A Pilot Study of Acalabrutinib with Bendamustine/Rituximab Followed By Cytarabine/Rituximab (R-ABC) for Untreated Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Daniel Guy ◽  
Marcus Watkins ◽  
Fei Wan ◽  
Nancy L. Bartlett ◽  
Amanda F Cashen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Complete Response ◽  
High Dose ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Grade 3 ◽  
Stem Cell Collection

Introduction The management of younger fit patients with mantle cell lymphoma (MCL) varies widely with no consensus on an optimal induction therapy. To date, the treatments with the longest progression-free survival incorporate a chemotherapy backbone that includes high dose cytarabine, followed by consolidation with an autologous stem-cell transplantation (ASCT) (Hermine et al. Lancet 2016, Eskelund et al. Br J Haematol 2016). Recent data showed that a regimen of bendamustine/rituximab followed by cytarabine/rituximab achieved high complete response rates with high minimal residual disease (MRD) negativity (Merryman RW et al. Blood Adv 2020). We hypothesized that adding the Bruton tyrosine kinase inhibitor acalabrutinib to the same chemotherapeutic backbone would be safe and increase complete response rates as well as minimal residual disease (MRD) negativity pre-transplant, and potentially improve clinical outcomes. Methods We conducted a single arm, single institution pilot study registered at clinicaltrials.gov (NCT03623373). Patients with untreated MCL, who were between ages 18-70 and were candidates for ASCT, were eligible. Patients received six 28-day cycles of treatment. Cycles 1-3 consisted of bendamustine 90 mg/m2 on days 1 and 2, rituximab 375 mg/m2 on day 1 and acalabrutinib 100mg BID on days 1 through 28. Cycles 4-6 consisted of rituximab 375 mg/m2 on day 1, cytarabine 2 g/m2 (1.5 g/m2 if age>60) q12 hours on days 1 and 2, and acalabrutinib 100mg BID on days 1 through 7 and 22 through 28. Restaging PET/CT and response assessment based on the Lugano classification were obtained following cycles 3 and 6. After cycle 6 patients underwent leukapheresis and stem-cell collection as preparation for ASCT. Blood for MRD status was collected after cycles 2, 4 and 6 and will be evaluated using the ClonoSeq assay (Adaptive Biotechnologies). The primary objective was to determine the stem cell mobilization success rate. Secondary objectives included safety and tolerability, overall response rate (ORR), pre-transplant complete response rate (CR), and the MRD negativity rate during and after completion of therapy. Results The trial enrolled 14 patients from December 2018 to February 2020. One patient withdrew consent prior to start of treatment and another was found to have an undiagnosed adenocarcinoma shortly after starting MCL treatment. Both are excluded from the analysis. The median age was 57 years (range 52-66). 11 patients were males (92%), all patients had an ECOG performance status of 0-1. 11 patients (92%) presented with stage IV disease. The mean MCL International Prognostic Index (MIPI) score was 6.3 (25% high-risk, 42% intermediate-risk and 33% low-risk). Of the 12 patients who began treatment, 9 completed all 6 cycles. Three patients did not complete therapy due to: insurance issues (n = 1), and thrombocytopenia (n = 2) following cycle 5 and 4. The side effect profile showed expected hematologic toxicities with grade 3-4 cytopenias in all patients, mostly during cytarabine cycles. In total, 100% of patients developed grade 3-4 thrombocytopenia and 83% of patients developed grade 3-4 neutropenia. Three episodes of febrile neutropenia were observed. One patient had a grade 3 transaminase increase, and one patient had grade 3 diarrhea. No bleeding events or treatment related deaths occurred. The remainder of the side effects were low grade and the treatment was generally well tolerated. Of the 12 evaluable patients, 10 responded (ORR 83%) with 9 achieving CR (75%). One patient achieved PR prior to being removed from the study due to thrombocytopenia and then achieved CR off study. Two patients experienced PD during induction. With a median follow up of 9 months, no responding patients have relapsed. The median CD34+ stem cell collection was 3.84x106 cells/kg (range 2.77 - 5.9). MRD results will be presented at the meeting. Conclusions This is the first study attempting to combine BTK inhibition with a high dose cytarabine containing regimen. The addition of acalabrutinib to a regimen of bendamustine/rituximab followed by cytarabine/rituximab appears to be safe. The R-ABC combination will be further tested in the recently activated intergroup trial EA4181. Disclosures Bartlett: Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding; ADC Therapeutics: Consultancy. Fehniger:ImmunityBio: Research Funding; HCW Biologics: Research Funding; Kiadis: Consultancy; Nkarta: Consultancy; Indapta: Consultancy; Wugen: Consultancy; Orca Biosystems: Consultancy; Compass Therapeutics: Research Funding. Ghobadi:Amgen: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; EUSA: Consultancy; WuGen: Consultancy. Mehta-Shah:Bristol Myers-Squibb: Research Funding; C4 Therapeutics: Consultancy; Celgene: Research Funding; Genetech/Roche: Research Funding; Innate Pharmaceuticals: Research Funding; Kyowa Hakko Kirin: Consultancy; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Corvus: Research Funding. Kahl:Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy.

Alternating Courses of 3x CHOP and 3x DHAP Plus Rituximab Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation (ASCT) Is Superior to 6 Courses CHOP Plus Rituximab Followed by Myeloablative Radiochemotherapy and ASCT In Mantle Cell Lymphoma: Results of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 110-110 ◽  
Author(s):  
Olivier Hermine ◽  
Eva Hoster ◽  
Jan Walewski ◽  
Vincent Ribrag ◽  
Nicole Brousse ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
High Dose ◽  
Advisory Committees ◽  
Overall Response ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 110 Background: Mantle Cell Lymphoma (MCL) has been characterized by poor long term prognosis with a median survival of only 3 to 4 years. However, outcome has improved during the last decades. In its first randomized trial, the MCL net demonstrated that myeloablative consolidation followed by ASCT resulted in a significant prolongation of PFS in advanced stage MCL (Dreyling et al Blood 2005). Recent phase II studies suggested that the addition of rituximab to CHOP like chemotherapy and/or high dose ARA-C may significantly improve remission rates and PFS. A French phase II trial using sequential R-CHOP/R-DHAP followed by ASCT showed an overall response rate of 95% with a CR rate of 61% translating into a median EFS of 83 months and a 75% survival rate at 5 years (Delarue et al ASH 2008). Methods: To evaluate the potential superiority of a high dose ARA-C containing regimen, the MCL net initiated a randomized trial comparing 6 courses of CHOP plus Rituximab followed by myeloablative radiochemotherapy (12 Gray TBI, 2×60mg/kg Cyclophosphamide) and ASCT (control arm A) versus alternating courses of 3x CHOP and 3x DHAP plus Rituximab followed by a high dose ARA-C containing myeloablative regimen (10 Gray TBI, 4×1,5 g/m2 Ara-C, 140mg/m2 melphalan) and ASCT (experimental arm B). Patient eligibility criteria included previously untreated MCL stage II-IV up to the age of 65 years. Histological diagnosis was confirmed by a central pathology review board. The primary end point time to treatment failure (TTF) was monitored continuously by a sequential procedure based on a one sided triangular test. Stable disease after induction, progression or death from any causes, were considered as treatment failure. Sample size was calculated to detect a hazard ratio of 52% for arm B with a power of 95%. Randomization was stopped as soon as a significant difference was observed between the two arms. Results: From July 2004 to May 2010, 497 patients were randomized in 4 countries (Germany, France, Poland, Belgium). The 391 patients evaluable for the primary analysis (19 no MCL, 87 not yet documented) displayed similar characteristics in both treatment arms: median age 55 vs 56 years, male 78% vs 79%, stage IV 85% vs 79%, B symptoms 43% vs 33%, ECOG >2 5% vs 5%, elevated LDH 37% vs 38%, and MIPI low/int/high risk 61%/25%/14% vs 62%/23%/15%, respectively. After induction overall response was similarly high in both arms (A: 90% vs B: 94%; p=0.19) and CR rate and combined CR/CRu rate were significantly higher in arm B (26% vs 39%; p=0.012 and 41% vs 60%; p=0.0003). The number of patients transplanted was similar in both arms (72% vs 73%) and after transplantation overall response and CR rates were comparable in both arms (97% vs 97% and 63% vs 65%, respectively). After a median follow up of 27 months, patients in arm B experienced a significantly longer TTF (49 months vs NR; p=0.0384, hazard ratio 0.68) mainly due to a lower number of relapses after CR/CRu/PR (20% vs 10%), whereas the rate of ASCT-related deaths in remission was similar in both arms (3% vs 4%). Although CR rate after ASCT was comparable in both arms, remission duration (RD) after ASCT was superior in Arm B (48m vs NR; p=0.047). Interestingly, for patients in CR after ASCT, RD after ASCT was also presumably superior in arm B (51 months vs NR; p=0.077). At the time of analysis overall survival was similar in both arms with medians not reached and 79% vs. 80% survival rates at 3 years (p=0.74). Safety after induction was comparable in both arms except for an increased grade 3/4 hematological toxicity (Hb 8% vs 28%, WBC 48% vs 75%, platelets 9% vs 74%, respectively), an excess of renal toxicity (creatinine grade 1/2: 8% vs 38%, grade 3/4: none vs 2%), and more frequent grade 1/2 nausea and vomiting in arm B. Toxicities of both conditioning regimen were similar, except for higher grade 3/4 mucositis (43% vs. 61%) in Arm B, and higher grade 1/2 liver toxicity and constipation in Arm A. Conclusions: High dose ARA-C in addition to R-CHOP+ASCT increases significantly complete response rates and TTF without clinically relevant increase of toxicity. Therefore, induction regimen containing high dose ARA-C followed by ASCT should become the new standard of care of MCL patients up to 65 years. Disclosures: Walewski: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stilgenbauer:Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Feugier:roche: Consultancy, Honoraria. Bosly:Roche: Membership on an entity's Board of Directors or advisory committees. Gisselbrecht:Roche: Research Funding.

A Comparison of Chemotherapy + G-CSF Versus Plerixafor (Mozobil®) + G-CSF for Stem Cell Mobilization In Patients with Multiple Myeloma Treated with Lenalidomide

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2258-2258
Author(s):  
Tomer M Mark ◽  
Adriana C Rossi ◽  
Roger N Pearse ◽  
Morton Coleman ◽  
David Bernstein ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Yield ◽  
High Dose ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Stem Cell Collection

Abstract Abstract 2258 Background: Prior use of lenalidomide beyond 6 cycles of therapy in the treatment of multiple myeloma (MM) has been shown to negatively impact stem cell yield, but this phenomenon can be overcome with the addition of high-dose cyclophosphamide to standard G-CSF mobilization. We hypothesized that the use of plerixafor (Mozobil®) would compare similarly to chemotherapy in rescuing the ability to collect stem cells in lenalidomide-treated myeloma. Methods: We performed a retrospective study comparing the efficacy of plerixafor + G-CSF mobilization (PG) to chemotherapy + G-CSF (CG) (either high-dose cyclophosphamide at 3g/m2 or DCEP [4-day infusional dexamethasone/ cyclophosphamide/ etoposide/cisplatin]) in 49 consecutive stem cell collection attempts in patients with MM exposed to prior lenalidomide. The primary endpoint was the ability to collect sufficient stem cells for at least two transplants (minimum 5×106 CD34+ cells/kg), comparing results in terms of total exposure to lenalidomide and time elapsed from lenalidomide exposure until the mobilization attempt. The secondary endpoint was number of apheresis days required to meet collection goal. Resilts: Twenty-four patients underwent PG mobilization and twenty-five with CG (21 with G-CSF + cyclophosphamide, 4 with G-CSF+DCEP). The two groups did not differ in terms of total amount of lenalidomide exposure: median number of lenalidomide cycles for patients mobilized with PG was 6.5 (range 1.2–86.6), vs. 6 (range 2–21.6), for patients mobilized with CG (P = 0.663). The median time between mobilization and last lenalidomide dose was also similar between the two groups: 57.5 (range 12–462) days for PG vs. 154 (range 27–805) days for CG (P = 0.101). There was an equivalent rate of successful collection of 100% for PG and 96% for CG, P = 0.322. One patient failed collection in the CG group due to emergent hospitalization for septic shock during a period of neutropenia; no patient collected with PG had a serious adverse event that interrupted the collection process. Stem cell yield did not differ between the two arms (13.9 vs. 18.8 × 106 million CD34+ cells/kg for PG vs. CG respectively, P = 0.083). Average time to collection goal was also equal, with a median of time of 1 day required in both groups, (range 1–2 days for PG, 1–5 days for CG, P = 0.073). There was no relationship between amount of lenalidomide exposure and stem cell yield with either PG (P = 0.243) or CG (P = 0.867). Conclusion: A plerixafor + G-CSF mobilization schedule is equivalent in efficacy to chemotherapy + G-CSF in obtaining adequate numbers of stem cells for two autologous stem cell transplants in patients with MM exposed to lenalidomide; however, PG may be a less toxic approach than chemomobilization. Number of lenalidomide cycles has no impact on chances of stem cell collection success using either method. Disclosures: Mark: Celgene Corp: Speakers Bureau; Millenium Corp: Speakers Bureau. Zafar: Celgene Corp: Speakers Bureau. Niesvizky: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding.

Carfilzomib Combined with Thalidomide and Dexamethasone (CARTHADEX) As Induction Treatment Prior to High-Dose Melphalan (HDM) in Newly Diagnosed Patients with Multiple Myeloma (MM). A Trial of the European Myeloma Network EMN

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 633-633 ◽  
Author(s):  
Pieter Sonneveld ◽  
Emilie Hacker ◽  
Sonja Zweegman ◽  
Marie Jose Kersten ◽  
Edo Vellenga ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Tumor Lysis Syndrome ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Tumor Lysis ◽  
Grade 3 ◽  
Cell Harvest

Abstract Abstract 633 Introduction: This independent phase 2 trial was designed to evaluate carfilzomib (C) combined with thalidomide and dexamethasone during induction and consolidation for feasibility, response and progression-free survival (PFS) in patients with newly diagnosed symptomatic MM, who were candidates for high-dose therapy. Patients with symptomatic MM and measurable disease, age 15 to 65 and no significant co-morbidity were eligible. At diagnosis Fluorescent in situ Hybridization (FISH) was performed of recurrent translocations, trisomy 9, del(17p), del (13q) and add(1q) Patients received 4 cycles of carfilzomib at 20 mg/m2 on days 1 & 2 followed by 27mg/m2 on days 8,9,15,16 of cycle 1 and on days 1,2, 8, 9, 15 & 16 of all subsequent 28-day cycles, thalidomide 200 mg days 1 – 28 of a 28 day cycle and dexamethasone 40 mg days 1, 8, 15 & 22 of a 28 day cycle. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Following HDM (200 mg/m2) and autologous stem cell transplantation (ASCT), consolidation therapy consisted of 4 cycles of carfilzomib 27 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle, thalidomide 50 mg days 1–28 of a 28 day cycle and dexamethasone 20 mg days 1, 8, 15, 22 of a 28 day cycle. The primary endpoint was response, other endpoints were complete response (CR) according to IMWG criteria, immunofixation-negative CR (sCR), VGPR all pre-and post HDM, PFS and overall survival (OS). An interim analysis was planned after 20 evaluable patients, primarily to guard against excessive toxicity and/or lack of response. Results: While recruitment is still ongoing, 34 patients have been included, of which the first 20 patients were are evaluated for response and toxicity, with a median follow-up of 5 months. One patient was excluded because unavailability of data. Median age was 60 yr and ISS stages I/II/III were 8/6/5, respectively. Four patients went off treatment because of intolerance to thalidomide (n=1), tumor lysis syndrome with renal failure (n=1) or respiratory infections (n=2). Adverse events CTC grade 3+4 included tumor lysis syndrome (n=2), metabolic disorders (n=4), cardiovascular including DVT (n=5), gastrointestinal (n=2), skin rash (n=2) and reversible renal failure (n=3). Peripheral polyneuropathy grades 1+ 2 was observed in 7 (35%) of patients, but no grade 3 or higher. Responses after cycle 1 were CR + sCR 5%, VGPR 32%, PR 47%, SD 10%, NE 5% and after induction overall CR + sCR 21%, VGPR 47%, PR 16%, SD 10%, NE 5%. Median time to maximum response was 1 cycle. Secondary analysis revealed that responses occurred across cytogenetic subgroups as determined by FISH, i.e. add (1q) (n=2), t(4;14) (n=2), del(17p) (n=1) and del(13q) (n=5). Stem cell harvest was accomplished with standard CD34+ yield in all patients and HDM/ASCT was performed with complete hematologic recovery in 4/4 patients. Conclusion: Carfilzomib combined with thalidomide and dexamethasone during induction and consolidation is feasible and effective. The complete data including response after consolidation will be reported at the ASH meeting. This EMN trial was registered as NTR2422. Carfilzomib and an unrestricted grant was provided by ONYX Pharmaceuticals. Disclosures: Sonneveld: Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Zweegman:Celgene: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Amgen: Honoraria.

Clinical, Metabolic and Molecular Responses After 4 Courses of R-DHAP and After Autologous Stem Cell Transplantation for Untreated Mantle Cell Lymphoma Patients Included in the LyMa Trial, a Lysa Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 152-152 ◽  
Author(s):  
Steven Le Gouill ◽  
Mary Callanan ◽  
Elizabeth Macintyre ◽  
marie-Hélène delfau-Larue ◽  
Caroline bodet-Milin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Response Rates ◽  
High Dose ◽  
Molecular Response ◽  
Advisory Committees ◽  
Mantle Cell

Abstract Abstract 152 Mantle cell lymphoma (MCL) is a rare B-cell malignancy characterized by the t(11;14) translocation. The European MCL network has demonstrated that a sequential R-CHOP/R-DHAP chemotherapy regimen prior to autologous stem cell transplantation (ASCT) provides better disease control than R-CHOP (Hermine et al, ASH 2010, abstract 110) and that molecular minimal residual disease (MRD) measured by IGH real-time quantitative polymerase chain reaction (PCR) before and after ASCT is an important prognostic factor to predict progression-free survival (PFS) (Pott et al. Blood. 2010;115(16):3215–23). Indeed, the use of high-dose aracytine upfront before ASCT is now recommended and molecular remission appears to be a major objective for future clinical trials in MCL. It therefore appeared interesting to appreciate response rates combining standard evaluation (Cheson 1999), FDG-PET imaging (Cheson 2007) and PCR techniques after rituximab plus upfront high-dose aracytine (R-DHAP) followed by ASCT. Response rates after 4 courses of R-DHAP were one of the objectives of the LyMa trial (NCT00921414). This trial is a randomized, open-label, phase III study that evaluates the efficacy of rituximab maintenance therapy in MCL patients aged between 18 and 66 years old, undergoing first-line treatment with 4xR-DHAP and exhibiting a response after ASCT (R-BEAM). Patients who do not reach a sufficient partial remission after R-DHAP are planned to receive 4 additional courses of R-CHOP before ASCT. The LyMa trial started in September 2008 and was designed to enroll 299 patients over a 4 years period. To date (August 2012), 295 patients have been included. Herein, we report response rates according to the combination of Cheson 1999 and 2007 criteria plus molecular response rates after 4xR-DHAP and after ASCT for the first 200 enrolled patients (last inclusion in August 2011). Results: One patient withdrew consent and the analysis is therefore on 199 patients. The cohort's median age is 57.2 years (range 29.7–65.7) and 41 patients are female (20%). At diagnosis, simplified MIPI was low in 104 cases (52%), intermediate in 55 (28%) and high in 40 (20%).Twenty-five patients (12.5%) presented with a blastoid variant. The panel of pathologist experts confirmed the diagnosis in all reviewed cases. Among the 199 evaluable patients, 182 (91%) received 4 courses of R-DHAP and 12 patients (all in PR according to Cheson 99 criteria) received 4 additional courses of R-CHOP because of insufficient clinical response after R-DHAP. Among these 12 patients, 5 reached CR/CRu after R-CHOP. Ultimately, 164 patients (82%) proceeded to ASCT (158 after R-DHAP and 6 after RDHAP/R-CHOP) and 154 (77.4%) have been randomized between rituximab maintenance or no maintenance. In an intention-to-treat (ITT) analysis and according to Cheson 1999 criteria, 152 patients (76.3%) reached CR (n=74) or CRu (n=78) after 4 courses of R-DHAP while 25 patients reached PR and 8 presented with SD/Prog. According to Cheson 2007 criteria (n= 170; PET not done in 17 cases and data missing in 12 cases), 129 patients reached CR while 41 patients remained FDG-TEP positive. Response rates according to Cheson 1999 and 2007 criteria for transplanted patients (n=164) were CR (n=109)/CRu (n=45) in 94% and CR in 84.5% (129 patients underwent FDG-PET after ASCT), respectively. Regarding MRD, diagnosis samples were available for 186/199 patients. Forty-one diagnosis samples have not yet been analyzed and 14 proved to be not informative. To date, the molecular response on peripheral blood (PB) after 4 courses of R-DHAP has been assessed in 103 cases and found negative in 80 cases and positive in 22 cases (not evaluable in one case). MRD on bone marrow (BM) after 4 courses of R-DHAP has been measured in 97 cases and found negative in 59 and positive in 36 (not evaluable in one case). After ASCT, PB and BM MRD were found negative in 91 patients (95 samples have been analyzed to date) and 67 (87 samples analyzed), respectively. Thus, in the LyMa trial,CR/CRu rates after only 4 courses of RDHAP, according to Cheson 1999 and 2007 criteria, are very high confirming the major anti-tumoral impact of high-dose aracytine upfront in MCL. In addition, these encouraging results seem to be confirmed at the molecular level strengthening the interest of an MRD-guided management of MCL patients. Results will be updated at the time of the meeting and patients' outcome according to disease status will be presented. Disclosures: Ribrag: Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Sanofi-Aventis: Research Funding; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

2-Hour Cryotherapy Effectively Reduces Severe Mucositis Associated with High-Dose Melphalan Followed By Stem Cell Rescue: Results from a Randomized Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3960-3960 ◽  
Author(s):  
Douglas W. Sborov ◽  
Misty Lamprecht ◽  
Don Benson ◽  
Karen Tackett ◽  
Yvonne A Efebera ◽  
...  
Keyword(s):  
Stem Cell ◽  
Creatinine Clearance ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Advisory Committees ◽  
Stem Cell Rescue ◽  
Grade 3 ◽  
High Dose Melphalan ◽  
Severe Mucositis

Abstract Introduction: Severe mucositis in the autologous transplant setting has been correlated with adverse outcomes; longer febrile neutropenia duration, doubling of infectious risk, 2.7 additional days of total parenteral nutrition, 2.6 additional days of IV narcotics, increased length of stay (LOS), 3.9-fold increase in 100-day mortality, and US$25,405 increase in hospital charges (Sonis, JCO, 2001 19(8)). In a 40 patient randomized trial investigating cryotherapy (6 hours versus none) following high dose melphalan, grade 3/4 mucositis occurred in only 14% of patients using cryotherapy compared to 74% of patients using saline rinses (Lilleby, BMT, 2006 37). Prolonged cryotherapy is a significant hardship for patients and has resulted in nausea, vomiting, headache, toothache, and chills. We performed a randomized study investigating 2 versus 6 hours of cryotherapy in multiple myeloma (MM) patients undergoing autologous stem cell transplant (ASCT) with melphalan conditioning. Hypothesis: We hypothesized that a 2-hour cryotherapy regimen would be non-inferior to 6-hours in severity of mucositis, LOS, and incidence of bacteremia. Methods: We conducted a non-inferiority investigation of 146 sequential MM patients undergoing high dose melphalan with autologous stem cell rescue. Patients were consented and randomized to either 2 (n = 73) or 6 hours (n = 73) of cryotherapy via block randomization based on hemoglobin (less or greater than 11 g/dL), fat free mass (30-50, 50-70, >70 kg), or measured 24hr creatinine clearance (<30, 30-60, >60 mL/min). The cryotherapy process consisted of patients’ melting shaved ice inside their mouth for the designated period of time; flavoring with snow cone syrup was permitted. Inpatient nurse practitioners graded mucositis via WHO criteria. Patients received antifungal (fluconazole) and antiviral (acyclovir or valacyclovir) prophylaxis. Subset analyses investigated the incidence of bacteremia in all patients. Results: Median age was 59 years (range 35 - 72) and 60 (range 38 – 71), and the median measured creatinine clearance was 90.6 mL/min (range 0.2 – 168.7) and 85.4 mL/min (range 21.5 – 196.5) for the 2 hour and 6 hour groups respectively. Length of hospitalization (mean of 15 days) did not differ significantly between the 2 cohorts (p = 0.54). Mucositis was graded daily after melphalan infusion. In the 2-hour cohort, 59% of the patients had mucositis (31 patients with grade 1, 10 with grade 2, and 2 patients with grade 3). In the 6-hour cohort, 64% had mucositis (35 patients with grade 1, 9 with grade 2, and 3 patients with grade 3). These results suggest that 2-hour cryotherapy was not inferior to 6-hour therapy in decreasing mucositis grade. In the entire 146 patient group, approximately 30% developed a positive blood culture after transplant, including 25 (34%) and 20 (27%) in the 6-hour and 2-hour groups respectively. The three most common infectious organisms included gram negatives (n = 12 patients), polymicrobial (n = 7), and non-group A streptococcus (n = 7). In the cohort treated with 2-hour cryotherapy, positive blood cultures did not correlate with grade of mucositis (r = 0.05, p = 0.65). Conclusions: In MM patients undergoing ASCT, 2-hour cryotherapy did not increase mucositis compared to 6-hours. The incidence of blood stream infection was not different between groups. In addition, having an infection did not correlate with grade of mucositis.These results suggest that a 2-hour cryotherapy regimen is not inferior to a 6-hour regimen, and may be considered a standard supportive care measure in patients receiving high dose melphalan. Disclosures Hofmeister: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Honoraria, Research Funding; ARNO Therapeutics: Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees.

Alternating Courses of 3x CHOP and 3x DHAP Plus Rituximab Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation (ASCT) Increases Overall Survival When Compared to 6 Courses of CHOP Plus Rituximab Followed by Myeloablative Radiochemotherapy and ASCT in Mantle Cell Lymphoma: Final Analysis of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 151-151 ◽  
Author(s):  
Olivier Hermine ◽  
Eva Hoster ◽  
Jan Walewski ◽  
Vincent Ribrag ◽  
Nicole Brousse ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Final Analysis ◽  
High Dose ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 151 Background MCL outcome has improved during the last decades. In its first randomized trial, the MCL net demonstrated that myeloablative consolidation followed by ASCT resulted in a significant prolongation of PFS in advanced stage MCL (Dreyling et al Blood 2005). Recent phase II studies suggest that the addition of rituximab and/or high dose ARA-C may significantly improve outcome. A phase II trial using sequential R-CHOP/R-DHAP followed by ASCT showed an ORR of 95% with a CR rate of 61%, a median EFS of 83m and a 75% survival rate at 5 years (Delarue et al Blood 20012). Two years ago we presented preliminary results of the the MCL randomized trial comparing 6 courses of CHOP plus Rituximab followed by myeloablative radiochemotherapy (12 Gray TBI, 2×60mg/kg Cyclophosphamide) and ASCT (control arm A) versus alternating courses of 3x CHOP and 3x DHAP plus Rituximab followed by a high dose ARA-C containing myeloablative regimen (10 Gray TBI, 4×1,5 g/m2 Ara-C, 140mg/m2 melphalan) and ASCT (experimental arm B) and have shown that after a follow up (FU) median of 27m patients of Arm B experienced a significantly better time to treatment failure (TTF) (49m vs NR; p=0.0384, HR 0.68), but no overall survival difference. Here, we present final results after a longer FU. Methods Patient eligibility criteria included previously untreated MCL stage II-IV up to the age of 65 years. Histological diagnosis was confirmed by a central pathology review board. The primary end point TTF was monitored continuously by a sequential procedure based on a one sided triangular test. Stable diseases after induction, progression or death from any causes were considered as treatment failure. Sample size was calculated to detect a relative risk of 52% for arm B with a power of 95%. Randomization was stopped as soon as a significant difference was observed between the two arms. Results From July 2004 to May 2010, 497 patients were randomized in 4 countries (Germany, France, Poland, Belgium). The 455 patients evaluable for the primary analysis (19 no MCL, 13 not yet documented, 7 lost of follow up, 2 stage 1, and 1 R bendamustine chemotherapy) displayed the following characteristics (A vs B): median age 54 vs 56 year, male 79% vs 79%, stage IV 82% vs 81%, B symptoms 43% vs 31%, ECOG >2 4% vs 4%, elevated LDH 39% vs 35%, and MIPI low/int/high risk 60%/25%/15% vs 64%/23%/13%, respectively. After induction overall response (OR) was similar in both arms (90% vs 95%; p=0.19) but CR and CR/CRu rates were significantly higher in arm B (25% vs 36%; p=0.012 and 40% vs 54%; p=0.0003). The number of patients transplanted was similar in both arms (72% vs 73%). After transplantation OR and CR rates were comparable in both arms (98% vs 97% and 63% vs 61%). After a median FU of 51 months, TTF was longer in Arm B (46m vs 88m; p=0.0382, HR 0.68) mainly due to a lower number of relapses after CR/CRu/PR (n= 81 vs 40). The rate of ASCT-related death in remission was similar in both arms (4% vs 4%). Although CR rate after ASCT was similar in both arms, remission duration (RD) after ASCT was superior in Arm B (49m vs 84m; p=0.0001). At the time of final analysis, OS was superior in Arm B (NR vs 82m, p=0.045). Safety after induction was comparable in both arms except for an increased grade 3/4 hematological toxicity (Hb 9% vs 30%, WBC 50% vs 75%, platelets 10% vs 74%), renal toxicity (creatinine grade 1/2: 10% vs 44%, grade 3/4: none vs 1%), and grade 1/2 nausea and vomiting in arm B. Toxicities of both conditioning regimen were similar. Conclusions With a longer FU, we confirmed that high dose ARA-C in addition to R-CHOP increases significantly complete response rates, TTF and in addition overall survival without clinically relevant increase of toxicity. Therefore, induction regimen containing high dose ARA-C followed by ASCT should become the new standard of care of MCL patients <65 y. Disclosures: Ribrag: Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; astrazeneca: Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees; bayer: Research Funding; sanofi: Research Funding. Gisselbrecht:roche: Consultancy, Research Funding; baxter: Research Funding.

scholarly journals A Phase II Study of Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Isatuximab in Newly Diagnosed, Transplant-Eligible Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 5043-5043
Author(s):  
Elizabeth K. O'Donnell ◽  
Clifton C. Mo ◽  
Andrew J. Yee ◽  
Omar Nadeem ◽  
Andrew R. Branagan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Stem Cell Collection ◽  
Minimal Residual

Abstract Background: Clinical data support the combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid for the treatment of newly diagnosed multiple myeloma (NDMM). Recently, the GRIFFIN study evaluated the addition of the CD38 antibody, daratumumab to lenalidomide, bortezomib, and dexamethasone in transplant-eligible NDMM and demonstrated improved efficacy with an acceptable safety profile. Isatuximab is a newer CD38 monoclonal antibody that binds to a specific epitope of the CD38 receptor. In addition to antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity, isatuximab eliminates MM cells via direct apoptosis without the need for crosslinking. Isatuximab enhances immune function by boosting the activation and cytotoxic activity of natural killer cells and by depleting CD38+ immune suppressor cells such as regulatory T cells and inducing clonal expansion of T cells. Isatuximab is approved in combination with carfilzomib and dexamethasone for relapsed, refractory MM based on the results of the IKEMA study. The MANHATTAN study evaluated the 4-drug combination of daratumumab, lenalidomide, carfilzomib, and dexamethasone. The primary end point, minimal residual disease negativity was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%). Building upon these data, our study evaluates the addition of isatuximab to weekly carfilzomib, lenalidomide, and dexamethasone. Study Design and Methods: A phase II, open-label clinical trial is being conducted to evaluate the efficacy of once weekly carfilzomib, lenalidomide, dexamethasone, and isatuximab (Isa-KRd) in 50 patients with newly diagnosed, transplant-eligible MM (NCT04430894). Eligible patients will have NDMM, age ≥18 years, ECOG PS of 0-2, and are deemed eligible for stem cell transplantation (SCT). All patients will receive 4 cycles of induction therapy with Isa-KRd followed by stem cell collection with the option to either proceed to upfront SCT versus deferred SCT. Patients undergoing upfront SCT will receive 4 cycles of therapy followed by stem cell collection, high-dose chemotherapy, and autologous SCT followed by 2 additional cycles of therapy then maintenance. Patients deferring SCT following collection will receive 4 cycles of therapy followed by stem cell collection followed by 4 additional cycles of therapy then maintenance. Each 28-day cycle will consist of isatuximab 10 mg/kg IV Q1 week for 8 weeks, then Q2 weeks for 16 weeks, thereafter Q4 weeks; carfilzomib (20 mg/m 2 Day 1 only) 56 mg/m 2 IV on Days 1, 8, 15; lenalidomide 25 mg po on Days 1-21; and dexamethasone 20 mg po day of and day after all doses of carfilzomib (Days 1, 2, 8, 9, 15, and 16) and isatuximab (Cycles 1 and 2 Days 22 and 23). For maintenance, patients will be stratified based on cytogenetics (high-risk cytogenetics include deletion (del) 17p, translocation t(4:14), t(14;16), t(14;20)). Patients with standard-risk cytogenetics will receive lenalidomide 10 mg po Days 1-21. Patients with high-risk cytogenetics will receive carfilzomib 56 mg/m 2 Days 1, 15; lenalidomide 10 mg po Days 1-21; and isatuximab 10 mg/kg IV Day 1. Dexamethasone, 20 mg orally or IV will be administered to patients as a pre-infusion medication prior to isatuximab dosing. Main Outcomes and Measures: The primary end point is complete response (CR + stringent CR) rate after 4 cycles of Isa-KRd as assessed by the International Myeloma Working Group (IMWG) Uniform Response Criteria. Secondary endpoints include determining safety and tolerability of Isa-KRd, minimal residual disease (MRD) after 4 cycles, at completion of consolidation (post-transplant) or induction (transplant-deferred), and sustained MRD at 24 months, progression-free survival, overall survival rates, and quality of life. Efficacy analysis will be performed both in the intent-to-treat (ITT) population and efficacy evaluable (EE) population. The ITT population will include all treated patients, and the EE population will include all patients who receive at least 1 cycle of study drug. The primary analysis will be based on the EE population, and will use the investigator-assessed response data evaluated according to consensus recommendations based on the IMWG criteria. CR (CR+sCR) rate after 4 cycles of Isa-KRd will be reported with 90% confidence interval. Support: Amgen and Sanofi Figure 1 Figure 1. Disclosures O'Donnell: Oncopeptide: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Bristol Myer Squibb: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy. Mo: Janssen: Honoraria; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee: Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Amgen: Consultancy; Oncopeptides: Consultancy; Adaptive: Consultancy; Janssen: Consultancy; GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Nadeem: GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy; Adaptive: Consultancy; Bristol Myer Squibb: Consultancy. Branagan: Sanofi-Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive: Consultancy; CSL Behring: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rosenblatt: Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imaging Endpoints: Consultancy; Attivare: Consultancy; Wolters Kluwer Health Inc: Consultancy, Patents & Royalties. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Richardson: AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; Oncopeptides: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Sanofi: Consultancy; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AstraZeneca: Consultancy; Regeneron: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding.

Rituximab Maintenance after Autologous Stem Cell Transplantation Prolongs Survival in Younger Patients with Mantle Cell Lymphoma: Final Results of the Randomized Phase 3 LyMa Trial of the Lysa/Goelams Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 145-145 ◽  
Author(s):  
Steven Le Gouill ◽  
Catherine Thieblemont ◽  
Lucie Oberic ◽  
Anne Moreau ◽  
Krimo Bouabdallah ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Standard Of Care ◽  
High Dose ◽  
Advisory Committees ◽  
Free Survival ◽  
Mantle Cell ◽  
High Dose Cytarabine

Abstract Mantle cell lymphoma (MCL) accounts for approximately 6% of non-Hodgkin's Lymphoma (NHL) in adults. MCL commonly responds to initial therapy but inevitably patients relapse and response duration decreases from one salvage therapy to the next. Indeed, there is an urgent need to control and/or eradicate residual MCL cells that are responsible for early and late relapses. Maintenance with Rituximab (RM) after R-CHOP has been shown to prolong OS in elderly MCL patients treated with R-CHOP (Kluin-Nelemans et al. NEJM). Induction with high-dose cytarabine followed by autologous stem cell transplant (ASCT) consolidation is standard of care for young patients but RM after ASCT has never been investigated so far. The LyMa trial (ClinicalTrials.gov, NCT00921414) is a prospective international randomized phase III trial that investigated RM after ASCT in young previously untreated MCL patients. Patients were included at diagnosis (<66y; stage >I, untreated, diagnosis of MCL according to WHO 2008 classification). Induction immuno-chemotherapy consisted of 4 courses of R-DHAP every 21 days (Rituximab, Dexamethasone, High-dose cytarabine, salt Platinum) followed by ASCT consolidation. Patients who were not in response (CR/CRu or PR) after R-DHAP received 4 additional courses of R-CHOP-14 before ASCT. The conditioning regimen for ASCT was R-BEAM. Patients in response after ASCT were randomized (1:1) between RM or no RM. RM consisted of one infusion of Rituximab (375mg/m2) every 2 months for 3 years. The primary endpoint was event-free survival (EFS) calculated from time of randomization; events were defined as disease progression, relapse, death, severe infection or allergy to Rituximab. Progression-free survival (PFS) and overall survival (OS) from time of diagnosis and time of randomization were secondary endpoints. The interim analysis showed a trend for a longer EFS and PFS in favor of RM arm. (Le Gouill et al, ASH 2014, abs 146). Herein, we present the results of the final analysis. RESULTS. Two hundred and ninety nine patients were enrolled from September 2008 to August 2012. Demographic and clinical characteristics of the patients were as followed: median age of 57y (27-65), 79% of male, MIPI-low in 53.2%, MIPI-I in 27.4% and MIPI-H in 19.4%. After inclusion, 277 patients completed the 4 courses of R-DHAP. The CR/CRu rate after R-DHAP was 77.3% and ORR was 89.3%. Twenty patients received R-CHOP. In all, 257 patients (including 12 patients who received R-DHAP/R-CHOP) underwent ASCT. After ASCT, 240 patients were randomized (RM, n=120; no RM, n=120). Median follow-up (mFU) from inclusion and from randomization were 54.4m (52.7-59.2) and 50.2m (46.5-54.2), respectively. The mPFS and mOS from inclusion in an intention to treat analysis were not reached; the 4y-PFS and OS were 67.8% (95%CI, 62.1 to 72.8) and 78% (95%CI; 72.8 to 82.3), respectively. According to EFS definition, 47 (39.2%) patients had an event in the no RM versus 25 (20.8%) in the RM arm. The mEFS from randomization was not reached in both arms. The 4y-EFS was 61.4% (95%CI; 51.3 to 69.9) in the no RM arm vs 78.9% (95%CI; 69.6 to 85.6) in the RM arm (p=0.0012). The EFS duration was significantly superior in the RM arm with a 54.3% reduction in the risk of event (Hazard ratio (HR)= 0.457; 95%CI, 0.28 to 0.74; p=0.0016). The median PFS and OS from randomization were not reached in both arms. The 4y-PFS and OS from randomization were superior in the RM arm: 82.2% (95%CI; 73.2 to 88.4) vs 64.6% (95%CI; 54.6 to 73) (p=0.0005) and 88.7% (95%CI; 80.7 to 93.5) vs 81.4% (95%CI; 72.3 to 87.7)(p=0.0413). Patients in the RM arm had a 60% reduction of risk of progression (HR=0.4; 95%CI, 0.23 to 0.68; p=0.0007) and a 50% reduction of risk of death (HR=0.5; 95%CI, 0.25 to 0.98; p=0.0454). The per protocol analysis yielded similar results. In conclusion, The LyMa trial demonstrates for the first time that RM after ASCT prolongs EFS, PFS and OS. Thus, 4 courses of R-DHAP plus ASCT (without TBI) followed by RM maintenance (one infusion every 2 month for 3 years) is a new standard of care for young MCL patients. Disclosures Thieblemont: Gilead: Consultancy; Roche: Consultancy; Janssen: Consultancy. Ribrag:Pharmamar: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; NanoString: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding. Casasnovas:BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; ROCHE: Consultancy, Honoraria, Research Funding. Haioun:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hermine:Celgene: Research Funding; AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Novartis: Research Funding; Alexion: Research Funding.

scholarly journals A Phase II Single Arm Study of Nivolumab As Maintenance Therapy after Autologous Stem Cell Transplantation in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2455-2455
Author(s):  
Carlos Bachier ◽  
Henning Schade ◽  
Behyar Zoghi ◽  
Aravind Ramakrishnan ◽  
Nirav N. Shah
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Residual Disease ◽  
Refractory Disease ◽  
Advisory Committees ◽  
Extranodal Disease

Abstract Introduction: Autologous stem cell transplants (ASCT) are standard of care for patients with primary refractory or recurrent Hodgkin lymphoma (HL). While transplant results in cure for some patients, others relapse and succumb from their disease. Studies have found high expression of programmed death ligand 1 (PD-L1) in HL cells. The anti-PD-1 monoclonal antibody, nivolumab, has been safe and efficacious in the treatment of relapsed, refractory HL (Ansell et al. 2015). We evaluated the safety and efficacy of nivolumab maintenance therapy post-ASCT in high risk for relapse Hodgkin disease. Methods: Patients with HL with high risk of residual disease following ASCT ( high risk defined as refractory disease, relapse &lt;12 months, or relapse ≥12 months with extranodal disease after frontline therapy) received nivolumab (240 mg IV every 2 weeks) starting 45-180 days post-transplant for a maximum of 6 months of treatment. Patients were followed for AEs through 100 days after the last dose of drug. PET-CT response assessments were performed 1-3 month, 6 month, and 12 month post-ASCT. The primary objective was to evaluate the safety and tolerability of nivolumab as maintenance therapy early after ASCT. The secondary objective was to evaluate progression-free survival (PFS) at 12 months post-transplant. Results: To date, 37 patients were enrolled; median age 36 years; 25 patients (68%) male. The median number of prior systemic regimens was 2 (range 2-4). 25 patients (68%) had relapsed disease, and 12 patients (32%) had primary refractory disease. 18 patients (49%) had extranodal disease at relapse, 6 patients (16%) had B-symptoms at relapse, and 11 patients (30%) had residual disease after salvage, including 10 patients (27%) of whom had 2-3 prior salvage therapies. 22 patients (60%) had received prior brentuximab, and 3 patients (8%) had received prior nivolumab or pembrolizumab. 36 patients received ASCT and 1 patient received tandem ASCT. At the time of data cutoff, 28 patients (76%) had discontinued nivolumab treatment, 22 patients (60%) because they had completed the 6-month treatment course, 4 patients (11%) due to an adverse event (AE) (1 patient each with pain, pneumonitis, rhabdomyolysis, or hypothyroidism), and 2 patients (5%) due to disease progression. The median duration of treatment was 22.1 weeks. 17 patients (46%) experienced a treatment-related AE (TRAE), of which 5 patients (14%) experienced a ≥Grade 3 TRAE. The most common (≥5%) TRAEs were diarrhea, fatigue, bone pain, neutrophil count decreased, pruritus, rash, and vomiting. 2 patients experienced a treatment-related serious AE (pneumonitis, rhabdomyolysis). There were no treatment-related deaths. With a median follow up of 9.2 months, the median PFS and overall survival (OS) have not been reached. The 6 month PFS is 92.1% and the 12-month OS is 100%. There were no differences in OS when stratified based on prior treatment. Conclusions: The use of nivolumab maintenance early after ASCT is safe and tolerable in this high risk patient population. Early efficacy data is promising, but data need to mature to determine the 12 month PFS. Figure 1 Figure 1. Disclosures Bachier: CRISPR: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Shah: Umoja: Consultancy; Incyte: Consultancy; Legend: Consultancy; Kite: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy.

Superiority of Lenalidomide-Dexamethasone Versus Thalidomide-Dexamethasone as Initial Therapy for Newly Diagnosed Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3884-3884
Author(s):  
Francesca Gay ◽  
Suzanne Hayman ◽  
Martha Q. Lacy ◽  
Francis Buadi ◽  
Morie A Gertz ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Initial Therapy ◽  
High Dose ◽  
Toxicity Profile ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Intention To Treat ◽  
High Dose Dexamethasone ◽  
Grade 3

Abstract Abstract 3884 Poster Board III-820 Background and Objective Thalidomide/dexamethasone (thal/dex) combination has shown high activity in newly diagnosed multiple myeloma (MM) (Rajkumar SV. at al, J Clin Oncol 2006;24:431-436). In newly diagnosed patients, lenalidomide/dexamethasone (len/dex) has demonstrated superiority compared with high-dose dexamethasone alone (Zonder JA et al, Blood 2007;110:77). Although both thal/dex and len/dex are active in newly diagnosed MM, no randomized trial has been reported comparing these two regimens, and unfortunately none are ongoing or planned. We compared the efficacy and the toxicity of thal/dex and len/dex as primary therapy in 411 newly diagnosed MM patients treated at the Mayo Clinic. Patients and methods 411 consecutive patients seen at Mayo Clinic between 2001 and 2008, who received induction with thal/dex (n=183) or len/dex (n=288) were retrospectively studied. Thalidomide was given at a dose ranging from 100 mg/day to 400 mg/day continuously; the lenalidomide dose was 25 mg/day, days 1-21 on a 28-day cycle. All patients received dexamethasone, either at high-dose (40 mg orally on days 1-4, 9-12, and 17-20) or at low-dose (40 mg orally day 1, 8, 15, 22); each cycle was repeated every 4 weeks. In addition, a case-matched subgroup analysis that adjusted for age, gender and transplantation status was performed among patients who received high-dose dexamethasone comparing the thal/dex (n=72) and len/dex (n=72) groups. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and all comparisons were determined by the log-rank test and by the Cox proportional hazards model. Results On intention-to-treat analysis, of 411 patients, 80.3% versus 61.2% patients, respectively in the len/dex group and in the thal/dex group (p < 0.001), achieved at least a partial response. A significant difference between the 2 groups was found in terms of both very good partial response or better (34.2% vs 12.0%, p < 0.001) and complete response rate (13.6% vs 3.3%, p < 0.001). Duration of therapy was significantly longer in len/dex patients as compared to thal/dex patients: 36.7% vs 12.6% of patients who did not stop treatment to receive SCT were still receiving therapy at 1 year (p < 0.001).Time-to-progression was significantly better in the len/dex group than in patients receiving thal/dex (median 27.4 vs 17.2 months, HR 0.64; 95% CI 0.44-0.93; p = 0.019). Similarly, progression-free-survival was significantly higher in len/dex patients (median 26.7 vs 17.1 months, HR 0.69; 95% CI 0.48-0.98; p = 0.036). This translated into an increase in overall survival (OS) (median not reached for len/dex group compared to 57.2 months in thal/dex patients, HR 0.60; 95% CI 0.40-0.92; p = 0.018). Survival advantages were evident in patients presenting with International Staging System Stage (ISS) I/II (HR 0.57; 95% CI 0.32-1.00; p = 0.052) at diagnosis but not in patients with ISS stage III in subgroup analysis. There was a trend toward better OS in len/dex group compared to thal/dex group both for patients who underwent transplant and for patients who did not. A similar rate of patients experienced at least one grade 3 or higher adverse event (57.5% vs 54.6% in len/dex and thal/dex groups, respectively, p = 0.568). However, the toxicity profile was different in the two groups: major grade 3-4 toxicities of len/dex were hematological, in particular neutropenia (14% with len/dex vs 0.6% with thal/dex, p<0.001) while the most common toxicities in thal/dex were venous thromboembolism (15.3% vs 9.2%, p = 0.058) and peripheral neuropathy (10.4% vs 0.9%, p < 0.001). The data on efficacy and safety shown above were also confirmed in the subgroup case-matched analysis which included only high-dose dexamethasone patients. Conclusions This cohort study shows the superiority of len/dex in terms of response rates and survival, compared to thal/dex. The toxicity profile of the 2 regimens is different and len/dex treatment, although more active, was not associated with increased toxicity (grade 3-4 AEs). These data need to be carefully evaluated and randomized prospective phase III studies are necessary to confirm these results and determine the optimal initial therapy for MM. Disclosures: Off Label Use: research drugs in combination to standard care. Lacy:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; Novartis: Research Funding; Genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Bergsagel:amgen: Membership on an entity's Board of Directors or advisory committees; genetech: Membership on an entity's Board of Directors or advisory committees; merck: Research Funding; celgene: Membership on an entity's Board of Directors or advisory committees. Witzig:celgene: Research Funding. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Greipp:celgene: Research Funding.

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