Rituximab Plus Bendamustine and Cytarabine (R-BAC) in Elderly Patients with Newly Diagnosed Mantle Cell Lymphoma: Long Term Follow-up and Mrd Results of a Phase 2 Study from the Fondazione Italiana Linfomi

Abstract The activity of the combination of rituximab, bendamustine, and low dose cytarabine (R-BAC) was evaluated in a phase 2 multicentre trial from the Fondazione Italiana Linfomi (FIL RBAC500) in previously untreated patients with mantle cell lymphoma (MCL) who were not eligible to stem cell transplant. Maintenance treatment was not planned after induction therapy, and no patient in the study received rituximab maintenance. Fifty-seven patients (median age 71 years, range 61-79) were recruited and treated with 4 to 6 cycles between 2012 and 2014. Despite some concern in terms of hematological toxicity, the R-BAC regimen was associated with high complete remission (CR) rate (91%), 2-years overall survival (OS) of 86% (74-93), and 2-years progression free survival (PFS) of 81% (68-89). Here, we present long-term survival outcomes. After 7 years of median follow-up (86 months, range 57-107), the median OS and PFS for all patients were not reached (Figure 1A and 1B). The 7-years PFS and OS rates were 56% (95%CI 41-67) and 63% (95%CI 46-72), respectively. Patients who achieved CR (n=53) had a 7 years PFS of 59% (95% CI 44-71), with the curve that appears to plateau after 6 years. Adverse predictive factors affecting PFS were blastoid morphology (p<0.05), elevated Ki67 > 30% (p<0.05), and failure to achieve CR after 2 cycles (p=0.03). Early-progression of disease (<24 months from start of R-BAC) was associated with impaired overall survival (p<0.05). Eight patients (14%) developed a secondary neoplasia: 1 parotid heteroplasia, 1 parotid nodular hyperplasia, 1 prostate cancer, 1 bladder cancer, 1 larynx, 1 thyroid cancer, 1 lung cancer and 1 secondary acute myeloid leukemia. Among the 25 relapsed patients, 8 did not receive any other treatment. Six had Ibrutinib monotherapy as second line, of whom 4 responded (3 are still in CR), 4 had CHOP or CHOP-like regimens with only partial responses. As per protocol, 31 patients with molecular marker at diagnosis and available samples were followed-up for minimal residual disease (MRD) with ASO-droplet digital polymerase chain reaction (D-PCR). Patients with MRD persistence at the end of induction, either in peripheral blood or bone marrow, had significantly worse 7 years-PFS (p<0.05 for them both). In conclusion, in elderly patients with newly diagnosed MCL, R-BAC showed sustained efficacy over time, which compared favorably with any other reported immuno-chemotherapy regimen (with or without maintenance) in similar populations. With a median OS exceeding 60% after 7-years this regimen has significantly impacted on the life-expectancy of elderly patients with MCL. Figure 1 Figure 1. Disclosures Tisi: Incyte: Membership on an entity's Board of Directors or advisory committees; BWS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nassi: Takeda: Consultancy; Incyte: Consultancy; Kyowa Kirin: Consultancy; Roche: Consultancy. Ferrero: Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Clinigen: Membership on an entity's Board of Directors or advisory committees. Zilioli: Takeda: Other: travel expenses, accommodation; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Roche, Italfarmaco: Consultancy, Honoraria; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau. Merli: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; MSD: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; EUSA Pharma: Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses.

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Bortezomib, Dexamethasone and Rituximab in Newly Diagnosed Patients with WaldenströM's Macroglobulinemia: Final Analysis of a Phase 2 Study after a Minimum Follow up of 6 Years

Blood ◽

10.1182/blood.v128.22.2957.2957 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2957-2957 ◽

Cited By ~ 1

Author(s):

Maria Gavriatopoulou ◽

Ramon Garcia-Sanz ◽

Efstathios Kastritis ◽

Pierre Morel ◽

Marie-Christine Kyrtsonis ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Death Rate ◽

Research Funding ◽

Primary Therapy ◽

Phase 2 ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Waldenström macroglobulinemia (WM) is a rare low grade lymphoma, with a prolonged course. With a median survival exceeding 7 years, prolonged follow up is needed in order to evaluate the outcomes of patients with WM after a specific primary therapy. Anti-CD20 monoclonal antibodies, such as rituximab, remain cornerstones of WM therapy, usually in combination with alkylating agents. Bortezomib is a proteasome inhibitor which has shown activity in myeloma but also has shown significant activity, especially in terms of rapid IgM reduction, in patients with relapsed/refractory or treatment naïve WM. Clinical and preclinical data have indicated potential synergistic activity for the combination of bortezomib and rituximab. Thus, in a large phase 2 trial we evaluated the activity of the chemotherapy free combination of bortezomib with dexamethasone and rituximab (BDR) in 59 newly diagnosed patients with WM fulfilling the contemporary criteria for diagnosis and treatment initiation. Here we present the results from the long term follow up of this study, focusing on long term outcomes and long term toxicity, after a minimum follow up of 6 years. A total of 5 cycles of therapy with BDR were planned. In order to manage complications that are associated with high IgM levels, reduce the need for plasmapheresis and the risk and severity of rituximab-associated "IgM flare", single-agent intravenous (iv) bortezomib at a dose of 1.3 mg/m2 was administered on days 1, 4, 8, and 11 of the first 21-day cycle. On cycles 2 to 5, bortezomib was administered IV weekly at a dose of 1.6 mg/m2 on days 1, 8, 15, and 22 in four 35-day consecutive cycles. On cycles 2 and 5, IV dexamethasone 40 mg and IV rituximab at a dose of 375 mg/m2 were given on days 1, 8, 15, and 22 (total of 8 infusions of rituximab). Fifty-nine patients were treated with BDR from March 2007 until June 2010. The characteristics of the patients, response rates and toxicity have been published previously (Dimopoulos MA, et al Blood. 2013 Nov 7;122(19):3276-82). Briefly, most patients had advanced age (61% were >65 years) and advanced disease with adverse prognostic factors such as, anemia (hemoglobin <11.5 g/dL in 82%) and elevated β2-microglobulin (≥3 mg/dL in 64%), so that 45.5% and 40% were rated as high and intermediate risk per the International Prognostic Scoring System for WM. On intent to treat, 85% of the patients responded [3% complete response (CR), 7% very good partial response (VGPR), 58% partial response (PR), 17% minor response (MR)] for a major response rate (≥PR) of 68%. Median follow up is86 months (range 0.6- 112). At 7 years 40 patients (68%) had disease progression or died due to WM, while 9 patients (15%) died due to unrelated causes without progression. Median progression-free survival (PFS) was 43 months (95% CI 23-63) and 10 patients (17%) still remain in remission after a median of 90 months (range 73.5-112). As per ISSWM stage PFS at 7-years was 62.5%, 42% and 15% for patients with low, intermediate and high risk disease respectively. Median duration of response for patients who achieved at least PR was 64.5 months. Among the 40 (68%) patients with disease progression or relapse, 21 (35.5%) received second line treatment. Up to the date of data cutoff (June 2016), 20 patients (34%) have died and accounting for WM-unrelated death as a competing event, WM-related death rate at 7 years was 18.5% and unrelated death rate was 15.5%. Overall survival (OS) rate at 7-years was 66% and OS rate was 87.5% for low, 68.2% for intermediate and 48% for high risk patients per ISSWM. No patient has developed secondary MDS and transformation to DLBCL occurred in 2 (3.3%) patients, who had received chemo-immunotherapy after BDR. In conclusion, BDR is a very active regimen, well tolerated and, importantly, with favorable long term toxicity profile. Primary therapy with this chemotherapy- free regimen, which was completed in 23 weeks, induced durable responses in newly diagnosed symptomatic WM patients with approximately 17% of patients still remaining in response after 7 years. Our data support the use of BDR as one of the recommended regimens for the treatment of this disease WM. Disclosures Kastritis: Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Genesis: Consultancy, Honoraria. Kyrtsonis:Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leleu:Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; TEVA: Membership on an entity's Board of Directors or advisory committees. Palladini:Prothena: Honoraria. Merlini:Takeda and Janssen-Cilag: Honoraria. Dimopoulos:Genesis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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High Efficacy of Lenalidomide Plus R-CHOP (R2CHOP) Combination in First Line Treatment of Activated B-Cell (ABC) DLBCL Defined Using Gene-Expression Prophyling: A Combined Analysis from Two Phase 2 Trials

Blood ◽

10.1182/blood-2018-99-119495 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2962-2962 ◽

Cited By ~ 1

Author(s):

Alessia Castellino ◽

Annalisa Chiappella ◽

Betsy Laplant ◽

Levy D. Pederson ◽

Giorgio Inghirami ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

International Prognostic Index ◽

Prognostic Index ◽

Phase 2 ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Introduction: Lenalidomide (Len) in association with standard Rituximab-CHOP (R2CHOP21) has been shown to be safe and effective in newly diagnosed Diffuse Large B-cell Lymphomas (DLBCL) [Nowakowski et al. JCO 2014, Vitolo et al. Lancet Oncol 2014]. The addition of lenalidomide appears to benefit primarily patients with non-Germinal Center B-cell (non-GCB) phenotype as determined by immunohistochemistry (IHC). These early results led to currently ongoing randomized trial in ABC subtype of DLBCL, however efficacy of R2CHOP in ABC DLBCL as defined by Gene Expression Prophyling (GEP) has not been reported. In the present combined analysis of two independent phase 2 studies, we report the long-term follow-up (FU) outcome in DLBCL patients treated with R2CHOP, comparing GCB and ABC according to Nanostring Platform. Methods: We included all newly diagnosed histologically-confirmed de-novo DLBCL patients enrolled in two R2CHOP21 phase 2 trials, conducted by Mayo Clinic (MC) and Italian Lymphoma Foundation (FIL). Inclusion criteria in the two trials were similar, main differences included: all age and all International Prognostic Index (IPI) vs age between 60 and 80 years old and IPI >1, in MC vs FIL study, respectively. All pts received R-CHOP21 plus Len at 25 mg/day for 10 days/cycle and 15 mg/day for 14 days/cycle in MC and FIL trial, respectively. Cell of origin (COO) was determined by IHC, according to Hans algorithm, and retrospectively, in patients with available pathological material, by Nanostring, performed according to Scott algorithm and Masque-Soler signature in MC and FIL study, respectively. We analyzed the long-term FU outcome in terms of progression-free survival (PFS), time to progression (TTP), overall survival (OS), comparing between GCB and ABC phenotypes according to GEP. Results: A total of 112 DLBCL pts (63 MC, 49 FIL) were included. Main characteristics were: median age 69 years (y) (range 22-87), male 65 (58%) pts, advanced stage III-IV in 94 (84%), B symptoms in 38 (34%), International Prognostic Index (IPI) intermediate-high/high in 71 (63%). At a median follow-up of 5.1 years (y), 5y-PFS was 63.5%, 5y-TTP 70.1% and 5y-OS 75.4%. A total of 32 relapses were observed, with only 2 cases of Central Nervous System (CNS) relapse. Late relapse occurring beyond 3 years was observed in 4 cases (3 cases with GCB phenotype and one case with missing COO data). In a subgroup analysis by IPI 0-2 vs 3-5 were: 5y-PFS, 5y-TTP and 5y-OS were: 69.0% vs 59.0% (p=0.100), 73.2% vs 67.4% (p=0.285) and 82.3% vs 70.2% (p=0.059), respectively. Regarding for COO defined by IHC, GCB phenotype vs non-GCB were 45 (40%) vs 41 (37%) patients respectively; 26 (23%) patients were not evaluable. 5y-PFS, 5y-TTP and 5y-OS were: 52.8% vs 64.5% (p=0.198), 61.6% vs 69.6% (p=0.444) and 68.6% vs 74.1% (p=0.238) in GCB vs non-GCB, defined by IHC, respectively. Regarding Nanostring analysis, GCB vs ABC vs Unclassified (Uncl) were 31 (46%) vs 22 (32%) vs 15 (22%) respectively; 44 pts were not evaluable. 5y-PFS, 5y-TTP and 5y-OS were: 62.3% vs 70.8% vs 64.2% (p=0.645), 68.1% vs 79.8% vs 64.2% (p=0.662) and 76.0% vs 74.8% vs 79.0% (p=0.658) in GCB vs ABC vs Uncl, defined by Nanostring, respectively (Table1, Fig1). Conclusions: The association of Len with R-CHOP21 appears to overcome the negative prognostic impact of ABC phenotype determined by GEP, with high PFS, TTP and OS rate, maintained at a long-term FU analysis. Figure 1. Figure 1. Disclosures Chiappella: Teva: Other: lecture fees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Nanostring: Other: lecture fees; Roche: Other: lecture fees; Amgen: Other: lecture fees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees. Gaidano:Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Morphosys: Honoraria. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Vitolo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sandoz: Speakers Bureau; Gilead: Speakers Bureau.

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Phase II Multicenter Study of the Safety and Efficacy of Single-Agent Lenalidomide in Subjects with Relapsed/Refractory Mantle Cell Lymphoma: Long-Term Follow-up Analysis of the NHL-003 Study.

Blood ◽

10.1182/blood.v120.21.2738.2738 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2738-2738

Author(s):

Pier Luigi Zinzani ◽

Julie M Vose ◽

Myron S. Czuczman ◽

Craig Reeder ◽

Corinne Haioun ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Advisory Committees ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 2738 Background: Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin's lymphoma (NHL) with poor prognosis that necessitates the development of new treatments. Lenalidomide is a unique immunomodulatory agent with antiproliferative and tumoricidal effects on MCL cells. NHL-003 was a phase II, open-label, multicenter trial for subjects with relapsed aggressive NHL that tested single-agent lenalidomide 25 mg PO days 1–21 every 28 days. The primary endpoint was overall response rate (ORR); secondary endpoints included complete response (CR) rate, duration of response (DOR), survival, and safety. At the time of the initial publication (Witzig et al. Ann Oncol.2011;22:1622–1627), MCL subgroup analysis showed an ORR of 42%; the median DOR had not been reached. The purpose of this report is to provide long-term efficacy and safety results for the MCL subgroup from NHL-003. Results: Subjects with MCL (N=57) had a median age of 68 y (range, 33–82), were predominantly male (77%) with good ECOG performance status (89% PS 0–1) and advanced-stage disease (88% stage III/IV). Subjects had received a median of 3 (range, 1–13) prior systemic therapies. According to the current central review at a median follow-up of 12.4 mo, subjects achieved an ORR of 35% (CR/CRu 12%) following lenalidomide, including a median DOR of 16.3 mo (Table 1). The ORR to single-agent lenalidomide was 44% (CR/CRu 21%) by independent assessment, with a median DOR not yet reached. Median PFS was 8.8 mo by central review and 5.7 mo according to investigators. Subjects responded quickly, with a median time to first response of 1.9 mo (central and investigator). Median DOR for subjects in CR and overall survival for all subjects have not yet been reached. The most common grade 3/4 adverse events (AEs) were neutropenia (46%), thrombocytopenia (30%), fatigue (9%), and diarrhea (5%). Other AEs included one subject with grade 1 to 2 tumor flare reaction, one subject with grade 3 deep vein thrombosis, and two subjects with second primary malignancies suspected of being related to treatment (one grade 3 squamous cell carcinoma of the skin that resolved and one grade 4 AML in a heavily pretreated individual with 5 prior cancer therapies). Conclusions: This subset analysis from a phase II study further confirms the efficacy of lenalidomide in subjects with relapsed MCL. Responders have a long DOR with manageable side effects. These results support continued investigation of lenalidomide alone or in combination for the treatment of MCL. Disclosures: Zinzani: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Czuczman:Celgene: Consultancy, Consultant Celgene Advisory Board Other. Reeder:Celgene: Mayo Clinic receives funding from Celgene to support clinical trials Other, Research Funding. Haioun:Celgene: Celgene Advisory Board Consultant Other, Consultancy. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pietronigro:Celgene: Employment. Ervin-Haynes:Celgene: Employment. Li:Celgene: Employment. Witzig:Celgene: Research Funding.

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Radioimmunotherapy for Mantle Cell Lymphoma: 5-Year Follow-up of 90 Patients from the International RIT-Registry

Blood ◽

10.1182/blood-2019-124192 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5263-5263

Author(s):

Karin Hohloch ◽

Christine Windemuth-Kieselbach ◽

Pier Luigi Zinzani ◽

Roberto E. Cacchione ◽

Wojciech Jurczak ◽

...

Keyword(s):

Follicular Lymphoma ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Primary Therapy ◽

First Line ◽

Advisory Committees ◽

Mantle Cell

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) (consolidation 44 pts., primary therapy 1 pt.) and at relapse in 45 (50%) patients (consolidation 24 pts., recurrence 12 pts., therapy refractory 3 pts., conditioning 2 pts., other 4 pts.). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%., 1 pt. (2%) PD, and for 4 pts. (9%) no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95%CI: 1.03-2.32) years, and median OS was 4.05 (95%CI 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib. Disclosures Zinzani: TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy. Jurczak:Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bayer: Research Funding; Gilead: Research Funding; MorphoSys: Research Funding; Incyte: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Truemper:Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding; Roche: Research Funding; Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy. Scholz:Janssen-Cilag: Consultancy; Hexal: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Pfizer: Speakers Bureau; Roche: Consultancy; GILEAD: Consultancy, Speakers Bureau; Daiichi Sankio: Consultancy. OffLabel Disclosure: Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) is approved for treatment of patients with relapsed follicular lymphoma and as consolidation therapy after chemo(immuno)therapy of patients with follicular lymphoma.

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Outcome and Prognostic Factors in Patients with Mantle Cell Lymphoma Relapsing After Autologous Stem Cell Transplantation: A Retrospective Study of the EBMT

Blood ◽

10.1182/blood.v120.21.474.474 ◽

2012 ◽

Vol 120 (21) ◽

pp. 474-474 ◽

Cited By ~ 1

Author(s):

Sascha Dietrich ◽

Herve Finel ◽

Ariane Boumendil ◽

Irit Avivi ◽

Liisa Volin ◽

...

Keyword(s):

Prognostic Factors ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Salvage Chemotherapy ◽

Refractory Disease ◽

Advisory Committees ◽

Mantle Cell ◽

One Year

Abstract Abstract 474 BACKGROUND: Autologous stem cell transplantation (autoSCT) is considered as standard treatment for non-frail patients with mantle cell lymphoma (MCL). However, little is known about outcome of MCL recurrence after autoSCT. We therefore conducted a retrospective analysis of patients with MCL who failed autoSCT using the EBMT database. PRIMARY OBJECTIVE was to analyse outcome and prognostic factors after relapse following autoSCT for MCL in the rituximab era. PRIMARY ENDPOINT was overall survival (OS) from relapse. ELIGIBLE were patients aged 18 years or more who relapsed following an autoSCT for MCL performed between 2000 and 2010 and who were registered with the EBMT. Centres were contacted to provide additional information on relapse treatment. STATISTICAL ANALYSIS was based on log-rank comparisons and multivariable testing using Cox regression models. RESULTS: 1054 patients meeting the eligibility criteria could be identified in the EBMT registry. Of these, a full data set could be retrieved for 382 patients. Sixteen patients had to be excluded due to loss of follow up (n=7), wrong diagnosis (n=6), or falsely reported relapse (n=3). Median age at autoSCT of 366 evaluable patients was 59 years (range: 37 to 76), 290 patients (79%) were men. 64% had undergone autoSCT as part of 1st-line therapy; 68% and 49% had documented exposure to rituximab (RTX) and high-dose ara-C (HA) before autoSCT; and 12% had had refractory disease at autoSCT. Median time from autoSCT to relapse was 20 months (range: 0.4 to 117). 21 relapses (6%) occurred beyond 5 years after autoSCT. With a median observation time of 37 months (95% CI 32–43), median OS after relapse of the whole study group was 20 months. By univariate analysis, a long (>12mo) interval between autoSCT and relapse (p<0.001; HR 0.26; Figure 1A), 1st-line autoSCT (p=0.006; HR 0.7) refractory disease at autoSCT (p<0.001, HR 2.0) and more recent year of relapse (p<0.001, HR per year 0.9) significantly influenced OS from relapse, whereas age, gender, RTX and HA exposure did not. By multivariate analysis refractory disease at autoSCT (p<0.001, HR=2.14), remission duration after autoSCT (p<0.001 HR per 3 months 0.88) and calendar year of relapse (p<0.03, HR per year 0.93) were confirmed to be predictors for OS. In addition, HA exposure prior autoSCT adversely affected OS from relapse (p=0.06, HR 1.38). Salvage chemotherapy after relapse resulted in only 31% complete responses and 29% partial responses, whereas 40% of patients have been refractory to first salvage chemotherapy. 83 patients (23%) received an allogeneic SCT (alloSCT), whereas only 7 patients (2%) received a second autoSCT after relapse. Median time after relapse to second SCT was 7 months (range: 1 to 40). Survival after relapse for patients who received a second autoSCT was poor with no long-term survivor. AlloSCT performed for late relapse (>12mo) after autoSCT was associated with superior OS compared to patients who received an allograft upon a shorter remission duration after autoSCT (5-year OS from alloSCT 50% vs 0%; p=0.001; Figure 1B). Achievement of CR before alloSCT (p=0.05 HR=0.5), but not donor source, T-cell depletion or conditioning intensity affected OS after alloSCT. CONCLUSIONS: Patients with MCL who relapse within one year after autoSCT have an extremely dismal outcome even with alloSCT. In contrast, about half of the patients who have MCL recurrence beyond one year after autoSCT and can undergo salvage alloSCT enjoy long-term survival. It remains to be shown if a similarly good outcome can be achieved without alloSCT in this favourable selection of patients. A 2nd autoSCT does not appear to be a promising option in patients with MCL failing a 1st autoSCT. Disclosures: Walewski: Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Cephalon: Research Funding.

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Phase 2 Trial of Ixazomib, Lenalidomide, Dexamethasone and Daratumumab in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-111065 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 304-304 ◽

Cited By ~ 8

Author(s):

Shaji K. Kumar ◽

Prashant Kapoor ◽

Betsy Laplant ◽

Eli Muchtar ◽

Francis K. Buadi ◽

...

Keyword(s):

Stem Cells ◽

Board Of Directors ◽

Mayo Clinic ◽

Research Funding ◽

Phase 2 ◽

Newly Diagnosed ◽

Advisory Committees ◽

Early Results ◽

Dose Modifications

Abstract Background: The combination of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and dexamethasone is the current standard induction therapy for myeloma. Daratumumab, a monoclonal antibody directed against CD38, is highly effective in treating myeloma and improves response rates and progression free survival (PFS) when added to PI or IMiD. Ixazomib, lenalidomide and dexamethasone (IRd) is an effective, all oral, induction regimen that has been studied in phase 2 and 3 trials. We designed this trial to examine the feasibility and efficacy of adding daratumumab to the IRd regimen. Patients and Methods: Patients with previously untreated MM, with measurable disease and adequate organ function were enrolled irrespective of their transplant eligibility. The primary objective was to determine the rate of complete response to the IRD-Dara combination in patients with NDMM. Treatment consisted of Ixazomib 4mg days 1, 8, 15; lenalidomide 25 mg days 1-21, dexamethasone 40 mg, weekly and daratumumab 16 mg/kg, weekly for two cycles, every other week during cycles 3-6 and then every 4 weeks after that. Overall, 40 patients were accrued; data on 38 patients were available for analysis as of July 02, 2018 (Table 1). Results: The median age was 62 (41-81); 52.6% female. All patients were alive and progression free at last assessment with a median follow up of 5.2 (2.0-12.9) months (median 5 cycles, range 2-13). One patient had gone off for alternate therapy. Responses were rapid with 90% partial response or better (32% VGPR) after 2 cycles, and 100% PR or better (50% VGPR) for 32 patients who have completed 4 cycles. The overall best confirmed response rate among the 38 patients was 95% including 11% CR and 47% VGPR. Overall, 231 cycles have been administered across the study, with dose modifications/ hold required for ixazomib, lenalidomide, daratumumab and dexamethasone in 3 (8%), 11 (29%), 2 (5%), and 8 (21%) patients respectively, the most common reasons being hematologic and skin rash. A grade 3 or higher adverse event at least possibly attributed to the study drugs was seen in 42% of patients, hematologic in 37% and non-hematologic in 11% (Figure). 11 patients have so far proceeded to stem cell collection, all have collected adequate numbers of stem cells for one or two intended transplants(median CD34+ collected 8.4 million/kg; range 3.8-12.3). Updated results with additional 6 months of follow up and MRD testing will be presented at the meeting. Conclusion: This represents the first reported results of this combination for treatment of newly diagnosed myeloma. The early results from the use of IRd-Dara in newly diagnosed myeloma suggests excellent efficacy with rapid responses that deepen quickly over the initial cycles of therapy. The regimen was well tolerated with limited dose modifications and no discontinuation for toxicity and no influence on the ability to collect stem cells. Figure. Figure. Disclosures Kumar: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding. Lacy:Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Prothena: Honoraria; Amgen: Consultancy; Abbvie: Consultancy; Teva: Consultancy; annexon: Consultancy; janssen: Consultancy; celgene: Consultancy; Alnylam: Honoraria; Medscape: Consultancy; Apellis: Consultancy; spectrum: Consultancy, Honoraria; Physicians Education Resource: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy.

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Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years

Blood ◽

10.1182/blood.v122.21.2310.2310 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2310-2310 ◽

Cited By ~ 11

Author(s):

Christina S Lee ◽

Allison Imahiyerobo ◽

Micha Thompson ◽

Marina Izak Karaev ◽

Waleed Ghanima ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Response Rate ◽

Newly Diagnosed ◽

Advisory Committees ◽

Platelet Counts ◽

Best Response

Abstract Background Adults with newly-diagnosed and persistent ITP usually respond to steroid based treatments such as prednisone but relapse with tapering. One 4-day cycle of Dexamethasone (dex) at 40 mg/day in newly diagnosed ITP resulted in a lasting effect in 50% of patients (pts) in 1 study. An Italian study showed that 3 cycles of dex are better than 1 cycle. Approximately 50% of pts with chronic ITP experience a complete or partial response (CR & PR) to rituximab, yet only 20% of pts have a lasting, unmaintained response after 3 years. Mechanistically, rituximab (which depletes B cells but not plasma cells) and dexamethasone (which may be the most potent anti-plasma cell agent) are a logical combination in treatment of antibody-mediated diseases such as ITP. In 2 studies of newly-diagnosed pts, dex 40mg/day x 4 followed by rituximab was more effective than dex alone (one study added more dex half way through). In our pilot study, pts at Weill Cornell Medical College (WCMC) with all stages of ITP were treated with a combination of rituximab (R) and usually 3 cycles of dex. The outcome of this combination was retrospectively analyzed. Methods Combination of standard-dose rituximab (weekly x 4) and usually 3 4-day cycles of 28mg/m2 (max. 40mg) dex at 2-week intervals (R+3Dex) was explored in 67 pediatric and adult pts with ITP at WCMC. Patients were monitored with CBCs obtained weekly and then at less frequent intervals if a response was achieved. Best response (after 8 weeks to avoid transient effects of dex) was determined. Patients were categorized as CR (platelet count≥100x109/L) or PR (50-100x109/L). Relapse was defined as either two consecutive platelet counts <50x109/L and/or need for additional therapy. The duration of response was calculated from date of first rituximab administration to relapse or latest follow-up as of July 31st 2013. Results Overall, 50 of 67 pts treated with R+3Dex achieved a best response of either a CR (n=43) or a PR (n=7) at 8 weeks or later from start of therapy for an overall response rate of 75%. Seventy-three percent of pts received R+3Dex; variations were primarily in the timing and amount of dex given. Fifteen responders, 9 CRs and 6 PRs, relapsed at a median of 9 months. Seventy percent of the responders (or 52% of all pts treated) maintain a continuous response with platelet counts ≥ 50 x 109/L as of their last visit at a median f/u of 20 months. Kaplan Meier Analysis estimates 44% of all pts treated (Figure) and 59% of responders (Figure) maintained a best response without relapse at 67 months after initiating treatment. If only those with ITP ≤ 24 months are included, the estimated long term response rate is 59% (p=0.0017) versus only 19% for those with a duration of ITP > 24 months (Figure). Of 36 responding children and adults who had ITP ≤ 24 months, 29 continued to respond as of last follow up. Adults initially responded better than children (p=0.0019) but the long-term responses were not different (Figure). Pts achieving a CR had longer response than those achieving a PR. Adverse events related to R+Dex were usually mild-moderate, although 3 pts had serum sickness and 2 had transient colitis. IgG levels fell to below the lower limit of normal for age in 14 of 67 pts, 10 of whom had their IgG levels return to normal. In 6 of 14, IgG levels were < 400 mg/dl, some of whom received IVIG. Fifteen patients had serial BK/JC levels without ever detecting virus. Conclusions R+3Dex provides clearly superior results to rituximab alone. Notably, there was a 75% response rate overall (50/67 pts) compared to 50% with R alone. The 5 year response rate was almost 50% of all patients and 3/5 of responders. In patients who had had ITP for ≤ 2 years, the response is comparable to what has been reported with splenectomy. Specifically the results in the ≤ 2 year group suggest that R+3Dex is an effective way to induce indefinitely normal platelet counts in pts with a “short” duration of ITP. R+3Dex was tolerable although patients had difficulty with 3 cycles of dex. The 21% rate of hypogammaglobulinemia, higher than that seen with R alone, is also evidence of the mechanism of R+3Dex affecting both B cells and plasma cells. The lasting, long-lived, unmaintained responses observed in this study suggest that this combination therapeutic strategy should be further tested in a controlled trial in patients with newly diagnosed, persistent, and early chronic ITP, whether or not they have been previously treated with other agents. Disclosures: Bussel: Sysmex: Research Funding; Cangene: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Non-Bcl2 Mutations Are Predominant in Patients (pts) with Venetoclax Resistant Mantle Cell Lymphoma (MCL) - Response and Clinical Outcomes in Ultra-Refractory MCL

Blood ◽

10.1182/blood-2019-126175 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2815-2815 ◽

Cited By ~ 1

Author(s):

Preetesh Jain ◽

Shuangtao Zhao ◽

Rashmi Kanagal-Shamanna ◽

Lucy Navsaria ◽

Holly Hill ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Advisory Board ◽

Advisory Committees ◽

Ki 67 ◽

Mantle Cell ◽

Btk Inhibitors

Introduction: Mantle cell lymphoma (MCL) patients (pts) who progress after ibrutinib and other lines of treatment "ultra-refractory MCL" have poor outcomes and exhibit BTK mutations infrequently (Jain P et al BJH 2018, Martin P et al Blood 2016). Venetoclax has shown promising efficacy in Phase I trial in NHL (Davids M et al JCO 2017) and is now under trials in MCL. Venetoclax response in pts with MCL after progression on ibrutinib was reported (Eyre T et al Haematologica 2018), however, genomic alterations associated with venetoclax resistance are not described. We present our experience in 24 pts with MCL treated with venetoclax and report their mutation profiles associated with progression on venetoclax. Methods: We collected data from 24 pts with MCL who were treated with venetoclax (off clinical trial) as a salvage measure after failing multiple lines of prior therapies. Pt characteristics were collected from the time of initiating venetoclax. Progression free survival (PFS) was calculated from the time of initiating venetoclax to the date of progression or to last follow up date/date of death while overall survival (OS) was calculated from the time of initiating venetoclax to the date of last follow up date/date of death. Post venetoclax survival was calculated from the date of discontinuing venetoclax to the date of last follow up/death. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed from evaluable biopsy samples from 7 pts (5 pts at/before starting venetoclax and 6 pts after progression of venetoclax), this included 5 pts who have pairs available for analysis (pre and post venetoclax). Results: Twenty four pts were treated with venetoclax (12 started as single agent and 8 started with combination with obinutuzumab and 3 with BTK inhibitors with/without obinutuzumab). Four pts had initial single agent venetoclax and later were rechallenged with combinations. Initial dose of venetoclax was dose escalation from 20 mg, then 50 mg then 100 mg PO daily up to 400 mg daily in 18/24 pts while in 3 pts it was 100 mg daily and in another 3 it was 400 mg daily. Median age at venetoclax start was 69 years (58-82). Median number of prior lines of therapy was 5 (range 1-11; including 17 pts who progressed on ibrutinib or other BTK inhibitors, 5 had exposure to ibrutinib and discontinued for intolerance, 4 had prior SCT and 2 had prior anti CD19 cellular therapy). At the baseline (pre/at-venetoclax start), 13 pts (54%) had blastoid/pleomorphic histology and 11 (46%) had classic variant morphology, the median Ki-67% was 60% (5-90%) and pts with Ki-67% ≥ 50 were 11 (55%), 4 pts did not have available Ki-67% values. Overall response rate (ORR) was 65% (13/20) - complete remission 25% (5/20) and partial remission 40% (8/20). Stable disease was observed in 10% (2/10), primary refractory were 25% (5/20). Four pts were not evaluable for response assessment. The median follow up after starting venetoclax was 17.5 months (1-27). The median PFS was 7.7 months (2 year 20%) and the median OS was 13.5 months (2 year 30%) Figure-1A-B. Pts in CR had a PFS of 15 months vs no CR 10 months (p=0.29). At the last follow up, 11 pts remained on venetoclax therapy (4 alive and 7 dead). Overall, 15 pts progressed and 14 pts were alive. The median post venetoclax survival was 6 months. Among 20 pts who discontinued venetoclax, 1 achieved CR and 3 PR on subsequent therapies. Among the 20 pts who discontinued venetoclax, 6 discontinued due to intolerance. In addition, we evaluated the somatic mutation profile in pts who progressed on venetoclax using WES. Figure-1C shows mutation spectrum. In our cohort, pts with MCL who progressed on venetoclax exhibited infrequent Bcl2 mutations (one pt at progression; 14 %; p.H3D) while the mutation frequency of other genes such as TP53 (71% vs. 40%), ATM (43% vs. 20%), KMT2D (57% vs. 20%), CELSR3 (57% vs. 20%), and KMT2C (43% vs. 20%) increased by > 2-fold at progression (compared to pretreatment samples, p=N.S due to small cohort size). The mutation of CARD11 (14%) and SMARCA4 (14%) was only observed at progression. Further details on copy number abnormalities will be presented. Conclusions: Venetoclax has promising results in refractory pts with MCL. Combination clinical trials with obinutuzumab, acalabrutinib are ongoing in MCL. We have characterized mutations and aneuploidy abnormalities in venetoclax resistant MCL pts and shown that unlike CLL, Bcl2 mutations are infrequent in venetoclax resistant MCL. Disclosures Nastoupil: Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Curis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding; Genentech: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Fowler:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Aviara: Research Funding; Dava Oncology: Honoraria; Juno Therapeutics: Research Funding; Celgene: Honoraria, Research Funding; BioInvent: Consultancy, Research Funding; Guidepoint Global: Consultancy; Kite Pharma: Consultancy, Research Funding; Acerta Pharma: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Loxo Oncology: Research Funding; VelosBio: Research Funding.

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Outcomes, Causes of Discontinuation and Mutation Profile of Patients with Mantle Cell Lymphoma Who Progressed on Acalabrutinib

Blood ◽

10.1182/blood-2018-99-115179 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4151-4151 ◽

Cited By ~ 3

Author(s):

Preetesh Jain ◽

Rashmi Kanagal-Shamanna ◽

Shaojun Zhang ◽

Chi Young Ok ◽

Makhdum Ahmed ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Copy Number ◽

Research Funding ◽

Cell Lymphoma ◽

Median Number ◽

Copy Number Alterations ◽

Advisory Committees ◽

Mantle Cell

Abstract Introduction: Acalabrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved for treatment of relapsed patients (pts) with mantle cell lymphoma. We have reported previously that ibrutinib refractory MCL pts have poor survival. However, outcomes, causes of discontinuation, management and the genomic landscape of MCL in pts who discontinued acalabrutinib are rarely reported. Method: We reviewed charts from all MCL pts treated with single agent acalabrutinib (n=28) in the relapsed setting and identified 15 pts who discontinued acalabrutinib and who are described in this analysis. Outcome after discontinuing acalabrutinib is reported. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed on 10 tumor specimens and 5 matched germline samples collected from 9 pts whose MCL progressed on acalabrutinib; among these pts 4 tumors were collected at baseline and 6 were collected after disease progression. One patient had sufficient DNAs available for both time points (baseline and progression). Results: The median duration on treatment with acalabrutinib was 6.5 months (1 to 29 months) and the median number of cycles of acalabrutinib treatment was 6 (range, 1-30). Seven pts had complete remission (CR) as their best response on acalabrutinib, 5 were primary refractory and 3 achieved partial remission. In 12 pts (80%) acalabrutinib was discontinued due to disease progression (2 pts transformed from classic to blastoid and pleomorphic type at progression) and 3 pts were discontinued due to intolerance (one for fatigue and idiopathic encephalopathy, one due to unrelated severe aortic stenosis and another for cytopenias secondary to therapy related myelodysplasia; all three pts were in CR). Nine pts had classic and 3 pts each had blastoid or pleomorphic features before starting acalabrutinib. Overall, median Ki-67 expression was 50% (range, 5-100) and all pts had high a MIPI score. The median number of prior treatments was 1 (range, 1-3); all chemo-immunotherapy (10 pts were previously treated with rituximab-hyper-CVAD) and none with ibrutinib. Two pts who transformed on acalabrutinib received acalabrutinib for a median duration of 12 months (range, 8-16.5). Median follow up after discontinuation was 27 months and the median survival was 25 months (26 months for progression and 1.5 months for intolerance; p <0.001, Figure-1A). Patients who discontinued due to intolerance did not get subsequent treatment for MCL. Among the 12 pts who progressed on acalabrutinib, 11 pts received systemic therapy for MCL [seven received ibrutinib based therapies (2 non responders, 3 achieved CR and 2 were PR and all pts progressed subsequently), 3 got chemo-immunotherapy and progressed and one pt did not receive any treatment and was lost to follow up and died. Six patients received a clinical trial with CAR-T cells (results will be reported separately). Overall, at the time of last follow up, 8 pts were alive and 7 were in CR. Recurrently mutated genes in these tumors included ATM (6/10; 60%), TP53 (4/10; 40%), KMT2C (3/10), MYCN (2/10), NOTCH1 (2/10), NOTCH3 (2/10), and MEF2B (2/10) (Fig. 1B). We did not detect any mutation or copy number alterations in BTK, PLCG2, TRAF2/3 and MYD88 that have been reported previously to be associated with ibrutinib resistance. Compared to tumors at baseline, ATM was mutated at a higher frequency in samples at progression (67% vs. 50%; p=NS). To investigate the mutation evolution on acalabrutinib treatment, mutation profiles, particularly the mutation variant allelic fractions (VAFs), were compared between the baseline and progression samples from pt-1 (Fig. 1C). Mutation of MYCN, MEF2B, ATM, and NOTCH1 were identified in both tumors at similar VAFs, whereas mutation of CARD11 (two mutations), NLRC5 and B2M were detected only at progression. In pt-1, both the NLRC5 and β2M mutations acquired at disease progression were truncating, suggesting loss-of-function alterations. Copy number analysis reveals frequent whole-genome doubling and intensive copy number alterations in all tumors, including recurrent losses of chromosome 9p, 17p, and chromosome 13, indicating chromosomal instability as a driver of disease progression. Conclusion: Patients who progress on acalabrutinib have a poor outcome, and newer therapies are required for their treatment. In this small cohort, we observed non-BTK mutations associated with acalabrutinib resistance and disease progression. Disclosures Nastoupil: Genentech: Honoraria, Research Funding; TG Therappeutics: Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Merck: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Honoraria, Research Funding; Karus: Research Funding; Novartis: Honoraria; Juno: Honoraria. Neelapu:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Unum Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Wang:Acerta Pharma: Honoraria, Research Funding; MoreHealth: Consultancy; AstraZeneca: Consultancy, Research Funding; Kite Pharma: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

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Rituximab, Bendamustine and Cytarabine (RBAC500) As Induction Therapy in Elderly Patients with Mantle Cell Lymphoma: Final Results of a Phase 2 Study from the Fondazione Italiana Linfomi

Blood ◽

10.1182/blood.v128.22.472.472 ◽

2016 ◽

Vol 128 (22) ◽

pp. 472-472 ◽

Cited By ~ 2

Author(s):

Carlo Visco ◽

Annalisa Chiappella ◽

Luca Nassi ◽

Caterina Patti ◽

Simone Ferrero ◽

...

Keyword(s):

Elderly Patients ◽

Board Of Directors ◽

Cell Lymphoma ◽

Hematologic Toxicity ◽

Phase 2 ◽

Advisory Committees ◽

Ki 67 ◽

Phase 2 Study ◽

Mantle Cell ◽

Grade 3

Abstract Background: The combination of rituximab (R, 375 mg/m2 intravenously [IV], day 1), bendamustine (B, 70 mg/m2IV, days 2 and 3), and cytarabine (800 mg/m2, IV on days 2 to 4) was highly active in patients with mantle-cell lymphoma (MCL) in a phase 2 study [R-BAC; Visco et al, JCO 2013]. This regimen was well tolerated, but hematologic toxicity was quite relevant, especially in terms of transient grade 3 to 4 thrombocytopenia (76% of cycles). Aiming at reducing hematologic toxicity, the Fondazione Italiana Linfomi (FIL) designed a phase 2 trial adopting the R-BAC schedule, but lowering cytarabine dose to 500 mg/m2 (RBAC500). Materials and Methods: Patients with newly diagnosed MCL, aged 61 to 80 years, not eligible for autologous transplant and fit according to the comprehensive geriatric assessment, were enrolled. Patients presenting with non-nodal leukemic disease were excluded. The primary endpoints were complete remission rate (CR) measured by FDG-PET according to Cheson criteria 2007, and safety. Secondary endpoints included rate of molecular response (MR) by nested-PCR using patient specific IGH or BCL1 based targets, progression-free (PFS) and overall survival (OS). The study was conducted according to the Bryant and Day two-stage design. Results: From May 2012 to February 2014, 57 patients with MCL from 29 centers were recruited and treated. Central pathology revision was performed in 87% of cases. Median age was 71 years (range 61-79), 75% were males, and 91% had Ann Arbor stage III/IV disease. Mantle Cell International Prognostic Index (MIPI) was low in 15%, intermediate in 40%, high in 45%, Ki-67 was ≥30% in 31%, and 9% had the blastoid cytological variant. Overall, 53 patients (91%) received at least 4 cycles, while 36 (63%) had 6 cycles (median 5.3 cycles per patient). Fifteen patients (26%) discontinued treatment before reaching cycle 6 because of toxicity/adverse events, that mainly consisted of prolonged hemato-toxicity between cycles. Only one patient discontinued due to progressive disease. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 49% and 52% of administered cycles, respectively. Febrile neutropenia occurred in 6% of cycles. Extra-hematologic toxicity was mainly cardiac (5%). Overall response rate was 96%, and CR was 93%. The MR rate at the end of treatment was 76% on peripheral blood and 55% on bone marrow (BM) samples. With a median follow-up of 34 months (28-52), the 2-years PFS (± confidence interval) was 81%±5% and the OS 85%±4%. Elevated Ki-67 (≥30%), and the blastoid variant were the strongest independent predictors of adverse PFS. Patients with either of these two features (33%), had a significantly inferior PFS (41% vs 97% after 34 months) compared to patients with classical/pleomorphic variants and low proliferative index (p<0.0001, Figure 1). Conclusions: The R-BAC500 regimen can be safely administered as first line therapy to elderly patients with MCL. Hematologic toxicity is substantially reduced compared to our previous experience. With 93% of FDG-PET negative CR, and a 2-years PFS of 81% without maintenance therapy, the R-BAC500 regimen is a highly effective treatment for patients with MCL, and compares favourably with previously reported regimens in this patient population, including R-bendamustine. Figure 1 Figure 1. Disclosures Visco: Gilead: Speakers Bureau; Lundbeck: Consultancy; Mundipharma: Research Funding; Celgene: Speakers Bureau. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Di Rocco:Celgene: Honoraria. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Honoraria; Celgene: Honoraria.

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