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Ash Newsletter 18 01 2010

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  • 1. MabThera at ASH 2009 The Essential Solution News and comments from the 51st Annual Meeting of the American Society of Hematology, New Orleans, Louisiana, USA 5–8 December 2009 Excellent results were also presented for the combination of MabThera 500 mg/m2 with chlorambucil and with bendamustine in first-line CLL, while in relapsed CLL high doses of MabThera monotherapy were shown to be very effective, inducing a high rate of complete responses even in patients who were fludarabine refractory. In NHL, MabThera-based therapy is established as standard treatment for both indolent and aggressive histologies. Several interesting studies were presented, investigating how MabThera treatment might be optimised to achieve the best outcome for patients. • A randomised trial in patients with follicular lymphoma and other indolent NHL suggested that the combination Headlines... of MabThera with bendamustine may be associated with higher efficacy and lower toxicity than the currently more widely used regimen of MabThera-CHOP. The ASH 2009 meeting saw the presentation • A quality-of-life analysis of patients with FL receiving MabThera of new data from the groundbreaking CLL8 trial maintenance therapy showed improvements in some of the of MabThera 500 mg/m2 plus FC versus FC alone studied physical and psychological endpoints in patients in 817 patients with first-line CLL. After 37.7 months’ receiving maintenance compared with observation. follow-up, the improvement in overall survival is now • Ten-year follow-up of the GELA-LNH-98.5 study in statistically significant. This is the first time that a elderly patients with diffuse large B-cell lymphoma significant improvement in overall survival has been confirmed that patients treated with MabThera-CHOP demonstrated for any regimen used in first-line live significantly longer than with CHOP alone treatment of patients with CLL. (10-year overall survival 43.5% versus 28%, respectively; p < 0.0001). • MabThera, in combination with FC, improves 3-year overall survival by almost 5%, from 82.5% with FC alone to 87.2% in the • A randomised study in patients with high-risk DLBCL MabThera-FC arm. This difference was statistically significant showed that high-dose therapy with autologous stem cell (p = 0.012), with a hazard ratio of 0.664 indicating a transplantation offers no advantage and is not needed for 33.6% reduction in risk of death over the 3-year period. patients treated with MabThera plus chemotherapy. • The PFS benefit for MabThera-FC that was first described at ASH last year also improved remarkably with longer follow- up. Median PFS was 51.8 months in the MabThera-FC arm compared with 32.8 months for FC alone (p < 0.001, hazard ratio 0.563), representing a 19-month improvement in median PFS and 43.7% reduction in risk of progression or death. MabThera highlights from ASH2009 | page one
  • 2. MabThera at ASH 2009 The Essential Solution MabThera 500 mg/m2 plus chemotherapy: Changing the natural course of CLL MabThera 500 mg/m2 plus chemotherapy became the standard of care in first-line CLL based on the results of the CLL8 trial, first presented at ASH 2008.1 This trial randomised 817 patients MabThera-FC 61.9 months with newly diagnosed CLL requiring treatment to 6 cycles of Binet A fludarabine/cyclophosphamide (FC) chemotherapy alone FC 41.8 months or to MabThera-FC. MabThera was administered at 500 mg/m , 2 0 20 40 60 reduced to 375 mg/m2 for the first cycle only. Professor Michael Hallek, the chair of the German CLL Study Group (GCLLSG), who presented the interim analysis in 2008, described the latest results MabThera-FC 68.8 months after 37.7 months’ follow-up (Hallek et al. Blood 2009; 114:Abstract Binet B 535). The auditorium was full for what was described by the chair, FC 44.9 months Professor Stephen Devreux, as an “historic session” on therapy 0 20 40 60 of CLL. As had been shown in the previous interim analysis, patients in the MabThera-FC arm experienced significantly longer progression-free survival (PFS) compared with FC alone (Median MabThera-FC 56.8 months PFS: 51.8 months versus 32.8 months, respectively; p < 0.001, Binet C hazard ratio [HR] 0.563) (Figure 1). FC 45.2 months 0 20 40 60 Median PFS (months) MabThera-FC 51.8 months Figure 2: PFS benefit of MabThera-FC over FC alone in patients with Binet p < 0.001 stage A, B and C disease 19 months He therefore concluded that MabThera-FC is superior to FC alone FC alone 32.8 months for the treatment of Binet stage C patients, as well as those with stage A and B disease. 0 20 40 60 Median PFS (months) “In Binet stage C patients…we can now see PFS curves start to separate.” Figure 1: PFS in the CLL8 study (37.7 months’ follow-up) Having explained the 19-month improvement in PFS and efficacy In the interim analysis in 2008, the PFS benefit of MabThera-FC 1 in different patient subgroups achieved with MabThera-FC in this was maintained in the subgroups of patients with Binet stage A analysis, Professor Hallek then went on to describe the most and B disease but not, with the initial short follow-up, in those with exciting part of the data, the improvement in overall survival. Binet stage C disease. Professor Hallek explained that a clinical At 3 years, as would be expected for a first-line CLL population, benefit for MabThera-FC in Binet stage C patients is now becoming median overall survival had not been reached in either arm. apparent in the latest analysis. Although the difference in PFS Three-year overall survival was 87.2% in the MabThera-FC arm in this subgroup of 239 patients still did not reach statistical and 82.5% in the FC arm. This remarkable difference of almost 5% significance (p = 0.081) (Figure 2), Professor Hallek described in deaths between the two arms after a relatively short time was how, with longer follow-up in Binet C patients, “we can now see significant to a level of p = 0.012, and the HR of 0.664 indicates that PFS curves start to separate”. patients in the MabThera-FC arm had a 33.6% reduction in the risk Professor Hallek also pointed out that other efficacy measures, of death – i.e. they were a third less likely to die during the 3-year including complete response rate and eradication of minimal follow-up period. residual disease, were markedly and significantly improved by MabThera-FC compared with FC alone in Binet C patients. MabThera highlights from ASH2009 | page two
  • 3. MabThera at ASH 2009 The Essential Solution “This is the first time that a randomised trial has been able to show that a 100 ORR 90.9% ORR 89.5% ORR 90.5% ORR 88.9% treatment can improve the natural 80 course of CLL” Patients (%) 60 ORR 42.9% Professor Hallek emphasised the important and historic nature of 40 the overall survival finding, in that it demonstrates that the most 20 CR CR CR CR effective treatment should be used in first-line CLL for the best 32.7% CR 15.8% 42.9% 0% 39.7% long-term outcome. ”This is the first time that a randomised trial 0 All patients Trisomy 12 11q- 17p- Unmutated has been able to show that a treatment can improve the natural (n = 110) (n = 19) (n = 21) (n = 7) IgVH course of CLL”, he concluded. (n = 63) Effective options for patients Figure 3: MabThera-bendamustine in first-line CLL: response rates with CLL who are ineligible Phase II trial in 100 patients with untreated CLL considered ineligible to receive fludarabine. The median age of patients in the for fludarabine trial was 70.5 years. The results of an interim analysis of the first 50 patients were presented and compared with a cohort of The progression-free and overall survival benefits of MabThera-FC case-matched patients from a previous study of chlorambucil alone. are achieved with an acceptable increase in toxicity compared with The median age of patients in this study was 70.1 years. The ORR FC alone, and physically fit patients, regardless of age, can be of 84% compared favourably with the 66.7% response rate ob- treated with this regimen without excessive toxicity. However, tained with chlorambucil alone (Figure 4). CR rates could not be some patients with comorbidities may not be physically fit enough compared between trials because of different criteria for response to tolerate FC chemotherapy and so other effective treatments evaluation. Nevertheless, the 17% improvement in ORR indicates are required. MabThera is approved in combination with any that MabThera-chlorambucil is a safe and effective regimen. chemotherapy for the treatment of CLL and two presentations highlighted the efficacy of MabThera-chemotherapy combinations other than MabThera-FC in first-line CLL. Fischer et al. (Blood 2009; 114:Abstract 205) described the PR 100 results of a Phase II study of MabThera plus bendamustine in ORR 84% nPR 80 CR 117 patients with previously untreated CLL. In 110 evaluable ORR 66.7% Patients (%) patients, an overall response rate (ORR) of 90.9% was obtained, 60 with 32.7% CRs. The response rate was largely maintained across 40 different subgroups of patients with adverse genetics (Figure 3). 20 As expected, patients with 17p deletion had a lower response rate. 0 This combination was well tolerated, with grade 3/4 haematological MabThera - Chlorambucil toxicity, including neutropenia, in only around 20% of patients. chlorambucil alone Dr Fischer concluded that MabThera-bendamustine appeared to have comparable efficacy to MabThera-FC in first-line CLL, with a lower incidence of haematological toxicity in this analysis. Figure 4: Response rates to MabThera-chlorambucil or chlorambucil alone (case-matched controls) in first-line CLL This combination may offer the opportunity to treat more patients with CLL with an effective regimen with improved tolerability. The two combinations are now being compared in a randomised study (CLL10) by the GCLLSG. The other MabThera-chemotherapy combination studied in first-line CLL was MabThera 500 mg/m2 plus chlorambucil (Hillmen et al., Blood 2009; 114:Abstract 3428). This was a MabThera highlights from ASH2009 | page three
  • 4. MabThera at ASH 2009 The Essential Solution MabThera-based treatment Optimising MabThera-based options in later lines of therapy therapy in indolent NHL For patients who experience PFS in excess of 1–2 years following While MabThera plus chemotherapy is standard treatment in first-line therapy, re-treatment with the same or similar therapy is both first-line and relapsed follicular lymphoma (FL), a variety often the most appropriate option at relapse, and MabThera 2 of MabThera-chemotherapy regimens have been evaluated and 500 mg/m2 plus chemotherapy is approved for treatment of CLL it is not yet established if any particular chemotherapy has an in both the first-line and relapsed settings. However, some patients advantage over another as a combination partner for MabThera. become refractory to standard treatment regimens and, particularly Rummel et al. (Blood 2009; 114:Abstract 405) presented data for patients who are refractory to fludarabine, treatment options from one of the first randomised studies directly comparing two may be limited. MabThera-chemotherapy regimens in first-line treatment of indolent NHL. A total of 513 patients with previously untreated Previous studies have shown that the activity of MabThera indolent NHL including FL, mantle cell lymphoma (MCL), small monotherapy is dose-dependent in CLL3,4 and Adiga and Wiernik lymphocytic lymphoma, marginal zone lymphoma (MZL) and et al. (Blood 2009; 114:Abstract 2380) presented a case series Waldenström’s macroglobulinaemia (WM) were randomised demonstrating activity of high-dose MabThera in patients to treatment with MabThera-CHOP (n = 253) or MabThera- with CLL, including relapsed and fludarabine-refractory disease. bendamustine (n = 260). More than half of the patients (54%) Twenty two patients with varying treatment histories were had a diagnosis of FL. analysed and the MabThera treatment schedule could be dose-escalated at the treating physician’s discretion. The maximum The ORRs were above 90% and did not differ significantly between dose given to any patient was 3000 mg/m (three patients). 2 the two regimens, but the CR rate was significantly superior for patients in the MabThera-bendamustine arm (39.6% versus An impressive ORR of 90.9% with 54.5% CR was obtained. 30.0%, p = 0.0262). After 34 months’ follow-up, PFS was also Moreover, even in fludarabine-refractory patients the ORR superior for MabThera-bendamustine (54.9 months versus was 75% with 37.5% CR (Figure 5). Such a high CR rate in 34.8 months; p = 0.00012). PFS was also significantly longer for fludarabine-refractory patients is uncommon, and the authors MabThera-bendamustine in the subgroups of patients with FL, noted that “Single-agent rituximab is at least as efficacious as MCL and WM (Table 1). other regimens available for treatment of fludarabine-refractory patients, with a superior toxicity profile”. Median PFS (months) MabThera MabThera- p- value HR 95% CI -benda- CHOP 100 ORR 90.9% ORR 84.6% mustine 80 ORR 75.0% FL NR 46.7 0.0281 0.63 0.42-0.95 (n = 279) Patients (%) 60 MCL 32.5 22.3 0.0146 0.52 0.28-0.87 (n = 93) 40 WM NR 34.8 0.0024 0.21 0.06-0.56 20 CR CR CR (n = 41) 54.5% 53.8% 37.5% NR = not reached 0 All patients Previously treated Fludarabine Table 1: MabThera-bendamustine versus MabThera-CHOP: PFS in (n = 22) (n = 13) refractory subgroups (n = 8) Figure 5: Response to high-dose MabThera-monotherapy in a case series of “For the first time, a first-line regimen 22 patients with CLL has been shown to improve overall Overall, the ASH 2009 meeting was a landmark event in CLL. survival” For the first time, a first-line regimen has been shown to improve overall survival, while the combination of MabThera with different chemotherapies offers additional effective treatment options. MabThera highlights from ASH2009 | page four
  • 5. MabThera at ASH 2009 The Essential Solution MabThera maintenance therapy: A further study (the MAXIMA study) reported ongoing experience with MabThera maintenance therapy after 8 cycles of MabThera- Efficacy, safety and quality of life containing induction therapy in 545 patients with first-line or MabThera maintenance therapy prolongs progression-free and relapsed FL (Witzens-Harig et al., Blood 2009; 114:Abstract 3756). overall survival in patients with relapsed FL5,6 and is currently being MabThera maintenance therapy was administered every 2 months evaluated in the first-line setting. A presentation by Walker for 2 years. A total of 1,367 of 5,367 infusions were delivered et al. (Blood 2009; 114:Abstract 2498) considered the effects of by rapid protocol (90 minutes) without significant side effects first-line MabThera maintenance therapy on patient quality of life, The authors reported that “there were no notable safety issues including symptom burden and psychological symptoms. associated with rituximab maintenance therapy”. This retrospective study compared health-related quality of life in 53 patients who received MabThera maintenance therapy with “[MabThera] maintenance treatment 84 observation patients, after any first-line treatment. All patients delivered via a rapid infusion protocol had completed Patient Care Monitor (PCM) questionnaires during was safe and well tolerated” induction and maintenance/observation. The PCM is a 38-item self-report measure with six major components: • General physical symptoms Eight cycles of MabThera- • Treatment side effects chemotherapy remains gold- • Acute distress • Despair and depression standard first-line treatment for • Impaired ambulation DLBCL • Impaired performance Eight cycles of MabThera-CHOP became gold-standard treatment The investigators found that scores for all six components were for patients with diffuse large B-cell lymphoma (DLBCL) based on either similar or superior for patients receiving MabThera the GELA-LNH-98.5 trial in 399 elderly patients, first published maintenance therapy versus observation, with significantly greater in 2002.7 At the ASH 2009 meeting, Professor Bertrand Coiffier improvements in general physical symptoms (p = 0.019) and a (Blood 2009; 114:Abstract 3741) presented updated data from this greater improvement in impaired performance. Overall there were trial with 10-year follow-up. The data showed that the benefit of no detrimental effects of MabThera maintenance on health-related MabThera-CHOP persisted over time with continued, highly quality of life, and the authors concluded that, “considering the significant superiority of MabThera-CHOP over CHOP alone in clinical benefit of rituximab maintenance, these findings provide all efficacy endpoints including event-free survival (34% versus further support for use of rituximab maintenance in patients with 19.0%), PFS (36.5% versus 20.0%), disease-free survival in follicular lymphoma.” CR patients (64.0% versus 43.0%) and overall survival (43.5% versus 28%) (p < 0.0001 for each). The overall survival curves show “Considering the clinical benefit of clear separation, even after 10 years’ follow-up in this elderly patient population (Figure 6). rituximab maintenance, these findings provide further support for use of 1.0 rituximab maintenance in patients 0.8 with follicular lymphoma.” Patients (%) 0.6 MabThera-CHOP 43.5% 0.4 0.2 CHOP 28.0% p < 0.0001 0 0 2 4 6 8 10 Overall Survival (Years) Figure 6: Overall Survival after 10 years’ follow-up in the GELA LNH- 98.5 study MabThera highlights from ASH2009 | page five
  • 6. MabThera at ASH 2009 The Essential Solution While the use of MabThera-CHOP has dramatically increased MabThera- MabThera- the cure rate in DLBCL over the last decade, efforts continue to CHOEP-14 megaCHOEP further improve outcome, particularly in high-risk patients. One EFS (%) 71.0 56.7 approach that has been considered is the use of high-dose therapy with autologous stem cell transplantation (HDT/ASCT) first line. PFS (%) 76.0 64.6 The German High-Grade Lymphoma Study Group (DSHNHL) has conducted a randomised study to determine whether MabThera in Overall survival (%) 83.8 75.3 combination with HDT/ASCT provides any advantage over standard MabThera-chemotherapy for young, high-risk patients, and interim Table 2: MabThera-CHOEP-14 versus MabThera-megaCHOEP: survival endpoints results of this study were presented by Professor Norbert Schmitz (Blood 2009; 114:Abstract 404). “These represent the best treatment Patients (n = 185) aged 18–60 years with high-risk DLBCL were randomised to treatment with MabThera in combination with results ever reported for young, CHOEP-14 (a modification of the standard CHOP regimen high-risk patients with aggressive involving the addition of etoposide and 2-weekly rather than CD20-positive B-cell lymphoma” 3-weekly cycles) or a high-dose regimen (MabThera plus megaCHOEP) with ASCT (Figure 7). “These represent the best treatment results ever reported for young, high-risk patients with aggressive CD20-positive B-cell lymphoma”, said Professor Schmitz, who also suggested that, in the MabThera 375 mg/m2 ASCT ASCT ASCT era of MabThera-chemotherapy as standard treatment, there is no place for HDT/ASCT in first-line treatment for DLBCL. MegaCHOEP MegaCHOEP MegaCHOEP MegaCHOEP Young patients with References 1 14 22 36 43 56 64 77 96 untreated, Days high-risk 1 15 29 43 57 71 83 99 1. Hallek M, et al. Blood 2008; 112:Abstract 325. DLBCL 2. Eichhorst B, et al. Ann Oncol 2009; 20 (suppl 4):102–104. CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 3. Byrd J, et al. J Clin Oncol 2001; 19:2153–2164. MegaCHOEP = cyclophosphamide 1500–6000 mg/m2, doxorubicin 70 mg/m2, vincristine 2 mg, 4. O’Brien S, et al. J Clin Oncol 2001; 19:2165–2170. etoposide 600–1480 mg/m2, prednisone 500 mg CHOEP-14 = cyclophosphamide 750 mg/2, doxorubicin 50 mg/m2, vincristine 2 mg, etoposide 5. van Oers MHJ, et al. Blood 2008; 112:Abstract 836. 300 mg/m2, prednisone 500 mg 6. Vidal L, et al. J Natl Cancer Inst 2009; 101:248–255. Figure 7: MabThera-CHOEP-14 versus MabThera-megaCHOEP: study 7. Coiffier B, et al. New Engl J Med 2002; 346:235–242. design Professor Schmitz explained that 3-year event-free survival was significantly superior for patients in the MabThera-CHOEP-14 arm (71% versus 56.7%; p = 0.05). PFS and overall survival were also superior for MabThera-CHOEP-14, but the differences were not statistically significant (Table 2). MabThera highlights from ASH2009 || page two MabThera highlights from ASH2009 page six
  • 7. MabThera at ASH 2009 The Essential Solution MabThera highlights from ASH2009 | page seven

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