipid microdomains of the plasma membrane where the molecule has a tendency to associate with other proteins, forming large supramolecular complexes. CD38-associated molecules in human B cells include the CD19/CD81 complex, the chemokine receptor CXCR4, and adhesion molecules such as CD49d. CD38 is also found in exosomes, membrane vesicles secreted by B cells, and is probably part of an intercellular communication network.
An initial function attributed to CD38 was the regulation of activation/ proliferation of human T lymphocytes. Stimulating monoclonal antibodies (mAbs) specific for CD38 induce rapid Ca2+ fluxes and trigger the phosphorylation of a cascade of intracellular substrates, leading to activation of the NF-κB complex. Protracted effects include initiation of genetic programs causing cytokine secretion and proliferation of T lymphocytes. CD31 (also known as PECAM-1) is a non-substrate CD38 ligand that can start the signaling cascade and recapitulate the biologic events observed in vitro using surrogate agonistic mAbs.
The functional properties of CD38 on human B cells appear to be strictly linked to the stage of maturation. Blocking mAbs in cultures of CD19+ B-cell precursors on stromal layers markedly suppresses B-cell lymphopoiesis by inducing apoptosis. Opposite effects are observed in mature circulating B lymphocytes and tonsillar germinal center B cells, where CD38 ligation is followed by activation, apoptosis inhibition, proliferation, and cytokine secretion. In both instances, the mechanisms are attributed to the activation of an intracellular signaling pathway ruled by CD38 and requiring an association with CD19. The ensuing phosphorylation cascade includes lyn and phosphatidylinositol 3-kinase, among other kinases.
CD38 has a striking similarity to the enzyme adenosine diphosphate (ADP) ribosyl cyclase. This enzyme has the unique characteristic of cyclizing NAD+ to generate cyclic ADP ribose (cADPR), a second messenger that releases Ca2+ from internal stores, independently of the IP3 pathway. cADPR is a ubiquitous second messenger in eukaryotic cells. A further enzymatic activity recently attributed to CD38 is the pH-dependent conversion of NADP+ to NAADP+. These products bind different receptors and channels involved in the regulation of Ca2+ and activating critical signaling pathways.
How these varied functional activities can be conducted by a single molecule is yet to be defined.
More persecution of Christians
From Barnabas Trust
A young Pakistani Christian man was shot dead in a violent Muslim takeover of land allocated to a Christian village by the government.
Saqib (Sabir) Masih (22) was killed on the spot, and 37 people, including a one-year-old and seven other children, were seriously injured as a mob of around 60 Muslims descended on the village in Mian Channu, Punjab, on Wednesday (5 October). The wounded were taken to hospital; six of them were described as being in a critical condition.
The Muslim aggressors came to the Christian village to claim a plot of land that had been allocated by the government to house a resident workman. It had been illegally sold to two Muslims by the worker who was being accommodated there; he then fled with the proceeds of US$1,500.
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Women from a mainly Christian ethnic group are being raped and murdered by the Burmese military as government forces intensify their offensive in Kachin State.
Human rights activists are reporting an increased incidence of rape against Kachin women since the government broke a 17-year ceasefire with the Kachin Independence Organisation, which controls the territory, by attacking ethnic forces in June.
The Kachin Women’s Association Thailand (KWAT), which has been documenting incidents, reported 18 cases of gang rape over an eight day period in June shortly after fighting broke out between the Burmese military and the Kachin Independence Army. Four of the victims were killed after being raped. KWAT said that in one village, soldiers caught three families who had not managed to flee in time; six women and girls were gang-raped, and seven small children killed.
IRIN, the news service of the UN Office for the Coordination of Humanitarian Affairs, said on 26 September that the number of reported rapes to date that month was 37 in areas where government troops are active.
David Scott Mathieson, a researcher for Human Rights Watch, said: The use of sexual violence is one of the most serious within a whole litany of abuses that include forced labour, torture and ill-treatment and extra-judicial execution.
More than 25,000 people are now believed to have been displaced by the fighting as the Burmese army repeatedly attacks Kachin villages. Most internally displaced persons are living in temporary bamboo shelters with plastic sheet roofing at makeshift camps on the Chinese border. They are surviving on a small amount of rice a day as Kachin aid groups are running out of means to help them. Crowded living conditions, poor sanitation and lack of clean water have led to illness and the death of a number of children. At one site, 2,000 people are sharing ten toilets. Over 90 per cent of the 1.2 million Kachins are Christian. Most Christians in Burma are members of non-Burman ethnic minorities; they are frequently targeted by the military, partly for their ethnicity and partly for their faith.
A Kachin leader said: They want to wipe out our ethnic group and force us to become Buddhists like them, speak like them and become one of them.
The military has been pushing into other border areas including Shan and Karen. Many analysts believe that they want to access and control areas that are rich in energy resources to supply neighbouring China with electricity.
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An Iraqi convert from Islam to Christianity was violently attacked in America over a poem he wrote about the Jewish Holocaust.
Alaa Alsaegh was targeted in St Louis, Missouri, because of his Arabic poem, “Tears at the Heart of the Holocaust”, which expresses pain over the loss of six million Jews at the hands of the Nazis.
The attackers carved the Star of David on Alsaegh’s back with a knife while laughing as they recited his poem. They had trapped the Iraqi immigrant using two cars as he was driving along in St Louis. One cut across and struck his car, forcing him to stop, while the other blocked his vehicle from behind. Two attackers then got out of the cars, opened Alsaegh’s door and pointed a gun at him. They pushed his upper body down against the steering wheel, stabbed him and pulled off his shirt before carving the Jewish symbol on his back.
Alsaegh, who survived the ordeal, said that the assailants may have been Somali Muslims; they told him not to publish any more poems. The FBI has opened an investigation into the incident, but no arrests have yet been made.
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More than 50 churches have been shut down or demolished by the authorities in Indonesia since the start of 2010, often following pressure from Islamist groups.
The Jakarta Christian Communication Forum (FKKJ), which includes leaders of all denominations, reported that 47 were closed in 2010, plus a further nine in the first four months of 2011.
The official reasons given for the closures were that the buildings were being used as places of worship without a licence or without the minimum required number of 60 worshippers. But the FKKJ questioned: Why is this only applied to the Christian churches and not other places of worship?
In most cases, measures were taken following protests from radical Muslim groups, especially in areas where there is a strong presence of the Islamic Defenders Front.
The treatment of GKI Yasmin Church in Bogor, West Java, is a recent example of blatant discrimination by the authorities. The congregation has been holding services on the street in front of its half-constructed church since its building permit was revoked in 2008. Bogor city chiefs, spearheaded by the mayor, have refused to comply with a Supreme Court order issued in December 2010 that the church be reopened. The mayor has said that churches should not be built on a street with an Islamic name; GKI Yasmin is situated on a road named after an Islamic leader from West Java.
As well as discrimination by the authorities, churches in Indonesia are often attacked by extremists. On 25 September, a suicide bomber detonated an explosive at the Bethel Injil Sepuluh church in Keputon, Solo, Central Java, as people were leaving the service; 28 were injured in the blast.
The FKKJ recommended a number of responses for Indonesian churches that face problems with the authorities. These included knowing the rules and responding with legal action, establishing fruitful dialogue with local Muslim leaders, meeting the civil authorities, and initiating positive activities in the community. It said that Christians in Indonesia “want to be a blessing to society and the nation.”
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A young Pakistani Christian man was shot dead in a violent Muslim takeover of land allocated to a Christian village by the government.
Saqib (Sabir) Masih (22) was killed on the spot, and 37 people, including a one-year-old and seven other children, were seriously injured as a mob of around 60 Muslims descended on the village in Mian Channu, Punjab, on Wednesday (5 October). The wounded were taken to hospital; six of them were described as being in a critical condition.
The Muslim aggressors came to the Christian village to claim a plot of land that had been allocated by the government to house a resident workman. It had been illegally sold to two Muslims by the worker who was being accommodated there; he then fled with the proceeds of US$1,500.
-----------------------------------------------------------------------------
Women from a mainly Christian ethnic group are being raped and murdered by the Burmese military as government forces intensify their offensive in Kachin State.
Human rights activists are reporting an increased incidence of rape against Kachin women since the government broke a 17-year ceasefire with the Kachin Independence Organisation, which controls the territory, by attacking ethnic forces in June.
The Kachin Women’s Association Thailand (KWAT), which has been documenting incidents, reported 18 cases of gang rape over an eight day period in June shortly after fighting broke out between the Burmese military and the Kachin Independence Army. Four of the victims were killed after being raped. KWAT said that in one village, soldiers caught three families who had not managed to flee in time; six women and girls were gang-raped, and seven small children killed.
IRIN, the news service of the UN Office for the Coordination of Humanitarian Affairs, said on 26 September that the number of reported rapes to date that month was 37 in areas where government troops are active.
David Scott Mathieson, a researcher for Human Rights Watch, said: The use of sexual violence is one of the most serious within a whole litany of abuses that include forced labour, torture and ill-treatment and extra-judicial execution.
More than 25,000 people are now believed to have been displaced by the fighting as the Burmese army repeatedly attacks Kachin villages. Most internally displaced persons are living in temporary bamboo shelters with plastic sheet roofing at makeshift camps on the Chinese border. They are surviving on a small amount of rice a day as Kachin aid groups are running out of means to help them. Crowded living conditions, poor sanitation and lack of clean water have led to illness and the death of a number of children. At one site, 2,000 people are sharing ten toilets. Over 90 per cent of the 1.2 million Kachins are Christian. Most Christians in Burma are members of non-Burman ethnic minorities; they are frequently targeted by the military, partly for their ethnicity and partly for their faith.
A Kachin leader said: They want to wipe out our ethnic group and force us to become Buddhists like them, speak like them and become one of them.
The military has been pushing into other border areas including Shan and Karen. Many analysts believe that they want to access and control areas that are rich in energy resources to supply neighbouring China with electricity.
-------------------------------------------------------------------------------------
An Iraqi convert from Islam to Christianity was violently attacked in America over a poem he wrote about the Jewish Holocaust.
Alaa Alsaegh was targeted in St Louis, Missouri, because of his Arabic poem, “Tears at the Heart of the Holocaust”, which expresses pain over the loss of six million Jews at the hands of the Nazis.
The attackers carved the Star of David on Alsaegh’s back with a knife while laughing as they recited his poem. They had trapped the Iraqi immigrant using two cars as he was driving along in St Louis. One cut across and struck his car, forcing him to stop, while the other blocked his vehicle from behind. Two attackers then got out of the cars, opened Alsaegh’s door and pointed a gun at him. They pushed his upper body down against the steering wheel, stabbed him and pulled off his shirt before carving the Jewish symbol on his back.
Alsaegh, who survived the ordeal, said that the assailants may have been Somali Muslims; they told him not to publish any more poems. The FBI has opened an investigation into the incident, but no arrests have yet been made.
---------------------------------------------------------------------------------
More than 50 churches have been shut down or demolished by the authorities in Indonesia since the start of 2010, often following pressure from Islamist groups.
The Jakarta Christian Communication Forum (FKKJ), which includes leaders of all denominations, reported that 47 were closed in 2010, plus a further nine in the first four months of 2011.
The official reasons given for the closures were that the buildings were being used as places of worship without a licence or without the minimum required number of 60 worshippers. But the FKKJ questioned: Why is this only applied to the Christian churches and not other places of worship?
In most cases, measures were taken following protests from radical Muslim groups, especially in areas where there is a strong presence of the Islamic Defenders Front.
The treatment of GKI Yasmin Church in Bogor, West Java, is a recent example of blatant discrimination by the authorities. The congregation has been holding services on the street in front of its half-constructed church since its building permit was revoked in 2008. Bogor city chiefs, spearheaded by the mayor, have refused to comply with a Supreme Court order issued in December 2010 that the church be reopened. The mayor has said that churches should not be built on a street with an Islamic name; GKI Yasmin is situated on a road named after an Islamic leader from West Java.
As well as discrimination by the authorities, churches in Indonesia are often attacked by extremists. On 25 September, a suicide bomber detonated an explosive at the Bethel Injil Sepuluh church in Keputon, Solo, Central Java, as people were leaving the service; 28 were injured in the blast.
The FKKJ recommended a number of responses for Indonesian churches that face problems with the authorities. These included knowing the rules and responding with legal action, establishing fruitful dialogue with local Muslim leaders, meeting the civil authorities, and initiating positive activities in the community. It said that Christians in Indonesia “want to be a blessing to society and the nation.”
-----------------------------------------------------------------------------------
CD38 - a review
In the September issue of Blood is a useful review of CD38 by Fabio Malavasi from Turin. I will be taking it to pieces in the next few days and weeks to make it available to a lay audience.
Currently we view CLL as a disease with a balance between cells in the blood and cells in the lymphoid organs. The former are primarily mature-looking small lymphocytes resistant to apoptosis (programmed cell death), whereas the latter are composed of lymphocytes that undergo either proliferation or apoptosis according to the environment.
The varying clinical outcome of CLL patients is dictated, at least in part, by the nature of these microenvironmental signals and interactions that can promote or impair accumulation of genetic alterations. Detailed immunophenotypic and genetic analyses of different neoplastic clones have led to the identification of a number of molecular markers, some of which are gaining relevance in clinical practice to predict disease outcome. Cell surface CD38 is one of these markers. It is generally accepted that CD38+ patients will have a shorter progression-free interval, require earlier and more frequent treatments, and ultimately die sooner.
The most obvious explanation for the ill-effect of CD38 expression is that it reflects events occurring inside the cell. Indeed, the percentage of CD38+ cells within a leukemic clone was originally described as one of two independent indicators (along with IGHV gene mutations) of clinical outcome in CLL. Because both indicators marked somewhat overlapping populations, a link with IGHV mutation status, signals mediated by B-cell receptor (BCR), and CD38 was proposed but these two parameters are not obligatorily linked: and an alternative (and not mutually exclusive) hypothesis is that the presence of cell surface CD38 provides a bridge to the environment, shifting the balance between survival/proliferation and apoptosis in favor of the former. Evidence sustaining this idea has been collected over the past decade and has contributed to the formulation of the current concept of CLL as a chronic disease in which the patient physiologically provides essential elements and conditions leading to the acquisition and accumulation of genetic alterations by the leukemic cells.
These changes begin at a preneoplastic stage (ie, monoclonal B-cell lymphocytosis), or possibly even before, and continue to occur in a clone that progresses to a full-fledged CLL. This scheme accommodates the existence of structures that provide replicating and surviving signals to B cells on their way to neoplastic transformation. A key element in this view is that leukemic B cells can and do proliferate, with division taking place not in the blood, but primarily in specialized morphologically discrete structures of lymph nodes (LN) and bone marrow (BM) known as proliferation centers (PCs).
Different sets of molecules may have different roles and confer at times the ability to localize in privileged sites, to receive signals from the external environment, to undergo apoptosis, or to modify surrounding cells. In this context, evidence so far uncovered on the role of CD38 expression provides new depth and relevance about the regulation of the social life of the neoplastic B cell. In future articles the authors will explore the available evidence providing a mechanistic link between CD38 expression and CLL progression.
Currently we view CLL as a disease with a balance between cells in the blood and cells in the lymphoid organs. The former are primarily mature-looking small lymphocytes resistant to apoptosis (programmed cell death), whereas the latter are composed of lymphocytes that undergo either proliferation or apoptosis according to the environment.
The varying clinical outcome of CLL patients is dictated, at least in part, by the nature of these microenvironmental signals and interactions that can promote or impair accumulation of genetic alterations. Detailed immunophenotypic and genetic analyses of different neoplastic clones have led to the identification of a number of molecular markers, some of which are gaining relevance in clinical practice to predict disease outcome. Cell surface CD38 is one of these markers. It is generally accepted that CD38+ patients will have a shorter progression-free interval, require earlier and more frequent treatments, and ultimately die sooner.
The most obvious explanation for the ill-effect of CD38 expression is that it reflects events occurring inside the cell. Indeed, the percentage of CD38+ cells within a leukemic clone was originally described as one of two independent indicators (along with IGHV gene mutations) of clinical outcome in CLL. Because both indicators marked somewhat overlapping populations, a link with IGHV mutation status, signals mediated by B-cell receptor (BCR), and CD38 was proposed but these two parameters are not obligatorily linked: and an alternative (and not mutually exclusive) hypothesis is that the presence of cell surface CD38 provides a bridge to the environment, shifting the balance between survival/proliferation and apoptosis in favor of the former. Evidence sustaining this idea has been collected over the past decade and has contributed to the formulation of the current concept of CLL as a chronic disease in which the patient physiologically provides essential elements and conditions leading to the acquisition and accumulation of genetic alterations by the leukemic cells.
These changes begin at a preneoplastic stage (ie, monoclonal B-cell lymphocytosis), or possibly even before, and continue to occur in a clone that progresses to a full-fledged CLL. This scheme accommodates the existence of structures that provide replicating and surviving signals to B cells on their way to neoplastic transformation. A key element in this view is that leukemic B cells can and do proliferate, with division taking place not in the blood, but primarily in specialized morphologically discrete structures of lymph nodes (LN) and bone marrow (BM) known as proliferation centers (PCs).
Different sets of molecules may have different roles and confer at times the ability to localize in privileged sites, to receive signals from the external environment, to undergo apoptosis, or to modify surrounding cells. In this context, evidence so far uncovered on the role of CD38 expression provides new depth and relevance about the regulation of the social life of the neoplastic B cell. In future articles the authors will explore the available evidence providing a mechanistic link between CD38 expression and CLL progression.
Scandinavian noir
The trouble with technicolor films from Sweden is that they are all back and white. It started with Wallender, but I am currently working my way though a series of foreign thrillers with English subtitles. As someone reared on Morse, Frost and Taggert, I find these continental thrillers much more brutal and callous, but also more convincing. The evil is more evil and the good guys, flawed, but more believable.
The Girl with the Dragon Tattoo is the first of the Millennium trilogy and I recommend it to those who won't be offended by scenes of rape and murder. Sadly these things take place in our society; they are painful to watch, but lest we should be soft about the perpetrators, it is as well to remember why we have the death penalty and why prison means punishment.
The French series, Spiral, is equally gritty and takes the evil into high places. From what we have recently heard about France corruption reaches into the very heart of government.
There is a Danish series entitled the Killing, which I have yet to watch, but I have it on my list.
The Girl with the Dragon Tattoo is the first of the Millennium trilogy and I recommend it to those who won't be offended by scenes of rape and murder. Sadly these things take place in our society; they are painful to watch, but lest we should be soft about the perpetrators, it is as well to remember why we have the death penalty and why prison means punishment.
The French series, Spiral, is equally gritty and takes the evil into high places. From what we have recently heard about France corruption reaches into the very heart of government.
There is a Danish series entitled the Killing, which I have yet to watch, but I have it on my list.
John 7:16. This is authority.
Jesus answered, "My teaching is not my own. It comes from him who sent me."
Not the careful unpicking of scribal works and historical documents. Not the wisdom of academics passed down through the ages by oral or written tradition. Not the brilliant insights of a genius. The teaching of Jesus comes directly from God.
Not the careful unpicking of scribal works and historical documents. Not the wisdom of academics passed down through the ages by oral or written tradition. Not the brilliant insights of a genius. The teaching of Jesus comes directly from God.
Wednesday, October 12, 2011
How to reduce the cost of cancer drugs
What could make the cost of new cancer drugs cheaper? In the latest Lancer Oncology, NICE has some suggestions.
1. Recent proposals by an international group of academic clinical investigators suggest that clinical trial costs could be decreased by 40–60% without detriment to their quality. (EL Eisenstein, PW Lemons and BE Tardiff, et al. Reducing the costs of phase III cardiovascular trials. Am Heart J, 149 (2005), pp. 482–488. EL Eisenstein, R Collins and BS Cracknell, et al. Sensible approaches for reducing clinical trial costs. Clin Trials, 5 (2008), pp. 75–84.)
2 Simple measures to reduce costs include electronic data capture, reduction in the length of case-management forms, and modified site-management practices. The latter should include greater use of statistical techniques to detect fraud, rather than over-reliance on site visits by regulators and sponsors.
3 Greater use of Bayesian techniques in the design and analysis of randomised controlled trials holds real promise in reducing trial duration and numbers of patients needed.
4 Oncologists and patient advocacy organisations should start challenging the data requirements demanded by regulatory authorities.
5 Rather than criticise organisations such as NICE for declining reimbursement on grounds of cost-effectiveness, clinicians and patient advocates should start challenging pharmaceutical companies about the high prices they seek for products with modest benefits.
6 We should all be more concerned about the difficulties facing low and middle income countries in accessing affordable cancer care, rather than constantly focusing on the problems facing developed countries.
1. Recent proposals by an international group of academic clinical investigators suggest that clinical trial costs could be decreased by 40–60% without detriment to their quality. (EL Eisenstein, PW Lemons and BE Tardiff, et al. Reducing the costs of phase III cardiovascular trials. Am Heart J, 149 (2005), pp. 482–488. EL Eisenstein, R Collins and BS Cracknell, et al. Sensible approaches for reducing clinical trial costs. Clin Trials, 5 (2008), pp. 75–84.)
2 Simple measures to reduce costs include electronic data capture, reduction in the length of case-management forms, and modified site-management practices. The latter should include greater use of statistical techniques to detect fraud, rather than over-reliance on site visits by regulators and sponsors.
3 Greater use of Bayesian techniques in the design and analysis of randomised controlled trials holds real promise in reducing trial duration and numbers of patients needed.
4 Oncologists and patient advocacy organisations should start challenging the data requirements demanded by regulatory authorities.
5 Rather than criticise organisations such as NICE for declining reimbursement on grounds of cost-effectiveness, clinicians and patient advocates should start challenging pharmaceutical companies about the high prices they seek for products with modest benefits.
6 We should all be more concerned about the difficulties facing low and middle income countries in accessing affordable cancer care, rather than constantly focusing on the problems facing developed countries.
John 7:14-15. Jesus the author of our faith
Not until halfway through the festival did Jesus go up to the temple courts and begin to teach. The Jews there were amazed and asked, “How did this man get such learning without having been taught?”
They should not have been surprised. Even at the age of 12 Jesus had shown that his insight into the Scriptures exceeded theirs. How could he know more than them when he had never studied at their universities? Because he wrote the Scriptures and was the author of what they were about.
They should not have been surprised. Even at the age of 12 Jesus had shown that his insight into the Scriptures exceeded theirs. How could he know more than them when he had never studied at their universities? Because he wrote the Scriptures and was the author of what they were about.
Monday, October 10, 2011
Two die from pancreatic cancer
By a strange coincidence two famous men died of pancreatic cancer last week. Steve Jobs, the co-founder of Apple succumbed and so did Ralph Steinman, who discovered the dendritic cell. Steinman was awarded the Nobel Prize for medicine, but when the telephone call came he had been dead for three days.
Ironically, Steinman was being treated for his pancreatic cancer with a dendritic cell approach.
So there you have it: pancreatic cancer is so terrible a disease that it cannot be defeated by all the money in the world or by the biggest brains on the planet.
Ironically, Steinman was being treated for his pancreatic cancer with a dendritic cell approach.
So there you have it: pancreatic cancer is so terrible a disease that it cannot be defeated by all the money in the world or by the biggest brains on the planet.
John 7:1-12. Worldly advice
After this, Jesus went around in Galilee. He did not want to go about in Judea because the Jewish leaders there were looking for a way to kill him. But when the Jewish Festival of Tabernacles was near, Jesus’ brothers said to him, “Leave Galilee and go to Judea, so that your disciples there may see the works you do. No one who wants to become a public figure acts in secret. Since you are doing these things, show yourself to the world.” For even his own brothers did not believe in him.
Therefore Jesus told them, “My time is not yet here; for you any time will do. The world cannot hate you, but it hates me because I testify that its works are evil. You go to the festival. I am not going up to this festival, because my time has not yet fully come.” After he had said this, he stayed in Galilee. However, after his brothers had left for the festival, he went also, not publicly, but in secret. Now at the festival the Jewish leaders were watching for Jesus and asking, “Where is he?” Among the crowds there was widespread whispering about him. Some said, “He is a good man.” Others replied, “No, he deceives the people.”
Jesus practice seems to have been to live and preach in Galilee and to go up to Jerusalem for the feasts. However, he had to be circumspect about his visits to Jerusalem since he had already raise the antagonism of the Jewish leaders and he had not yer completed his preparation for the final Passover act. Therefore, when his brothers advise him to go to the capital, for what are worldly reasons, he easily resists them while intending to go up secretly afterwards.
Although his brother James later became leader of the church in Jerusalem, at this time his brothers were unbelievers.
We must all be circumspect about taking advice from the world even if it comes from people close to home.
Therefore Jesus told them, “My time is not yet here; for you any time will do. The world cannot hate you, but it hates me because I testify that its works are evil. You go to the festival. I am not going up to this festival, because my time has not yet fully come.” After he had said this, he stayed in Galilee. However, after his brothers had left for the festival, he went also, not publicly, but in secret. Now at the festival the Jewish leaders were watching for Jesus and asking, “Where is he?” Among the crowds there was widespread whispering about him. Some said, “He is a good man.” Others replied, “No, he deceives the people.”
Jesus practice seems to have been to live and preach in Galilee and to go up to Jerusalem for the feasts. However, he had to be circumspect about his visits to Jerusalem since he had already raise the antagonism of the Jewish leaders and he had not yer completed his preparation for the final Passover act. Therefore, when his brothers advise him to go to the capital, for what are worldly reasons, he easily resists them while intending to go up secretly afterwards.
Although his brother James later became leader of the church in Jerusalem, at this time his brothers were unbelievers.
We must all be circumspect about taking advice from the world even if it comes from people close to home.
Saturday, October 08, 2011
Interlude
There is something delightful in watching a craftsman at work. Whether it is a bricklayer, a carpenter or a lady knitting, it is a delightful and satisfying experience.
In the old days of monochrome TV when the BBC had a monopoly, in the gaps betwen programs, instead of adverts and trailers we used to have 'interludes'. The most popular of these interludes was watching a pair of hands form a pot on a potter's wheel. I found out this week that the hands belonged to the grandfather of my brother-in-law. He used to work at Watt's gallery in Compton in Surrey.
In the old days of monochrome TV when the BBC had a monopoly, in the gaps betwen programs, instead of adverts and trailers we used to have 'interludes'. The most popular of these interludes was watching a pair of hands form a pot on a potter's wheel. I found out this week that the hands belonged to the grandfather of my brother-in-law. He used to work at Watt's gallery in Compton in Surrey.
Why I am quiet.
My time has mostly been spent drowsing. The combination of chemotherapy and pain-killers has kept me from blogging.
John 6:70-71. The ultimate betrayal
Then Jesus replied, “Have I not chosen you, the Twelve? Yet one of you is a devil!” (He meant Judas, the son of Simon Iscariot, who, though one of the Twelve, was later to betray him.)
From these verses we know that Jesus was omniscient; that the plan of salvation was there right from the beginning; that his betrayal was pre-planned and deliberate; that Judas was irredeemable; that the devil was sucked into the plan; that Jesus bravely faced a terrible outcome for him; that there could have been no other way; that God so loved the world that he gave his one and only son that everyone who believed on him should not perish but have everlasting life.
From these verses we know that Jesus was omniscient; that the plan of salvation was there right from the beginning; that his betrayal was pre-planned and deliberate; that Judas was irredeemable; that the devil was sucked into the plan; that Jesus bravely faced a terrible outcome for him; that there could have been no other way; that God so loved the world that he gave his one and only son that everyone who believed on him should not perish but have everlasting life.
Saturday, October 01, 2011
Aid to Palestine
The Palestinian leadership yesterday accused the US Congress of inflicting "collective punishment" upon its people by holding up almost $200m in aid earmarked for the West Bank and Gaza by the Obama administration. The freeze on funds earlier allocated for the financial year which ends today is the first concrete Congressional reprisal against Palestinian President Mahmoud Abbas to come to light since he angered US legislators by pursuing his application for full UN membership last week. The unpublicised block has been in force since August and was imposed in response to the then planned UN recognition bid and to earlier – so far fruitless – efforts to effect reconciliation between Mr Abbas's own Fatah faction and Hamas.
But no-one has a right to aid. The palestinians were warned that to elect a party like Hamas in Gaza would result in the US withdraing its goodwill. They thought the US was bluffing. It was not.
But no-one has a right to aid. The palestinians were warned that to elect a party like Hamas in Gaza would result in the US withdraing its goodwill. They thought the US was bluffing. It was not.
Laziness in the workplace
You would never think there was a recession going on. It has taken 4 days to get a technician out ro fix my cable connexion for my TV. Even when I threatened to go to their competitor, I couldn't budge them. They offered me £25 off my next bill for the lost connexion, but nothing would induce them to improve their service. I would pay an extra £25 to get the job done quickly. I wonder whether Richard Branson knows what is being done in his name.
You would think that the threat of competition would induce them to improve, but a great depression has set upon the country. No-one seems to have any initiative. Everyone is beset by the attitude that nothing can be done. I remember the same attitude beset the country in the 1970s before Mrs Thatcher came to power.
We see it in hospitals. Despite the perception that things are going downhill, no-one seems to recognize that it is in their hands to change things. Recently I heard that bone marrow trephines were being booked at a famous hospital at one hourly intervals. The dostor doing the operations can do them in 15 minutes, but the times are dictated by the nurse who doesn't start work until 9-30 am and can therefor only accommodate 3 trephines in her working day. What does the nurse do? Does she lay up the trolley? No. Does she do the trephine biopsy? No. Does she collect the specimens for the lab? No. Does she consent the patient? No. What doe she do? Apparently she holds the patient's hand during the procedure and whispers encouraging words.
Do you remember when elevators in department stores had elevator operators who called out what departments were on each floor? Before they realized that customers could actually read. They used to call it overmanning.
If the nurse could actually do something then they might do 10 trephines in a morning, but instead patinets and doctors spend hours wasting their time.
One of the reasons that people enjoy being self employed is the ability to set their own pace for work. It is immensely frustrating to be at the behest of laziness in colleagues.
You would think that the threat of competition would induce them to improve, but a great depression has set upon the country. No-one seems to have any initiative. Everyone is beset by the attitude that nothing can be done. I remember the same attitude beset the country in the 1970s before Mrs Thatcher came to power.
We see it in hospitals. Despite the perception that things are going downhill, no-one seems to recognize that it is in their hands to change things. Recently I heard that bone marrow trephines were being booked at a famous hospital at one hourly intervals. The dostor doing the operations can do them in 15 minutes, but the times are dictated by the nurse who doesn't start work until 9-30 am and can therefor only accommodate 3 trephines in her working day. What does the nurse do? Does she lay up the trolley? No. Does she do the trephine biopsy? No. Does she collect the specimens for the lab? No. Does she consent the patient? No. What doe she do? Apparently she holds the patient's hand during the procedure and whispers encouraging words.
Do you remember when elevators in department stores had elevator operators who called out what departments were on each floor? Before they realized that customers could actually read. They used to call it overmanning.
If the nurse could actually do something then they might do 10 trephines in a morning, but instead patinets and doctors spend hours wasting their time.
One of the reasons that people enjoy being self employed is the ability to set their own pace for work. It is immensely frustrating to be at the behest of laziness in colleagues.
silence for a while
The long time spent away from my computer is not entirely down to ill health. The fan disintegrated on my lap top and the hard drive overheated and broke. I am now pretty well restored to function, though I haven't worked out why my wide screen monitor isn't working. I did have a period of poor health after restarting the chemotherapy, but that lasted a day or two and was largely due to an inadvertent overdose of the anti-emetic levo-promazine. I should have only taken a quarter of a tablet rather than a whole one.
To add to my woes, my TV went down so I have not had much to detract me; apart from arguing with the cable company on the telephone.
Anyway I am back up to speed again and should now be able to start blogging again.
To add to my woes, my TV went down so I have not had much to detract me; apart from arguing with the cable company on the telephone.
Anyway I am back up to speed again and should now be able to start blogging again.
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