Vincristine Sulfate Liposome Injection (Marqibo®) and Rituximab For Patients With Relapsed and Refractory Diffuse Large B-Cell Lymphoma Or Mantle Cell Lymphoma In Need Of Palliative Therapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4355-4355
Author(s):  
Lawrence D. Kaplan ◽  
Steven R. Deitcher ◽  
Jeffrey A. Silverman ◽  
Gareth J Morgan
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Palliative Therapy ◽  
B Cell Lymphoma ◽  
Response Duration ◽  
Hematologic Toxicity ◽  
Median Response ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Grade 3

Abstract Background Despite advances in combination immuno-chemotherapy and hematopoietic cell transplant (HCT) and improvements in long-term disease-free survival and cure rates for patients with diffuse large B-cell lymphoma (DLBCL) and other B-cell aggressive non-Hodgkin lymphomas (NHL), nearly half of patients will fail therapy and require disease palliation. Vincristine sulfate liposome injection (VSLI; Marqibo®) was developed to optimize vincristine (VCR) pharmacokinetics, dose-intensification, and target-tissue delivery. VSLI is active in relapsed and refractory NHL as a single-agent and in untreated aggressive NHL as replacement for non-liposomal VCR in CHOP±R combination chemotherapy. Because of a primarily non-hematologic toxicity profile, VSLI may be useful in patients considered unable to tolerate myelosuppressive therapies. Methods Twenty-two patients with heavily pre-treated, relapsed and refractory CD20+ DLBCL or mantle cell lymphoma (MCL) were treated with combination therapy consisting of VSLI 2.0 mg/m2, without a dose cap, every 2 weeks plus 4 weekly doses of rituximab 375 mg/m2. Objective response rate (ORR), consisting of achievement of complete response (CR) or partial response (PR), was the primary efficacy endpoint. Secondary efficacy endpoints included response duration, time to progression (TTP), and overall survival (OS). Safety variables included adverse events and neurologic assessments. Results The ORR was 59% (13/22) including CR in 6 (27%) patients and PR in 7 (32%) patients. Stable disease was documented in an additional 3 (14%) patients. Median response duration, TTP and OS were 147 days, 121 days and 322 days, respectively. The median number of VSLI doses was 5, the median individual VSLI dose was 3.5 mg, and the maximum cumulative VSLI dose was 43 mg. There were no toxicity-associated deaths during the study period. Treatment-related Grade 3 peripheral neuropathy and constipation were reported in 4 patients and 1 patient, respectively. There was no Grade 4 neuropathy. Grade 3 febrile neutropenia developed in 2 patients. Conclusion High dose VSLI plus rituximab, as palliative therapy for heavily pre-treated, predominantly older, patients with advanced, relapsed and refractory DLBCL and MCL, was generally well-tolerated and resulted in a meaningful ORR of 59%, median response duration of approximately 5 months, and median OS of almost 11 months. The toxicity profile of this combination was predictable and manageable with limited hematologic toxicity. Despite near universal prior VCR exposure (96%) and doses of VSLI normally unachievable with non-liposomal VCR, peripheral neuropathy and constipation incidences were modest. Older patients, those who are multiply relapsed, and others who are unlikely to tolerate prolonged periods of myelosuppression are often considered best suited for palliative therapy intended to prolong and maintain quality life. VSLI combined with rituximab may provide such palliation. Disclosures: Off Label Use: Marqibo is currently approved for the treatment of adults with Ph- relapsed/refractory ALL. Deitcher:Talon Therapeutics: Employment, Equity Ownership. Silverman:Talon Therapeutics: Employment.

Rituximab-Pecc Induction Followed By 90y-Ibritumomab Tiuxetan Consolidation in Relapsed or Refractory DLBCL Patients Who Are Not Eligible for or Have Failed ASCT: Results from a Phase II HOVON Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2707-2707
Author(s):  
Pieternella J Lugtenburg ◽  
Josée M Zijlstra ◽  
Jeanette K Doorduijn ◽  
Lara H Böhmer ◽  
Marinus van Marwijk Kooy ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Response Duration ◽  
Ibritumomab Tiuxetan ◽  
Median Response ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Background: Patients with relapsed/ refractory diffuse large B-cell lymphoma (DLBCL) after- or not eligible for autologous stem cell transplantation (ASCT) have a poor prognosis. Treatment with salvage chemotherapy has generally been disappointing. In many centers in the Netherlands the oral PECC regimen is used for such patients. 90Y-ibritumomab tiuxetan (Zevalin®, Spectrum Pharmaceuticals) radioimmunotherapy (RIT) is clinically active as a single agent in relapsed DLBCL. We conducted a prospective multi-center phase II study evaluating salvage therapy with Rituximab (R)-PECC, in responsive patients followed by 90Y-ibritumomab tiuxetan consolidation. Methods: Adult patients with refractory/relapsed DLBCL, more than one year after or not eligible for ASCT, were treated with R-PECC (Prednisone 40 mg/m2 po D1-5; Etoposide 100 mg/m2 po D1-5; Chlorambucil 8 mg/m2 po D1-5; Lomustine 80 mg/m2 po D1 and Rituximab 375 mg/m2 iv D1) q 28 days for 4 cycles. Complete (CR) or partial responders (PR) received consolidation with a single dose 90Y-ibritumomab tiuxetan (15 MBq/kg, 0.4 mCi/kg). Response was evaluated according to the revised Cheson criteria (2007). Results: Between November 2008 and February 2012 62 patients were enrolled. Median age was 70 years (range, 45-82). Secondary IPI score was high-intermediate or high in 42% patients. All patients had received CHOP at first-line, 12 without rituximab. Prior therapies consisted of (R)-CHOP (65%), R-CHOP and R-DHAP/VIM (24%) or R-CHOP and R-DHAP/VIM plus ASCT (11%). Fourteen patients (23%) were refractory to the last prior therapy. After 4 cycles of R-PECC the overall response rate (ORR) was 31/62 (50%), with 14 of 62 (23%) patients achieving a CR and 17 of 62 (27%) achieving a PR, 13 of 62 (21%) patients had progressive disease. ORR of relapsed patients was significantly higher than that of patients refractory to their last prior treatment (63% vs 7%, p=0.0001). 29 of 31 responsive patients received consolidation with RIT. The remaining two patients with PR did not proceed to RIT because of one toxic death and one misinterpretation of the response. The ORR after the end of the entire treatment was 29% (23% CR, 6% PR), RIT consolidation improved the overall best response (from PR to CR) in 5 of the 17 PR pts after the R-PECC only regimen. The median follow-up time of patients still alive is 48 months (range, 0-67 months). The median response duration in the patients that received R-PECC only was 9 months (range 3-63 months). The median response duration in the patients that received RIT consolidation was 20 months (range 0-59 months). The failure free survival at 1 yr from start of RIT consolidation was 52% (95% CI=[33%,68%]) and the overall survival 62% (95% CI=[42%,77%]). There was one treatment related death, due to sepsis and pneumonia after the first R-PECC cycle. The R-PECC regimen was well tolerated by most patients. The most common grade 3 or 4 adverse events during R-PECC treatment were hematological toxicity (27%), infection (19%) and malaise (11%). Adverse events after RIT were primarily hematologic. Grade 3 to 4 trombocytopenia and neutropenia occurred in 8 patients (28%) and 5 patients (17%), respectively. Eight patients received platelet transfusions and 6 patients red blood cell transfusions. Conclusions: The R-PECC regimen shows good clinical activity in relapsed DLBCL patients. Its activity in refractory patients is low. This largely oral regimen provides patients not eligible for high-dose salvage treatment with a convenient treatment schedule with an acceptable safety profile. Consolidation with RIT was well tolerated and resulted in long response durations in half of the patients. Disclosures Lugtenburg: Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Roche: Consultancy; Celgene: Consultancy. Off Label Use: 90Ytrium-ibritumomab tiuxetan for diffuse large B-cell lymphoma. Zijlstra:Celgene: Consultancy; Roche: Consultancy. Doorduijn:Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Hoogendoorn:Gilead: Consultancy; Novartis: Consultancy.

Encouraging Activity of Obinutuzumab (GA101) Monotherapy in Relapsed/Refractory Aggressive Non-Hodgkin's Lymphoma: Results From a Phase II Study (BO20999),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3655-3655 ◽  
Author(s):  
Franck Morschhauser ◽  
Guillaume Cartron ◽  
Catherine Thieblemont ◽  
Philippe Solal-Celigny ◽  
Corinne Haioun ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Response Duration ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Anti Cd20 ◽  
Large B Cell

Abstract Abstract 3655 Obinutuzumab (GA101) is a type II glycoengineered, humanized anti-CD20 monoclonal antibody that has increased antibody-dependent cellular cytotoxicity and direct cell death activity but lower complement-dependent cytotoxicity compared with type I anti-CD20 antibodies such as rituximab and ofatumumab. GA101 is in clinical development for the treatment of lymphoma and chronic lymphocytic leukemia. The Phase I/II study BO20999 has evaluated the efficacy and safety of GA101 monotherapy in patients with relapsed/refractory aggressive non-Hodgkin's lymphoma (aNHL). Here, we report updated Phase II results including progression-free survival (PFS) and best overall response (BOR). Patients (n = 40) were randomized to receive GA101 (D1, D8 and D22, then 3-weekly for total of 9 infusions) at either a high dose (1,600 mg on D1 and D8, then 800 mg thereafter; 1,600/800 mg cohort; n = 19), or a flat low dose of 400 mg (400/400 mg cohort; n = 21). Baseline patient characteristics were similar for both cohorts (Table 1). The median observation time for all patients was 9.5 months (0.3–26.1 months). BOR rates are given in Table 2, with 8/25 diffuse large B-cell lymphoma (DLBCL) patients (32%) and 4/15 mantle cell lymphoma (MCL) patients (27%) responding to GA101. Among the patients with rituximab-refractory disease, a response was observed in 1/13 patients (7.7%) and 4/12 patients (33.3%) treated in the 400/400 mg and 1,600/800 mg cohorts, respectively. Of these, 4 patients (1,600/800 mg cohort) had a response duration > 6 months, with 2 patients having an ongoing response (response duration: 9.8, 16.5+, 19.5 and 20.0+ months). Median PFS for patients with DLBCL (Figure 1) was 1.9 months (range: 0.3–15.7 months) for the 400/400 mg cohort and 2.7 months (range: 0.2–22.3) months) for the 1,600/800 mg cohort (hazard ratio: 0.70; 95% CI: 0.30–1.66). For the DLBCL subgroup, response duration was 3.1, 3.1+, 5.8, 16.5+ and 19.5 months for the 5 responders in the 1,600/800 mg cohort, compared with 6.3, 8.6 and 9.8 months for the 3 responders in the 400/400 mg cohort. Individual response data indicated that 2 MCL patients had an ongoing response for ≥ 20 months (20.0 and 20.4 months). GA101 was well tolerated in both cohorts. Infusion-related reactions (IRRs; all grades) were the most common adverse event (AE), occurring in 81% of patients in the 400/400 mg cohort and 68% of patients in the 1600/800 mg cohort. Grade 3/4 AEs occurring in >5% of patients across both cohorts included IRRs (10%), tumor lysis syndrome (10%), cardiac failure (not treatment-related; 10%), anemia (14%) and thrombocytopenia (14%) in the 400/400 mg cohort and IRRs (5%) and anemia (5%) in the 1,600/800 mg cohort.Table 1.Baseline patient characteristicsCharacteristic400/400 mg (n = 21)1,600/800 mg (n = 19)All (n = 40)Median age, years (range)70 (43–80)72 (22–85)71 (22–85)Histology, nDLBCL101525MCL11415Median number of prior treatments, n (range)4 (1–17)3 (1–6)3 (1–17)Previous rituximab, n211940Rituximab refractory*, n131225Prior stem cell transplant, n268DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma.*Rituximab refractory defined as patients who had a response of < 6 months or who failed to respond to a rituximab-containing regimen (rituximab monotherapy or in combination with chemotherapy) at any point during their treatment history.Table 2.Best overall response according to diagnosis and cohortDLBCLMCLResponse, n (%)400/400 mg (n = 10)1,600/800 mg (n = 15)400/400 mg (n = 11)1,600/800 mg (n = 4)Complete response (CR)0 (0.0)3 (20.0)2 (18.2)0 (0.0)CR unconfirmed1 (10.0)0 (0.0)0 (0.0)0 (0.0)Partial response2 (20.0)2 (13.3)0 (0.0)2 (50.0)Stable disease1 (10.0)1 (6.7)3 (27.3)0 (0.0)Progressive disease5 (50.0)9 (60.0)6 (54.5)2 (50.0)No response assessment1 (10.0)0 (0.0)0 (0.0)0 (0.0)DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma.Figure 1.Progression-free survival for patients with diffuse large B-cell lymphomaFigure 1. Progression-free survival for patients with diffuse large B-cell lymphoma In conclusion, GA101 shows encouraging single-agent efficacy in these heavily pretreated patients with relapsed/refractory aNHL (DLBCL or MCL). A Phase III trial of rituximab plus CHOP vs GA101 plus CHOP in first-line DLBCL has recently started. Disclosures: Morschhauser: Roche: Honoraria; Celgene: Consultancy, Honoraria. Cartron:Roche: Consultancy, Honoraria; GSK: Honoraria; LFB: Honoraria. Milpied:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wenger:Roche: Employment. Wassner-Fritsch:Roche: Employment. Asikanius:Roche: Employment. Salles:Roche: Consultancy, Honoraria.

Correlation Analysis Between Hematological Toxicity and Body Composition in Patients With Diffuse Large B Cell Lymphoma Treated With CHOP±R Regimen

2020 ◽  
Author(s):  
Wenhao Zhao ◽  
Xuelian Liu ◽  
Xiangliang Liu ◽  
Haimei Yang ◽  
Wei Ji ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematological Toxicity ◽  
Hematologic Toxicity ◽  
Skeletal Muscle Index ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Purpose: The tolerance of patients withdiffuse large B cell lymphoma（DLBCL） receiving CHOP±R regimen was significantly different, and grade 3~4 hematologic toxicity after chemotherapy in some patients resulted in prolonged hospital stay, increased risk of infection, delayed treatment, and directly or indirectly affected short-term efficacy and long-term prognosis. Lean body mass（LBM）and L3 skeletal muscle index （L3SMI）obtained from abdominal CT of DLBCL patients were analyzed to determine whether they could be used as independent predictors of hematological toxicity of CHOP± R regimen in DLBCL patients.Methods: The patients with DLBCL who underwent CHOP±R regimen at the Cancer Center of the First Hospital of Jilin University from January 2015 to November 2018 were retrospectively analyzed. The abdominal CT of the patient was analyzed by sliceOmatic5.0 software. The third lumbar disc planar imaging was selected, and two consecutive images were taken to calculate LBM and L3SMI. Single factor and multivariate analysis were performed on the correlation of LBM, L3SMIand chemotherapy-related grade 3~4 hematologic toxicity. The ROC curve was drawn to investigate the predictive value of various human indicators on the hematologic toxicity of grade 3~4 related to chemotherapy.Results: The L3 skeletal muscle index is associated with the occurrence of grade 3~4 hematologic toxicity (leukocyte and neutropenia) in patients with diffuse large B-cell lymphoma treated with CHOP±R regimen. Those with lower L3SMI are prone to grade 3~4 hematologic toxicity.LBM is associated with the occurrence of grade 3~4 hematologic toxicity (leukopenia) in patients with diffuse large B-cell lymphoma treated with CHOP±R regimen. This with lower LBM is prone to grade 3~4 hematologic toxicity.The L3 skeletal muscle index can be used as an independent predictor of grade 3~4 hematologic toxicity (leukocyte and neutropenia) in patients with diffuse large B-cell lymphoma treated with CHOP ± R regimen. The cut-off value can be defined as 39.91 cm2/m2.Conclusion: We can draw the following conclusions:The L3 skeletal muscle index is associated with the occurrence of grade 3~4 hematologic toxicity (leukocyte and neutropenia) in patients with diffuse large B-cell lymphoma treated with CHOP±R regimen. Those with lower L3SMI are prone to grade 3~4 hematologic toxicity.LBM is associated with the occurrence of grade 3~4 hematologic toxicity (leukopenia) in patients with diffuse large B-cell lymphoma treated with CHOP±R regimen. This with lower LBM is prone to grade 3~4 hematologic toxicity.The L3 skeletal muscle index can be used as an independent predictor of grade 3~4 hematologic toxicity (leukocyte and neutropenia) in patients with diffuse large B-cell lymphoma treated with CHOP ± R regimen. The cut-off value can be defined as 39.91 cm2/m 2.

Interim Report of Phase II Study of Bortezomib Plus CHOP Every 2 Weeks in Patients with Disseminated Stage Diffuse Large B-Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2688-2688
Author(s):  
Jeong Eun Kim ◽  
Dae Ho Lee ◽  
Soon Il Lee ◽  
Jae Hoon Lee ◽  
Won Seog Kim ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Large B Cell Lymphoma ◽  
Number Of Patients ◽  
Grade 3 ◽  
Dose Dense ◽  
Large B Cell

Abstract Abstract 2688 Poster Board II-664 Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and dose-dense CHOP therapy has improved the treatment results of diffuse Large B-cell lymphoma (DLBCL) patients. Nevertheless, a substantial number of patients progress or relapse. Bortezomib is a proteasome inhibitor that is widely used in myeloma treatment and was recently approved for use in mantle cell lymphoma treatment. Its antitumor activity in DLBCL patients was reported in several studies, both as a single agent and in combination with chemotherapy. In this study, we tried to add bortezomib to dose-dense CHOP every 2 weeks to evaluate the complete response (CR) rate and safety of the treatment. Patients with previously untreated disseminated stage DLBCL and age 70 years or less were eligible. All patients received CHOP (Cyclophosphamide 750 mg/m2 IV, doxorubicin 50mg/m2 IV, vincristine 1.4mg/m2 IV on day 1, and prednisolone 100mg PO on days 1 to 5) and granulocyte colony-stimulating factor at a dose of 5μg/kg from days 4 to 13 every 2 weeks. Bortezomib, as recommended by the previous phase I trial, was administered at a dose of 1.6mg/m2 on days 1 and 4 of each cycle. Thirty-five patients were enrolled from March, 2007 to March 2009. Total 188 cycles of treatment were done. Twenty-six patients finished planned 6 cycles of treatment, while 9 patients could not continue all planned treatment due to treatment related toxicities and one patient experienced disease progression after 5 cycles of treatment. Twenty-four patients had a CR (92.4%), one patient had a partial response (3.8%), and one patient had a progressive disease (3.8%). Grade 3 hematologic toxicity episodes occurred including 20 anemia (10.7%), 4 neutropenia (2.1%), and 6 thrombocytopenia (3.2%). Grade 4 hematologic toxicity episodes comprised 2 anemia (1.6%), 11 neutropenia (5.9%), and 6 thrombocytopenia (3.2%). One patient died of severe infection with neutropenia. Among 35 patients, grade 3 non-hematologic toxicity occurred with fatigue (11.4%), nausea (2.9%), vomiting (5.7%), diarrhea (8.6%), abdominal pain (8.6%), and sensory neuropathy (20.0%). One patient experienced grade 4 constipation. This interim analysis shows that bortezomib plus dose-dense CHOP every two weeks showed promising activity in disseminated DLBCL patients as the first-line treatment with acceptable toxicity. Further accrual will be continued till the planned patient enrollment goal for phase II results. Disclosures: No relevant conflicts of interest to declare.

Obinutuzumab (GA101) Monotherapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma or Mantle-Cell Lymphoma: Results From the Phase II GAUGUIN Study

2013 ◽  
Vol 31 (23) ◽  
pp. 2912-2919 ◽  
Author(s):  
Franck Andre Morschhauser ◽  
Guillaume Cartron ◽  
Catherine Thieblemont ◽  
Philippe Solal-Céligny ◽  
Corinne Haioun ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Treatment Response ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Grade 3 ◽  
Large B Cell

Purpose Obinutuzumab (GA101), a type II, glycoengineered, humanized anti-CD20 monoclonal antibody, was superior to rituximab in human diffuse large B-cell lymphoma (DLBCL) and mantle-cell lymphoma (MCL) xenograft models. In phase I of our study, obinutuzumab (GA101) exhibited encouraging activity but no clear dose-response relationship, and few patients had aggressive histologies. The efficacy and safety of two doses of obinutuzumab (GA101) were explored in our randomized phase II trial in patients with heavily pretreated DBLCL and MCL. Patients and Methods Patients were randomly assigned to receive eight cycles of obinutuzumab (GA101) either as a flat dose of 400 mg for all infusions (days 1 and 8 of cycle 1; day 1 of cycles 2 to 8) or 1,600 mg on days 1 and 8 of cycle 1 and 800 mg on day 1 of cycles 2 to 8. Results Forty patients were enrolled: 21 patients in the 400/400-mg treatment arm (DLBCL, n = 10; MCL, n = 11) and 19 patients in the 1,600/800-mg arm (DLBCL, n = 15; MCL, n = 4). End-of-treatment response was 28% (32% and 24% in the 1,600/800-mg and 400/400-mg study arms, respectively). Best overall response rates were 37% in the 1,600/800-mg arm and 24% in the 400/400-mg study arm (DLBCL, eight [32%] of 25 patients; MCL, four [27%] of 15 patients). Five (20%) of 25 rituximab-refractory patients exhibited treatment response, including four of 12 in the 1,600/800-mg group. The most common adverse events were infusion-related reactions (IRRs), which were manageable. Three patients had grade 3/4 IRRs. Grade 3/4 neutropenia was seen in only one patient. Conclusion Obinutuzumab (GA101) 1,600/800 mg achieves early steady-state concentration and clinical activity with an acceptable safety profile in relapsed/refractory DLBCL and MCL, supporting further exploration.

Bortezomib Plus CHOP-Rituximab for Previously Untreated Diffuse Large B-Cell Lymphoma and Mantle Cell Lymphoma

2011 ◽  
Vol 29 (6) ◽  
pp. 690-697 ◽  
Author(s):  
Jia Ruan ◽  
Peter Martin ◽  
Richard R. Furman ◽  
Shing M. Lee ◽  
Ken Cheung ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Grade 3 ◽  
Large B Cell

PurposeThe proteasome inhibitor bortezomib may enhance activity of chemoimmunotherapy in lymphoma. We evaluated dose-escalated bortezomib plus standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (R) in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).Patients and MethodsSeventy-six subjects with untreated DLBCL (n = 40) and MCL (n = 36) received standard CHOP every 21 days (CHOP-21) with R plus bortezomib at 0.7 mg/m2(n = 4), 1.0 mg/m2(n = 9), or 1.3 mg/m2(n = 63) on days 1 and 4 for six cycles.ResultsMedian age was 63 years (range, 20 to 87), and International Prognostic Index (IPI) scores were generally unfavorable (39% with IPI of 2, and 49% with IPI of 3 to 5), as were Mantle Cell Lymphoma International Prognostic Index scores in patients with MCL (28% intermediate risk and 39% high risk). Toxicity was manageable, including neuropathy in 49 subjects (8% grade 2 and 4% grade 3) and grade 3/4 anemia (13%), neutropenia (41%), and thrombocytopenia (25%). For DLBCL, the evaluable overall response rate (ORR) was 100% with 86% complete response (CR)/CR unconfirmed (CRu; n = 35). Intent-to-treat (ITT, n = 40) ORR was 88% with 75% CR/CRu, 2-year progression-free survival (PFS) of 64% (95% CI, 47% to 77%) and 2-year overall survival (OS) of 70% (95% CI, 53% to 82%). For MCL, the evaluable ORR was 91% with 72% CR/CRu (n = 32). The ITT (n = 36) ORR was 81% with 64% CR/CRu, 2-year PFS 44% (95% CI, 27% to 60%) and 2-year OS 86% (95% CI, 70% to 94%). IPI and MIPI correlated with survival in DLBCL and MCL, respectively. Unlike in DLBCL treated with R-CHOP alone, nongerminal center B cell (non-GCB) and GCB subtypes had similar outcomes.ConclusionBortezomib with R-CHOP-21 can be safely administered and may enhance outcomes, particularly in non-GCB DLBCL, justifying randomized studies.

scholarly journals An Open-Label Phase II Study of Buparlisib (BKM120) in Patients with Relapsed and Refractory Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma or Follicular Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1718-1718 ◽  
Author(s):  
Anas Younes ◽  
Gilles Salles ◽  
R. Gregory Bociek ◽  
Giovanni Martinelli ◽  
Dolores Caballero ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Grade 3 ◽  
Large B Cell

Abstract Background: Non-Hodgkin's lymphoma (NHL), which includes diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL), is associated with a high unmet need in the relapsed and refractory setting. The PI3K/AKT/mTOR pathway has been shown to play a key role in the pathogenesis of NHL. Overexpression of PIK3CD (encoding the PI3Kd isoform) is common in B-cell malignancies and is therefore widely viewed as a therapeutic target in NHL. PIK3CA and PIK3CB are also expressed in B-cell malignancies, with PIK3CA overexpression seen particularly at relapse, thereby justifying exploration of pan-PI3K inhibitors in the relapsed or refractory setting. Buparlisib (BKM120) is an oral pan-class I PI3K inhibitor which has demonstrated activity in patients with solid tumors as well as in in vitro and in vivo models of hematologic malignancies. Methods: The primary objective of this Phase II study (NCT01693614) was to evaluate the efficacy of buparlisib in three parallel cohorts of adult patients with relapsed or refractory DLBCL, FL, or MCL. Secondary objectives were to evaluate safety and tolerability, progression-free survival, duration of response, and overall survival. Inclusion criteria were: patients with relapsed or refractory disease who have received at least one prior line of therapy; at least one measurable nodal lesion (≥2 cm); ECOG performance status ≤2; and adequate bone marrow and organ function. Patients with DLBCL must have received, or be ineligible for, autologous or allogeneic stem cell transplant. All patients received single-agent buparlisib 100 mg orally QD continuously until progression, intolerance, or patient withdrawal. Tumor response was evaluated by investigators per standard criteria (Cheson, 2007). Results: At data cut-off (June 19, 2014), 64 patients had been enrolled; 26 DLBCL, 24 FL, and 14 MCL. Here, results are presented for the DLBCL cohort only. Updated results from the DLBCL cohort including biomarker analyses and results for the FL cohort will be presented at the meeting. The MCL cohort is currently enrolling. For the DLBCL cohort, median age (range) was 63.5 (28–81) years and 69% were male. The median (range) number of prior therapy regimens was 3 (1–12). Specific prior therapies included: rituximab (n=25, 96%) and bendamustine/carmustine (n=8, 31%); all patients had received prior anthracycline and an alkylating agent (e.g. cyclophosphamide), and 6 (23%) patients had undergone prior stem cell transplantation. The most common (≥15%) AEs (all grades) regardless of causality were hyperglycemia and nausea (39% each), depression (31%), anxiety and fatigue (23% each), vomiting and diarrhea (19% each), and abdominal pain (15%). Alanine transaminase or aspartate transaminase elevations were rare (4% each, with no Grade 3/4 AEs). The most common (>5%) Grade 3/4 AEs regardless of causality were hyperglycemia (23%), and nausea, depression, anxiety, urinary tract infection, and neutropenia (8% each). Six (23%) patients discontinued therapy due to AEs (potentially treatment-related). Seven on-treatment deaths were reported: 6 were disease-related and 1 was suspected to be treatment-related (unexplained death following a gastrointestinal [GI] bleed in a patient with massive GI lymphoma involvement). Overall response rate was 12% (95% CI = 2.4, 30.2) with 3 responses: 1 complete response (4%) and 2 partial responses (8%). Five patients had stable disease (19%). Eight patients (31%) experienced some decrease in tumor burden (Figure 1). At data cut-off, 2 patients demonstrated durable responses, as they were still on study treatment after 9.2 and 7.4 months, respectively. Figure 1 Figure 1. Conclusions: Early results from this Phase II study of the pan-PI3K inhibitor, buparlisib, demonstrate encouraging clinical activity, and a favorable safety profile in heavily pretreated patients with relapsed or refractory DLBCL. These data suggest that targeting all 4 PI3K isoforms in DLBCL is a viable strategy and worthy of further exploration in patients with NHL. Future combination studies with buparlisib will take a mechanism-based approach. Disclosures Younes: Novartis, Curis, J&J: Research Funding; Bayer, BMS, Celgene, Incyte, Janssen R&D: Honoraria; Sanofi, Seattle Genetics, Takeda Millenium: Honoraria. Mukherjee:Novartis Healthcare Pvt. Ltd. India: Employment. Williams:Novartis: Employment. Herbst:Novartis: Employment. Tavorath:Novartis: Employment. Kim:Novartis, Celgene, Takeda: Research Funding.

Safety and Efficacy of Bendamustine with or without Rituximab for the Treatment of Heavily Pretreated CLL and Lymphoma Patients. A Multicenter Retrospective Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1662-1662 ◽  
Author(s):  
Luigi Rigacci ◽  
Benedetta Puccini ◽  
Enrico Orciuolo ◽  
Alfonso D'Arco ◽  
Sergio Storti ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Large B Cell

Abstract Abstract 1662 Poster Board I-688 Introduction Bendamustine is an alkylating agent with a nitrogen mustard group and a purine like benzimidazol group. Recently this drug was introduced in Italy. We analized all pts treated in sixteen haematological Italian centers with Bendamustine alone or in combination with anti-CD20 antibody. Patients and methods On an intention to treat basis pts who have received at least one complete cycle were evaluable for response and toxicity. The treatments consisted of: Bendamustine 60-90 mg/m2 days 1,2 alone or in combination with Rituximab 375 mg/m2 day 0, every 21 or 28 days. 173 pts were analized, median age was 67 (range 31-87), 114 were male, 63 chronic lymphatic leukaemia 41 indolent non-follicular lymphoma, 26 diffuse large B cell lymphoma, 26 follicular lymphoma, 15 mantle cell lymphoma, 2 Peripheral T cell lymphoma. Pts were heavily pretreated, the median number of previous treatments was 3,5 (range 1-8), 121 pts have experienced more than three chemotherapy schemes. One hundred and twenty-seven pts were previously treated with Rituximab and 24 performed an autologous peripheral blood stem cell transplantation. The Bendamustine pre-treatment condition was: 70 relapsed pts, 40 with refractory disease and 63 with a progressive disease after partial response. The median number of Bendamustine cycles was 4.3 (range 1-11). Results All patients were evaluable for response: 48 pts (28%) obtained a complete remission, 78 (45%) a partial response or stable disease with an overall response rate of 73% and 47 were non responders. According to histotype we observed that 10/15 pts (67%) with mantle cell lymphoma obtained a response (6 CR;4 PR), 37/41 (9 CR; 28 PR) indolent non follicular lymphoma and 25/26 (96%) follicular lymphoma obtained a response (12 CR;13 PR), 46/63 CLL obtained a response and 8/26 (31%) DLBCL obtained a response to therapy (4 CR;4 PR), none of the two T lymphoma pts responded to therapy. With a median period of observation of 12 months (1-46) 121 (70%) pts are alive and 83 pts are in complete remission or with stable disease without any other treatment. The overall survival was 82%, 72%, 68% and 27% respectively for indolent, CLL, mantle cell and diffuse large B cell lymphoma. The progression free survival was 31%, 27%, 15% and 10% respectively for indolent, CLL, mantle cell and diffuse large B cell lymphoma. Fifthy-two pts died, 47 for progressive disease, 11 due to infection and sepsis (6%) and 2 due to other causes not related with therapy or disease. In this group of heavily pretreated pts 760 cycles were performed. The extrahematological toxicity was mild the most important problem were infections (Herpes Zooster, pneumonia, enteritis) reported in 16 pts, hepatic in 4 and cardiologic in 2 pts. The hematological toxicity was trombocytopenia grade 3-4 in 20 pts (12%), neutropenia grade 3-4 in 40 pts (23%) and anemia grade 3-4 in 19 pts (11%). Discussion In conclusion this retrospective study shows that treatment with Bendamustine alone or in combination with Rituximab is a safe and efficacy regimen in a subset of pluriresistent patients. This data shows also that the best results could be obtained in indolent lymphoma and CLL incouraging data in mantle cell lymphoma are reported. Disclosures No relevant conflicts of interest to declare.

Long-term survival with 90yttrium ibritumomab tiuxetan and rituximab as treatment for relapsed or refractory diffuse large B-cell lymphoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8558-8558
Author(s):  
Jon E. Arnason ◽  
Katarina Luptakova ◽  
Jacalyn Rosenblatt ◽  
Jeffrey Zwicker ◽  
James D. Levine ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Ibritumomab Tiuxetan ◽  
Term Survival ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

8558 Background: Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) are salvaged with high dose chemotherapy followed by autologous stem cell rescue. Ibritumomab tiuxetan is an anti-CD20 antibody conjugated to the radionuclide 90yttrium. 90Y ibritumomab tiuxetan has demonstrated clinical efficacy in DLBCL with a favorable toxicity profile relative to transplant. Methods: This phase II trial investigated the overall response rate (ORR), event free survival (EFS), overall survival (OS) and toxicity of treatment with ibritumomab followed by rituximab in patients with relapsed or refractory DLBCL, not candidates for transplant. Patients were treated with an initial dose of rituximab (250 mg/m2) followed one week later by ibritumomab (0.4 mCi90Y/kg or 0.3 mCi90Y/kg based on plateles) followed by 4 weekly doses of rituximab (375mg/m2). All non-progressing patients received maintenance rituximab (375 mg/m2) weekly for 4 doses every 6 months for 4 cycles. Results: 25 patients were enrolled. Median age was 79 (range 45-95). 12 of 25 (48%) had stage 3 or 4 disease. 13 (52%) had 2 or more prior regimens. At 12 weeks 5 patients (21%) had a complete response (CR), 3 (13%) a partial response, 2 (8%) stable disease and 14 (58%) progressed for an ORR of 32% (8/25). At best response 7 patients obtained a CR. Median EFS was 2.5 months. Median OS was 8.1 months. No patient who obtained CR later relapsed, with follow up of 18.3-100.1 months. Deaths unrelated to treatment occurred in remission in 5 patients. 2 patients remain free of disease at 67.4 and 100.1 months. 11 (65%) patients had grade 3 or 4 thrombocytopenia, but no significant bleeding was observed. 9 (36%) patients had grade 3 non-hematologic toxicity. Grade 1 and 2 fatigue occurred in 41%. Patients who progressed through a rituximab containing regimen were at high risk of early progression. Conclusions: The ORR of ibritumomab as salvage therapy for DLBCL compares favorably to other regimens with acceptable toxicity. Those patients with disease refractory to rituximab are not likely to benefit. For a subset of patients not candidates for salvage with autologous transplant, this treatment can produce a durable remission. Clinical trial information: NCT00110149.

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