Italian Guidelines

In its mandate to promote the best hematological care, the Italian Society of Hematology (SIE) and the affiliate societies SIES (Società Italiana di Ematologia Sperimentale) and GITMO (Gruppo Italiano Trapianto di Midollo Osseo) issued guidelines for the management of patients with CLL in 2006. They have now updated these guidelines in Leukemia Research.

Recommendations

In order to plan an optimal clinical management, they recommended that the following information should be obtained at the time of CLL diagnosis: serum lactate dehydrogenase and β2-microglobulin level; imaging of adenomegalies as assessed either by total body computed tomography or by the combination of chest X-ray and abdomen ultrasound; direct Coombs’ test in patients with anemia.

Del [11q], del [17p] and the IgVH mutational profile should be investigated, especially in patients who are eligible for more intensive treatments. In patients with no del [17p], testing of p53 deletions or mutations is recommended.

The indication for treatment initiation includes the presence of at least one of the following features: B symptoms (i.e. fever, sweats, fatigue or weight loss), rapid lymphocyte doubling time, progressive enlargement of lymph nodes or hepatosplenomegaly, obstructive adenopathy, development or worsening of thrombocytopenia or anemia, immune hemolysis or thrombocytopenia not responsive to steroids.

In the clinical practice, the presence of an unfavourable biologic profile is not a reason to start treatment when the disease is in an early stage and clinically stable.

In patients with no treatment indication, a disease monitoring should be made at least every 6 months and should include: physical examination, hematologic evaluation and biochemistry, including serum lactate dehydrogenasis and β2-microglobulin. Patients with a poor prognostic biologic profile or clinical signs of a more aggressive disease should be evaluated more frequently, at least every 3 months. An abdominal ultrasound should be monitored every 6–12 months. Chest X-ray should be evaluated when informative at diagnosis.

Before starting treatment, the following information should be obtained in order to evaluate the more appropriate treatment approach: physical examination, performance status, co-morbidity assessment, peripheral blood count with morphologic examination, when required, bone marrow evaluation, serum biochemistry including serum lactate dehydrogenasis and β2-microglobulin, Coombs’ test, imaging of adenomegalies, assessed either by CT scan or by the combination of chest X-ray and abdomen ultrasound.

Treatment Recommendations

In summary, even though superior CR and OR rates were observed across all trials comparing fludarabine with chlorambucil, no advantage in terms of PFS and OS were demonstrated in 2 out of 3 analyzed trials. The panel, concluded that first-line therapy with fludarabine given as a single agent had better benefit/risk profile compared with chlorambucil in younger patients but not in elderly patients where fludarabine was associated with a higher myelotoxicity and no advantage in terms of PFS and OS.

Should fludarabine monotherapy or fludarabine plus cyclophosphamide combination therapy be preferred to chlorambucil monotherapy in first- line therapy for previously untreated CLL patients? Recommendation - Use it, weak positive evidence.

Bendamustine and chlorambucil given as single agents were compared in a RCT including 319 patients with B or C Binet stage. Bendamustine arm yielded a higher OR rate (68% vs. 31%) and CR rate (31% vs. 3%) than chlorambucil arm. Furthermore, the median PFS was superior for bendamustine than chlorambucil arm (21.6 vs. 8.3 months). However, severe infections were more frequently observed in bendamustine than in chlorambucil-treated patients (8% vs. 3%). The strength of evidence was judged weak due to the fact that a single trial could not make consistency of the results possible (weak positive). The EP judged that the benefit of using bendamustine instead of chlorambucil as first line treatment of patients with CLL results in a better clinical benefit/risk ratio.

Should bendamustine be preferred to chlorambucil in first-line therapy for previously untreated CLL patients? Recommendation Use it, weak positive evidence.

Alemtuzumab was compared with chlorambucil in a RCT (CAM307. Patients treated with alemtuzumab obtained a significantly higher CR rate (24.2% vs. 2%) and median PFS (14.6 vs. 11.7 months) than patients treated with chlorambucil. However, serious drug-related AEs were more common in patients treated with alemtuzumab (26.5% vs. 6.8%). The EP deemed a higher activity of alemtuzumab as compared to chlorambucil. However, the EP judged that the benefit of alemtuzumab was offset by an increase in the toxicity.

Should alemtuzumab monotherapy be preferred to chlorambucil in first-line therapy for previously untreated CLL patients? Recommendation Probably don’t use it, weak negative evidence.

Since the publication of the last SIE guidelines in 2006, the results of two RCTs comparing FC combination to fludarabine as single agent have been published. Both studies demonstrated the superiority of FC in terms of CR rate and PFS. Moreover, a meta-analysis performed by Catovsky et al. focused on the published RCTs comparing FC combination versus fludarabine monotherapy confirmed the superiority of FC schedule in terms of PFS. On this basis, the panel judged that the benefit/risk ratio of using FC combination was higher than that proved by fludarabine given as single agent.

Non RCTs evaluated alternative FC schedules and were also discussed by the EP, even though they were not considered for the strength of evidence. Two trials proved the efficacy and safety of the oral FC schedule. In a Spanish study the addition of mitoxantrone to the FC combination resulted in a high response rate (90%).

Should fludarabine-cyclophosphamide combination be preferred to fludarabine monotherapy in first- line therapy for previously untreated CLL patients? Recommendation Probably use it, weak positive evidence.

The efficacy of cladribine as single agent or in combination with other drugs has been investigated by the Polish Adult Leukemia Group. Front-line cladribine-cyclophosphamide-mitoxantrone (CCM) combination was associated with a higher CR rate as compared to cladribine-cyclophosphamide (CC) or cladribine (C) monotherapy. However CCM regimen showed no advantage in terms of PFS and OS and was associated with a higher myelotoxicity. In a more recent RCT including previously untreated patients, no significant differences in the CR rates, PFS, OS and severe AEs were observed between patients treated with CC or FC. Both combinations proved unsatisfactory activity in patients with deletion 17p-. Due to the patient sample size and the short follow-up, the evidence provided by these studies was judged too weak by the EP to formulate a recommendation.

In a open-label randomized trial by the GCLLSG, the activity and safety of FC regimen (409 patients) was compared to that of FC plus rituximab (FCR; 408 patients). The primary end-point of the study was PFS. FCR was more effective than FC in terms of CR rate (44% vs. 22%), PFS (at 3 years: 65% vs. 45%) and OS (at 3 years: 87% vs. 83%). Despite the higher rate of grade 3–4 granulocytopenia, FCR was not associated with a significant increase in the infection rate. In addition, no differences in the health related quality of life were noted between the 2 arms. The presence of deletion 17p- was the strongest unfavourable prognostic variable for both PFS and OS. The evidence derived from this trial was judged of good quality and on this basis, the EP produced a strong positive recommendation in favour of front-line FCR for CLL patients with good physical fitness.

Should Rituximab be added to FC in first- line therapy for previously untreated CLL patients? Recommendation Use it, strong positive evidence.

Treatment options for patients with deletion 17p- and/or p53 mutations were separately discussed. In the study by Hillmen et al., previously untreated patients with deletion 17p- showed a better OR rate with alemtuzumab than with chlorambucil (64 vs. 20%). In a study by Stilgenbauer et al. presented in an abstract form at the 2010 ASH meeting, 25 previously untreated patients with del [17p] showed a very high OR rate (96%) with 24% CR rate after a front-line treatment including alemtuzumab and dexamethasone. In a study by the GIMEMA group presented in an abstract form at the same meeting, fludarabine and alemtuzumab combination (FluCam) was investigated in 43 younger patients with an adverse biologic profile. The CR rate for the 9 patients with del [17p] included in this study was 46%.

Recommendation

Younger CLL patients and selected older patients with a good performance status, no clinically significant co-morbidities and with no deletion 17p-and/or p53 mutations, should receive FCR regimen.

Patients not eligible for FCR regimen should be treated with a less toxic regimen in order to pursue a control of the diseases and a good quality of life, while preserving overall survival. Chlorambucil, bendamustine, fludarabine, cladribine, as single agents, fludarabine or cladribine associated with cyclophosphamide have been tested in RCTs and there is evidence of the efficacy and safety of use. The lack of RCTs, the small sample size or the poor directness of the existing evidence, do not allow to grade alternative treatment options that have demonstrated efficacy and safety such as fludarabine and rituximab schedule, modified FCR regimens (FCR lite, FCR according to Sloan Kettering), pentostatin including regimen (PCR), chlorambucil or bendamustine combined with rituximab.

In patients with del [17p] and/or p53 mutations and active disease the EP agreed that the use of alemtuzumab-based treatments should be preferred. In younger patients with del [17p] and/or p53 mutations, adequate fitness status and no significant co-morbidities, the strategy approach should include an allogeneic SCT.

Monitoring

Patients in clinical CR or PR after therapy should have the following parameters assessed during follow-up: physical examination (every 3–6 months), peripheral blood count (every 3–6 months), imaging of abdomen every 6–12 months.

Minimal residual disease (MRD) assessment performed by any method on bone marrow is not recommended since the eradication of MRD cannot be considered a therapeutic goal for all patients outside clinical trials.

Consolidation

Only one randomized controlled trial tackled the key question of appropriateness of a consolidation therapy in CLL. Patients in CR or PR after fludarabine or FC first-line treatment were randomized to receive alemtuzumab or only clinical observation. The primary endpoint was the PFS. The trial was prematurely stopped after the enrolment of the first 21 patients because of a severe infection rate in the alemtuzumab group. However, the PFS at month 36 after randomization was 81.8% for patients in the alemtuzumab arm vs. 20.6% in the observation arm. On the basis of these results and data derived from a non RCT the EP deemed that at present there was no evidence that patients in CR or PR may benefit from a consolidation treatment and provided the following recommendations: The panel agreed that at present a consolidation/maintenance treatment approach in CLL patients should be undertaken only in the setting of controlled clinical trials.

Relapsed and refractory patients

Robak et al. randomized 552 patients (≤70 years: 83% of patients) who had received one prior line of therapy. Eligible patients were required to be sensitive (55% of patients) or refractory (27% of patients) to prior alkylating agents but had to be sensitive to fludarabine (prior responses ≥6 months; 17% of patients). A prior treatment with interferon, rituximab, other monoclonal antibodies, alkylators/nucleoside analogues combinations or transplantation was not allowed. Patients treated with FCR showed a significantly higher PFS than patients treated with FC (median PFS, FCR vs. FC: 30.6 vs. 20.6 months). The CR rate was also in favour of the FCR group. Of note, both Binet stage B and C patients benefited from FCR, as did patients with high lymphocyte count, poor renal function, poor prognostic factors such as del [11q], unmutated IgVH, positive ZAP-70 while no benefit emerged for patients with del [17p]. Univariate and multivariate Cox regression analyses for PFS confirmed the advantage of FCR over FC. The AEs rate leading to dose modification or treatment interruption were 39% for the FCR group and 51% for the FC group. The evidence was graded as strong and the EP decided that the benefit of using FCR rather than FC in patients relapsed or refractory after single agent therapy overcome the risks.

In order to analyze the effect of the prior therapy on the response to FCR, Badoux et al. explored the efficacy of FCR given to 284 patients beyond first relapse. The overall RR in patients who were previously exposed to a single agent such as rituximab, fludarabine, alkylating agents were 92%, 90%, 78%, respectively, while the response rate of patients previously exposed to fludarabine combined with an alkylating agent was 73%. Patients refractory to fludarabine and those who had received more than three prior therapies, experienced short PFS. Del [17p] was also an adverse factor for PFS. Moreover, elderly patients were less likely to complete more than three courses of FCR, had a lower CR rate and experienced more infectious complications. Taken together these data suggest that FCR is an effective treatment option in relapsed and fit patients without del [17p].

Engert et al. presented at the 2010 ASH meeting the results of a multicentre randomized study including 335 relapsed or refractory patients after one prior regimen that included fludarabine in only 15% of the cases. Patients were randomized to receive fludarabine as single agent or fludarabine and alemtuzumab (FluCam) combination. Patients treated with FluCam showed a better outcome in terms of CR rate (12.5% vs. 4%) and PFS (24 vs. 18 months) with a similar infection rate.

Should R-FC be preferred to FC in previously treated CLL patients? Recommendation Use it, weak positive evidence

Oblimerson

In a RCT including 241 patients with relapsed or refractory CLL after one prior first line fludarabine, patients were randomized to receive FC or FC plus oblimersen. Patients treated with FC-oblimersen showed a better response rate (17% vs. 7%). However, the OS between the 2 groups was not significantly different. The evidence was graded as weak.

Should oblimersen plus fludarabine and cyclophosphamide be preferred to fludarabine and cyclophosphamide in previously treated CLL patients? Recommendation Probably don’t use it, weak negative evidence

Allogeneic stem cell transplantation (SCT)

No prospective RCTs comparing allogeneic SCT to conventional chemotherapy or immunochemotherapy have been carried out in the setting of CLL patients. Phase II studies with a follow-up longer than 2 years were considered by the EP. Among these, the study by Dreger et al. including 90 poor risk CLL patients, ≤65 years, who underwent allogeneic SCT. The CR and overall response rates were 73% and 94%, respectively. The OS, relapse rate and EFS at 4 years were 65%, 40% and 42%, respectively.

Sorror et al. treated 82 patients (median age, 56 years) with fludarabine-refractory CLL with a conditioning regimen including 2 Gy TBI alone or combined with fludarabine followed by an allogeneic SCT from a related (52 patients) or unrelated (30 patients) donor. A CR and a PR were observed in 55% and 15% of patients respectively. After a median follow-up of 5 years, the non transplant related mortality (NTRM), the OS and the PFS were 23%, 50% and 39%, respectively.

A retrospective analysis of the European Blood and Marrow Transplantation Group (EBMTR) included 44 patients (median age, 54 years) with deletion 17 p-. Patients received an allogeneic SCT after a median number of 3 prior treatments. The OS, PFS, and NTRM at 3 years were 44%, 37% and 32%, respectively.

Treatment options for patients refractory to a prior fludarabine-based treatment, patients with early relapse and patients with del [17p] and/or p53 mutations.

In an analysis from the GCLLSG CLL8 trial comparing FC and FCR regimens an inverse relationship between response duration and survival probability has been observed. The median OS of patients with a PFS lower than 12 months (47 patients), between 12 and 24 months (45 patients) or higher than 24 months from the time point of a second-line treatment, were 13.1, 20.3 and 44.6 months, respectively (p< 0.01). These findings indicate that the small subgroup of patients who relapse within 24 months after a fludarabine based treatment is characterized by a very poor prognosis.

Second-line treatment options for this subgroup of patients have been separately discussed. The evidence derived from subgroup analysis of comparative trials carried on relapsed or refractory patients was integrated by the EP with the results of phase II non RCTs. Stilgenbauer et al. reported an OR rate of 34% with a median PFS of 8 months in 103 fludarabine-refractory patients treated with alemtuzumab given as single agent. The OR rate of the 31 patients with del [17p] included in this study was 39% with a median PFS of 6 months. In a study presented in an abstract form at the 2010 ASH meeting by the same Author, alemtuzumab and dexamethasone combination was given to 23 fludarabine-refractory patients and to 12 patients with del [17p] treated in first relapse. The OR rate was 56% for the fludarabine-refractory patients and 75% for the relapsed patients with del [17p].

Recently, a new anti-CD20 monoclonal antibody, ofatumumab has been investigated by Wierda et al. in a non RCT including patients with CLL refractory to both fludarabine and alemtuzumab or refractory to fludarabine with bulky lymphadenopathy. The OR rates in the two groups were 58% and 47%, respectively. The median PFS and OS were 5.7 months and 13.7 months, respectively, for the first group, 5.9 and 15.4 months, respectively, for the second group. Survival parameters seemed to be higher than those reported from a historical assessment of other salvage therapies in a corresponding group of patients.

Recommendations

In patients requiring a second-line treatment, del [17p] and/or p53 mutations should be checked. In patients with no del [17p] and/or p53 mutations and relapsed after 24 months, the same front-line therapy including rituximab can be considered.

In patients with del [17p] and/or p53 mutations, in patients refractory or relapsed within 24 months from a fludarabine-based treatment, alemtuzumab containing regimens, or experimental treatment approaches within controlled trials should be given.

Furthermore, in poor prognosis younger patients with adequate fitness status and no significant co-morbidities, a treatment approach including an allogeneic SCT, from either a sibling or well-matched unrelated donor, should be offered after an appropriate cytoreductive treatment.