Lenalidomide, Bendamustine, and Rituximab As First-Line Therapy For Patients >65 Years With Mantle Cell Lymphoma: Preliminary Results From The Nordic Lymphoma Group MCL4 (LENA-BERIT) Phase I-II Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4377-4377 ◽  
Author(s):  
Mats Jerkeman ◽  
Alexandra Albertsson-Lindblad ◽  
Arne Kolstad ◽  
Anna Laurell ◽  
Riikka Räty ◽  
...  
Keyword(s):  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Mantle Cell

Abstract Background Mantle cell lymphoma is a disease of the elderly, with a median age of 70 years. Younger patients may be treated with potentially curative treatment including high dose chemotherapy. For elderly patients, however, no standard therapy has been defined. In the current trial, we investigate if the addition of lenalidomide (LEN) to rituximab (R)+bendamustine (B) (B 90 mg/m2 D1-2 and R 375 mg/m2 D1) followed by maintenance with LEN for 7 months may enhance efficacy, with manageable toxicity, for the older population of MCL patients. Methods Eligibility criteria were age > 65 years, or ≤ 65 years, unable to tolerate high dose chemotherapy, with untreated mantle cell lymphoma, stage II-IV. BR was given for 6 cycles q4w. In the phase I part, the MTD of LEN was established as 10 mg days 1-14 during the induction phase, cycles 2-6. Prednisolone 20 mg days 1-14 was given during cycle 2. When LEN was initially given from cycle 1, we encountered unexpected grade III-IV toxicity in the form of cutaneous and allergic reactions. In the maintenance phase, LEN single therapy was given as follows: cycles 7-8 - 10 mg days 1-21, cycles 9-13 - 15 mg days 1-21. Results The trial was concluded June 1, 2013, after inclusion of 51 patients, of whom 24 were in the phase I part. The median age is 72 years. According to MIPI, 55% were high risk. Presently, 29 patients are evaluable for response after 6 cycles LBR. ORR is 28/29 (97%), CR+CRu 23 (79%). 17 out of 28 evaluable patients (61%) were MRD-negative after 6 cycles. After a median follow-up of 18 months, the median PFS has not been reached, and the estimated PFS at 2 years is 74%. Eight patients have died, 3 due disease progression, 3 due to treatment related toxicity, 1 of lung cancer in a heavy smoker, 1 of CMML. Overall survival at 2 years is 87%. Conclusions When omitted in cycle 1, lenalidomide in combination with R-bendamustine is feasible as first-line therapy in older patients with MCL, and is associated with a high response rate, also as assessed by MRD. The long term efficacy of this regimen remains to be established by longer follow-up. Disclosures: No relevant conflicts of interest to declare.

Lenalidomide, Bendamustine, and Rituximab As First-Line Therapy for Patients > 65 Years with Mantle Cell Lymphoma: Results From the Phase I Portion of the Nordic Lymphoma Group MCL4 (LENA-BERIT) Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2700-2700 ◽  
Author(s):  
Mats Jerkeman ◽  
Arne Kolstad ◽  
Anna Laurell ◽  
Riikka Räty ◽  
Kirsten Grønbæk ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
First Line ◽  
Mantle Cell

Abstract Abstract 2700 Background: Mantle cell lymphoma is a disease of the elderly, with a median age of 70 years. Younger patients may be treated with potentially curative treatment including high dose chemotherapy. For elderly patients, however, no standard therapy has been defined. In a randomized comparison between R-CHOP and R-bendamustine (R-B) by the German StiL Group, R-B was associated with less toxicity and improved outcomes, making R-B a preferable first-line treatment option. Lenalidomide (LEN) is another active agent in MCL, with a response rate of 53% as a single agent in relapsed/refractory MCL. In the current trial, we investigate if the addition of lenalidomide to R-B may enhance efficacy, with manageable toxicity, for the older population of MCL patients. Methods: In phase I, the MTD of LEN was to be determined, starting with 5 mg/day increasing up to 25 mg/day in a sequential dose escalation using a 3+3 design. LEN, bendamustine and rituximab are given in 6 cycles/28 days. LEN D1-21, B 90 mg/m2 D1-2 and R 375 mg/m2 D1. The maintenance phase consists of LEN 25 mg/day, D1-21, for 7 cycles. Eligibility criteria are age > 65 years or ≤ 65 years, unable to tolerate high dose chemotherapy, with stage II-IV untreated mantle cell lymphoma. Results: The trial was commenced in October 2009.The phase I portion initially recruited 12 pts according to the original protocol design in 3 cohorts with LEN dose from 5–15 mg d 1–21. Median age was 72.5 years, range 66–85. MIPI high risk n=8, intermediate risk n=4. Response after 6 cycles: CR/CRu n=9/10, PR n=1/10 (ORR 100%). Molecular remission in BM: 5/9 pts. Toxicity was more profound than expected, mostly during cycle 1 (SAE n=9, AE Grade III/IV n=14). Notable was a high incidence of cutaneous and allergic AE. No patients could receive more than 10 cycles, median 6.5. A dose limiting toxicity (DLT) was noted at the dose of 15 mg. This led to a modification of the phase I protocol: Cohort A: No LEN in cycle 1, cycles 2–6: 10 mg LEN days 1–14. During maintenance, cycles 7–8: LEN 10 mg days 1–21, cycles 9–13: LEN 15 mg days 1–21. Cohort B: Same as Cohort A, but reducing B to 70 mg/m2 in cycles 2–6. Cohort C: as Cohort B, but reducing LEN to 5 mg days 1–14 cycles 2–6. In Cohort A, 2 of 6 patients experienced a DLT. Evaluation of Cohort B (6 pts) is ongoing. Conclusions: The addition of LEN to the R-B regimen leads to increased toxicity in elderly patients with MCL. Early data indicate a high response rate. Disclosures: No relevant conflicts of interest to declare.

Final Results of the RiPAD+C Regimen Including Velcade In Front Line Therapy for Elderly Patients with Mantle Cell Lymphoma. A Phase II Prospective Study of the GOELAMS Group.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2791-2791 ◽  
Author(s):  
Remy Gressin ◽  
Roch Houot ◽  
Mario Ojeda Uribe ◽  
Christiane Mounier ◽  
Krimo Bouabdallah ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
Elevated Serum ◽  
Current Phase ◽  
First Line ◽  
Chop Regimen ◽  
First Line Therapy ◽  
Line Therapy ◽  
Mantle Cell

Abstract Abstract 2791 Introduction: Elderly mantle cell lymphoma (MCL) patients (pts) do not benefit from dose-intensive chemotherapy upfront.1 The GOELAMS group recently demonstrated that a regimen comprising Vincristine/Adriamycine/Dexamethasone plus Chlorambucil (VAD+C) was well tolerated, had a good efficacy/toxicity profile and induced similar PFS than R-CHOP (median PFS between 16 to 18 months2,3,4). Additionally, it has been shown that bortezomib (Velcade®), with or without Rituximab has efficacy in relapsed/refractory MCL patients5,6. These data prompted, our group to conducte a phase II prospective non randomized clinical trial evaluating the combination of Velcade plus Rituximab/Adriblastine/Dexamethasone/Chlorambucil (RiPAD+C) as a first line therapy for elderly MCL patients. Aims: To evaluate the overall response rate (ORR) and toxicity after 4 cycles of RiPAD+C regimen (main objective) and to evaluate prognostic factors for survival (secondary objective). Protocol: RiPAD+C : Rituximab 375 mg/m2 on d1 (and d8 for cycle 1); PS 341, Velcade® 1.3 mg/m2 on d1, 4, 8 and 11; Adriblastine 9mg/m2/d as a continuous infusion for 4 days; Dexamethasone 20 mgx2/d from d1 to d4; Chlorambucil 12 mg/d, d20 to d29. Repeat cycles every 35d. After 4 cycles, responding pts (Cheson 1999 criteria) received 2 additional cycles for a maximum of 6. Patients and methods: Inclusion criteria: All untreated elderly (65 to 80 years old) MCL patients (including blastoid forms) presenting with a stage II to IV disease with a good PS (ECOG<3) were eligible. Histologic samples were centrally reviewed and Ki67 expression was evaluated for each sample according to the European guidelines7. Results: Population: from June 2007 to December 2009, 39 pts were enrolled in the study with a majority of males (n=30). Median age at diagnosis was 72 years [65-80]. All patients had stage III/IV disease and PS was ≥2 in 5 cases (15%). Elevated serum LDH were observed in 47% of cases. According to the MIPI, 28 patients (80%) had an intermediate or high score. Eleven (30%) patients presented with a blastoid variant and Ki67 staining was superior to 30% in 12 cases (37%). Toxicity: A total of 195 courses have been performed. Fourteen hospitalization (median duration = 7 days [1 and 55]) due to toxicity were necessary involving 12 pts (34%). Seven pts (18%) experienced grade 3 peripheral neuropathy. ten (25%) pts required blood transfusions for a total of 8 red blood cells and 14 platelets transfusions. Response after 4 cycles: ORR was 80% (n=31) including 51% of CRs. Eight pts discontinued the treatment before reaching cycle 4, two of them for toxicity reasons. Six patients (15%) were refractory or in progression. Response after 6 cycles (n=25; 64%): ORR was 74% including 20 pts in CRs (59%). Survival: With a median follow-up of 24 months, 27 pts are still alive. Two pts died of toxicity (severe sepsis) and 10 pts progressed. The median PFS is 26 months and the median OS has not been reached yet. According to the MIPI score, no differences in PFS were between pts with low and int/high scores. Conversely, the recently described Goelams index2 stratified pts with a low score (normal LDH, Ki67≤26%, PS≤1, and no B symptoms) from patients with an int/high score (p=.055). Conclusion: The results of the current phase II trial indicate that the RiPAD+C regimen, integrating bortezomib, is feasible and well tolerated as a first line therapy in elderly MCL pts. Historical comparisons suggest that this regimen compares favourably to the classical R-CHOP regimen in terms of response rates and duration. Bibliography: 1 Romaguera JE et al, JCO 2005; 2 Gressin R et al., Haematological 2010; 3 Howard OM et al., JCO 2002; 4 Lenz G et al., Blood 2005; 5 Fisher RI et al., JCO 2006; 6 Goy A et al., JCO 2009; 7 Klapper W et al., Haematopathol 2009. Disclosures: Off Label Use: velcade is of label in France for the treatment of mantle cell lymphoma.

Autologous Stem Cell Transplantation as First Line Therapy in Peripheral T Cell Lymphomas. Update of a Prospective Multicenter Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 904-904 ◽  
Author(s):  
Peter Reimer ◽  
Thomas Ruediger ◽  
Tobias Schertlin ◽  
Eva Geissinger ◽  
Florian Weissinger ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
High Dose ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
T Cell Lymphomas ◽  
Peripheral T Cell Lymphomas

Abstract Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of non-Hodgkin’s lymphomas, which in general show a poor outcome following conventional chemotherapy. Long-term remissions are achieved in only 15 to 35 %. However, the impact of more aggressive therapeutic approaches such as myeloablative therapy with autologous stem cell transplantation (ASCT) as first line therapy is poorly defined mainly due to the lack of prospective PTCL-restricted studies. In 6/00 we initiated the first prospective PTCL-restricted multicenter study of myeloablative radiochemotherapy in primary diagnosed PTCL. The results of the first 30 patients (pts) are in press. We update our data on all pts entering the study. Study design: Pts < 65 years with PTCL of all subtypes without primary cutaneous lymphoma and ALK1 expressing anaplastic large cell lymphoma were included. Treatment consisted of 4–6 courses of CHOP protocol followed by DexaBEAM or ESHAP regimen and collection of stem cells. Subsequently pts underwent total body irradiation (TBI) and high dose cyclophosphamide chemotherapy (60 mg/kg body weight) with ASCT. Patient characteristics: From 6/00 to 8/04 65 pts (42 male) with a median age of 50 years were enrolled. Main subtypes were Peripheral T-cell lymphoma not otherwise specified (NOS, n= 26) and Angioimmunioblastic T-cell lymphoma (AILT, n= 19). According to the Ann Arbor classification, 81% of the pts had stage III/IV disease. The International Prognostic Index (IPI) was low/low intermediate in 54% and intermediate high/high in 46% of the pts, respectively. Results: So far 54 of 65 pts are eligible for evaluation, while the remaining 11 pts are still under therapy. Thirty-three pts could be transplanted (61%). After a median follow up of 10 months after transplantation 22 pts (67%) are in sustained remission and 8 pts (27%) had relapsed. Post transplantation two pts died treatment-related (one secondary AML, one multiorgan failure). Twenty-one pts (39%) did not proceed to ASCT mainly due to progressive disease (n= 16). Treatment-related toxicity was comparable to other high-dose studies in malignant lymphomas. Conclusion: Our data show feasibility and efficacy of first-line ASCT following myeloablative radiochemotherapy in PTCL. Sustaining remission seems achievable for a majority of pts. However, additional treatment strategies are required to prevent early progression prior myeloablative therapy. Longer follow-up is necessary to confirm long-term remission rate.

The EBMT Lymphoma Working Party-European Mantle Cell Lymphoma Network Consensus Project On The Role Of Autologous and Allogeneic Stem Cell Transplantation In Mantle Cell Lymphoma: Recommendations Applying The Delphi Procedure

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3405-3405 ◽  
Author(s):  
Stephen Paul Robinson ◽  
Paolo Corradini ◽  
Peter Dreger ◽  
Dolores Caballero ◽  
Christian H Geisler ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Mantle Cell Lymphoma ◽  
Cell Transplantation ◽  
Cell Lymphoma ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Mantle Cell

Abstract Introduction The role of both autologous (autoSCT) and allogeneic stem cell transplantation (alloSCT) in the management of patients with mantle cell lymphoma (MCL) remains to be clarified. In the absence of prospective comparative trials decision making for clinicians remains challenging. We have conducted a consensus project to provide guidance on how stem cell transplantation should be employed in MCL. Methods This was a collaborative project between the Lymphoma Working Party of the EBMT and the European Mantle Cell Lymphoma Network. The RAND modified Delphi consensus procedure was used. 12 clinicians, recognized for their expertise in MCL, from both transplant and non-transplant centres contributed. A literature search was performed and consensus statements were formulated. Panel members ranked each statement. The statements were reviewed and modified and then a second round of ranking was performed. Results Consensus agreement was reached on the following statements: 1. Patients should be considered for transplant strategies based on their biological age and comorbidities and not just chronological age. 2. An autoSCT should be considered as the standard first line consolidation therapy in all patients considered suitable for high dose therapy. 3. First line induction therapy prior to SCT should incorporate high dose cytarabine and Rituximab based regimens. 4. Patients achieving either complete remission or partial remission following induction therapy should be considered for autoSCT. 5. Patients failing to achieve a PR or CR following induction therapy should not proceed directly to an autoSCT. 6. Patients undergoing an allogeneic SCT should receive reduced intensity conditioning regimens. There was consensus disagreeing with the following statement: Prognostic criteria are available that permit the identification of low risk patients in need of first line therapy who should be considered for non-transplant based treatment. There was partial consensus agreeing with the following statements: 1. Patients relapsing after an autoSCT should be considered for an allogeneic stem cell transplant following reinduction therapy.2. Patients with evidence of MRD relapse post alloSCT should, in the absence of graft versus host disease, be considered for rapid withdrawal of immunesuppression and donor lymphocyte infusions. There was a partial consensus disagreeing with the following statements: 1 Patients should receive Rituximab maintenance following first line autologous stem cell transplant. 2. There are sufficient prognostic criteria to identify patients who should undergo an allogeneic stem cell transplantation as first line consolidation. 3. In patients relapsing after non-transplant first line therapy there are sufficient prognostic criteria to determine whether autoSCT or alloSCT consolidation should be used. Finally there was no consensus with respect to the following statements. 1. Disease response to induction therapy prior to autoSCT should be assessed by PET scan. 2. Minimal residual disease (MRD) negativity is mandatory prior to autoSCT. 3. A TBI based regimen should be considered as the standard for conditioning prior to autoSCT. 4. Patients undergoing an autoSCT should receive in-vivo purging with Rituximab at the time of high dose conditioning therapy. 5. Patients with relapsed disease following non-transplant first line therapy should be considered for an autologous stem cell transplant to consolidate second (or higher) response. 6. Patients with relapsed disease following non-transplant first line therapy should be considered for an allogeneic SCT to consolidate second (or higher) response. 7. Patients undergoing autoSCT should be monitored for MRD post transplant. 8. Patients with evidence of MRD relapse post autoSCT should receive preemptive Rituximab. 9. Patients undergoing alloSCT should be monitored for MRD post transplant. Conclusions Consensus was obtained with regard to the role of autologous SCT in first line consolidation. However, the application of appropriate clinical and molecular prognostic factors to guide therapeutic decisions and the role of allogeneic transplantation warrant further clinical investigation. Disclosures: No relevant conflicts of interest to declare.

Autologous Stem Cell Transplantation as First-Line Therapy in Peripheral T-Cell Lymphomas. A Prospective Multicenter Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2074-2074 ◽  
Author(s):  
Peter Reimer ◽  
Thomas Ruediger ◽  
Tobias Schertlin ◽  
Eva Geissinger ◽  
Florian Weissinger ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
High Dose ◽  
Sustained Remission ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
T Cell Lymphomas

Abstract Peripheral T-cell lymphomas (PTCL) are rare diseases representing only 10–15% of all non Hodgkin’s lymphomas and show a poor outcome following conventional chemotherapy. Long-term remissions are achieved in only 15 to 35% of patients following conventional chemotherapy. However, the impact of more aggressive therapeutic approaches such as high-dose therapy with autologous stem cell transplantation (ASCT) as first-line therapy is poorly defined mainly due to the lack of prospective PTCL-restricted studies. Therefore, in 2000 we initiated the first prospective PTCL-restricted multicenter study in PTCL. The results of the first 30 patients (pts) have recently been published. Here we update our data on all pts. entering the study. Study design: Pts. < 65 years with PTCL of all subtypes without primary cutaneous lymphoma and ALK1+ anaplastic large cell lymphoma were included. Treatment consisted of 4–6 courses of CHOP followed by DexaBEAM or ESHAP regimens before collection of stem cells. Subsequently, pts. underwent total body irradiation (TBI) and high dose cyclophosphamide (60 mg/kg body weight) chemotherapy with ASCT. Patient characteristics: From 6/00 to 7/05 75 pts. (65% male) with a median age of 50 years were enrolled. Main subtypes were Peripheral T-cell lymphoma not otherwise specified (NOS, 41%) and Angioimmunoblastic T-cell lymphoma (AIL, n= 31%). According to the Ann Arbor classification, 75% of the pts had stage III/IV disease. The International Prognostic Index (IPI) was low/low intermediate in 51% and high intermediate/high in 49% of pts, respectively. Results: So far 65 pts are eligible for evaluation. Forty pts could be transplanted (62%). After a median follow-up of 10 months post-transplant 22 pts (42%) are in sustained remission and 8 pts (15%) have relapsed. Treatment-related mortality was 2/65 (3%, one secondary AML, one multiorgan failure). Twenty-five pts (38%) did not proceed to ASCT mainly due to progressive disease (n= 18). Treatment-related toxicity was comparable to other high-dose studies in B-cell lymphomas. The IPI does not seem to have a significant impact on response to therapy, progression during CHOP therapy, or relapse rate following ASCT. Conclusion: Our data confirm the feasibility and efficacy of first line ASCT following myeloablative radiochemotherapy in PTCL. A sustained remission seems achievable for a significant proportion of pts. However, additional treatment strategies are required to prevent early progression before myeloablative therapy. Longer follow up is necessary to confirm long term remission rates.

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