Walking a tightrope: clinical use of ibrutinib in mantle cell lymphoma in the elderly

Abstract Representative clinical case. A 74-year-old male patient was diagnosed with stage 3 mantle cell lymphoma in 2012. Because he was ineligible for intensive treatment (age, previous myocardial infarction [MI]), he received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemoimmunotherapy for 6 cycles (reaching complete response) and then rituximab maintenance (RM) for 2 years. One year after the end of RM, he relapsed with disseminated disease. He was started on ibrutinib 560 mg/day. Two weeks after the start of ibrutinib, he developed grade 3 diarrhea that required interruption of ibrutinib. Two weeks after the regular dose was restarted (month 3), the patient had repeated bleeding (patient was receiving aspirin for previous MI) and had to stop ibrutinib again. Because the patient was in partial response (PR) with lack of disease-associated symptoms, he was restarted on ibrutinib 280 mg/day with no further adverse events, and he had maintained PR at last follow-up (month 9 on ibrutinib).

Download Full-text

VcR-CVAD Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma: A Phase II Study from the Wisconsin Oncology Network

Blood ◽

10.1182/blood.v112.11.265.265 ◽

2008 ◽

Vol 112 (11) ◽

pp. 265-265 ◽

Cited By ~ 9

Author(s):

Brad Kahl ◽

Julie Chang ◽

Jens Eickhoff ◽

Leslie Gilbert ◽

Eric Rogers ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Complete Response Rate ◽

Phase Ii Study ◽

Cell Lymphoma ◽

Treatment Strategies ◽

Complete Response ◽

Mantle Cell ◽

Induction Regimen ◽

Grade 3

Abstract Introduction: There is no standard treatment for Mantle cell lymphoma (MCL). Intensive treatment strategies such as conventional R-hyperCVAD with alternating R-cytarabine/methotrexate or autologous stem cell transplant appear to improve PFS but the effect on OS is unclear. In addition, approximately 50% of newly diagnosed patients are not candidates for intensive therapies. Novel treatment strategies are needed. We have published the results of a study using a modified R-hyperCVAD induction followed by maintenance rituximab (Kahl et al, Ann Oncol 2006). This induction strategy yielded a complete response (CR) rate of 64% and the entire treatment program yielded a median PFS of 37 months. Bortezomib (Velcade) has demonstrated promising activity in relapsed MCL (Fisher et al, J Clin Onc, 2006). We hypothesized that the incorporation of Velcade (Vc) into the induction regimen would improve the CR rate. The new regimen, VcRCVAD, was tested for safety and efficacy in a phase II study at the University of Wisconsin and within the Wisconsin Oncology Network. Methods: Eligible patients had histologically confirmed mantle cell lymphoma, PS 0–2, and adequate end organ function. The final treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1–3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1–2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1–4. Due to excessive painful peripheral neuropathy (PN), 2 dose modifications were required during the course of the study. Patients 1–7 received 1.5 mg/m2 Velcade and 2 mg vincristine. Patients 8–14 received 1.3 mg/m2 Velcade and 2 mg vincristine. Patients 15–30 received 1.3 mg/m2 Velcade and 1 mg vincristine. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF cytokine support. Patients achieving at least a PR receive maintenance rituximab therapy for 5 years. Results: Enrollment is complete and all 30 patients are evaluable for response to VcRCVAD induction. Baseline characteristics include median age 60.5 (48–74), 24M:6F, 26/30 (87%) stage IV, and 12 (40%) low-risk, 8 (27%) int-risk, and 10 (33%) high-risk by MIPI. 3 patients (10%) experienced PD during induction therapy and 27 (90%) responded with 23 CR/CRu (77%) and 4 PR (13%). With a median follow up of approximately 18 months, the 18-month PFS and OS are 73% and 97%, respectively. The major toxicity of this treatment regimen is painful PN and expected hematologic toxicity. 5/7 patients in cohort 1 and 3/7 patients in cohort 2 developed grade 3 painful PN and 1 patient in cohort 2 developed grade 4 painful PN. Only 1/16 patients in the final cohort experienced grade 3 painful PN. All neuropathy eventually improved to ≤ grade 2, but 10 patients require chronic medication for symptom relief. 13/167 (8%) of the treatment cycles were complicated by neutropenic fever/infection. There were no treatment related deaths. Conclusion: The VcR-CVAD induction has produced high overall response (90%) and CR rate (77%) in a very representative MCL patient population. Comparing these data to our previous frontline MCL study, the CR rate appears to be enhanced (77% vs 64%) by the addition of Velcade. Longer follow up is needed before determining if the higher CR rate will translate into an improved PFS and OS. Because of the risk for painful PN, caution must be exercised when using vincristine and Velcade in combination. The MTD for this combination was 1 mg vincristine and 1.3 mg/m2 Velcade. The encouraging complete response rate provided the rationale for ECOG study E1405, which is testing the safety and efficacy of this induction regimen in a cooperative group setting.

Download Full-text

Ibrutinib-Lenalidomide-Rituximab in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Final Results from the Nordic Lymphoma Group MCL6 (PHILEMON) Phase II Trial

Blood ◽

10.1182/blood-2020-133298 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-36

Author(s):

Mats Jerkeman ◽

Martin Hutchings ◽

Riikka Räty ◽

Karin Fahl Wader ◽

Anna Laurell ◽

...

Keyword(s):

Bone Marrow ◽

Mantle Cell Lymphoma ◽

Research Funding ◽

Tp53 Mutation ◽

Phase Ii Trial ◽

Cell Lymphoma ◽

Molecular Remission ◽

Mantle Cell ◽

Grade 3

Introduction: In spite of improvements in treatment of mantle cell lymphoma (MCL), this is still considered an incurable lymphoma entity, and the majority of patients eventually relapse. Ibrutinib is a very active agent in MCL, but in vitro has been shown to partially antagonize the activity of rituximab, by suppression of NK cell activity and subsequent ADCC. Lenalidomide, on the other hand, improves rituximab-induced ADCC. In this multi-centre open-label phase II trial, we evaluated safety and efficacy of this triplet combination in patients with relapsed or refractory MCL. Methods: Patients with MCL, relapsing after or refractory to at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and measurable disease were eligible. The primary endpoint was maximal overall response rate (ORR) measured with CT and PET/CT. Minimal residual disease (MRD) monitoring by PCR was performed during follow-up, according to EuroMRD criteria. Ion Torrent sequencing of the most frequently mutated genes in MCL was performed on frozen tumor cells from bone marrow at time of relapse. Health-related quality of life was assessed by the EORTC-QLQ C30 questionnaire before and during treatment. Treatment schedule: Induction phase: Up to twelve 28-day cycles with: Lenalidomide 15 mg p o daily, days 1-21, Ibrutinib 560 mg p o days 1-28, Rituximab 375 mg/m2 i v day 1 in cycle 1, then 1400 mg s c (or 375 mg/m2i v) days 8, 15 and 22 in cycle 1, then day 1 in cycles 3, 5, 7, 9 and 11. Maintenance phase: For patients in CR, PR or SD, not in need of other treatment, given until progression, cycle duration 56 days. Ibrutinib: 560 mg p o days 1-56, 2. Rituximab 1400 mg s c (or 375 mg/m2i v) day 1 of each cycle. Results: Accrual of 50 pts was completed in June 2016, at 10 centres in Sweden, Norway, Denmark and Finland. The median age was 69.5 years, with a median MIPI score of 6.2. Patients had received a median of two previous regimens, four had progressed after single agent ibrutinib, and three had received prior allo-SCT. A TP53 mutation was detected in 11 of 49 evaluable cases (22%), 8 cases were of blastoid/pleomorphic histology, and 22 of 40 evaluable cases had a Ki67 >30%. Treatment emergent-AEs of any grade in ≥20% of patients were rash (24%) and fatigue (20%). Five pts (10%) experienced rash grade 3, mainly during cycle 1. Hematological toxicity was generally of low grade, apart from grade 3-4 neutropenia in 5 patients. One patient died due to possible treatment-related toxicity (septic shock). In total, 27 patients achieved CR (54%) and 10 PR (20%). Among evaluable patients with a TP53 mutation, blastoid/pleomorphic histology or Ki67 >30%, the CR rates were 7/11 (64%), 15/8 (62%) and 11/22 (50%), respectively. After a median follow-up of 40 months, the median PFS is 18 months (95% CI 6.5-28), and median OS 47 months (95% CI 30-64). Patients with a detectable TP53 mutation at relapse (n=11) had a median PFS of 13 months (95% CI 4.2-21), whereas pts without a TP53 mutation had a median PFS of 34 months (95% CI 8.3-60). Of the 28 patients evaluable for MRD at 6 months, 15/27 (56%) patients achieved molecular remission in blood and 12/28 (43%) in bone marrow. After 12 months, MRD-negativity in BM was 68% (13/19). Out of 4 patients with TP53-mutated MCL, 2 were MRD-negative in BM after 12 months, as well as 2 out of 4 patients with blastoid/pleomorphic histology. By self-reported HRQOL, a lower level of emotional functioning (EF), as well as a higher level of pain (PA) at baseline, was associated with inferior PFS. In addition, low EF was associated with inferior OS. By a Cox regression multivariable analysis, including MIPI, TP53, histology, Ki67, EF and PA, only MIPI was prognostic for PFS or OS with this regimen. Conclusions: The combination of ibrutinib, lenalidomide and rituximab has been shown to be an active and well tolerated regimen in this cohort of high risk R/R MCL, associated with a high rate of molecular remission. The activity in TP53 mutated MCL is lower than in unmutated disease, but this regimen may still serve as an option for a bridge to an allogeneic transplantation or CAR-T therapy in this category of patients. Disclosures Jerkeman: Roche: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Gilead: Research Funding. Hutchings:Genmab: Honoraria; Genmab: Consultancy; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Daiichi: Research Funding; Sankyo: Research Funding; Genmab: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Roche: Honoraria; Roche: Consultancy; Takeda: Honoraria.

Download Full-text

High Remission Rates and Prolonged Progression Free Survival in Newly Diagnosed Patients with Mantle Cell Lymphoma Treated with R-MACLOIVAM-T

Blood ◽

10.1182/blood.v112.11.3597.3597 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3597-3597 ◽

Cited By ~ 2

Author(s):

Peter J Hosein ◽

Daniel Morgensztern ◽

Francine Coleman ◽

Gail Walker ◽

Maricer Escalon ◽

...

Keyword(s):

Bone Marrow ◽

Mantle Cell Lymphoma ◽

Relapse Rate ◽

Cell Lymphoma ◽

Progression Free Survival ◽

Newly Diagnosed ◽

Free Survival ◽

Mantle Cell ◽

Grade 3

Abstract Background: Mantle cell lymphoma (MCL) is an unfavorable subtype of B-cell non-Hodgkin lymphoma characterized by median progression-free survival (PFS) and median overall survival (OS) of only 1.5 and 3–4 years respectively. Although high-dose therapy and an autotransplant may prolong OS, it does not result in a long-term disease free survival. Therefore, there is a need for novel therapeutic approaches for this entity. Methods: We conducted a single-arm phase II study in subjects with newly-diagnosed MCL to assess efficacy and safety of a novel intensive regimen R-MACLO-IVAM-T, a modification of a protocol designed by Magrath et al (JCO1996;14:925). The study size of 22 patients was based on precision of a two-sided 95% confidence interval for the 18-month progression free survival rate. Eligible subjects had a confirmed diagnosis of MCL using WHO criteria, age 18–75 years, ECOG PS ≤ 2, adequate organ function and no history of HIV or prior cancer. Lymphoma extent at presentation was assessed by standard staging procedures as well as esophagogastroduodenoscopy and colonoscopy. Prior to initiating thalidomide maintenance, subjects were enrolled in the STEPS® program. Cycle 1 consisted of R-MACLO: rituximab 375 mg/m2 IV on day 1, doxorubicin 45 mg/m2 IV on day 1, cyclophosphamide 800 mg/m2 IV on day 1 and 200 mg/m2/day on days 2–5, vincristine 1.5 mg/m2 on days 1 and 8 capped to 2mg, methotrexate 1.2 g/m2 IV on day 10 over 1 hour followed by 5.52 g/m2 IV over 23 hours followed by leucovorin 36 hours later. G-CSF was begun on day 13. When the ANC was >1.5×109/L, cycle 2 with R-IVAM was begun: rituximab 375 mg/m2 IV day 1, cytarabine 2 g/m2 IV every 12 hours on days 1 and 2, etoposide, 60 mg/m2 on days 1–5 and ifosfamide 1.5 g/m2 on days 1–5 with mesna. Fourteen days after ANC recovery from cycle 2, cycles 3 and 4 were given in identical fashion to 1 and 2. Four weeks after ANC recovery from cycle 4, subjects were re-staged and responses were assessed by standard criteria. Subjects achieving CR at the end of therapy received thalidomide 200 mg/day until MCL relapse or intolerable toxicity. Results: Accrual started in 4/2004 and ended in 3/2008 when the planned 22 subjects were enrolled. All subjects were evaluable for toxicity and 21 were evaluable for response. Median age was 56.5 years (range 39–73). All subjects had at least stage 3 disease with bone marrow involvement in 19 and gastrointestinal involvement in 10. Distribution according to IPI: 0–1 factor, 3; 2 factors, 8; 3 factors, 8; and 4 factors, 3. Twenty subjects had diffuse variant and 2 had blastic variant. Nineteen subjects completed all 4 cycles of therapy; treatment was stopped in 2 subjects after 2 and 3 cycles respectively, and one subject died during the first cycle. Of the 21 subjects completing 2 cycles of therapy, 20 achieved CR and one PR. Two subjects relapsed at 9 and 33 months respectively, while 19 remain relapse free after median follow-up of 25 months (range 5–51). With a total follow-up of 545 months, the estimated relapse rate is 4.4 per 100 patients per year. There were two deaths: 1 from sepsis on cycle 1 day 8 and the other in CR at 38 months from non-small cell lung cancer diagnosed 19 months after MCL. Common severe toxicities were grade 3–4 neutropenia, thrombocytopenia and anemia in 33%, 19% and 17% of R-MACLO cycles and in 50%, 88% and 68% of R-IVAM cycles respectively. There were 14 bacteremias in 82 cycles, 12 of which were after R-IVAM therapy. Six episodes of reversible grade 1–2 renal toxicity occurred after methotrexate. The thalidomide maintenance dose was reduced in 6 subjects due to grade 3–4 neutropenia and reduced or stopped in 8 subjects because of grade 3–4 peripheral neuropathy. Patients remain under follow-up for relapse and survival. Conclusions: R-MACLO-IVAM-T results in a high overall response rate of 100% (95% CR and 5% PR) and a low relapse rate. At a median follow-up of 25 months, median PFS and OS were not reached. The 2-year actuarial PFS of 94% compares favorably with previously reported 2-year actuarial PFS of 40% and 67% for CHOP-like regimens without and with upfront bone marrow transplantation (Blood2005;105: 2677). The contribution of thalidomide maintenance to this outcome requires additional study. A multicenter clinical trial is suggested.

Download Full-text

The VcR-CVAD Regimen Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma (MCL): First Analysis of E1405 – A Phase II Study of VcR-CVAD with Maintenance Rituximab for MCL.

Blood ◽

10.1182/blood.v114.22.1661.1661 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1661-1661 ◽

Cited By ~ 6

Author(s):

Brad S Kahl ◽

Hailun Li ◽

Mitchell R Smith ◽

Randy D. Gascoyne ◽

Elisabeth Paietta ◽

...

Keyword(s):

Phase Ii ◽

Research Funding ◽

Response Rate ◽

Complete Response Rate ◽

Phase Ii Study ◽

Cell Lymphoma ◽

Complete Response ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 1661 Poster Board I-687 Introduction One approach to improving outcomes in Mantle Cell Lymphoma (MCL) is to incorporate newer targeted agents into standard chemotherapy regimens. As the proteasome inhibitor bortezomib (Velcade‘) achieved a 33% response rate in relapsed MCL, we hypothesized that the incorporation of Velcade (Vc) into a modified R-hyperCVAD chemotherapy backbone would result in a high complete response rate (CR). The new regimen, VcR-CVAD, was tested for safety and efficacy in a phase II study within the Wisconsin Oncology Network (UW) and demonstrated a CR rate of 77% (Kahl, ASH 2008). To determine the safety and efficacy of this regimen in a cooperative group setting, we initiated E1405: a phase II study of VcR-CVAD with maintenance rituximab (MR) for untreated MCL. Methods Eligible patients had histologically confirmed, previously untreated MCL, PS 0-2, and adequate end organ function. The treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1-3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1-2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1-4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients had an option to receive high dose chemotherapy and autologous stem cell transplantation (off protocol) rather than MR. The primary endpoint of the trial was the CR rate, incorporating PET imaging, to VcR-CVAD induction therapy. Results Seventy-six eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40-76), 59M:17F, 91% stage III/IV, and 39% with elevated LDH. Sixty-four patients (84%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), patient preference (2), and other/unknown (5). Response information is available on 74 patients while data is outstanding on 2 patients. The ORR was 96% (73/76; 95% CI, 89%-99%), CR rate 75% (57/76; 95% CI, 64%-84%) and the PR rate 21% (16/76; 95% CI, 13%-32%). Six of the PR patients were coded as such because of protocol violations in which a post-treatment bone marrow biopsy or PET scan was not obtained. The CR rate in the 68 completely restaged patients was 84%. Forty-four patients proceeded to planned MR while 21 patients went off protocol to SCT consolidation. Median follow up is currently too short (9 months) to assess PFS and OS. The major toxicity of the treatment regimen was expected myelosuppression. Grade 3-4 non hematologic toxicities were rare. No patients developed grade 3-4 neuropathy. There were no treatment related deaths. Conclusion The VcR-CVAD induction produced high overall response (96%) and CR rate (75%) in a representative MCL patient population treated on a cooperative group protocol. The CR rate was high and comparable to the UW pilot study (77%). No episodes of severe painful peripheral neuropathy were reported using the reduced vincristine dosage and the overall toxicity profile was very acceptable. Longer follow up is needed to determine if the high CR rate will translate into improved PFS and OS. Disclosures Kahl: Genentech: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Off Label Use: Bortezomib as front line treatment in MCL. Smith:Genentech: Research Funding; Millennium: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding. Horning:Genentech: Honoraria, Research Funding.

Download Full-text

High Complete Response Rates with Dose Dense/Dose Intense Chemotherapy Plus Radioimmunotherapy in High Risk Diffuse Large B Cell and Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v118.21.2681.2681 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2681-2681 ◽

Cited By ~ 1

Author(s):

Anne W Beaven ◽

David A. Rizzieri ◽

Zachary Powell ◽

Zhiguo Li ◽

Peggy Alton ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Complete Response ◽

Mantle Cell ◽

Dose Dense ◽

Large B Cell

Abstract Abstract 2681 Background: Despite recent advances, the 5 year overall survival for patients with high risk diffuse large B cell lymphoma (DLBCL) is approximately 50% and there is still no known cure for patients with mantle cell lymphoma (MCL). This phase II study of multimodal dose dense therapy evaluated 2 courses of dose intense chemotherapy followed by radioimmunotherapy (RIT) consolidation in patients with previously untreated, mantle cell or high/high intermediate (int) risk aggressive B cell lymphoma. Aim: To evaluate the efficacy and safety of dose intense/dose dense, multimodal chemo-immunotherapy combined with RIT. Methods: Patients with untreated MCL or high int/high risk DLBCL were enrolled. Treatment regimen involved 3 phases of therapy: induction 1, induction 2 and consolidation with RIT (Table 1). Induction 2 occurred approximately 5 weeks after induction 1 and RIT was given 12–24 weeks after rituximab was completed. Patients were evaluated after each treatment phase and those with stable disease (SD) or better and blood count recovery could proceed to the next phase of therapy. Results: Thirty nine patients (pts) with high/high int risk DLBCL (n=25) or MCL (n=14) were enrolled. The median age was 60 years (range 21–80). Toxicity: Common, anticipated toxicities in the induction phases were thrombocytopenia, neutropenia, nausea, fatigue, and anemia. During Ind1 (n=39), grade (gr) III mucositis occurred in 13 pts (33%) and febrile neutropenia (FN) in 31 (79%). Three pts did not proceed to Ind2 due to death (1 candidemia, 1 septic knee prosthesis, 1 from complications of colectomy for prolonged diverticulitis after count recovery) and 2 withdrew to pursue less intense chemotherapy. During Ind2 (n=34) gr III mucositis occurred in 12pts (35%) and FN in 24 (67%). Two pts had gr III/IV cerebellar toxicity that was disabling in 1 pt. Of the 34 pts who received the Ind2, 9 did not receive RIT due to progressive disease (PD) (4), prolonged cytopenias (4), or diagnosis of pancreatic cancer (1). Twenty five pts received RIT and 3 (12%) had FN, 20 (80%) had gr III/IV neutropenia, 23 (92%) had gr III/IV thrombocytopenia, 1 pt died from bacteremia. Two pts developed myelodysplasia 21 and 48 months after starting therapy. Response: Pts were evaluated for response after Ind1, Ind2 and RIT. 38/39 pts were evaluable for response, with 1 pt withdrawing prior to assessment. The pts who died prior to response evaluation were counted as non-responders. The best overall response rate (ORR) was 95% (36/38) with a complete response rate (CR) of 84% (32/38). See tables 2 and 3 for more detailed response data by phase of treatment and disease type. After a median follow up of 17.2 months, 30 pts (77%) are alive (see figure). The median overall survival for MCL has not been reached and is 36.5 months for DLBCL. Deaths were from Hodgkin lymphoma (1), infection (3), DLBCL (2), complications of surgery (1), MCL (2). The median progression free survival is 36.5 months with 11/14 (79%) MCL and 14/25 (56%) DLBCL pts alive and in continued CR. Conclusion: The combination of dose dense, dose intense chemotherapy, monoclonal antibody, and RIT demonstrates considerable efficacy, despite expected toxicity, in high risk DLBCL and MCL pts. The response rates seen in this study are higher than expected from standard R-CHOP in this pt population. Further follow up to determine impact on OS and long term complications will be required to confirm these promising outcomes. Disclosures: Beaven: Glaxo Smith Kline: Family Member Employed by GSK. Off Label Use: Tositumomab is approved for use in relapsed/refractory low grade CD20 positive NHL. It is not FDA approved for first line use in diffuse large B cell lymphoma or mantle cell lymphoma. Neither cytarabine nor etoposide are approved for use in non-Hodgkin lymphoma. Rizzieri:Glaxo Smith Kline: Speakers Bureau. Moore:Glaxo Smith Kline: Speakers Bureau.

Download Full-text

Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01188-x ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Michael Wang ◽

Radhakrishnan Ramchandren ◽

Robert Chen ◽

Lionel Karlin ◽

Geoffrey Chong ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Tumor Lysis Syndrome ◽

Complete Response ◽

Clinical Activity ◽

Phase 3 ◽

Increased Risk ◽

Mantle Cell ◽

Data Informed

AbstractIbrutinib plus venetoclax, given with an ibrutinib lead-in, has shown encouraging clinical activity in early phase studies in mantle cell lymphoma (MCL). The ongoing phase 3 SYMPATICO study evaluates the safety and efficacy of concurrently administered, once-daily, all-oral ibrutinib plus venetoclax in patients with relapsed/refractory MCL. A safety run-in (SRI) cohort was conducted to inform whether an ibrutinib lead-in should be implemented for the randomized portion. Patients received concurrent ibrutinib 560 mg continuously plus venetoclax in a 5-week ramp-up to venetoclax 400 mg for up to 2 years. The primary endpoint was occurrence of tumor lysis syndrome (TLS) and dose-limiting toxicities (DLTs). The SRI cohort enrolled 21 patients; six and 15 were in low- or increased-risk categories for TLS, respectively. During the 5-week venetoclax ramp-up, three patients had DLTs, and one patient at increased risk for TLS had a laboratory TLS; no additional TLS events occurred during follow-up. With a median follow-up of 31 months, the overall response rate was 81% (17/21); 62% (13/21) of patients had a complete response. SRI data informed that the randomized portion should proceed with concurrent ibrutinib plus venetoclax, with no ibrutinib lead-in. Ibrutinib plus venetoclax demonstrated promising efficacy; no new safety signals were observed.Trial registration: ClinicalTrials.gov, NCT03112174. Registered 13 April 2017, https://clinicaltrials.gov/ct2/show/NCT03112174.

Download Full-text

Phase II Multicenter Study of Bendamustine Plus Rituximab in Patients With Relapsed Indolent B-Cell and Mantle Cell Non-Hodgkin's Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2008.17.0001 ◽

2008 ◽

Vol 26 (27) ◽

pp. 4473-4479 ◽

Cited By ~ 247

Author(s):

K. Sue Robinson ◽

Michael E. Williams ◽

Richard H. van der Jagt ◽

Philip Cohen ◽

Jordan A. Herst ◽

...

Keyword(s):

B Cell ◽

Mantle Cell Lymphoma ◽

Hodgkin’S Lymphoma ◽

Cell Lymphoma ◽

Complete Response ◽

Hodgkin's Lymphoma ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Mantle Cell ◽

Grade 3

PurposeBendamustine HCl is a bifunctional mechlorethamine derivative with clinical activity in the treatment of non-Hodgkin's lymphoma. This study evaluated bendamustine plus rituximab in 67 adults with relapsed, indolent B-cell or mantle cell lymphoma without documented resistance to prior rituximab.Patients and MethodsPatients received rituximab 375 mg/m2intravenously on day 1 and bendamustine 90 mg/m2intravenously on days 2 and 3 of each 28-day cycle for four to six cycles. An additional dose of rituximab was administered 1 week before the first cycle and 4 weeks after the last cycle. Sixty-six patients (median age, 60 years) received at least one dose of both drugs.ResultsOverall response rate was 92% (41% complete response, 14% unconfirmed complete response, and 38% partial response). Median duration of response was 21 months (95% CI, 18 to 24 months). Median progression-free survival time was 23 months (95% CI, 20 to 26 months). Outcomes were similar for patients with indolent or mantle cell histologies. The combination was generally well tolerated; the primary toxicity was myelosuppression (grade 3 or 4 neutropenia, 36%; grade 3 or 4 thrombocytopenia, 9%).ConclusionBendamustine plus rituximab is an active combination in patients with relapsed indolent and mantle cell lymphoma.

Download Full-text

One-Year Follow-up of ZUMA-2, the Multicenter, Registrational Study of KTE-X19 in Patients (Pts) with Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL)

Transplantation and Cellular Therapy ◽

10.1016/s2666-6367(21)00440-1 ◽

2021 ◽

Vol 27 (3) ◽

pp. S342

Author(s):

Michael L. Wang ◽

Javier Munoz ◽

Andre H. Goy ◽

Frederick L. Locke ◽

Caron A. Jacobson ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Mantle Cell ◽

One Year

Download Full-text

ECOG-ACRIN E1411 randomized phase 2 trial of bendamustine-rituximab (BR)-based induction followed by rituximab (R) ± lenalidomide (L) consolidation for Mantle cell lymphoma: Effect of adding bortezomib to front-line BR induction on PFS.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7503 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 7503-7503

Author(s):

Mitchell Reed Smith ◽

Opeyemi Jegede ◽

Peter Martin ◽

Brian G. Till ◽

Samir S. Parekh ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Progressive Disease ◽

Cell Lymphoma ◽

Induction Treatment ◽

Phase 2 ◽

Mantle Cell ◽

Grade 3 ◽

Ecog Ps ◽

Randomized Phase 2

7503 Background: Optimal initial therapy for mantle cell lymphoma (MCL) remains uncertain. The randomized phase 2 NCTN trial E1411 tested if progression-free survival (PFS) is prolonged by addition of bortezomib (V) (1.6 mg/m2 SC/IV days 1, 8) to bendamustine-rituximab (BVR vs BR) induction and/or by addition of lenalidomide (L) to rituximab (LR vs R) consolidation. Here we report efficacy and toxicity of induction BVR vs BR. Methods: 373 pts, accrued 2012–16, stratified by MIPI and age (≥60) received 1 of 4 arms: A) BR induction x 6 followed by R x 2 yrs, B) BVR followed by R, C) BR followed by LR or D) BVR followed by LR. Eligible pts had untreated MCL, ≥ age 18 (amended from ≥60 when S1106 for < 65 closed), ECOG PS 0-2 and adequate hematologic and organ function. Pts without progressive disease during induction proceeded to consolidation. Primary induction objective was whether adding bortezomib (BVR) (Arms B + D) to BR (Arms A + C) improves PFS, irrespective of consolidation R vs LR. Design of 360 eligible treated pts would provide 93.8% power to detect 10% improvement in 2-yr PFS from 70% hypothesized for BR, corresponding to 37.4% reduction in hazard using stratified log-rank test at 1-sided 10% alpha. Efficacy population was 179 (BVR) and 180 (BR), induction treatment completed in 144 vs 153, progressive disease during induction 6 vs 7 and registration to consolidation 140 vs 145. Results: Baseline demographics did not differ between the groups, with median age 67 (range 42-90) and 13% < 60 yr, 73% men, ECOG PS 0-1 97%, MIPI Low/Med/Hi 37/29/34%. Estimated PFS at 2 yrs 79.6% BVR (95% CI 73.8-85.9) vs 74.5% BR (95% CI 68.2-81.4) (1-sided stratified log-rank p = 0.268). With median PFS follow-up 51 mos, median PFS estimated at 64.1 and 64.0 mos. Overall response rate (ORR) for BVR was 88.9% (CR 65.5%) vs 89.5% (CR 60.5%) BR (z-test 1 sided p = 0.577 for ORR). Treatment related deaths during induction were 2 in BVR (cardiac arrest, hepatitis) and 1 in BR (tumor lysis). Grade ≥ 3 toxicities were 88.1% (163/185) BVR vs 77.5% (145/187) BR. For BVR vs BR grade ≥ 3 neutropenia occurred in 52 vs 39 pts, though febrile neutropenia (7 vs 6), anemia (7 vs 8) and thrombocytopenia (18 vs 16) did not differ. Peripheral neuropathy (PN) grade 2 was 8 sensory for BVR vs 2 sensory/1 motor for BR, while grade 3 PN was 6 sensory/1 motor for BVR vs 0 with BR. The only non-hematologic grade ≥ 3 toxicity in > 5% of pts was rash (9 vs 12 pts). Conclusions: Bortezomib did not significantly improve the primary endpoint of PFS when added to BR as initial MCL therapy. ORR and CR rates at end of induction were also similar. Follow-up continues to assess the entire treatment regimen, including consolidation R vs LR, but the PFS > 5 yrs, high ORR and MRD negativity rate (Smith et al ASH 2019) in this BR-based trial support BR as a platform for MCL induction therapy. Clinical trial information: NCT01415752.

Download Full-text

Efficacy and Safety of Thalidomide In Mantle Cell Lymphoma: Results of the French ATU Program.

Blood ◽

10.1182/blood.v116.21.1794.1794 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1794-1794 ◽

Cited By ~ 3

Author(s):

Stéphanie Harel ◽

Emmanuel Bachy ◽

Corinne Haioun ◽

Emmanuel Gyan ◽

Gandhi Damaj ◽

...

Keyword(s):

Adverse Events ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Stage Iv ◽

Efficacy And Safety ◽

Mantle Cell ◽

Male Sex ◽

Grade 3 ◽

Experienced Grade

Abstract Abstract 1794 Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that represents approximately 8% of lymphoma cases. Up-front treatment with intensive chemotherapy and autologous stem cell transplantation (ASCT) for younger patients has demonstrated improvement in prognosis and outcome but virtually all patients experience relapse. Thalidomide is an antiangiogenic and immunomodulatory drug whose mechanism of action is unclear. Promising results were reported but only on small series, with a limited median follow up. Thalidomide in France is currently not approved in this indication, but its use is allowed by French authorities (AFSSAPS) after reviewing unique patient medical chart, mainly indication (relapsed/refractory MCL) and absence of appropriate alternative treatment. There is no other inclusion or exclusion criteria based on past medical history or biological findings. Authorization has to be confirmed every 3 months, based on efficacy and safety data. Patient informed consent was required prior to inclusion. Overall, 58 patients (pts) with available data were included in this program between 06/2001 and 09/2009. There were 38 males and 20 females. At time of diagnosis, median age was 62.8 years (range 39.2–77.9); 89.5% of pts had PS £ 1; 89.7% presented with stage IV, including 78.9% with documented bone marrow involvement, 61.4% with leukemic phase and 28% with gastro-intestinal involvement. Before Thalidomide, pts received a median of 2 lines of chemotherapy (range 1–5), including ASCT for 39. All but 6 received prior Rituximab. Median time between diagnosis and start of Thalidomide was 41.8 months (range 3.5–196.8) and 2.1 months between last line of chemotherapy and Thalidomide (range 0–126.8). At time of inclusion, median age was 66.8 years (43.9-82.7); 86.2% of pts presented with stage IV and 18 (31%) with PS > 1. Thalidomide was administrated alone in 19 patients (32.7%), associated with Rituximab (n=19; 32.7%), Bortezomib (n=5; 8.6%), or both (n=9; 15.5%), or with others treatments (n=8; 13.8%). Initial dosage was 200 mg/d for 24 patients or less (100 or 50 mg/d) for 33 patients (unknown for 1 pt), according to physician decision. Grade 1–2 adverse events included fatigue, constipation and neuropathy as previously described with Thalidomide. Three pts experienced grade 3 neuropathy. There were 6 events related to thromboembolism (deep-vein thrombosis: n=5; stroke: n=1). Hematological toxicity consisted in 4 pts with grade 3 neutropenia, including 2 with febrile neutropenia. A patient experienced severe hepatitis but link with thalidomide was doubtful. Overall, 7.3% of pts experienced grade 3–4 adverse events. Finally, 13 pts discontinued Thalidomide because of toxicity, including 6 who received Rituximab and Bortezomib. The overall response rate (CR + PR) was 50%, with 12 pts (20.7%) who achieved a CR and 17 pts (29.3%) a PR, 17 pts (29.3%) had stable disease and 12 (20.7%) progressive disease. Median time to response was 3 months (range 1–8). Median follow-up was 41.3 months. For the entire cohort, 1-y TTF and OS rates were 29.3% (95% CI: 17.4–41.3) and 61.9% (95% CI: 49.0–74.8) respectively; 2-y TTF and OS rates were 10.9% (95% CI: 2.2–19.6) and 49.6% (95% CI: 36.0–63.2) respectively. In univariate analysis, factors predictive for better OS were male sex (p=0.037), stage < 4 (p=0.043), PS 0–1 (p<0.001), time since last treatment > 6 months (p=0.004) and addition of Rituximab (p=0.013). Addition of Bortezomib was not predictive for OS. LDH, leukocytes count at time of inclusion and Thalidomide dosage (200 mg/d) were only predictive for better TTF (respectively p=0.014; 0.008 and 0.041). In multivariate analysis, male sex (p=0.002), stage <4 (p=0.025), PS 0–1 (p<0.001) and time since last chemotherapy > 6 months (p=0.010) showed prognostic relevance for OS. In conclusion, in this cohort of unselected patients, efficacy of Thalidomide compare favorably with currently approved drugs for relapsed MCL such as Bortezomib (ORR : 33%, median duration of response : 9.2 months) or Temsirolimus (ORR : 22%, median PFS : 4.8 months), with less toxicity. This efficacy is comparable with others Imids such as Lenalidomide with a trend to less toxicity and a better side effect profile, justifying its use with Rituximab for relapsed MCL as well as in a maintenance schedule. Disclosures: No relevant conflicts of interest to declare.

Download Full-text