But if I do judge, my decisions are right, because I am not alone. I stand with the Father who sent me.
Note the further "I AM". Jesus is not bereft of the ability to judge; he could have judged the world when he came first time, because he stood, co-equal, with the Father. But he was sent by the Father with a particular purpose: not to judge but to warn and to save. The judgment next time.
Sunday, November 27, 2011
treasure in pots of clay
One of the enduring questions that Christians must ask themselves is why such terrible things are happening to them. From time to time I have posted about suffering Christians garnered from Open Doors or Barnabas Trust. It is not just in Muslim lands, but in parts of India, in former Communists states, In China and North Korea, but also in South America and in so-called Christian lands like Greece that true Christians are suffering. We have also seen Christians persecuted in Britain, Germany and America by secular humanists.
On an individual basis Christians do not have an especial prosperity or freedom from sickness compared to other people. Some Christians have lost their assurance because other Christians have told them that their faith is deficient and they cannot withstand the devil. This is all nonsense of course. A weak faith in a strong God is superior to a strong faith in a weak God.
In Paul's second letter to the Corinthians chapter 4 v 7 Paul tells us that we have the treasure of the Gospel in jars of clay. We don't have the treasure in a fine setting like the Crown Jewels in the Tower of London. It is not their setting that makes them beautiful; in fact the contrast of what we are like against the beauty of the truth is what enhances it.
It is all the more likely that when we are at our lowest will come the opportunity to share the Gospel.
There is no doubt that while the Arab Spring is a good time for freedom and democracy it is also a perilous time for Christians who are being persecuted in Egypt, Libya, Tunisia and next in Syria. Yet in Mali, at the University of Timbuktu, where Christians are very few in number, a remarkable thing is happening. Muslims are seeing visions of a man in bright clothes carrying a book. There have been thousands of such visions and they want to know what it means.
There is a Muslim tradition that Jesus will return, but how to reconcile this vision of the Angel of the LORD with Jesus. They have sought out a solitary secret Christian and set him up in a stall in the Mosque where queues have gathered to quiz him about the story of Jesus. There have been many conversions. You see the vision has coincided with the translation by the Wycliffe Bible Translators of the New Testament into the local Malian language.
We should pray that as the church in North Africa is persecuted, that God would act supernaturally to overcome the Devil and work a great wonder of conversion in its wake. Perhaps our best approach for secular persecution in our own countries is prayer, not the law courts.
On an individual basis Christians do not have an especial prosperity or freedom from sickness compared to other people. Some Christians have lost their assurance because other Christians have told them that their faith is deficient and they cannot withstand the devil. This is all nonsense of course. A weak faith in a strong God is superior to a strong faith in a weak God.
In Paul's second letter to the Corinthians chapter 4 v 7 Paul tells us that we have the treasure of the Gospel in jars of clay. We don't have the treasure in a fine setting like the Crown Jewels in the Tower of London. It is not their setting that makes them beautiful; in fact the contrast of what we are like against the beauty of the truth is what enhances it.
It is all the more likely that when we are at our lowest will come the opportunity to share the Gospel.
There is no doubt that while the Arab Spring is a good time for freedom and democracy it is also a perilous time for Christians who are being persecuted in Egypt, Libya, Tunisia and next in Syria. Yet in Mali, at the University of Timbuktu, where Christians are very few in number, a remarkable thing is happening. Muslims are seeing visions of a man in bright clothes carrying a book. There have been thousands of such visions and they want to know what it means.
There is a Muslim tradition that Jesus will return, but how to reconcile this vision of the Angel of the LORD with Jesus. They have sought out a solitary secret Christian and set him up in a stall in the Mosque where queues have gathered to quiz him about the story of Jesus. There have been many conversions. You see the vision has coincided with the translation by the Wycliffe Bible Translators of the New Testament into the local Malian language.
We should pray that as the church in North Africa is persecuted, that God would act supernaturally to overcome the Devil and work a great wonder of conversion in its wake. Perhaps our best approach for secular persecution in our own countries is prayer, not the law courts.
Saturday, November 26, 2011
F v FA as second line: a phase 3 trial
This report on a second line treatment for CLL from Lancet Oncology today
Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial
Despite the increasing number of treatment options, chronic lymphocytic leukaemia (CLL) remains an incurable disease. Estimates of median survival range from more than 10 years for patients with early-stage CLL to less than 1 year for patients with fludarabine-resistant disease. In view of the incurable and chronic nature of CLL, and the worsening prognosis for patients as their disease becomes more advanced or refractory, the development of alternative regimens in earlier treatments is essential to improve their outcome.
Preclinical data suggested that the addition of alemtuzumab to fludarabine-based regimens could have a synergistic effect due to their complementary modes of action. In a report by Kennedy and colleagues, five of six patients with CLL who were refractory to both drugs when administered as single agents achieved remission with the combination of fludarabine and alemtuzumab.
Results from a single-group phase 2 study further suggested that fludarabine and alemtuzumab combination could improve outcomes in patients with relapsed or refractory CLL, with an overall response rate (ORR) of 83% and a median overall survival of 35·6 months. Therefore, we compared the efficacy and safety of this combination treatment with fludarabine monotherapy in patients with relapsed or refractory CLL.
The study was done in five centres in North America and 43 in Europe. Eligible patients had relapsed or refractory CLL according to the National Cancer Institute Working Group's 1996 criteria, with evidence of progressive disease that required therapy after one previous line of treatment for CLL. Patients could have had past treatment with fludarabine or alemtuzumab provided the duration of their response was longer than 12 months. Additional 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 previous treatment for CLL with more than one previous regimen or the combination of fludarabine and alemtuzumab; positive Coombs test and active haemolysis; absolute neutrophil count (ANC) of less than 1·5×10e9 cells per L or platelet count of less than 75×10e9 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.
This study was approved by the institutional review board or ethics committee from each of the participating sites. All patients provided written informed consent before enrolment to the study.
An interactive voice response system (IVRS) was used to randomly assign patients in a 1:1 ratio to fludarabine plus alemtuzumab or fludarabine monotherapy in an open-label trial. At call-in from the site to enrol the patients, IVRS conveyed stratification data to a computer system and initiated the randomisation program. The system retrieved stratification and treatment assignment data for previously enrolled patients, and a computer-generated next random number was provided by the sponsor's statistician. The system used the minimisation method9 with the probability parameter 0·80 to assign patients to treatment. The stratification factors were study centre, Rai stage (I or II vs III or IV), disease status (relapsed vs refractory), age (≥65 vs <65 years), sex (male vs female), past exposure to fludarabine therapy (yes vs no), and maximum lymph node size (≥5 vs <5 cm or none).
During the first treatment cycle, patients in the combination group were given escalating doses of alemtuzumab; 3 mg/day, 10 mg/day, 30 mg/day, intravenously over 2 h. 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 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.
If patients developed haematological toxicities with a recovery time (ie, retreatment criteria ANC ≥1·0×10e9 cells per L, platelet count ≥100×10e9 per L, and no active infection) from the scheduled start of the new cycle of 14 days or less (days 29–43 of previous cycle), no dose modification was required in those assigned to combination treatment or monotherapy; 15–28 days (days 44–57 of previous cycle), patients assigned to combination treatment were given fludarabine 30 mg/m2 per day plus alemtuzumab 30 mg/day for 2 days every 28 days, and those assigned to monotherapy were administered 16·75 mg/m2 per day for 5 days every 28 days; and more than 28 days (after day 57 of previous cycle), treatment was discontinued in the combination treatment or monotherapy group.
In the event of a non-haematological toxicity of grade 1 or 2, no dose modification was required with combination treatment or monotherapy; grade 3, patients assigned to combination treatment were given fludarabine 30 mg/m2 per day plus alemtuzumab 30 mg/day for 2 days every 28 days, and those assigned to monotherapy were administered 16·75 mg/m2 per day for 5 days every 28 days; if a patient recovered more than 28 days after the date of the originally scheduled start of the next treatment cycle, the patient was withdrawn from the study; grade 4, treatment was discontinued in patients assigned to combination treatment or monotherapy. Patients with a creatinine clearance of 0·50–1·17 mL/s per 1·73 m2 were treated with fludarabine at a 20% dose reduction. Other protocol-mandated reasons for treatment delay or discontinuation were neurotoxicity; serious infection; grade 3 or higher pulmonary, renal, or hepatic toxicity; autoimmune thrombocytopenia; and symptomatic autoimmune anaemia.
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.
Clinical, radiographic (chest radiography or CT if clinically indicated), and laboratory assessments for response or progression were done every two cycles during treatment and every 3 months after treatment until disease progression. Thereafter, patients were followed up for survival only. Patients with a clinical complete response (CR) or partial response (PR) without recovery of blood counts underwent bone-marrow assessment and testing for minimal residual disease (MRD) 2 months after the end of treatment.
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.8 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.
Toxicities were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). All patients who were given at least one dose of study drug were included in the safety analysis.
The planned sample size for this study of 300 patients (150 per group) to observe 190 events of progression or death, irrespective of treatment group, was designed to detect a 50% improvement in PFS in either group with 80% power and a two-sided α of 0·05. Two interim analyses were planned to assess safety and efficacy at a third and two-thirds of the total planned events under the jurisdiction of a data safety monitoring board. To protect the overall α of 0·05 for the analysis of the primary endpoint, a Lan and DeMets error spending function with an O'Brien–Fleming boundary was used to allow flexibility with the timing of the interim analyses.
Differences in PFS and overall survival between the treatment groups were tested by use of the Cox proportional hazard model, stratified by Rai stage (I or II vs III or IV). Differences in ORR and CR were tested with the Cochran-Mantel-Haenzsel method stratified by Rai stage (I or II vs III or IV). The main analysis was done on an intention-to-treat (ITT) basis for all patients who were randomly assigned. To control family-wise error rate at the 0·05 level, a multiple-tests' adjustment with the Hochberg procedure12 was prespecified for the three clinically important secondary endpoints: ORR, CR, and overall survival. Statistical analyses were done with the Statistical Application Software (version 9.1.3).
The study is registered with ClinicalTrials.gov, number NCT00086580
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.
In both groups, patients were given a median of six treatment cycles (range 1–6), and 105 (64%) of 164 patients in the combination treatment group and 107 (65%) of 165 in the monotherapy group were given six cycles. The median cumulative dose of alemtuzumab was 583 mg (range 3–653) and fludarabine 494·5 mg/m2 (0–568·4) in the combination treatment group, and fludarabine 687·5 mg/m2 (20·6–776·5) in the monotherapy group.
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 overall incidence of severe haematological toxicity (defined as laboratory changes from less than grade 3 at baseline to grade 3 or greater post-baseline, or changes from grade 3 at baseline to grade 4 post-baseline) during the treatment period are shown in table 5. 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 [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 oral 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. 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. 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. 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.
The combination of fludarabine and alemtuzumab resulted in a significant improvement in PFS, CR rate, and overall survival compared with fludarabine alone in patients with previously treated relapsed or refractory CLL. Although the difference in ORR between these regimens was not significant, the improvement in PFS and overall survival shows the clinical benefit of the combination treatment. This combination also seemed to provide significant clinical benefit to patients with advanced disease (Rai stage III or IV), a particularly important subset of patients for whom further investigation is warranted.
When compared with single-agent fludarabine, treatment with fludarabine plus alemtuzumab resulted in a similar overall frequency and severity of infectious complications, similar frequency of grade 3 or 4 neutropenia and thrombocytopenia, a lower frequency of anaemia, and, as expected, a higher frequency of lymphopenia. The rate of cytomegalovirus PCR positivity and infections in the combination treatment group was 14% which is lower than the previously reported frequency of 68% with first-line alemtuzumab monotherapy given three times a week. Although there was a discrepancy in grade 3 or 4 adverse events between treatment groups, most of these events were anticipated and they were related to the mechanism of action of alemtuzumab (particularly lymphopenia or leucopenia and infusion-associated reactions). Despite the difference in the occurrence of grade 3 or 4 adverse events, the percentage of patients who discontinued treatment or deaths during treatment was similar in both groups.
Despite the recent advances in treatment options for first-line treatment for patients with CLL, the disease remains incurable, thus treatment decisions require that benefit-to-risk assessments are undertaken for each patient. The National Comprehensive Cancer Network guidelines and European Society of Medical Oncology guidelines suggest consideration of a variety of therapeutic regimens to treat patients with CLL throughout the course of their illness. The substantial heterogeneity of patients with CLL with respect to disease burden, age, and comorbid illnesses means that several options should be available.
Systematic review
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, we designed this study for further assessment of combination treatment.
The findings of our 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, we view 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. It has been 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. 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 (25 in fludarabine plus alemtuzumab group and 26 in fludarabine monotherapy group], 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 Food and Drug Administration 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
Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial
Despite the increasing number of treatment options, chronic lymphocytic leukaemia (CLL) remains an incurable disease. Estimates of median survival range from more than 10 years for patients with early-stage CLL to less than 1 year for patients with fludarabine-resistant disease. In view of the incurable and chronic nature of CLL, and the worsening prognosis for patients as their disease becomes more advanced or refractory, the development of alternative regimens in earlier treatments is essential to improve their outcome.
Preclinical data suggested that the addition of alemtuzumab to fludarabine-based regimens could have a synergistic effect due to their complementary modes of action. In a report by Kennedy and colleagues, five of six patients with CLL who were refractory to both drugs when administered as single agents achieved remission with the combination of fludarabine and alemtuzumab.
Results from a single-group phase 2 study further suggested that fludarabine and alemtuzumab combination could improve outcomes in patients with relapsed or refractory CLL, with an overall response rate (ORR) of 83% and a median overall survival of 35·6 months. Therefore, we compared the efficacy and safety of this combination treatment with fludarabine monotherapy in patients with relapsed or refractory CLL.
The study was done in five centres in North America and 43 in Europe. Eligible patients had relapsed or refractory CLL according to the National Cancer Institute Working Group's 1996 criteria, with evidence of progressive disease that required therapy after one previous line of treatment for CLL. Patients could have had past treatment with fludarabine or alemtuzumab provided the duration of their response was longer than 12 months. Additional 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 previous treatment for CLL with more than one previous regimen or the combination of fludarabine and alemtuzumab; positive Coombs test and active haemolysis; absolute neutrophil count (ANC) of less than 1·5×10e9 cells per L or platelet count of less than 75×10e9 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.
This study was approved by the institutional review board or ethics committee from each of the participating sites. All patients provided written informed consent before enrolment to the study.
An interactive voice response system (IVRS) was used to randomly assign patients in a 1:1 ratio to fludarabine plus alemtuzumab or fludarabine monotherapy in an open-label trial. At call-in from the site to enrol the patients, IVRS conveyed stratification data to a computer system and initiated the randomisation program. The system retrieved stratification and treatment assignment data for previously enrolled patients, and a computer-generated next random number was provided by the sponsor's statistician. The system used the minimisation method9 with the probability parameter 0·80 to assign patients to treatment. The stratification factors were study centre, Rai stage (I or II vs III or IV), disease status (relapsed vs refractory), age (≥65 vs <65 years), sex (male vs female), past exposure to fludarabine therapy (yes vs no), and maximum lymph node size (≥5 vs <5 cm or none).
During the first treatment cycle, patients in the combination group were given escalating doses of alemtuzumab; 3 mg/day, 10 mg/day, 30 mg/day, intravenously over 2 h. 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 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.
If patients developed haematological toxicities with a recovery time (ie, retreatment criteria ANC ≥1·0×10e9 cells per L, platelet count ≥100×10e9 per L, and no active infection) from the scheduled start of the new cycle of 14 days or less (days 29–43 of previous cycle), no dose modification was required in those assigned to combination treatment or monotherapy; 15–28 days (days 44–57 of previous cycle), patients assigned to combination treatment were given fludarabine 30 mg/m2 per day plus alemtuzumab 30 mg/day for 2 days every 28 days, and those assigned to monotherapy were administered 16·75 mg/m2 per day for 5 days every 28 days; and more than 28 days (after day 57 of previous cycle), treatment was discontinued in the combination treatment or monotherapy group.
In the event of a non-haematological toxicity of grade 1 or 2, no dose modification was required with combination treatment or monotherapy; grade 3, patients assigned to combination treatment were given fludarabine 30 mg/m2 per day plus alemtuzumab 30 mg/day for 2 days every 28 days, and those assigned to monotherapy were administered 16·75 mg/m2 per day for 5 days every 28 days; if a patient recovered more than 28 days after the date of the originally scheduled start of the next treatment cycle, the patient was withdrawn from the study; grade 4, treatment was discontinued in patients assigned to combination treatment or monotherapy. Patients with a creatinine clearance of 0·50–1·17 mL/s per 1·73 m2 were treated with fludarabine at a 20% dose reduction. Other protocol-mandated reasons for treatment delay or discontinuation were neurotoxicity; serious infection; grade 3 or higher pulmonary, renal, or hepatic toxicity; autoimmune thrombocytopenia; and symptomatic autoimmune anaemia.
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.
Clinical, radiographic (chest radiography or CT if clinically indicated), and laboratory assessments for response or progression were done every two cycles during treatment and every 3 months after treatment until disease progression. Thereafter, patients were followed up for survival only. Patients with a clinical complete response (CR) or partial response (PR) without recovery of blood counts underwent bone-marrow assessment and testing for minimal residual disease (MRD) 2 months after the end of treatment.
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.8 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.
Toxicities were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). All patients who were given at least one dose of study drug were included in the safety analysis.
The planned sample size for this study of 300 patients (150 per group) to observe 190 events of progression or death, irrespective of treatment group, was designed to detect a 50% improvement in PFS in either group with 80% power and a two-sided α of 0·05. Two interim analyses were planned to assess safety and efficacy at a third and two-thirds of the total planned events under the jurisdiction of a data safety monitoring board. To protect the overall α of 0·05 for the analysis of the primary endpoint, a Lan and DeMets error spending function with an O'Brien–Fleming boundary was used to allow flexibility with the timing of the interim analyses.
Differences in PFS and overall survival between the treatment groups were tested by use of the Cox proportional hazard model, stratified by Rai stage (I or II vs III or IV). Differences in ORR and CR were tested with the Cochran-Mantel-Haenzsel method stratified by Rai stage (I or II vs III or IV). The main analysis was done on an intention-to-treat (ITT) basis for all patients who were randomly assigned. To control family-wise error rate at the 0·05 level, a multiple-tests' adjustment with the Hochberg procedure12 was prespecified for the three clinically important secondary endpoints: ORR, CR, and overall survival. Statistical analyses were done with the Statistical Application Software (version 9.1.3).
The study is registered with ClinicalTrials.gov, number NCT00086580
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.
In both groups, patients were given a median of six treatment cycles (range 1–6), and 105 (64%) of 164 patients in the combination treatment group and 107 (65%) of 165 in the monotherapy group were given six cycles. The median cumulative dose of alemtuzumab was 583 mg (range 3–653) and fludarabine 494·5 mg/m2 (0–568·4) in the combination treatment group, and fludarabine 687·5 mg/m2 (20·6–776·5) in the monotherapy group.
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 overall incidence of severe haematological toxicity (defined as laboratory changes from less than grade 3 at baseline to grade 3 or greater post-baseline, or changes from grade 3 at baseline to grade 4 post-baseline) during the treatment period are shown in table 5. 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 [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 oral 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. 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. 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. 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.
The combination of fludarabine and alemtuzumab resulted in a significant improvement in PFS, CR rate, and overall survival compared with fludarabine alone in patients with previously treated relapsed or refractory CLL. Although the difference in ORR between these regimens was not significant, the improvement in PFS and overall survival shows the clinical benefit of the combination treatment. This combination also seemed to provide significant clinical benefit to patients with advanced disease (Rai stage III or IV), a particularly important subset of patients for whom further investigation is warranted.
When compared with single-agent fludarabine, treatment with fludarabine plus alemtuzumab resulted in a similar overall frequency and severity of infectious complications, similar frequency of grade 3 or 4 neutropenia and thrombocytopenia, a lower frequency of anaemia, and, as expected, a higher frequency of lymphopenia. The rate of cytomegalovirus PCR positivity and infections in the combination treatment group was 14% which is lower than the previously reported frequency of 68% with first-line alemtuzumab monotherapy given three times a week. Although there was a discrepancy in grade 3 or 4 adverse events between treatment groups, most of these events were anticipated and they were related to the mechanism of action of alemtuzumab (particularly lymphopenia or leucopenia and infusion-associated reactions). Despite the difference in the occurrence of grade 3 or 4 adverse events, the percentage of patients who discontinued treatment or deaths during treatment was similar in both groups.
Despite the recent advances in treatment options for first-line treatment for patients with CLL, the disease remains incurable, thus treatment decisions require that benefit-to-risk assessments are undertaken for each patient. The National Comprehensive Cancer Network guidelines and European Society of Medical Oncology guidelines suggest consideration of a variety of therapeutic regimens to treat patients with CLL throughout the course of their illness. The substantial heterogeneity of patients with CLL with respect to disease burden, age, and comorbid illnesses means that several options should be available.
Systematic review
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, we designed this study for further assessment of combination treatment.
The findings of our 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, we view 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. It has been 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. 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 (25 in fludarabine plus alemtuzumab group and 26 in fludarabine monotherapy group], 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 Food and Drug Administration 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
Friday, November 25, 2011
John 8:15. Judgment next time, not this
You pass judgment by human standards; I pass judgment on no-one.
Shall not the judge of all the earth do right? Abraham so challenged the Angel of the LORD above Sodom and after that in a roundabout way the LORD demonstrated that His judgment was certainly right.
Human judgment is fallible. How often do we see it in our courts! Just as the judgment of the Jews here was flawed, so it is always so. No wonder that Jesus said in the Sermon on the Mount, "Judge not that ye be not judged."
Even here while in person, Jesus refused to judge. He came to warn and to save. Judgment next time.
Shall not the judge of all the earth do right? Abraham so challenged the Angel of the LORD above Sodom and after that in a roundabout way the LORD demonstrated that His judgment was certainly right.
Human judgment is fallible. How often do we see it in our courts! Just as the judgment of the Jews here was flawed, so it is always so. No wonder that Jesus said in the Sermon on the Mount, "Judge not that ye be not judged."
Even here while in person, Jesus refused to judge. He came to warn and to save. Judgment next time.
Health report
I am waiting at the moment to hear whether I will be able to have the monoclonal antibody cetuximab. I am cheered by the finding in European Journal of Cancer that response to cetuximab does not depend on previous response to irinotecan, since my response to that drug was not splendid,
I quote, "these findings indicate that the efficacy of irinotecan plus cetuximab in MCRC patients with wild-type KRAS did not differ by previous sensitivity to irinotecan".
I have been waiting for 2 weeks for news and I rang the oncologist this morning to ask him to chase it up.
I am up one day and down the next. Partially, it is the dexamethasone that makes me emotionally labile. I had a weepy day yesterday as I contemplated the things I had left undone. At the end of Schindler's List, Liam Neeson has a scene where he looks at his luxury car and his gold ring and thinks of how many more Jews these could have bought. "I could have done more," he exclaims.
That is how I felt. I told this to Dr John when he visited and he reassured me. None of us can ever do enough. We mustn't reproach ourselves.
Today I am much more cheerful. I went out for the first time in 2 weeks and bought some flowers for my wife. The Scripture tells us not to be weary in well-doing. The Restaurant where we had the reception for my daughter's wedding 2 years ago has just gone bankrupt; I guess they did not market aggressively enough and charged too little. Another shop in our parade has closed. I was glad to patronize the little florist shop. It is a splendid feeling to be able to help out. Some of us with savings should be spreading our wealth around at the present time.
In a rash moment I had bought tickets to see my granddaughter in a school musical tomorrow, but it is a two hour drive and I shall not be well enough to go. Let's hope that the cetuximab will work and I will be able to do these sorts of things again. If I get any sort of response I shall seize the day.
I quote, "these findings indicate that the efficacy of irinotecan plus cetuximab in MCRC patients with wild-type KRAS did not differ by previous sensitivity to irinotecan".
I have been waiting for 2 weeks for news and I rang the oncologist this morning to ask him to chase it up.
I am up one day and down the next. Partially, it is the dexamethasone that makes me emotionally labile. I had a weepy day yesterday as I contemplated the things I had left undone. At the end of Schindler's List, Liam Neeson has a scene where he looks at his luxury car and his gold ring and thinks of how many more Jews these could have bought. "I could have done more," he exclaims.
That is how I felt. I told this to Dr John when he visited and he reassured me. None of us can ever do enough. We mustn't reproach ourselves.
Today I am much more cheerful. I went out for the first time in 2 weeks and bought some flowers for my wife. The Scripture tells us not to be weary in well-doing. The Restaurant where we had the reception for my daughter's wedding 2 years ago has just gone bankrupt; I guess they did not market aggressively enough and charged too little. Another shop in our parade has closed. I was glad to patronize the little florist shop. It is a splendid feeling to be able to help out. Some of us with savings should be spreading our wealth around at the present time.
In a rash moment I had bought tickets to see my granddaughter in a school musical tomorrow, but it is a two hour drive and I shall not be well enough to go. Let's hope that the cetuximab will work and I will be able to do these sorts of things again. If I get any sort of response I shall seize the day.
New review of iron metabolism
This article from Trends in Molecular Medicine appeals to my long-standin interest in Iron Metabolism. It will only appeal to molecular Biologists and those affected by iron-related diseases. But it adds to the sum of my knowledge as the field moves on.
Iron must enter the body from the diet through absorption in the proximal small intestine. Although some plasma iron is derived from iron absorption, most is derived from the recirculation of hemoglobin-derived iron from senescent red blood cells. This process is carried out by macrophages. Iron that enters the plasma is bound by transferrin and distributed around the body to sites of utilization and storage. Transferrin delivers its iron to cells via an interaction with transferrin receptor 1 (TFR1) found on the plasma membrane of most cells. Iron in excess of immediate cellular needs is stored within ferritin. The coordinated regulation of TFR1 and ferritin is mediated by RNA binding proteins known as iron regulatory proteins. Systemically, iron entry into the plasma is controlled by the liver-derived peptide hepcidin, which is secreted by hepatocytes and acts through its effect on ferroportin, the only known iron export protein. Hepcidin expression is increased by high plasma iron and decreased by low plasma iron. HFE, TFR2 (transferrin receptor 2) and HJV (hemojuvelin) are positive stimuli of hepcidin expression, whereas matriptase-2 is a negative stimulus. In its free form, iron is compatible neither with its transport in the plasma (it would precipitate) nor with the intracellular milieu where it would exert immediate toxicity. Therefore, the human body has developed ways for enabling both iron transport (through transferrin) and intracellular deposition (through ferritin).
Approximately 10% of dietary iron content is absorbed every day in the duodenum, corresponding to 1–2 mg. It is delivered, through the ferroportin channel, to the blood where it is taken up by circulating transferrin which delivers iron, via TFR1, mainly to the bone marrow to contribute to the build-up of red blood cells. Red blood cell degradation within the spleen, and to a lesser degree within the liver, occurs 120 days after production and quantitatively provides the main source of iron to the plasma. Iron of splenic origin is taken up by transferrin and a new iron cycle begins. Almost all cells are able to take up iron from transferrin but in a much smaller amount than erythroid cells. Nevertheless, this small amount of iron is essential to serve in many enzymatic reactions, particularly within the respiratory chain. The total amount of body iron approximates 4 g, with 70% within red blood cells and the remainder within liver, spleen and muscles. Circulating iron represents only 0.05% of total body iron but is functionally of major importance. The amount of iron leaving the body each day (mainly in the feces and urine) is equivalent to the amount entering (i.e. 1–2 mg).
Hepcidin (encoded by the HAMP gene) is the hormone that regulates iron metabolism. It is a 25 amino acid peptide primarily produced by hepatocytes. Released into the blood stream, it mainly interacts with enterocytes of the duodenum and macrophage in the spleen by targeting ferroportin. Ferroportin, once bound to hepcidin, is internalized and then degraded. Iron egress from the cell is subsequently hampered by decreased ferroportin activity. It should be noted that the hepcidin control of iron egress from duodenal cells might also involve modulation of DMT1 degradation. The overall result is an inhibition of intestinal and recycled macrophage iron release to circulating transferrin that occurs particularly in response to increased body iron load to compensate for this increase. The reverse mechanism occurs in cases of body iron deficiency (i.e. increased release of iron from the cell related to increased export activity of ferroportin). Hepcidin regulation is mainly characterized as a multifactorial transcriptional process. A major factor that increases hepcidin levels, in addition to increased iron stores, is inflammation. In addition to reduced iron stores, hypoxia, anemia and increased erythropoiesis are hepcidin-reducing factors. The molecular regulators of hepcidin expression are numerous. The bone morphogenetic proteins (BMPs) signaling pathway is implicated in responding to levels of iron stores. Schematically, BMP6 activates its receptors (BMPRI and II) in the presence of hemojuvelin (BMPRI–II coreceptor), which activates the SMAD (Son of Mothers against Decapentaplegic) proteins 1, 5 and 8. A complex is then formed with SMAD4, leading to translocation to the nucleus and activation of hepcidin transcription. The HFE–TFR1–TFR2 complex is an iron sensor for plasma diferric transferrin, leading to hepcidin transcription by a yet not fully identified pathway. TMPRSS6 (transmembrane protease serine 6) encodes matriptase-2, a negative regulator of hemojuvelin expression that decreases hepcidin expression. The STAT3 signaling pathway is involved in IL-6-dependent hepcidin expression. IL-6, produced during inflammatory processes, interacts with its receptor and leads to phosphorylation of the STAT3 protein, which is then translocated into the nucleus where it interacts with the hepcidin promoter.
HFE-related iron overload disease is, by far, the most frequent form of genetic iron overload disorders. Type 1 hemochromatosis is a recessive disease that is linked to mutations of the HFE gene located on chromosome 6. Homozygosity for the p.Cys282Tyr (C282Y) mutation explains more than 90% of type 1 hemochromatosis. The p.Cys282Tyr mutation inhibits the molecular cascade that results in decreased hepatic production of hepcidin. As a consequence, increased plasma iron leads to increased transferrin saturation, which is associated with the appearance of non-transferrin bound iron (NTBI). NTBI is avidly taken up by parenchymal cells in the liver, the pancreas and the heart, leading to excess iron in these organs. In addition, when transferrin saturation is over 75%, NTBI is considered labile plasma iron (LPI), which might generate radical oxygen species and represents the potentially toxic form of circulating iron. The damaging effect of LPI contributes to the clinical expression of chronic iron overload disorders. The liver increases in volume (hepatomegaly), releases more transaminases into the plasma due to hepatocytic iron-related damage and can develop scarring called fibrosis that can lead to cirrhosis and, later on, to hepatocellular carcinoma. Excessive iron deposition in the pancreas, endocrine glands (pituitary, gonads) and heart can lead to insulin-dependent diabetes, hypogonadism (with impotence in males) and cardiac failure, respectively. Moreover, bone and joints can be affected, leading to osteoporosis and chronic arthritis. The skin becomes hyperpigmented (bronzed) and chronic fatigue is a major symptom.
Of Celtic origin (and not Viking origin), as suggested by the mutation date before 4000 BC, the p.Cys282Tyr mutation is highly prevalent in this population, affecting one allele in more than 10% of Caucasian individuals. At least 1 person in 1000 is homozygous for this mutation, and the usual frequency is approximately 3 people in 1000, with even greater frequency in some areas, such as Brittany (France) and Ireland. Penetrance is partial, but if severe clinical presentation is rare, biochemical penetrance is high. Current research efforts are targeting identification of other genes and polymorphisms that modulate HFE function and the interaction between the C282Y genetic background and environmental factors.
Diagnosis of type 1 hemochromatosis is based on a three-step strategy: the first step is recognizing clinical symptoms, the second is confirming excess iron and the third is molecular diagnosis by genetic testing. Clinical symptoms are numerous, including, more or less combined, chronic fatigue, impotence, joint pains, osteoporosis, mild elevated plasma transaminases, hepatomegaly, cirrhosis, diabetes, cardiac rhythm disturbances, heart failure and skin pigmentation. It should be pointed out, however, that many patients, including those with advanced iron overload, have few or no symptoms and that many symptoms lack specificity.
Confirming iron excess is the diagnostic cornerstone. Plasma iron and transferrin saturation are increased in patients, reflecting the basic metabolic dysregulation of the disease. Increased plasma ferritin concentration reflects intracellular iron overload and is the most frequent surrogate marker for tissue iron overload. Magnetic resonance imaging (MRI) is a valuable tool for confirming hepatic iron overload as it shows a characteristic hyposignal that is correlated with the degree of iron excess. By contrast, no iron overload is observed in the spleen. In addition, the T2-star MRI technique has been developed for the assessment of cardiac iron overload. Liver biopsy to evaluate iron excess is performed less and less, considering the combined value of the ferritin assay and MRI. The main use of biopsy is to evaluate possible cofactors of hepatotoxicity (fatty infiltration or signs of alcoholism) and to search for cirrhosis which exposes the patient to the development of hepatocellular carcinoma, especially when associated to iron-free foci. Deducing iron overload from the amount of withdrawn iron required to reach iron depletion remains a valuable, although retrospective, method.
The third step is molecular diagnosis via genetic tests that detect the presence of p.C282Y homozygosity in the HFE gene. It should be emphasized that p.C282Y heterozygosity cannot be considered, alone, to be responsible for clinically significant body iron excess. This is true even for HFE compound heterozygosity, which is commonly the association of heterozygosity for p.Cys282Tyr and heterozygosity for the other frequent mutation, p.His63Asp (p.H63D), which can only lead to a limited increase in plasma transferrin saturation and ferritin. Likewise, p.H63D homozygosity, despite some experimental data and rare case reports, is not generally considered to account for significant iron excess. In practice, the search for the p.H63D mutation is no longer recommended in France and should be confined to clinical research. The same holds true for other HFE protein mutations, such as p.Ser65Cys (S65C), p.Val59Met (V59 M), p.Arg66Cys (R66C), p.Gly93Arg (G93R), p.Ile105Thr (I105T), p.Arg224Gly (R224G) and p.Val295Ala (V295A). Whenever a p.Cys282Tyr mutation in the heterozygous state is associated with significant visceral iron overload (hepatic iron concentration more than 3-fold the upper normal limit), one must evoke an associated rare HFE mutation , a homozygous deletion of HFE, or associated non-HFE mutations. In practice, testing for mutations other than p.CysC282Tyr (and p.His63Asp) remains confined to specialized laboratories.
Treatment for type 1 hemochromatosis consists of repeated venesections on the principle that removing red blood cells, which are iron-rich, obliges the body to compensate for this erythrocyte loss by mobilizing iron from its storage locations. Provided this therapy is started before the development of severe complications (cirrhosis, insulin-dependent diabetes or cardiomyopathy), the efficacy is excellent, and patients recover both an overall good quality of life (except for arthritis) and a normal life expectancy. Oral chelation might be used, particularly in the case of contraindications of phlebotomies, such as poor venous access or patient unwillingness. Future therapy might consist of normalizing hepcidin levels to prevent absorption of additional quantities of excess iron and excessive iron release from macrophages.
Non-HFE-related genetic iron overload diseases are rare but are distributed worldwide. Type 2 hemochromatosis (juvenile hemochromatosis) is linked to mutations in the hemojuvelin gene (HJV, located on chromosome 1 or the hepcidin gene (HAMP, located on chromosome 19, which correspond to hemochromatosis types 2A and 2B, respectively. Type 2 hemochromatosis produces massive iron overload, specifically targeting the heart and the endocrine glands, and is mainly expressed, in individuals under 30 years old, as cardiac failure and/or hypopituitary hypogonadism. Repeated phlebotomies are the mainstay of treatment, possibly combined with oral iron chelation. Genetic testing, which is not routinely available, would find hemojuvelin or hepcidin mutations, either as homozygous mutations (for HAMP[30] and most often for HJV but also as compound heterozygosity. The hepcidin promoter is also studied by sequencing, as mutations have been described in this region.
Type 3 hemochromatosis is due to mutations in the transferrin receptor 2 (TFR2) gene. When TFR2 is mutated, hepcidin production by the liver is decreased, leading, in turn, to body iron excess. The clinical picture mimics type 1 hemochromatosis; however, cases have also been reported in young patients that resemble juvenile hemochromatosis. Molecular diagnosis, if available, would identify homozygous TFR2 mutations, but compound heterozygosity has also been reported. Genetic testing is performed as for HJV and HAMP.
Type 4 hemochromatosis is due to mutations of the ferroportin gene (SLC40A1) and is also called ferroportin disease. It has a dominant pattern of transmission and incomplete penetrance. Typical ferroportin disease (‘loss-of-function’ or type A), the most frequent form of non-HFE genetic iron overload, is due to mutations affecting iron export capacity. The ‘loss-of-function’ profile is that of a predominantly macrophagic iron overload with normal or low plasma iron (and transferrin saturation). Ferritin levels are often high (>1000 μg/l) contrasting with normal or low plasma iron and transferrin saturation levels. MRI shows marked splenic iron excess and relatively less pronounced hepatic iron overload. Clinical symptoms are rare and this disease does not seem to have, at the time of diagnosis, significant morbidity in the absence of acquired or genetic cofactors. Genetic testing is not routinely available, but identified mutations are mainly located on the cytoplasmic portion or transmembrane segments of ferroportin [including p.Val162del, p.Asp157Gly (D157G), p.Gly80ser (G80S) and p.Gly490Asp (G490D). The p.Gln248His (Q248H) mutation might be associated with iron overload in male African Americans. Phlebotomies remain the basis for treatment but, given the impaired iron recycling process, are less well tolerated than in the case of hepcidin deficiency related iron overload (hemochromatosis types 1, 2 and 3). Atypical ferroportin disease (‘gain-of-function’ or type B) is rare, and by generating a hepcidin resistance phenotype it mimics type 1 hemochromatosis. Several mutations linked to this phenotype have been reported: p.Asn144Asp/Thr (N144D/T), p.Tyr64Asn (Y64N) and particularly p.Cys326Ser/Tyr (C326S/Y).
Hereditary aceruloplasminemia is a rare but widely distributed recessive disease arising from mutation of the ceruloplasmin gene located on chromosome 3. Plasma ceruloplasmin, through its ferroxidase activity, is involved in cellular iron egress. It is required for oxidizing ferrous iron, the redox iron species that crosses the membranes, into ferric iron, the iron species transported by circulating transferrin. In the absence of plasma ceruloplasmin, which is related to mutations in the ceruloplasmin gene, the process of cellular iron release is impaired because of subsequent alterations in ferroportin functioning. Therefore, cellular iron overload develops in a way similar to that observed in ferroportin disease, namely iron trapping within the cells associated with decreased iron release into the plasma, accounting for hyposideremia and low transferrin saturation levels. However, aceruloplasminemia is more severe than ferroportin disease, with marked anemia and brain involvement, suggesting that further mechanisms not yet fully elucidated are involved. The clinical picture is peculiar, combining, in an adult individual, anemia with low plasma iron and transferrin saturation, high plasma ferritin levels and neurological symptoms. Iron overload is found by MRI not only in the liver and spleen but also within the basal ganglia. The diagnosis rests first on biochemical assessment of plasma ceruloplasmin and plasma ferroxidase activity, which show no detectable activities in affected individuals. Genetic testing, if available, serves for diagnostic confirmation in a given individual and as a diagnostic marker for family members, and mutations are predominantly identified in the homozygous state. Phlebotomies are contraindicated because of pre-existing anemia, and treatment is therefore primarily based on iron chelation, with uncertain results on the brain iron load.
Hereditary atransferrinemia is a rare recessive disease affecting young individuals. It is responsible for severe anemia (the normal fate of transferrin iron is to provide bone marrow for red blood cell production) associated with cellular iron overload, which is related to plasma NTBI because transferrin is absent. The diagnosis rests on the fact that affected individuals show no detectable plasma transferrin. Molecular diagnosis, if performed, will identify either homozygosity or compound heterozygosity and serves both as an individual confirmation and as a family marker.
Divalent metal transporter1 (DMT1)-related iron overload is due to the fact that DMT1protein is not only involved in dietary iron uptake at the apical membrane of duodenal enterocytes but is also involved in the release of iron from acidified endosomes into the cytosol. Therefore, mutations in the SLC11A2 gene encoding DMT1, as first shown in Belgrade rats and mk/mk mice, give rise to a rare recessive disease expressed as microcytic anemia that is present from birth, is refractory to oral supplementation and is associated with visceral iron overload with only mildly elevated plasma ferritin. Molecular diagnosis, showing either homozygosity or compound heterozygosity, is the key diagnostic approach, although it is not feasible in routine practice. Treatment is mainly based on iron chelation therapy, but can be augmented with erythropoietin.
Finally, genetic sideroblastic anemias are characterized by iron accumulation in perinuclear mitochondria of erythroblasts and combine microcytic anemia with iron excess. They encompass two X-linked forms, delta-aminolevulinic synthase 2 acid mutations (in the ALAS2 gene) and ATP-binding cassette B7 deficiency (related to mutations in the ABCB7 gene), and two recessive forms, one related to SLC25A38 mutations and the other due to mutations in the glutaredoxin X5 gene (GLRX5).
Iron deficiency of genetic origin is essentially represented by iron-refractory iron deficiency anemia (IRIDA). It is a recessive disorder due to mutations in the gene TMPRSS6, which encodes the enzyme matriptase-2. The mutations relieve a form of inhibition on the HJV–BMP–SMAD signaling pathway, resulting in chronic elevation of plasma hepcidin levels. This elevation impairs duodenal iron absorption as well as iron release from the spleen. This process is close to that observed in the anemia of chronic disease, where increased plasma hepcidin levels are related to STAT3 pathway activation by interleukin 6 (IL-6). IRIDA is characterized by severe microcytic anemia with very low transferrin saturation and normal or high plasma ferritin. Hepcidin levels are normal or high, which is strongly abnormal in the setting of profound anemia, which, ‘physiologically’, should result in low plasma hepcidin levels. Anemia is more pronounced in children than in adults. Oral iron supplementation is ineffective and parenteral iron is only partially effective as iron recycling from macrophages – the first site of deposition of parenteral iron – is hampered by ferroportin deficiency subsequent to increased plasma hepcidin levels. Decreasing hepcidin levels, through the use of hepcidin antagonists, represents an important area of translational research.
In conclusion, several novel genetic iron-related disorders have been recently identified, corresponding either to primary hepcidin disorders or to disorders implicating iron transport, utilization and recycling. From a diagnostic viewpoint, molecular confirmation is easy for HFE-related hemochromatosis, but for all other genetic entities highly specific laboratories are needed due to the high cost of time-consuming techniques that are used infrequently given the rarity of these diseases, so that, in practice, only countries that have set up Reference Centers are able to provide clinicians with molecular confirmation. From a therapeutic viewpoint, the improved mechanistic understanding of these various disorders opens the way for the development of innovative treatment approaches.
Questions for future research
Iron metabolism
• What is the precise pathway whereby HFE regulates hepcidin transcription?
• Identification of new candidates for therapeutic targets in iron metabolism diseases among the signal transduction cascade involved in hepcidin transcription.
• Can cellular iron egress be regulated independently of the hepcidin–ferroportin interaction?
• How is iron metabolism controlled in the brain?
Diagnostic aspects
* What are the acquired and/or genetic cofactors accounting for phenotypic variability in the various forms of hemochromatosis?
• Evaluation of plasma hepcidin determination as a diagnostic and/or prognostic tool in the management of hemochromatosis and iron related diseases.
• Development of genetic, functional and metabolic tools to optimize quick diagnosis of iron overload diseases.
Therapeutic aspects
• Determination of the most appropriate means for normalizing hepcidin levels in patients with hepcidin-deficient hemochromatosis.
• Finding ways to manipulate iron metabolism in the brain.
Iron must enter the body from the diet through absorption in the proximal small intestine. Although some plasma iron is derived from iron absorption, most is derived from the recirculation of hemoglobin-derived iron from senescent red blood cells. This process is carried out by macrophages. Iron that enters the plasma is bound by transferrin and distributed around the body to sites of utilization and storage. Transferrin delivers its iron to cells via an interaction with transferrin receptor 1 (TFR1) found on the plasma membrane of most cells. Iron in excess of immediate cellular needs is stored within ferritin. The coordinated regulation of TFR1 and ferritin is mediated by RNA binding proteins known as iron regulatory proteins. Systemically, iron entry into the plasma is controlled by the liver-derived peptide hepcidin, which is secreted by hepatocytes and acts through its effect on ferroportin, the only known iron export protein. Hepcidin expression is increased by high plasma iron and decreased by low plasma iron. HFE, TFR2 (transferrin receptor 2) and HJV (hemojuvelin) are positive stimuli of hepcidin expression, whereas matriptase-2 is a negative stimulus. In its free form, iron is compatible neither with its transport in the plasma (it would precipitate) nor with the intracellular milieu where it would exert immediate toxicity. Therefore, the human body has developed ways for enabling both iron transport (through transferrin) and intracellular deposition (through ferritin).
Approximately 10% of dietary iron content is absorbed every day in the duodenum, corresponding to 1–2 mg. It is delivered, through the ferroportin channel, to the blood where it is taken up by circulating transferrin which delivers iron, via TFR1, mainly to the bone marrow to contribute to the build-up of red blood cells. Red blood cell degradation within the spleen, and to a lesser degree within the liver, occurs 120 days after production and quantitatively provides the main source of iron to the plasma. Iron of splenic origin is taken up by transferrin and a new iron cycle begins. Almost all cells are able to take up iron from transferrin but in a much smaller amount than erythroid cells. Nevertheless, this small amount of iron is essential to serve in many enzymatic reactions, particularly within the respiratory chain. The total amount of body iron approximates 4 g, with 70% within red blood cells and the remainder within liver, spleen and muscles. Circulating iron represents only 0.05% of total body iron but is functionally of major importance. The amount of iron leaving the body each day (mainly in the feces and urine) is equivalent to the amount entering (i.e. 1–2 mg).
Hepcidin (encoded by the HAMP gene) is the hormone that regulates iron metabolism. It is a 25 amino acid peptide primarily produced by hepatocytes. Released into the blood stream, it mainly interacts with enterocytes of the duodenum and macrophage in the spleen by targeting ferroportin. Ferroportin, once bound to hepcidin, is internalized and then degraded. Iron egress from the cell is subsequently hampered by decreased ferroportin activity. It should be noted that the hepcidin control of iron egress from duodenal cells might also involve modulation of DMT1 degradation. The overall result is an inhibition of intestinal and recycled macrophage iron release to circulating transferrin that occurs particularly in response to increased body iron load to compensate for this increase. The reverse mechanism occurs in cases of body iron deficiency (i.e. increased release of iron from the cell related to increased export activity of ferroportin). Hepcidin regulation is mainly characterized as a multifactorial transcriptional process. A major factor that increases hepcidin levels, in addition to increased iron stores, is inflammation. In addition to reduced iron stores, hypoxia, anemia and increased erythropoiesis are hepcidin-reducing factors. The molecular regulators of hepcidin expression are numerous. The bone morphogenetic proteins (BMPs) signaling pathway is implicated in responding to levels of iron stores. Schematically, BMP6 activates its receptors (BMPRI and II) in the presence of hemojuvelin (BMPRI–II coreceptor), which activates the SMAD (Son of Mothers against Decapentaplegic) proteins 1, 5 and 8. A complex is then formed with SMAD4, leading to translocation to the nucleus and activation of hepcidin transcription. The HFE–TFR1–TFR2 complex is an iron sensor for plasma diferric transferrin, leading to hepcidin transcription by a yet not fully identified pathway. TMPRSS6 (transmembrane protease serine 6) encodes matriptase-2, a negative regulator of hemojuvelin expression that decreases hepcidin expression. The STAT3 signaling pathway is involved in IL-6-dependent hepcidin expression. IL-6, produced during inflammatory processes, interacts with its receptor and leads to phosphorylation of the STAT3 protein, which is then translocated into the nucleus where it interacts with the hepcidin promoter.
HFE-related iron overload disease is, by far, the most frequent form of genetic iron overload disorders. Type 1 hemochromatosis is a recessive disease that is linked to mutations of the HFE gene located on chromosome 6. Homozygosity for the p.Cys282Tyr (C282Y) mutation explains more than 90% of type 1 hemochromatosis. The p.Cys282Tyr mutation inhibits the molecular cascade that results in decreased hepatic production of hepcidin. As a consequence, increased plasma iron leads to increased transferrin saturation, which is associated with the appearance of non-transferrin bound iron (NTBI). NTBI is avidly taken up by parenchymal cells in the liver, the pancreas and the heart, leading to excess iron in these organs. In addition, when transferrin saturation is over 75%, NTBI is considered labile plasma iron (LPI), which might generate radical oxygen species and represents the potentially toxic form of circulating iron. The damaging effect of LPI contributes to the clinical expression of chronic iron overload disorders. The liver increases in volume (hepatomegaly), releases more transaminases into the plasma due to hepatocytic iron-related damage and can develop scarring called fibrosis that can lead to cirrhosis and, later on, to hepatocellular carcinoma. Excessive iron deposition in the pancreas, endocrine glands (pituitary, gonads) and heart can lead to insulin-dependent diabetes, hypogonadism (with impotence in males) and cardiac failure, respectively. Moreover, bone and joints can be affected, leading to osteoporosis and chronic arthritis. The skin becomes hyperpigmented (bronzed) and chronic fatigue is a major symptom.
Of Celtic origin (and not Viking origin), as suggested by the mutation date before 4000 BC, the p.Cys282Tyr mutation is highly prevalent in this population, affecting one allele in more than 10% of Caucasian individuals. At least 1 person in 1000 is homozygous for this mutation, and the usual frequency is approximately 3 people in 1000, with even greater frequency in some areas, such as Brittany (France) and Ireland. Penetrance is partial, but if severe clinical presentation is rare, biochemical penetrance is high. Current research efforts are targeting identification of other genes and polymorphisms that modulate HFE function and the interaction between the C282Y genetic background and environmental factors.
Diagnosis of type 1 hemochromatosis is based on a three-step strategy: the first step is recognizing clinical symptoms, the second is confirming excess iron and the third is molecular diagnosis by genetic testing. Clinical symptoms are numerous, including, more or less combined, chronic fatigue, impotence, joint pains, osteoporosis, mild elevated plasma transaminases, hepatomegaly, cirrhosis, diabetes, cardiac rhythm disturbances, heart failure and skin pigmentation. It should be pointed out, however, that many patients, including those with advanced iron overload, have few or no symptoms and that many symptoms lack specificity.
Confirming iron excess is the diagnostic cornerstone. Plasma iron and transferrin saturation are increased in patients, reflecting the basic metabolic dysregulation of the disease. Increased plasma ferritin concentration reflects intracellular iron overload and is the most frequent surrogate marker for tissue iron overload. Magnetic resonance imaging (MRI) is a valuable tool for confirming hepatic iron overload as it shows a characteristic hyposignal that is correlated with the degree of iron excess. By contrast, no iron overload is observed in the spleen. In addition, the T2-star MRI technique has been developed for the assessment of cardiac iron overload. Liver biopsy to evaluate iron excess is performed less and less, considering the combined value of the ferritin assay and MRI. The main use of biopsy is to evaluate possible cofactors of hepatotoxicity (fatty infiltration or signs of alcoholism) and to search for cirrhosis which exposes the patient to the development of hepatocellular carcinoma, especially when associated to iron-free foci. Deducing iron overload from the amount of withdrawn iron required to reach iron depletion remains a valuable, although retrospective, method.
The third step is molecular diagnosis via genetic tests that detect the presence of p.C282Y homozygosity in the HFE gene. It should be emphasized that p.C282Y heterozygosity cannot be considered, alone, to be responsible for clinically significant body iron excess. This is true even for HFE compound heterozygosity, which is commonly the association of heterozygosity for p.Cys282Tyr and heterozygosity for the other frequent mutation, p.His63Asp (p.H63D), which can only lead to a limited increase in plasma transferrin saturation and ferritin. Likewise, p.H63D homozygosity, despite some experimental data and rare case reports, is not generally considered to account for significant iron excess. In practice, the search for the p.H63D mutation is no longer recommended in France and should be confined to clinical research. The same holds true for other HFE protein mutations, such as p.Ser65Cys (S65C), p.Val59Met (V59 M), p.Arg66Cys (R66C), p.Gly93Arg (G93R), p.Ile105Thr (I105T), p.Arg224Gly (R224G) and p.Val295Ala (V295A). Whenever a p.Cys282Tyr mutation in the heterozygous state is associated with significant visceral iron overload (hepatic iron concentration more than 3-fold the upper normal limit), one must evoke an associated rare HFE mutation , a homozygous deletion of HFE, or associated non-HFE mutations. In practice, testing for mutations other than p.CysC282Tyr (and p.His63Asp) remains confined to specialized laboratories.
Treatment for type 1 hemochromatosis consists of repeated venesections on the principle that removing red blood cells, which are iron-rich, obliges the body to compensate for this erythrocyte loss by mobilizing iron from its storage locations. Provided this therapy is started before the development of severe complications (cirrhosis, insulin-dependent diabetes or cardiomyopathy), the efficacy is excellent, and patients recover both an overall good quality of life (except for arthritis) and a normal life expectancy. Oral chelation might be used, particularly in the case of contraindications of phlebotomies, such as poor venous access or patient unwillingness. Future therapy might consist of normalizing hepcidin levels to prevent absorption of additional quantities of excess iron and excessive iron release from macrophages.
Non-HFE-related genetic iron overload diseases are rare but are distributed worldwide. Type 2 hemochromatosis (juvenile hemochromatosis) is linked to mutations in the hemojuvelin gene (HJV, located on chromosome 1 or the hepcidin gene (HAMP, located on chromosome 19, which correspond to hemochromatosis types 2A and 2B, respectively. Type 2 hemochromatosis produces massive iron overload, specifically targeting the heart and the endocrine glands, and is mainly expressed, in individuals under 30 years old, as cardiac failure and/or hypopituitary hypogonadism. Repeated phlebotomies are the mainstay of treatment, possibly combined with oral iron chelation. Genetic testing, which is not routinely available, would find hemojuvelin or hepcidin mutations, either as homozygous mutations (for HAMP[30] and most often for HJV but also as compound heterozygosity. The hepcidin promoter is also studied by sequencing, as mutations have been described in this region.
Type 3 hemochromatosis is due to mutations in the transferrin receptor 2 (TFR2) gene. When TFR2 is mutated, hepcidin production by the liver is decreased, leading, in turn, to body iron excess. The clinical picture mimics type 1 hemochromatosis; however, cases have also been reported in young patients that resemble juvenile hemochromatosis. Molecular diagnosis, if available, would identify homozygous TFR2 mutations, but compound heterozygosity has also been reported. Genetic testing is performed as for HJV and HAMP.
Type 4 hemochromatosis is due to mutations of the ferroportin gene (SLC40A1) and is also called ferroportin disease. It has a dominant pattern of transmission and incomplete penetrance. Typical ferroportin disease (‘loss-of-function’ or type A), the most frequent form of non-HFE genetic iron overload, is due to mutations affecting iron export capacity. The ‘loss-of-function’ profile is that of a predominantly macrophagic iron overload with normal or low plasma iron (and transferrin saturation). Ferritin levels are often high (>1000 μg/l) contrasting with normal or low plasma iron and transferrin saturation levels. MRI shows marked splenic iron excess and relatively less pronounced hepatic iron overload. Clinical symptoms are rare and this disease does not seem to have, at the time of diagnosis, significant morbidity in the absence of acquired or genetic cofactors. Genetic testing is not routinely available, but identified mutations are mainly located on the cytoplasmic portion or transmembrane segments of ferroportin [including p.Val162del, p.Asp157Gly (D157G), p.Gly80ser (G80S) and p.Gly490Asp (G490D). The p.Gln248His (Q248H) mutation might be associated with iron overload in male African Americans. Phlebotomies remain the basis for treatment but, given the impaired iron recycling process, are less well tolerated than in the case of hepcidin deficiency related iron overload (hemochromatosis types 1, 2 and 3). Atypical ferroportin disease (‘gain-of-function’ or type B) is rare, and by generating a hepcidin resistance phenotype it mimics type 1 hemochromatosis. Several mutations linked to this phenotype have been reported: p.Asn144Asp/Thr (N144D/T), p.Tyr64Asn (Y64N) and particularly p.Cys326Ser/Tyr (C326S/Y).
Hereditary aceruloplasminemia is a rare but widely distributed recessive disease arising from mutation of the ceruloplasmin gene located on chromosome 3. Plasma ceruloplasmin, through its ferroxidase activity, is involved in cellular iron egress. It is required for oxidizing ferrous iron, the redox iron species that crosses the membranes, into ferric iron, the iron species transported by circulating transferrin. In the absence of plasma ceruloplasmin, which is related to mutations in the ceruloplasmin gene, the process of cellular iron release is impaired because of subsequent alterations in ferroportin functioning. Therefore, cellular iron overload develops in a way similar to that observed in ferroportin disease, namely iron trapping within the cells associated with decreased iron release into the plasma, accounting for hyposideremia and low transferrin saturation levels. However, aceruloplasminemia is more severe than ferroportin disease, with marked anemia and brain involvement, suggesting that further mechanisms not yet fully elucidated are involved. The clinical picture is peculiar, combining, in an adult individual, anemia with low plasma iron and transferrin saturation, high plasma ferritin levels and neurological symptoms. Iron overload is found by MRI not only in the liver and spleen but also within the basal ganglia. The diagnosis rests first on biochemical assessment of plasma ceruloplasmin and plasma ferroxidase activity, which show no detectable activities in affected individuals. Genetic testing, if available, serves for diagnostic confirmation in a given individual and as a diagnostic marker for family members, and mutations are predominantly identified in the homozygous state. Phlebotomies are contraindicated because of pre-existing anemia, and treatment is therefore primarily based on iron chelation, with uncertain results on the brain iron load.
Hereditary atransferrinemia is a rare recessive disease affecting young individuals. It is responsible for severe anemia (the normal fate of transferrin iron is to provide bone marrow for red blood cell production) associated with cellular iron overload, which is related to plasma NTBI because transferrin is absent. The diagnosis rests on the fact that affected individuals show no detectable plasma transferrin. Molecular diagnosis, if performed, will identify either homozygosity or compound heterozygosity and serves both as an individual confirmation and as a family marker.
Divalent metal transporter1 (DMT1)-related iron overload is due to the fact that DMT1protein is not only involved in dietary iron uptake at the apical membrane of duodenal enterocytes but is also involved in the release of iron from acidified endosomes into the cytosol. Therefore, mutations in the SLC11A2 gene encoding DMT1, as first shown in Belgrade rats and mk/mk mice, give rise to a rare recessive disease expressed as microcytic anemia that is present from birth, is refractory to oral supplementation and is associated with visceral iron overload with only mildly elevated plasma ferritin. Molecular diagnosis, showing either homozygosity or compound heterozygosity, is the key diagnostic approach, although it is not feasible in routine practice. Treatment is mainly based on iron chelation therapy, but can be augmented with erythropoietin.
Finally, genetic sideroblastic anemias are characterized by iron accumulation in perinuclear mitochondria of erythroblasts and combine microcytic anemia with iron excess. They encompass two X-linked forms, delta-aminolevulinic synthase 2 acid mutations (in the ALAS2 gene) and ATP-binding cassette B7 deficiency (related to mutations in the ABCB7 gene), and two recessive forms, one related to SLC25A38 mutations and the other due to mutations in the glutaredoxin X5 gene (GLRX5).
Iron deficiency of genetic origin is essentially represented by iron-refractory iron deficiency anemia (IRIDA). It is a recessive disorder due to mutations in the gene TMPRSS6, which encodes the enzyme matriptase-2. The mutations relieve a form of inhibition on the HJV–BMP–SMAD signaling pathway, resulting in chronic elevation of plasma hepcidin levels. This elevation impairs duodenal iron absorption as well as iron release from the spleen. This process is close to that observed in the anemia of chronic disease, where increased plasma hepcidin levels are related to STAT3 pathway activation by interleukin 6 (IL-6). IRIDA is characterized by severe microcytic anemia with very low transferrin saturation and normal or high plasma ferritin. Hepcidin levels are normal or high, which is strongly abnormal in the setting of profound anemia, which, ‘physiologically’, should result in low plasma hepcidin levels. Anemia is more pronounced in children than in adults. Oral iron supplementation is ineffective and parenteral iron is only partially effective as iron recycling from macrophages – the first site of deposition of parenteral iron – is hampered by ferroportin deficiency subsequent to increased plasma hepcidin levels. Decreasing hepcidin levels, through the use of hepcidin antagonists, represents an important area of translational research.
In conclusion, several novel genetic iron-related disorders have been recently identified, corresponding either to primary hepcidin disorders or to disorders implicating iron transport, utilization and recycling. From a diagnostic viewpoint, molecular confirmation is easy for HFE-related hemochromatosis, but for all other genetic entities highly specific laboratories are needed due to the high cost of time-consuming techniques that are used infrequently given the rarity of these diseases, so that, in practice, only countries that have set up Reference Centers are able to provide clinicians with molecular confirmation. From a therapeutic viewpoint, the improved mechanistic understanding of these various disorders opens the way for the development of innovative treatment approaches.
Questions for future research
Iron metabolism
• What is the precise pathway whereby HFE regulates hepcidin transcription?
• Identification of new candidates for therapeutic targets in iron metabolism diseases among the signal transduction cascade involved in hepcidin transcription.
• Can cellular iron egress be regulated independently of the hepcidin–ferroportin interaction?
• How is iron metabolism controlled in the brain?
Diagnostic aspects
* What are the acquired and/or genetic cofactors accounting for phenotypic variability in the various forms of hemochromatosis?
• Evaluation of plasma hepcidin determination as a diagnostic and/or prognostic tool in the management of hemochromatosis and iron related diseases.
• Development of genetic, functional and metabolic tools to optimize quick diagnosis of iron overload diseases.
Therapeutic aspects
• Determination of the most appropriate means for normalizing hepcidin levels in patients with hepcidin-deficient hemochromatosis.
• Finding ways to manipulate iron metabolism in the brain.
New treatment for DLCBL.
For a long time it has been accepted wisdom that R-CHOP is as good as anything else for diffuse large cell lymphoma. More intensified regimens are possible, but a meta-analysis of some years ago found no advantage for them.
In today's Lancet there is a paper from France reporting a trial that suggests that this is no longer true. Here is the abstract:
We did an open-label randomised trial comparing dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with subsequent consolidation versus standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). Random assignment was done with a computer-assisted randomisation-allocation sequence with a block size of four. Patients were aged 18–59 years with untreated diffuse large B-cell lymphoma and an age-adjusted international prognostic index equal to 1. Our primary endpoint was event-free survival. Our analyses of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00140595.
One patient withdrew consent before treatment and 54 did not complete treatment. After a median follow-up of 44 months, our 3-year estimate of event-free survival was 81% (95% CI 75–86) in the R-ACVBP group and 67% (59–73) in the R-CHOP group (hazard ratio [HR] 0·56, 95% CI 0·38–0·83; p=0·0035). 3-year estimates of progression-free survival (87% [95% CI, 81–91] vs 73% [66–79]; HR 0·48 [0·30–0·76]; p=0·0015) and overall survival (92% [87–95] vs 84% [77–89]; HR 0·44 [0·28–0·81]; p=0·0071) were also increased in the R-ACVBP group. 82 (42%) of 196 patients in the R-ACVBP group experienced a serious adverse event compared with 28 (15%) of 183 in the R-CHOP group. Grade 3–4 haematological toxic effects were more common in the R-ACVBP group, with a higher proportion of patients experiencing a febrile neutropenic episode (38% [75 of 196] vs 9% [16 of 183).
Compared with standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves survival of patients aged 18–59 years with diffuse large B-cell lymphoma with low-intermediate risk according to the International Prognostic Index. Haematological toxic effects of the intensive regimen were raised but manageable.
Here is an editorial from Julie Vose on the trial
In The Lancet, Christian Récher and colleagues report the findings of their randomised trial of dose-intense chemo therapy with rituximab, doxorubicin,
cyclo phos pha mide, vindesine, bleomycin, and pred nisone (R-ACVBP) versus rituximab, cyclophosphamide, doxo rubicin, vincristine, and prednisone
(R-CHOP).
379 patients aged 18–59 years with diffuse large B-cell lymphoma and an age-adjusted International Prognostic Index of 1 were randomly assigned to receive either dose-intense chemotherapy with four cycles of R-ACVBP with a subsequent sequential consolidation with two cycles of methotrexate and calcium folinate rescue, four cycles of rituximab with etoposide and ifosfamide, and two cycles of cytarabine or to receive eight cycles of R-CHOP at intervals of 21 days. On the basis of previous studies in this population of patients, 3-year event-free survival would be expected to range from 70% to 80%.3 The study by Récher and colleagues had a 3-year event-free survival of 67% (95% CI 59–73) in the R-CHOP group, which seems slightly low.
In terms of the trial’s primary endpoint, event-free survival, there was an advantage to R-ACVBP versus R-CHOP (hazard ratio 0·56, 95% CI 0·38–0·83, p=0·0035). The dose-intense R-ACVBP regimen with sequential consolidation has an expected higher rate of toxic effects, with significantly increased haematological toxic effects over R-CHOP identified in this and previous trials. Also, the additional chemotherapeutic drugs, higher haemopoietic growth factor use, and higher neutropenic fever rate would lead to higher health-care resource consumption. Therefore, this dose-intense regimen should only be used in patients in whom the expected relapse rate is sufficient to justify the higher toxic effects and cost profile.
Possible risk stratification factors for the use of more dose-intense treatments include: International Prognostic Index, bulky disease, gene expression profiling results (eg, activated B cell v germinal centre B cell), oncogenic profile (eg, MYC positive or so-called double hit lymphomas), or interim PET positivity. Clinical features, such as International Prognostic Index or bulky disease, are the easiest to use in clinical practice. However, more biologically relevant assays, such as genetic profiles, interim PET, or a combination approach, might be more accurate in predicting which patients are at higher risk. Once patients at higher risk are identified by biologically relevant assays or procedures, future study designs will address the use of these biological prognostic factors for direction of treatment by dose intensification or pathway-directed drugs.
Some of the newer pathway-directed drugs seem to be less toxic and, if earlier-phase studies show that they can be combined with standard chemotherapy, this might represent a more directed treatment for patients at higher risk. Examples of drugs tested in this manner include lenalidomide, bortezomib, or drugs directed at
the B-cell signalling pathway. In the meantime, who should receive dose-intensified
treatment? Récher and colleagues report convincing evidence that patients younger than 59 years with an International Prognostic Index of 1, who can tolerate the
additional toxic effects of R-ACVBP with consolidation, do have a better 3-year event-free survival. Unfortunately, some of the drugs in the regimen are not available in all countries and testing of substitute drugs or modifications would be needed. Furthermore, a direct comparison of other dose-intensive chemo therapy regimens such as a dose-adjusted regimen of rituximab, etoposide, vincristine,
cyclophosphamide, and doxorubicin (R-EPOCH) versus the R-ACVBP regimen is needed, pending the results of the present R-CHOP versus dose-adjusted R-EPOCH protocol being done by the United States Cooperative Group Mechanism (registered with ClinicalTrials.gov, number NCT00118209). Although we continue to identify subsets of patients at higher risk, further international clinical trials are needed to assess the best individualised approach to treatment for these patients.
Of course for CLL patients, we have to question whether the standard treatment for Richter syndrome should remain R-CHOP, but I fear that patients with Richter Syndrome may not be able to withstand this intensity of treatment.
In today's Lancet there is a paper from France reporting a trial that suggests that this is no longer true. Here is the abstract:
We did an open-label randomised trial comparing dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with subsequent consolidation versus standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). Random assignment was done with a computer-assisted randomisation-allocation sequence with a block size of four. Patients were aged 18–59 years with untreated diffuse large B-cell lymphoma and an age-adjusted international prognostic index equal to 1. Our primary endpoint was event-free survival. Our analyses of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00140595.
One patient withdrew consent before treatment and 54 did not complete treatment. After a median follow-up of 44 months, our 3-year estimate of event-free survival was 81% (95% CI 75–86) in the R-ACVBP group and 67% (59–73) in the R-CHOP group (hazard ratio [HR] 0·56, 95% CI 0·38–0·83; p=0·0035). 3-year estimates of progression-free survival (87% [95% CI, 81–91] vs 73% [66–79]; HR 0·48 [0·30–0·76]; p=0·0015) and overall survival (92% [87–95] vs 84% [77–89]; HR 0·44 [0·28–0·81]; p=0·0071) were also increased in the R-ACVBP group. 82 (42%) of 196 patients in the R-ACVBP group experienced a serious adverse event compared with 28 (15%) of 183 in the R-CHOP group. Grade 3–4 haematological toxic effects were more common in the R-ACVBP group, with a higher proportion of patients experiencing a febrile neutropenic episode (38% [75 of 196] vs 9% [16 of 183).
Compared with standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves survival of patients aged 18–59 years with diffuse large B-cell lymphoma with low-intermediate risk according to the International Prognostic Index. Haematological toxic effects of the intensive regimen were raised but manageable.
Here is an editorial from Julie Vose on the trial
In The Lancet, Christian Récher and colleagues report the findings of their randomised trial of dose-intense chemo therapy with rituximab, doxorubicin,
cyclo phos pha mide, vindesine, bleomycin, and pred nisone (R-ACVBP) versus rituximab, cyclophosphamide, doxo rubicin, vincristine, and prednisone
(R-CHOP).
379 patients aged 18–59 years with diffuse large B-cell lymphoma and an age-adjusted International Prognostic Index of 1 were randomly assigned to receive either dose-intense chemotherapy with four cycles of R-ACVBP with a subsequent sequential consolidation with two cycles of methotrexate and calcium folinate rescue, four cycles of rituximab with etoposide and ifosfamide, and two cycles of cytarabine or to receive eight cycles of R-CHOP at intervals of 21 days. On the basis of previous studies in this population of patients, 3-year event-free survival would be expected to range from 70% to 80%.3 The study by Récher and colleagues had a 3-year event-free survival of 67% (95% CI 59–73) in the R-CHOP group, which seems slightly low.
In terms of the trial’s primary endpoint, event-free survival, there was an advantage to R-ACVBP versus R-CHOP (hazard ratio 0·56, 95% CI 0·38–0·83, p=0·0035). The dose-intense R-ACVBP regimen with sequential consolidation has an expected higher rate of toxic effects, with significantly increased haematological toxic effects over R-CHOP identified in this and previous trials. Also, the additional chemotherapeutic drugs, higher haemopoietic growth factor use, and higher neutropenic fever rate would lead to higher health-care resource consumption. Therefore, this dose-intense regimen should only be used in patients in whom the expected relapse rate is sufficient to justify the higher toxic effects and cost profile.
Possible risk stratification factors for the use of more dose-intense treatments include: International Prognostic Index, bulky disease, gene expression profiling results (eg, activated B cell v germinal centre B cell), oncogenic profile (eg, MYC positive or so-called double hit lymphomas), or interim PET positivity. Clinical features, such as International Prognostic Index or bulky disease, are the easiest to use in clinical practice. However, more biologically relevant assays, such as genetic profiles, interim PET, or a combination approach, might be more accurate in predicting which patients are at higher risk. Once patients at higher risk are identified by biologically relevant assays or procedures, future study designs will address the use of these biological prognostic factors for direction of treatment by dose intensification or pathway-directed drugs.
Some of the newer pathway-directed drugs seem to be less toxic and, if earlier-phase studies show that they can be combined with standard chemotherapy, this might represent a more directed treatment for patients at higher risk. Examples of drugs tested in this manner include lenalidomide, bortezomib, or drugs directed at
the B-cell signalling pathway. In the meantime, who should receive dose-intensified
treatment? Récher and colleagues report convincing evidence that patients younger than 59 years with an International Prognostic Index of 1, who can tolerate the
additional toxic effects of R-ACVBP with consolidation, do have a better 3-year event-free survival. Unfortunately, some of the drugs in the regimen are not available in all countries and testing of substitute drugs or modifications would be needed. Furthermore, a direct comparison of other dose-intensive chemo therapy regimens such as a dose-adjusted regimen of rituximab, etoposide, vincristine,
cyclophosphamide, and doxorubicin (R-EPOCH) versus the R-ACVBP regimen is needed, pending the results of the present R-CHOP versus dose-adjusted R-EPOCH protocol being done by the United States Cooperative Group Mechanism (registered with ClinicalTrials.gov, number NCT00118209). Although we continue to identify subsets of patients at higher risk, further international clinical trials are needed to assess the best individualised approach to treatment for these patients.
Of course for CLL patients, we have to question whether the standard treatment for Richter syndrome should remain R-CHOP, but I fear that patients with Richter Syndrome may not be able to withstand this intensity of treatment.
Thursday, November 24, 2011
BBC unfair?
The BBC are a one-eyed bunch of left wingnut clowns who have lost all credibility. Worse though, they are parasites, demanding unearned income with threat of fines and inprisonment. Disband them and sell the bits to real corporations.
So says one commentator on the news that the BBC has apologised to a local council after it complained about a One Show report on the travellers' site at Dale Farm. A BBC report said that the programme had ‘failed to clarify that the site had been developed on green belt land’
It also said it had been ‘unfair’ to the council in allowing a traveller to allege the local authority was ‘throwing us out on the road’ with ‘nowhere to go’ without giving it a right of reply. The committee also found a studio discussion between presenters Matt Baker and Alex Jones and actor Neil Morrissey, who was a guest on the show, created an ‘overall impression’ that was ‘unfair’ to the council.
The report went on to say that Morrissey, who speculated whether the land had been ‘earmarked for development’, had ‘been placed in a very difficult position’ when he was asked to comment.
A BBC spokeswoman said: 'We note the findings of the ESC bulletin, which we have taken very seriously. 'Moving forward, The One Show has reviewed and will continue to strengthen its editorial procedures to ensure accuracy, fairness and due impartiality on all the programme's output.' In response Tony Ball, Leader of the Council, said:
'We are satisfied with the findings. 'The site clearance of Dale Farm has always been about the protection of the green belt, but this was not accurately portrayed by The One Show report, nor the fact that we had made several offers of housing to traveller families.
'Since we made the complaint, these key facts have been more accurately
broadcast, helping to aid the public understanding of what the whole issue
was about.'
The six-acre site in Crays Hill was cleared earlier this year following a decade-long row over unauthorised plots. Tensions centred over 51 plots which had been created on green belt land not authorised for development.
So says one commentator on the news that the BBC has apologised to a local council after it complained about a One Show report on the travellers' site at Dale Farm. A BBC report said that the programme had ‘failed to clarify that the site had been developed on green belt land’
It also said it had been ‘unfair’ to the council in allowing a traveller to allege the local authority was ‘throwing us out on the road’ with ‘nowhere to go’ without giving it a right of reply. The committee also found a studio discussion between presenters Matt Baker and Alex Jones and actor Neil Morrissey, who was a guest on the show, created an ‘overall impression’ that was ‘unfair’ to the council.
The report went on to say that Morrissey, who speculated whether the land had been ‘earmarked for development’, had ‘been placed in a very difficult position’ when he was asked to comment.
A BBC spokeswoman said: 'We note the findings of the ESC bulletin, which we have taken very seriously. 'Moving forward, The One Show has reviewed and will continue to strengthen its editorial procedures to ensure accuracy, fairness and due impartiality on all the programme's output.' In response Tony Ball, Leader of the Council, said:
'We are satisfied with the findings. 'The site clearance of Dale Farm has always been about the protection of the green belt, but this was not accurately portrayed by The One Show report, nor the fact that we had made several offers of housing to traveller families.
'Since we made the complaint, these key facts have been more accurately
broadcast, helping to aid the public understanding of what the whole issue
was about.'
The six-acre site in Crays Hill was cleared earlier this year following a decade-long row over unauthorised plots. Tensions centred over 51 plots which had been created on green belt land not authorised for development.
John 8:14: The testimony of the Father.
Jesus answered, “Even if I testify on my own behalf, my testimony is valid, for I know where I came from and where I am going. But you have no idea where I come from or where I am going.
Count the I AMs. Jesus retained the knowledge of his life in heaven with the Father. The Jews did not even know of his birth in Bethlehem, let alone his pre-existence in heaven.
Some sects believe that Jesus was a created being, others that he was never divine, yet others that he 'became God', but the testimony of this Gospel is that he was 'with God in the beginning'. We have the wonderful testimony that he who has seen Jesus has seen the Father, for "I and the Father are one."
Count the I AMs. Jesus retained the knowledge of his life in heaven with the Father. The Jews did not even know of his birth in Bethlehem, let alone his pre-existence in heaven.
Some sects believe that Jesus was a created being, others that he was never divine, yet others that he 'became God', but the testimony of this Gospel is that he was 'with God in the beginning'. We have the wonderful testimony that he who has seen Jesus has seen the Father, for "I and the Father are one."
Unfairness at the GMC
It is very dangerous to touch on the subject of sudden infant death syndrome (SIDS) and Munchausen-by-proxy. A very powerful vigilante group patrols the web seeking out postings from bloggers on the subject. They are in denial over the possibility that a parent could harm a child. So I was surprised to see that two pediatricians had raised their heads above the parapet and commented on the subject in the BMJ. The only time I deigned to comment on the subject I was subject to vile invective which can still be traced on Google.
This is what Leonard Williams wrote:
Professor David Southall must have been investigated more than any other doctor. He has appeared before the General Medical Council on five separate charges, and has been investigated by the police, his trust, and his strategic health authority. He has been cleared at every stage. He has been compared to Dr Mengele in parliament and vilified by the media, and a website is devoted to his downfall. Yet he is highly respected by pediatricians throughout the world. How is this possible?
His reputation was forged through his work on SIDS. His investigations led him to believe that some infants were being smothered, which he confirmed by covert video surveillance. His team videoes 30 mothers smothering their babies. Each episode was interrupted and no baby was harmed. Most important of all, these babies had 41 older siblings, of whom 12 had died suddenly with 11 of them being certified as SIDS. It is clear that in retrospect that they were likely to have been killed.
A vigilante group began to co-ordinate assistance for parents charged with abuse and to orchestrate multiple complaints to the GMC and other authorities, Professor Southall was prevented from working while these many investigations took place.
Even more importantly, the use of covert video surveillance was almost completely stopped. But there is no reason to believe that the smothering has ceased. Southall's analysis of the siblings showed that smothering is highly dangerous, but the actions of the GMC and other authorities have prevented use of a means of detection. One is left to wonder, how many babies have died and will die because of these actions.Derek Summerfield has written:
As an observer of the story of Professor Southall and the General Medical Council over many years, I entirely endorse Bridson’s reflections. GMC decisions at Southall’s hearings have seemed so perverse and devoid of natural justice that each time I have predicted that they would be overturned at a higher level, and they have been.
I recall that one of the GMC's judgments described Southall of having a deep-seated "attitudinal problem", but the GMC seems to have the attitudinal problem. The judgments in Southall's favor at the Court of Appeal and the like attest to the GMC's persistently prejudiced and unprofessional behavior towards him. I believe that Southall has grounds to bring a case against the GMC for a persistent breach of the duty of care it has towards him, as it has to all UK doctors.
My comment on this story is less to do with the actual story, since I am no expert on its content. What I object to is unfairness. I think that the GMC is a corrupt institution. It was once a regulatory body that kept a register of doctors and struck doctors off the register for behaving inappropriately, like performing abortions, having affairs with patients, getting into trouble with the law etc. Doctors funded it with a registration fee of £5 and doctors were judge and jury. Today doctors still fund it with an annual retention fee of over £400, but they no longer act as judge and jury - lay people form a majority on fitness-to-practise 'courts'. It has taken on a lot of extra work for the government (for which the taxpayer pays nothing) and retired doctors are expected to relinquishing their license to practise. They can't even write up a script for acyclovir for a granddaughter with a cold sore.
The GMC having been over-ruled by the Court of appeal over both Meadows and Southall, it seems that they are subject to influence by lay-pressure groups in a way that is unfair. There is a lot of unfairness about who has access to information and how the press presents it. Keep watching the Levenson Inquiry.
This is what Leonard Williams wrote:
Professor David Southall must have been investigated more than any other doctor. He has appeared before the General Medical Council on five separate charges, and has been investigated by the police, his trust, and his strategic health authority. He has been cleared at every stage. He has been compared to Dr Mengele in parliament and vilified by the media, and a website is devoted to his downfall. Yet he is highly respected by pediatricians throughout the world. How is this possible?
His reputation was forged through his work on SIDS. His investigations led him to believe that some infants were being smothered, which he confirmed by covert video surveillance. His team videoes 30 mothers smothering their babies. Each episode was interrupted and no baby was harmed. Most important of all, these babies had 41 older siblings, of whom 12 had died suddenly with 11 of them being certified as SIDS. It is clear that in retrospect that they were likely to have been killed.
A vigilante group began to co-ordinate assistance for parents charged with abuse and to orchestrate multiple complaints to the GMC and other authorities, Professor Southall was prevented from working while these many investigations took place.
Even more importantly, the use of covert video surveillance was almost completely stopped. But there is no reason to believe that the smothering has ceased. Southall's analysis of the siblings showed that smothering is highly dangerous, but the actions of the GMC and other authorities have prevented use of a means of detection. One is left to wonder, how many babies have died and will die because of these actions.Derek Summerfield has written:
As an observer of the story of Professor Southall and the General Medical Council over many years, I entirely endorse Bridson’s reflections. GMC decisions at Southall’s hearings have seemed so perverse and devoid of natural justice that each time I have predicted that they would be overturned at a higher level, and they have been.
I recall that one of the GMC's judgments described Southall of having a deep-seated "attitudinal problem", but the GMC seems to have the attitudinal problem. The judgments in Southall's favor at the Court of Appeal and the like attest to the GMC's persistently prejudiced and unprofessional behavior towards him. I believe that Southall has grounds to bring a case against the GMC for a persistent breach of the duty of care it has towards him, as it has to all UK doctors.
My comment on this story is less to do with the actual story, since I am no expert on its content. What I object to is unfairness. I think that the GMC is a corrupt institution. It was once a regulatory body that kept a register of doctors and struck doctors off the register for behaving inappropriately, like performing abortions, having affairs with patients, getting into trouble with the law etc. Doctors funded it with a registration fee of £5 and doctors were judge and jury. Today doctors still fund it with an annual retention fee of over £400, but they no longer act as judge and jury - lay people form a majority on fitness-to-practise 'courts'. It has taken on a lot of extra work for the government (for which the taxpayer pays nothing) and retired doctors are expected to relinquishing their license to practise. They can't even write up a script for acyclovir for a granddaughter with a cold sore.
The GMC having been over-ruled by the Court of appeal over both Meadows and Southall, it seems that they are subject to influence by lay-pressure groups in a way that is unfair. There is a lot of unfairness about who has access to information and how the press presents it. Keep watching the Levenson Inquiry.
Wednesday, November 23, 2011
del 13 q14: size matters
In Leukemia Research on line
Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease which has proven amenable to subtyping through genomic microarray analysis. Initially, 13q14 deletions as an isolated finding were associated with a favorable prognosis. However, recent evidence has revealed significant heterogeneity within the 13q14 deletion subtype, thus, there is a clear clinical need for more precise stratification of 13q14 deletions at the genomic level. The minimal deleted region (MDR) includes: DLEU2, DLEU7, MIR15A/MIR16-1 and part of DLEU1. Recent studies suggest that in addition to the MDR, the size of the deletion and the involvement of the nearby tumor suppressor gene RB1 serve as an independent prognostic biomarker for disease progression. Nine individuals in whom a 13q deletion had previously been identified by bacterial artificial chromosome (BAC) array were re-analyzed using the Cancer Cytogenomics Microarray Consortium's consensus design on an Agilent (Santa Clara, CA) 180K oligonucleotide platform. Based on the size and location of the 13q14 deletion, cases were further classified as having type (smaller, not including RB1) or type II (larger, including RB1) deletions, as described by Ouilette et al. (Cancer Res, 2008). Type I deletions were seen in 77% of cases, and Type II deletions in 22%. There was a single case of a biallelic 13q14 deletion. Deleted regions ranged in size from 1.0 to 9.8 Mb. Unlike older BAC technologies that are subject to limited resolution, the CCMC 180K oligonucleotide array allowed for further clarification of 13q deletion cases, providing valuable clinical and prognostic information for CLL.
Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease which has proven amenable to subtyping through genomic microarray analysis. Initially, 13q14 deletions as an isolated finding were associated with a favorable prognosis. However, recent evidence has revealed significant heterogeneity within the 13q14 deletion subtype, thus, there is a clear clinical need for more precise stratification of 13q14 deletions at the genomic level. The minimal deleted region (MDR) includes: DLEU2, DLEU7, MIR15A/MIR16-1 and part of DLEU1. Recent studies suggest that in addition to the MDR, the size of the deletion and the involvement of the nearby tumor suppressor gene RB1 serve as an independent prognostic biomarker for disease progression. Nine individuals in whom a 13q deletion had previously been identified by bacterial artificial chromosome (BAC) array were re-analyzed using the Cancer Cytogenomics Microarray Consortium's consensus design on an Agilent (Santa Clara, CA) 180K oligonucleotide platform. Based on the size and location of the 13q14 deletion, cases were further classified as having type (smaller, not including RB1) or type II (larger, including RB1) deletions, as described by Ouilette et al. (Cancer Res, 2008). Type I deletions were seen in 77% of cases, and Type II deletions in 22%. There was a single case of a biallelic 13q14 deletion. Deleted regions ranged in size from 1.0 to 9.8 Mb. Unlike older BAC technologies that are subject to limited resolution, the CCMC 180K oligonucleotide array allowed for further clarification of 13q deletion cases, providing valuable clinical and prognostic information for CLL.
anecdotes about non-hemic autoimmunity
Unusual Autoimmune Complications in Chronic Lymphocytic Leukemia
Moonjung Jung1, Lawrence Rice1The Methodist Hospital, Weill Cornell Medical College, Houston, TX
1. Myasthemia Gravis (MG)
A 56-year-old man was recently diagnosed with MG. His muscle weakness and difficulty swallowing had improved only moderately with weekly plasmapheresis, azathioprine and mestinon. Following a diarrheal illness treated with ciprofloxacin, he was admitted to the ICU for respiratory failure from respiratory muscle weakness. Hemoglobin rapidly fell to 6.7 g/dL. His peripheral blood smear, flow cytometry and Coombs' tests revealed CLL and autoimmune hemolytic anemia. After chemotherapy, his blood counts normalized and his symptoms of MG resolved; he remains in clinical remission of CLL and MG off therapy.
2. Von Willebrand's Disease (vWD)
A 48-year-old man presented with severe headache and was found to have a spontaneous subdural hematoma by CT scan. He had experienced weight loss, easy bruising and epistaxis recently. There was lymphadenopathy on exam. Blood counts, flow cytometry, and coagulation tests revealed CLL and type IIA vWD with a circulating vWF inhibitor. After chemotherapy, the CLL remitted and coagulation studies normalized. With relapse of CLL four years later, the bleeding diathesis re-emerged
3. Aquired Angioedema
Three patients with known stable CLL for years, presented with episodes of severe abdominal cramping, nausea and vomiting. This led to numerous Emergency Room visits, hospital admissions, invasive diagnostic tests, and disability. A deficiency of C1 esterase inhibitor was discovered in all cases. With danazol and chemotherapy for CLL, the patients had response of CLL, normalization of C1 esterase inhibitor, and no recurrence of abdominal pains.
In some of our patients, signs and symptoms of CLL were neglected at the onset of the autoimmune problem. Earlier consideration of underlying CLL would have facilitated earlier effective treatment. In all our patients, the activity of the autoimmune complications closely correlated with the activity of CLL. Immune dysregulation characterizes CLL, and effective treatment offers the possibility of reversing the environment ripe for autoimmunity.
These are more anecdotes. The plural of anecdote is not evidence. I would dismiss these cases as coincidence.
Moonjung Jung1, Lawrence Rice1The Methodist Hospital, Weill Cornell Medical College, Houston, TX
1. Myasthemia Gravis (MG)
A 56-year-old man was recently diagnosed with MG. His muscle weakness and difficulty swallowing had improved only moderately with weekly plasmapheresis, azathioprine and mestinon. Following a diarrheal illness treated with ciprofloxacin, he was admitted to the ICU for respiratory failure from respiratory muscle weakness. Hemoglobin rapidly fell to 6.7 g/dL. His peripheral blood smear, flow cytometry and Coombs' tests revealed CLL and autoimmune hemolytic anemia. After chemotherapy, his blood counts normalized and his symptoms of MG resolved; he remains in clinical remission of CLL and MG off therapy.
2. Von Willebrand's Disease (vWD)
A 48-year-old man presented with severe headache and was found to have a spontaneous subdural hematoma by CT scan. He had experienced weight loss, easy bruising and epistaxis recently. There was lymphadenopathy on exam. Blood counts, flow cytometry, and coagulation tests revealed CLL and type IIA vWD with a circulating vWF inhibitor. After chemotherapy, the CLL remitted and coagulation studies normalized. With relapse of CLL four years later, the bleeding diathesis re-emerged
3. Aquired Angioedema
Three patients with known stable CLL for years, presented with episodes of severe abdominal cramping, nausea and vomiting. This led to numerous Emergency Room visits, hospital admissions, invasive diagnostic tests, and disability. A deficiency of C1 esterase inhibitor was discovered in all cases. With danazol and chemotherapy for CLL, the patients had response of CLL, normalization of C1 esterase inhibitor, and no recurrence of abdominal pains.
In some of our patients, signs and symptoms of CLL were neglected at the onset of the autoimmune problem. Earlier consideration of underlying CLL would have facilitated earlier effective treatment. In all our patients, the activity of the autoimmune complications closely correlated with the activity of CLL. Immune dysregulation characterizes CLL, and effective treatment offers the possibility of reversing the environment ripe for autoimmunity.
These are more anecdotes. The plural of anecdote is not evidence. I would dismiss these cases as coincidence.
More on scientific fraud
In last week's BMJ they drew attention to an outbreak of scientific fraud. There was mention of the pharmaceutical company GSK, paying $3 billion to settle a dispute with the US government over the incorrect marketing of Rosiglitazone (Avandia) and bupropion (Wellbutrin), a London GP was struck off the register by the GMC for using inappropriate tests and treatment for chronic fatigues syndrome, The Fraud Agency investigated conflicts of interest at the European Medicines Agency over the use of benfluorex (Mediator) as an appetite suppressant, the Dutch Health Minister was quizzed about excessive contacts with the tobacco industry, US organizations challenged the financial interests behind the recommendation of the use of HPV vaccine for boys and a Dutch psychologist was shown to have falsified data in dozens of studies in one of the biggest cases of scientific fraud on record. Diederik Stapel from Tilburg was responsible for 150 papers.
Then there was ongoing coverage of the MMR fraud committed by Andrew Wakefield, indicating that several of his colleagues were also culpable and that there seems to have been an ongoing cover-up at University College, London.
There is a good article by Elizabeth Wager of COPE detailing the ways of coping with scientific misconduct.
Then there was ongoing coverage of the MMR fraud committed by Andrew Wakefield, indicating that several of his colleagues were also culpable and that there seems to have been an ongoing cover-up at University College, London.
There is a good article by Elizabeth Wager of COPE detailing the ways of coping with scientific misconduct.
John 8:13. The testimony of one.
The Pharisees challenged him, “Here you are, appearing as your own witness; your testimony is not valid.”
On a technical Jewish point of law, the self-testimony of a single witness was not valid. But they make a mistake in who was doing the testifying. This was not a mere man; The "I am" makes a claim of divine authority as does the mention of light. Light is Yahweh in action - Ps 44:3
On a technical Jewish point of law, the self-testimony of a single witness was not valid. But they make a mistake in who was doing the testifying. This was not a mere man; The "I am" makes a claim of divine authority as does the mention of light. Light is Yahweh in action - Ps 44:3
The racism scandal in football
A judge in the Court of Appeal had stated that a policeman in London should not be offended by being aggressively sworn at by a criminal. This should not be construed as 'resisting arrest'.
I wonder how the judge would feel if the same criminal addressed him in court? No doubt the accused would be held in 'contempt of court'. Suppose such a person were to let off a stream of invective in an old person's home populated by old ladies born in the 1920s? My mother would be offended and so would I.
One of the current cases being considered by the Football Association concerns the English Football captain, John Terry, who it is alleged, abused the Queen's Park Rangers' defender, Anton Ferdinand, by the words, "F---ing black c---". Excuse me if I do not spell it out. Anton Ferdinand is a member of a large footballing family which includes Rio, a former England captain and well known twitterer, and Les, a previous England centre forward who is now a coach at Totenham Hotspur. He is also an evangelical Christian who has led prayer groups at his former clubs. Who would not be offended by being described by such an epithet?
John Terry is a yob who cuckolded former full back, Wayne Bridge, (a rather intelligent Southampton lad, who happened to play as a schoolboy against my son), and who withdrew from the International game because of the incident. Terry's elder brother, recently had an affair with another footballer's girlfriend, leading to the footballer committing suicide.
There are plenty of decent minded footballers around. I hope we have seen the last of Terry and his kin. Cappello, the England manager, has a reputation as a strictly moral boss who stands no nonsense. Let us hope he does not let us down.
I wonder how the judge would feel if the same criminal addressed him in court? No doubt the accused would be held in 'contempt of court'. Suppose such a person were to let off a stream of invective in an old person's home populated by old ladies born in the 1920s? My mother would be offended and so would I.
One of the current cases being considered by the Football Association concerns the English Football captain, John Terry, who it is alleged, abused the Queen's Park Rangers' defender, Anton Ferdinand, by the words, "F---ing black c---". Excuse me if I do not spell it out. Anton Ferdinand is a member of a large footballing family which includes Rio, a former England captain and well known twitterer, and Les, a previous England centre forward who is now a coach at Totenham Hotspur. He is also an evangelical Christian who has led prayer groups at his former clubs. Who would not be offended by being described by such an epithet?
John Terry is a yob who cuckolded former full back, Wayne Bridge, (a rather intelligent Southampton lad, who happened to play as a schoolboy against my son), and who withdrew from the International game because of the incident. Terry's elder brother, recently had an affair with another footballer's girlfriend, leading to the footballer committing suicide.
There are plenty of decent minded footballers around. I hope we have seen the last of Terry and his kin. Cappello, the England manager, has a reputation as a strictly moral boss who stands no nonsense. Let us hope he does not let us down.
Tuesday, November 22, 2011
Cancer survival
There is a report in today's newspapers in the UK about progress in cancer survival. There has been some improvement but it is not a record of magnificent success. Most of the improvement has come from surgery, particularly with breast and colon surgery - often when combined with adjuvent chemotherapy. Some of the improvement has been because of early diagnosis - not that patients are living longer than they did, merely that are living with the diagnosis for longer. This is particularly true for breast and prostate cancer.
Hormones have made a great impact on cancer survival, particularly for breast cancer.
Chemotherapy has made a great impact on Hodgkin disease and childhood acute leukemia but limited impact elsewhere except in the adjuvent setting. Adult AML has shown little if any benefit from chemotherapy
Monoclonal antibodies have made an impact in CLL, diffuse large cell lymphoma and follicular lymphoma (actually it's all rituximab).
Targeted therapy ahs made an impact on CML, and possibly kidney cancer and a rare form of adenocarcinoma of the lung in Indian female non-smokers. There is some promising news about melanoma.
Bone marrow transplantation has saved some lives but the risk is so great that the butcher's bill is hard to calculate.
Longer survival may come from better disease definition as in some skin cancers and lymphomas.
As for the common solid tumors like lung cancer, pancreatic cancer, brain cancer and the rest, there has been very little improvement since I became and oncologist 37 years ago
Hormones have made a great impact on cancer survival, particularly for breast cancer.
Chemotherapy has made a great impact on Hodgkin disease and childhood acute leukemia but limited impact elsewhere except in the adjuvent setting. Adult AML has shown little if any benefit from chemotherapy
Monoclonal antibodies have made an impact in CLL, diffuse large cell lymphoma and follicular lymphoma (actually it's all rituximab).
Targeted therapy ahs made an impact on CML, and possibly kidney cancer and a rare form of adenocarcinoma of the lung in Indian female non-smokers. There is some promising news about melanoma.
Bone marrow transplantation has saved some lives but the risk is so great that the butcher's bill is hard to calculate.
Longer survival may come from better disease definition as in some skin cancers and lymphomas.
As for the common solid tumors like lung cancer, pancreatic cancer, brain cancer and the rest, there has been very little improvement since I became and oncologist 37 years ago
Monday, November 21, 2011
John 8:12: The Light of the World
When Jesus spoke again to the people, he said, “I am the light of the world. Whoever follows me will never walk in darkness, but will have the light of life.”
This is another of the great 'I AM' statements where Jesus is declaring himself to be God. We go right back to the start of the Gospel, "That life was the light of men".
We now know that light is a form of energy. To the Jews, the main source of life was the sun, which gave light, heat and energy. It was the source of life. Not only that, it permits no dark corners, for men love darkness rather than light. With light there is nowhere to hide.
Jesus is claiming to be the source of all life and the dismisser of darkness.
This is another of the great 'I AM' statements where Jesus is declaring himself to be God. We go right back to the start of the Gospel, "That life was the light of men".
We now know that light is a form of energy. To the Jews, the main source of life was the sun, which gave light, heat and energy. It was the source of life. Not only that, it permits no dark corners, for men love darkness rather than light. With light there is nowhere to hide.
Jesus is claiming to be the source of all life and the dismisser of darkness.
Syria
Syria is proving a harder nut to crack than the Western Media imagined. The uprisng is largely confined to a few towns where there has been trouble in the past and generally the Syrian army is in control.
If there were elections who would win? And if Assad won would the elections be declared by the Western Media as corrupt? Are America and the EU opposed to Syria because Russia and China support it? Or is it the other way round?
Syria is Israel's implacable enemy, giving aid to Hamas, Hezbollah and Iran.
But Syria is also a safe haven for Christians. Many Iraqi Christians have found sanctuary there.
It is a conundrum.
If there were elections who would win? And if Assad won would the elections be declared by the Western Media as corrupt? Are America and the EU opposed to Syria because Russia and China support it? Or is it the other way round?
Syria is Israel's implacable enemy, giving aid to Hamas, Hezbollah and Iran.
But Syria is also a safe haven for Christians. Many Iraqi Christians have found sanctuary there.
It is a conundrum.
The remedy for the ills of the world
What has happened this year politically? The 'Arab spring' has toppled a few dictators, but has it been a real victory for militant Islam? We have seen the deaths of Ghaddafi and Bin Laden, but were there really 'players' in any meaningfull sense? Financial markets have collapsed, but why? The polarization between the Senate and the House in America? The Chinese currency inequality> The folly of the European single currency? WE are watching the failure of democracy. People no longer vot for something, but against something. They no longer see solutions. Like the Occupy protestors that can only complain but all the proposed solutions have already failed.
We have seen riots in London, buthow does stealing two left-footed luxury trainers help matters? We have seen scandals in the press phone hacking. Neither the police nor politicians can be trusted. At least two journalists have been fired for high level plagiarism or misrepresentation. Global warming is suspected of being a sham. Scientific fraud is rife. Even in cricket the players cheat.
This has been a year when the Devil has taken control.
You know what my remedy is. This is how I became a Christian:
I was 30 years old. I had just been appointed as consultant hematologist in a beautiful seaside town. I had a wonderful wife and two lovely children. I was financially secure for the rest of my life. I was well on my way to making a name for myself as a research scientist. One day I was going to be famous in my field. I was moving into a circle of smart people with every material luxury. I could see that it would soon be mine.
And yet I was profoundly unhappy. Something was obviously missing in my life.
One day (these were the days when doctors did house calls) I visited a patient at home. As he opened the door to me, he greeted me with, “Hello, doctor, I’m a committed Christian, how about you?”
What an embarrassment. I muttered something about being sent to Sunday School as a child, but, in truth, I had given up on religion. I had taken home the message that if you went around doing good, or at least did your best, you would end up in heaven. I was honest enough to know that I couldn’t do good all the time, and indeed, much of the time I didn’t even do my best. Nevertheless, he sent me on my way with, “Why don’t you come to our church. You will find Francis Dixon a wonderful preacher.”
Six months went by and I did nothing. I was sinking into an ever deeper despair, particularly so as all the skills that I had relied on to answer examination questions were letting me down. I could get the diagnosis right and give the right treatment, but my leukemia patients still died.
Eventually my wife cajoled to me to going to my patient’s church. On the first Sunday I tried, I couldn’t find it so I returned home empty. I found it the second time, and looked around, expecting to see at least one friendly face. It was difficult because the church was absolutely packed with hardly a seat to be found, not the way I envisioned churches. The reason I couldn’t find him soon became apparent. He had died the previous Thursday. The sermon that Francis Dixon preached that day was clearly designed to console his widow.
His text was from John 11:25-26. It was the story of the raising of Lazarus. Remember the story, the sisters of Lazarus, Mary and Martha, had sent word to Jesus that their brother was dying. Rather than hurrying to Bethany, where they lived, Jesus stayed where he was across the River Jordan for two more days. Eventually he decided to go. When he arrived at Bethany Lazarus had died and had been in the grave for 4 days. Jesus had deliberately delayed because he was about to perform the miracle of raising Lazarus from the dead. When he arrived Martha scolded him, “Lord, if you had been here my brother would not have died.”
Jesus replied, “I am the resurrection and the life, he that believeth in me, though he were dead, yet shall he live, and whosoever liveth and believeth in me shall never die.” (In those days they used the KJV)
Jesus then asked Martha, “Do you believe this?”
And Francis Dixon points straight at me and asks, “Do you believe this?”
Martha replied, “Yes, Lord, I believe that you are the Christ, the Son of God, who was to come into the world.”
This was the pointed question I was asked. Did I believe that? Now was the time to stop pussyfooting around. This was the real question. Did I believe that Jesus was the Son of God, with power over Life and Death or was he just a prophet or a wise man or even just a good man? If I believed that he was the Christ I would live my life one way; if I believed he was not then I would live my life completely differently.
You cannot figure this out by logic or by examining the world or by any type of science. You have to make a decision, because in not making a decision that he is the Christ you are making a decision that he is not. People talk about a leap of faith. I never knew what that meant. But then I did. To believe that Jesus is the Christ means to live it and only by living it do you discover that it is true.
On that day, I trusted it was true and today I testify that it is true.
I later learned that my patient’s wife and two other women had been meeting every week to pray for the conversion of his doctor.
We have seen riots in London, buthow does stealing two left-footed luxury trainers help matters? We have seen scandals in the press phone hacking. Neither the police nor politicians can be trusted. At least two journalists have been fired for high level plagiarism or misrepresentation. Global warming is suspected of being a sham. Scientific fraud is rife. Even in cricket the players cheat.
This has been a year when the Devil has taken control.
You know what my remedy is. This is how I became a Christian:
I was 30 years old. I had just been appointed as consultant hematologist in a beautiful seaside town. I had a wonderful wife and two lovely children. I was financially secure for the rest of my life. I was well on my way to making a name for myself as a research scientist. One day I was going to be famous in my field. I was moving into a circle of smart people with every material luxury. I could see that it would soon be mine.
And yet I was profoundly unhappy. Something was obviously missing in my life.
One day (these were the days when doctors did house calls) I visited a patient at home. As he opened the door to me, he greeted me with, “Hello, doctor, I’m a committed Christian, how about you?”
What an embarrassment. I muttered something about being sent to Sunday School as a child, but, in truth, I had given up on religion. I had taken home the message that if you went around doing good, or at least did your best, you would end up in heaven. I was honest enough to know that I couldn’t do good all the time, and indeed, much of the time I didn’t even do my best. Nevertheless, he sent me on my way with, “Why don’t you come to our church. You will find Francis Dixon a wonderful preacher.”
Six months went by and I did nothing. I was sinking into an ever deeper despair, particularly so as all the skills that I had relied on to answer examination questions were letting me down. I could get the diagnosis right and give the right treatment, but my leukemia patients still died.
Eventually my wife cajoled to me to going to my patient’s church. On the first Sunday I tried, I couldn’t find it so I returned home empty. I found it the second time, and looked around, expecting to see at least one friendly face. It was difficult because the church was absolutely packed with hardly a seat to be found, not the way I envisioned churches. The reason I couldn’t find him soon became apparent. He had died the previous Thursday. The sermon that Francis Dixon preached that day was clearly designed to console his widow.
His text was from John 11:25-26. It was the story of the raising of Lazarus. Remember the story, the sisters of Lazarus, Mary and Martha, had sent word to Jesus that their brother was dying. Rather than hurrying to Bethany, where they lived, Jesus stayed where he was across the River Jordan for two more days. Eventually he decided to go. When he arrived at Bethany Lazarus had died and had been in the grave for 4 days. Jesus had deliberately delayed because he was about to perform the miracle of raising Lazarus from the dead. When he arrived Martha scolded him, “Lord, if you had been here my brother would not have died.”
Jesus replied, “I am the resurrection and the life, he that believeth in me, though he were dead, yet shall he live, and whosoever liveth and believeth in me shall never die.” (In those days they used the KJV)
Jesus then asked Martha, “Do you believe this?”
And Francis Dixon points straight at me and asks, “Do you believe this?”
Martha replied, “Yes, Lord, I believe that you are the Christ, the Son of God, who was to come into the world.”
This was the pointed question I was asked. Did I believe that? Now was the time to stop pussyfooting around. This was the real question. Did I believe that Jesus was the Son of God, with power over Life and Death or was he just a prophet or a wise man or even just a good man? If I believed that he was the Christ I would live my life one way; if I believed he was not then I would live my life completely differently.
You cannot figure this out by logic or by examining the world or by any type of science. You have to make a decision, because in not making a decision that he is the Christ you are making a decision that he is not. People talk about a leap of faith. I never knew what that meant. But then I did. To believe that Jesus is the Christ means to live it and only by living it do you discover that it is true.
On that day, I trusted it was true and today I testify that it is true.
I later learned that my patient’s wife and two other women had been meeting every week to pray for the conversion of his doctor.
Latest on Occupy London
Occupy London St Pauls has been trying to raise its image. Here what an independent investigation has found: ‘Desecration: graffiti have been scratched and painted on to the great west doors of the cathedral, the chapter house door and most notably a sacrilegious message painted on the restored pillars of the west portico.
‘Human defecation has occurred in the west portico entrance and inside the cathedral on several occasions.’
There have been noisy interruptions during services, foul language directed at staff and the use of alcohol and ‘other stimulants’ that appeared to ‘fuel the noise levels day and night'.
More than half of schools scheduled to visit the cathedral had cancelled since the occupation began on October 15. Drop-in visitor numbers were also down by half.
A further witness statement from a police inspector expressed ‘mounting concern of drugs within the camp’ including ‘what is currently believed to be a liquid class A drug'.
Social workers have also raised concerns the camp is attracting vulnerable people with mental health and substance abuse problems.
Anti-capitalist protesters were served with an eviction notice by the City of London Corporation last week
Another activist admitted there had been problems with protesters urinating on each other’s tents, and called for a ban on drink and drugs, telling the group: ‘Recreational drinking isn’t something we should passionately support — this is a movement trying to overthrow capitalism,’ she said, adding that anyone wanting to have a drink or 'do a few lines’ (presumably of cocaine) could go off-site.
A member of the so-called Tranquillity Team, a roster of protesters who spend the nights trying to quell trouble, says they have been rushed off their feet dealing with problems, and that people carousing on the cathedral steps have been keeping everyone awake until dawn.
Meanwhile, a member of the finance team implored people to stop asking for money that has been donated to the camp. 'We won’t give out money for cigarettes or booze,’ he said, clearly exasperated. 'Please don’t even bother asking.’
Legal notice was served on the camp on Thursday, a day after U.S. police cleared the Occupy Wall Street camp in New York. The Corporation had halted earlier court action to hold talks with protesters. But policy chairman Stuart Fraser said the negotiations went ‘nowhere’.
Naomi Colvin, for Occupy London, insisted the threat of eviction ‘was not something we need to be remotely worried about’. She added: ‘It could take months. We will contest it.’
Apparently 'The Great Unwashed's' 'headquarters' is the nearby Starbucks because there's free WiFi, its warm and dry and they need somewhere to spend their job seekers allowance (paid for by us tax payers who include a few capitalists I imagine!).
‘Human defecation has occurred in the west portico entrance and inside the cathedral on several occasions.’
There have been noisy interruptions during services, foul language directed at staff and the use of alcohol and ‘other stimulants’ that appeared to ‘fuel the noise levels day and night'.
More than half of schools scheduled to visit the cathedral had cancelled since the occupation began on October 15. Drop-in visitor numbers were also down by half.
A further witness statement from a police inspector expressed ‘mounting concern of drugs within the camp’ including ‘what is currently believed to be a liquid class A drug'.
Social workers have also raised concerns the camp is attracting vulnerable people with mental health and substance abuse problems.
Anti-capitalist protesters were served with an eviction notice by the City of London Corporation last week
Another activist admitted there had been problems with protesters urinating on each other’s tents, and called for a ban on drink and drugs, telling the group: ‘Recreational drinking isn’t something we should passionately support — this is a movement trying to overthrow capitalism,’ she said, adding that anyone wanting to have a drink or 'do a few lines’ (presumably of cocaine) could go off-site.
A member of the so-called Tranquillity Team, a roster of protesters who spend the nights trying to quell trouble, says they have been rushed off their feet dealing with problems, and that people carousing on the cathedral steps have been keeping everyone awake until dawn.
Meanwhile, a member of the finance team implored people to stop asking for money that has been donated to the camp. 'We won’t give out money for cigarettes or booze,’ he said, clearly exasperated. 'Please don’t even bother asking.’
Legal notice was served on the camp on Thursday, a day after U.S. police cleared the Occupy Wall Street camp in New York. The Corporation had halted earlier court action to hold talks with protesters. But policy chairman Stuart Fraser said the negotiations went ‘nowhere’.
Naomi Colvin, for Occupy London, insisted the threat of eviction ‘was not something we need to be remotely worried about’. She added: ‘It could take months. We will contest it.’
Apparently 'The Great Unwashed's' 'headquarters' is the nearby Starbucks because there's free WiFi, its warm and dry and they need somewhere to spend their job seekers allowance (paid for by us tax payers who include a few capitalists I imagine!).
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