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

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.

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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.

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First-line treatment with Bendamustine plus Rituximab for patients with indolent non-Hodgkin’s lymphoma or Mantle cell lymphoma: Real-world experience.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e19540 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e19540-e19540

Author(s):

Rouslan Kotchetkov ◽

David Susman ◽

Lauren Gerard ◽

Erica DiMaria ◽

Derek Wayne Nay

Keyword(s):

Adverse Events ◽

Hodgkin’S Lymphoma ◽

Cell Lymphoma ◽

Hodgkin's Lymphoma ◽

First Line ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Mantle Cell ◽

Grade 3

e19540 Background: Bendamustine plus rituximab (B+R) was established as a preferred first line therapy for patients with previously untreated indolent non-Hodgkin’s lymphoma based on the BRIGHT and STIL trials. However, only few reports on efficacy and safety data of this combination in the real-world setting are available to-date. Methods: We conducted a retrospective review of patients who received therapy with standard doses of B+R in our cancer center from June 2013 to January 2021. Patients with indolent non-Hodgkin’s lymphoma (iNHL) and mantle cell lymphoma (MCL) who received more than one cycle of B+R were evaluated. Results: Amongst a total of 201 patients 56% were males and 44% females. Median age at B+R initiation was 72 years (range 34-94). Follicular lymphoma (FL) (50.3%), marginal zone lymphoma (MZL) (19.4%), and lymphoplasmacytic lymphoma (LPL) (14.5%) were the most common iNHL. Stage 3 and 4 diseases represented 19.9% and 68.6% of patients. Extranodal disease was found in 35.8%. The proportion of patients with high risk disease was 48.5% for FL (FLIPI ≥3), 86.6% for LPL (WMISS score ≥2), and 80.5% for MCL (MIPI score ≥6.2). Prior history of secondary malignancy had 23.4% of patients; 11.4% patients had ECOG 3. Most common indications for B+R initiation were bulky symptomatic lymphadenopathy (69.1%), cytopenia (36.8%) and constitutional symptoms (36.8%). Fifty-eight percent of patients had more than one indication for therapy. Median number of B+R cycles delivered was 6 (range: 1-6), median dose of bendamustine was 90 mg/m2 (range 45-90). Full doses of treatment were given in 66.7% of patients, reduced in 33.3% with mean dose 78.3 mg/m2. A total of 50.8% completed 6 cycles with no delays, in 49.2% treatment was delayed (mean delay time 1.8 weeks). Overall response was 94.5%, with 77.6% complete and 16.9% partial remission. Median duration of follow-up was 35 months (range: 4-91). At the end of follow-up, event free survival (EFS) was 77.1% and overall survival (OS) was 79.6%. Six percent of patients relapsed, 8% developed secondary hematological malignancies, including 14 cases of aggressive B-cell lymphoma and 2 cases of MDS. 16.9% of patients required support with G-CSF. Grade 3-4 neutropenia was recorded in 22.4%, febrile neutropenia in 7.5%, grade 3-4 anemia in 7.9%, and grade 3-4 thrombocytopenia in 3.9% of patients. Rituximab-associated infusion reactions, skin rash, thrombophlebitis, and infection were the most common non-hematological adverse events. A total of 80.6% of patients proceeded to rituximab maintenance. Conclusions: B+R chemoimmunotherapy is feasible to administer in non-clinical trial setting. Despite more dose reduction as compared to STIL trial, B+R retained its efficacy with comparable EFS and OS. No new adverse events or increase in secondary malignancies were found.

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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.

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Updated Efficacy and Safety, and Exploratory Ki-67 Results For The MCL-001 Study Of Lenalidomide In Mantle Cell Lymphoma Patients Who Relapsed Or Were Refractory To Bortezomib

Blood ◽

10.1182/blood.v122.21.3057.3057 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3057-3057 ◽

Cited By ~ 2

Author(s):

Andre Goy ◽

Michael E. Williams ◽

Sevgi Kalayoglu Besisik ◽

Johannes Drach ◽

Radhakrishnan Ramchandren ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

High Dose ◽

Efficacy And Safety ◽

High Dose Therapy ◽

Ki 67 ◽

Mantle Cell ◽

Heavily Pretreated

Abstract Introduction Patients with mantle cell lymphoma (MCL) typically respond to initial therapy and almost inevitably relapse with frequent chemoresistance over time and poor outcome. Multiple phase II studies have established the efficacy and safety of lenalidomide, an immunomodulatory agent with tumoricidal and antiproliferative properties, in relapsed/refractory MCL. The prospective phase II multicenter MCL-001 “EMERGE” study led to FDA approval of lenalidomide for patients with relapsed/refractory MCL after 2 prior treatments, that included bortezomib. The activity of lenalidomide was seen regardless of MIPI, number of prior therapies, prior high dose therapy, bulky disease or high tumor burden. One of the most established prognostic factors in MCL is the proliferation index Ki67 (MIB1), now confirmed both in standard and dose-intensive high-dose therapy strategies. We present here longer follow-up of efficacy and safety from the MCL-001 study in patients relapsed/refractory to bortezomib and the potential relationship between Ki-67 and efficacy outcomes. Methods Patients with heavily pretreated MCL, that included prior bortezomib, received lenalidomide 25 mg/day PO, days 1-21 in 28-day cycles until disease progression or intolerability. Primary study endpoints were overall response rate (ORR) and duration of response (DOR); secondary endpoints included complete response (CR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and safety. Response rates and time-to-event data were analyzed by independent central reviewers per modified IWG criteria and Kaplan-Meier estimates respectively (data cut-off March 20, 2013). Ki-67 was examined as an exploratory endpoint by immunohistochemistry for 81/134 patients (60%) either performed on biopsy samples for 24 patients, or based on the Ki-67 scores reported in local pathology reports for 57 patients. Results Median age for the enrolled intent-to-treat patient population (N=134) was 67 years (range, 43-83; 63% ≥65 years). The median number of previous therapies was 4 (range, 2-10; 78% received ≥3), 93% stage III/IV, and 72% were <6 months from last prior treatment. At a median follow-up of 13.2 months, the ORR was 28% (CR/CRu 8%), with a median DOR of 16.6 months (95% CI, 9.2-26.7; median not reached in patients with CR/CRu) by central review. Median TTR was 2.3 months (95% CI, 1.7-13.1), with a median time to CR/CRu of 4.1 months (95% CI, 1.9-13.2). Median PFS was 4.0 months (95% CI, 3.6-6.9), and median OS was 20.9 months (95% CI, 13.7-24.4). The average dose intensity of lenalidomide was 20 mg/day, for a median duration of 94.5 days (range, 1-1,256). Dose reductions or interruptions due to adverse events (AEs) occurred in 40% and 58% of patients, respectively. Neutropenia (44%), thrombocytopenia (28%), and anemia (11%) were the most common treatment-related grade 3/4 AEs. Ki-67 results were available in 81/134 patients, and efficacy data were categorized using 30% and 50% cut-off thresholds for Ki-67 expression (Table 1). Although patient numbers were limited, the ORR was similar in both lower and higher Ki-67 group, but those with lower Ki-67 levels demonstrated better CR rates, DOR and survival outcomes compared with patients with elevated Ki-67. Conclusions Single-agent lenalidomide in heavily pretreated patients with relapsed/refractory MCL post-bortezomib showed durable long-term efficacy with a consistent safety profile. Consistent with what is reported in the literature, high Ki-67 is associated with poor outcome in our cohort with shorter OS. Though based on retrospective evaluation and subsets of patients, the ORR to lenalidomide was similar in both low and high Ki-67 groups, suggesting lenalidomide can be active in patients expressing high levels of Ki67. Prospective studies are needed to confirm these findings. Disclosures: Goy: Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Williams:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Drach:Celgene: Honoraria. Ramchandren:Celgene: Research Funding. Zhang:Celgene: Employment. Cicero:Celgene: Employment. Fu:Celgene: Employment. Heise:Celgene: Employment, Equity Ownership. Witzig:Celgene: Research Funding.

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Safety Results from the United States Cohort of the Ibrutinib Early Access Treatment Protocol (EAP: MCL4001) in Patients with Relapsed or Refractory Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v124.21.4461.4461 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4461-4461

Author(s):

Peter Martin ◽

Andre Goy ◽

Radhakrishnan Ramchandren ◽

Lucille Ferrante ◽

Vijay Reddy ◽

...

Keyword(s):

Adverse Events ◽

Mantle Cell Lymphoma ◽

Progressive Disease ◽

Cell Lymphoma ◽

Serious Adverse Events ◽

Major Hemorrhage ◽

Once Daily ◽

Mantle Cell ◽

The Us ◽

Grade 3

Abstract Background: Bruton’s tyrosine kinase (BTK) is a critical signaling molecule in the B-cell receptor pathway. Ibrutinib is a first-in-class, once daily, oral covalent inhibitor of BTK that was approved in the US (November 2013) based on an international multi-center Phase 2 study in patients with relapsed or refractory mantle cell lymphoma (MCL), with an ORR of 68% (CR 21% and PR 47%) and median progression free survival of 13.9 months (Wang et al. NEJM 2013). This EAP was conducted in a similar patient population to provide access to ibrutinib prior to market authorization and to collect additional safety data. The results of the US cohort are reported here. Methods: This was an open-label EAP in patients with relapsed or refractory MCL, who resided in areas where ibrutinib was not available and were ineligible for ongoing ibrutinib trials. Key entry criteria were as follows: age ≥ 18 years, relapsed or refractory MCL, and no prior ibrutinib therapy. Patients received ibrutinib 560mg orally once daily in 28 day cycles until progressive disease, unacceptable toxicity, no further benefit or end of study (US approval). Adverse events (Grade ≥ 3), serious adverse events, and adverse events of interest (major hemorrhage, intracranial hemorrhage) were collected. Results: In total,149 patients participated in the EAP at 46 US sites from May 2013 to April 2014. Median age was 68 years (range: 39-90 years) and 89% were white. Median treatment exposure was 3.65 months (range: 0.0-7.7 months), with approximately 26% of patients receiving treatment for more than 6 months. Of the 149 patients, 58.5% had refractory disease and 66.7% had received ≥3 prior lines of therapy. Adverse events grade ≥3 were reported in 59 patients (39.6%), the most common of which were neutropenia (6.7%), dyspnea (4%), anemia (3.4%) and thrombocytopenia (3.4%). Serious adverse events were reported in 46 patients (30.9%). Adverse events of interest were reported in two patients (1.3%): 1 major hemorrhage (0.7%) and 1 intracranial hemorrhage (0.7%). Ten patients (6.7%) discontinued treatment due to adverse events. The primary reason for discontinuation was progressive disease in 20 patients (13.4%) and death in 12 patients (8.1%). The majority of patients (66%) continued on therapy until the end of study (US approval). Conclusions: The safety profile observed in this US cohort of the EAP was consistent with that observed during the registration trial for MCL. No new safety signals were observed in this predominantly refractory population of patients. Moreover, this EAP provided an important mechanism for patients to receive ibrutinib prior to US approval. Disclosures Martin: Janssen: Honoraria. Ferrante:Janssen Scientific Affairs, LLC: Employment. Reddy:Janssen Scientific Affairs, LLC: Employment. Londhe:Janssen Scientific Affairs, LLC: Employment. Wildgust:Janssen Global Services: Employment. McGowan:Janssen Scientific Affairs, LLC: Employment.

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Salvage Treatment with Lenalidomide and Dexamethasone in Patients with Relapsed Refractory Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v114.22.1713.1713 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1713-1713

Author(s):

Francesco Zaja ◽

Stefano De Luca ◽

Umberto Vitolo ◽

Lorella Orsucci ◽

Alessandro Levis ◽

...

Keyword(s):

Adverse Events ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Response To Treatment ◽

Induction Phase ◽

Preliminary Evaluation ◽

Safety And Efficacy ◽

Off Label ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 1713 Poster Board I-739 Introduction: Previous reports have highlighted the activity of Lenalidomide (Len) in patients with relapsed or refractory mantle cell lymphoma (MCL), achieving a 53% overall response rate (ORR), which included 20% complete responses (CR) (Haberman et al. Br J Haematol. 2009). In vitro studies on Burkitt's Lymphoma and MCL cell lines showed that combining Dexamethasone (Dex) with Len results in potent and synergistic anti-proliferative effects. To assess whether this effect translates to a clinical setting, and on the basis of data coming from multiple myeloma, we initiated a prospective, multicenter, phase II study, to evaluate safety and efficacy of Len administered in combination with Dex for adult patients with relapsed or refractory MCL. Methods: Patients had to have ≥1 prior treatment regimen, and were either not eligible for, or had relapsed after, more intensive treatments including stem cell transplantation (SCT). During the induction phase (month 1 to 3), patients received Len 25 mg/day on days 1 to 21 and Dex 40 mg/day on days 1, 8, 15, 22 of a 28-day cycle (Len Dex). Enoxiparin 4.000 U/day was administered as anti-thrombotic prophylaxis. Patients who achieved a partial response (PR) or stable disease (SD) at the end of the induction phase continued to the consolidation phase, which consisted of treatment with Len Dex until disease progression, unacceptable toxicity, or a CR, for a maximum of 12 months. Patients with a CR at the end of the induction phase, or those who achieved a CR during consolidation, received an additional 3 courses of Len Dex. The primary objective is to evaluate the ORR and CRR (IWG criteria Cheson et al 2007). Secondary objectives include safety, response duration (RD), overall survival (OS), and to explore changes in tumour biomarkers relative to response to treatment with Len Dex. Severity of adverse events (AE) is graded on a scale of 1 to 5 (NCI CTCAE v.3). Results: Between July 2008 and July 2009, 33 patients were enrolled on this study, representing the intent to treat population. Patients' median age is 68 years (range 51-80); 30 have the classic histology while 3 patients have the blastoid variant; 9 patients previously received two lines of therapy, 9 patients had three lines and 12 patients had >3 prior lines (median 3; range 1-7). Twelve patients previously underwent an autologous SCT and 7 received prior therapy with Bortezomib. At present, 21 out 33 enrolled patients are evaluable for response to the induction phase of the study: 11 patients responded to Len Dex (52% OR), including 3 CRs (14%); 1 patient (5%) has SD and 9 patients (43%) either had not responded or had progressed while on study. Nine patients discontinued treatment for the following reasons: skin reaction in 1 patient, progression in 7 patients, 1 patient died while on study. So far, 28 patients are valuable for safety during the induction phase. Most common Grade 3-4 adverse events were hematologic and included leucopenia (n=6; 21%), neutropenia (n=10; 36%), thrombocytopenia (n=4; 14%) and anemia (n=1; 3%). Other events included 3 patients (10%) with grade 3-4 neutropenic fever and 2 patients (7%) with grade 3 bacterial pneumonia. Grade 3-4 hypotension and dyspnea developed in 1 patient each, and none of the patients developed thromboembolic or neuropathic complications. Initial results from this study confirm the high therapeutic activity of Len in patients with relapsed and refractory MCL. Conclusions: Preliminary evaluation of the safety and efficacy of the Len Dex regimen indicates that the combination has a favourable safety profile, but the addition of Dex does not appear to substantially improve the activity of Len in the treatment of patients with relapsed or refractory MCL. Disclosures: Off Label Use: Lenalidomide is off label for treatment of Non Hodgkin Lymphoma.. Vitolo:Celgene: Lecture fees.

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Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma

Blood ◽

10.1182/blood-2018-07-859769 ◽

2018 ◽

Vol 132 (19) ◽

pp. 2016-2025 ◽

Cited By ~ 34

Author(s):

Jia Ruan ◽

Peter Martin ◽

Paul Christos ◽

Leandro Cerchietti ◽

Wayne Tam ◽

...

Keyword(s):

Adverse Events ◽

Maintenance Therapy ◽

Mantle Cell Lymphoma ◽

Initial Treatment ◽

Cell Lymphoma ◽

Chronic Therapy ◽

Key Points ◽

Mantle Cell

Key Points Lenalidomide plus rituximab as induction and maintenance therapy for MCL can achieve durable MRD-negative complete remissions. Chronic therapy–associated adverse events are generally nonaccumulative and remain manageable.

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Phase I Trial of Rituximab, Cladribine and Temsirolimus (RCT) for Initial Therapy of Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v120.21.3661.3661 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3661-3661 ◽

Cited By ~ 1

Author(s):

David J. Inwards ◽

Paul Fishkin ◽

Betsy R. LaPlant ◽

Matthew T. Drake ◽

Paul Kurtin ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Mantle Cell Lymphoma ◽

Dose Level ◽

Cell Lymphoma ◽

Maximum Tolerated Dose ◽

Hematologic Toxicity ◽

Mantle Cell ◽

Grade 3 ◽

Dose Levels

Abstract Abstract 3661 Objective: We conducted this trial to determine the maximum tolerated dose (MTD) and schedule of temsirolimus added to an established regimen comprised of rituximab and cladribine for the initial treatment of mantle cell lymphoma and to generate preliminary information on the toxicity and efficacy of this combination. Methods: A standard phase I cohort of 3 study design was utilized. MTD was defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). DLT was defined as grade 4 ANC (<500) for ≥5 days, grade 4 ANC (<500) associated with fever (>100.5 F) and/or active infection, PLT <25,000, grade 4 infection, or ≥grade 3 non-hematologic toxicity during the first cycle of therapy as per NCI Common Terminology Criteria for Adverse Events v3.0. The fixed doses of rituximab and cladribine were 375 mg/m2 IV day 1 and 5 mg/m2/d IV days 1–5 of a 28 day cycle, respectively, as previously published. There were 5 planned temsirolimus IV dose levels: 15 mg day 1; 25 mg day 1; 25 mg days 1 and 15; 25 mg days 1,8 and 15; and 25 mg days 1,8,15, and 22. The fifth dose level is as previously published in combination with rituximab. Results: A total of 17 patients were treated: 3 each at dose levels 1–4 and 5 at dose level 5 (25 mg temsirolimus days 1,8,15, and 22). The median age was 75 years (52–86). There were 11 males and 6 females. At presentation 88% had stage IV disease, and 94% had extranodal disease. MIPI scores were low in 6% (1 patient), intermediate in 59% (10 patients), and high in 35% (6 patients). There was a single DLT recorded at dose level 3 based on the initial DLT criteria, though this cytokine release syndrome was clearly rituximab related, and occurred prior to the first dose of temsirolimus. Five patients were treated at the highest planned temsirolimus dose level (25 mg days 1,8,15, and 22) with no DLT observed. No further dose escalation was planned, and this level was determined to be tolerated, though higher levels may be tolerable. All patients were evaluable for adverse events. Hematologic toxicity was frequent, with grade 3 anemia in 12% of patients, grade 3 thrombocytopenia in 35%, grade 4 thrombocytopenia in 30%, grade 4 lymphopenia in 47%, grade 3 neutropenia in 24%, and grade 4 neutropenia in 18% of patients. There were 3 thrombotic episodes, 2 of which were attributed to therapy, and 3 episodes of pneumonitis. The overall response rate was 94% with 53% CR and 41% PR. The median progression free survival was 18.7 months. Conclusions: Temsirolimus 25 mg IV weekly may be safely added to rituximab and cladribine at 375 mg/m2 IV day 1 and 5 mg/m2/d IV days 1–5 of a 28 day cycle, respectively. This regimen had promising preliminary activity in an elderly cohort of patients with mantle cell lymphoma. Disclosures: Off Label Use: Temsirolimus for mantle cell lymphoma.

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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.

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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.

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