Results of a Phase I Trial of Lenalidomide, Rituximab (R2) and Ixazomib for Frontline Treatment of High Risk Follicular and Indolent Non-Hodgkin Lymphoma

INTRODUCTION: Lenalidomide and Rituximab (R2) is an effective frontline treatment regimen for patients (pts) with indolent B-cell lymphoma including follicular lymphoma (FL). Recent phase III data from the RELEVANCE trial comparing R2 to traditional chemoimmunotherapy showed that this regimen is generally well-tolerated and has favorable clinical efficacy [61% overall response, 53% CR rate, 77% 3-year progression free survival (PFS) (Morschhauser, et al)]. Proteasome inhibitors such as bortezomib disrupt NF-KB signaling and have shown clinical activity in indolent NHL. Although randomized trials have failed to demonstrate clinical benefit of adding bortezomib to standard chemoimmunotherapy regimen bendamustine + rituximab (BR) for frontline treatment of FL, the addition of proteasome inhibitors to lenalidomide is a mainstay of treatment for plasma cell neoplasms due to synergistic antitumor effect. The oral proteasome inhibitor ixazomib has less potential for dose-limiting neuropathy than bortezomib, making it an attractive option to incorporate into the R2 regimen. We sought to investigate the safety and efficacy of the addition of ixazomib to R2 for FL and indolent B-cell NHL through a phase I clinical trial of this combination for patients with high risk disease. METHODS: Adult (age ≥ 18) pts with untreated FL or other indolent lymphoma, adequate organ function and performance status were enrolled. To be enrolled, FL patients were required to have stage 2, 3 or 4 disease, with high tumor burden by GELF criteria and/or FLIPI score of 3-5. During 3 x 3 dose escalation, ixazomib was given at a dose of 2 mg (n=3), 3 mg (n=3) or 4 mg (n=12) PO on days 1, 8, and 15 with lenalidomide 20 mg PO on days 1-21 every 28 days. Rituximab was administered at standard dosing on days 1,8,15,21 for cycle 1, once every 28 days for cycles 2-6 and then once every 2 months for cycles 7-12. Treatment was continued for 12 cycles and no maintenance therapy was specified per protocol. All pts received low dose aspirin for venous thromboembolism prophylaxis and acyclovir for prevention of VZV reactivation. Response assessments by CT were performed after cycle 3 and 6 and by PET/CT at the end-of-treatment (cycle 12). RESULTS: 20 pts were enrolled and 18 were eligible for treatment [15 FL (14 grade 1-2, 1 grade 3A), 2 splenic marginal zone lymphoma and 1 nodal marginal zone lymphoma].The median age of treated pts was 61 (range 40-83) years old. 55% of patients were female. Stage at diagnosis was II (n =2), III (n = 4) and IV (n = 12). For FL pts, FLIPI scores at enrollment were low (n=2), intermediate (n = 5) and high risk (n=8) and FLIPI-2 scores were low (n=3), intermediate (n = 2) and high risk (n=10). There were no dose limiting toxicities during 3 x 3 dose escalation. Grade (G) 1/2 and G3/4 treatment-related hematologic adverse events (AEs) included neutropenia (6%, 28%), thrombocytopenia (16.7%, 5.6%) and anemia (16.7%, 0%). The most common treatment-related AEs included nausea/vomiting (44% G1, 11% G2), diarrhea, (50% G1, 22% G2, 5% G3), rash (33% G1, 6% G2, 11%G3), peripheral neuropathy (22% G1, 6% G2), myalgia/arthralgia (17% G1, 17% G2), and infection (33% G2, 17% G3). There was one pulmonary embolism and no cases of febrile neutropenia. As of June, 2020, median follow-up among living pts was 21 months. 4 pts discontinued treatment due to disease progression; 2 with transformation to aggressive lymphoma. Of the transformed cases, one subject died on study due to progression disease and one developed CNS disease on study treatment but proceeded to autologous stem cell transplant. The best overall response rate was 61.2% [55.6% CR, 5.6% PR): 22.2% had stable disease and 16.7% had disease progression. 18-month Kaplan-Meier estimates of PFS and overall survival were 71% and 94%, respectively (Figure). CONCLUSION: R2 can safely be combined with at the target dose of 4 mg of ixazomib for treatment-naïve indolent NHL patients. Non-hematologic AEs were generally consistent with known toxicity of each component of therapy. CR rate and PFS were was similar to the outcomes reported in the RELEVANCE trial despite enrolling high risk patient. R2 may serve as backbone for future studies of novel treatment combinations for high risk FL after thorough evaluation for occult transformation to aggressive lymphoma. Disclosures Hill: Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Jagadeesh:MEI Pharma: Research Funding; Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Smith:Takeda: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Ixazomib is off-label for treatment of NHL

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Effect Of Treatment With The JAK2-Selective Inhibitor Fedratinib (SAR302503) On Bone Marrow Histology In Patients With Myeloproliferative Neoplasms With Myelofibrosis

Blood ◽

10.1182/blood.v122.21.2823.2823 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2823-2823 ◽

Cited By ~ 3

Author(s):

Catriona HM Jamieson ◽

Robert P Hasserjian ◽

Jason Gotlib ◽

Jorge E. Cortes ◽

Richard M. Stone ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Phase I ◽

Board Of Directors ◽

Clinical Benefit ◽

Research Funding ◽

Selective Inhibitor ◽

Advisory Committees ◽

Grade 3

Abstract Introduction Fedratinib, a JAK2-selective inhibitor, demonstrated clinical benefit through a reduction in splenomegaly and symptoms in patients with myelofibrosis (MF), including post-polycythemia vera MF (post-PV MF), post-essential thrombocythemia MF (post-ET MF) and primary MF (PMF), in Phase I and II studies (J Clin Oncol 2011;29:789; Haematologica 2013;98:S1113). Bone marrow fibrosis (BMF) has been associated with splenomegaly and cytopenias (Ann Hematol 2006;85:226). Hence, stabilization and/or reversal of BMF remain important therapeutic goals. This report represents an exploratory analysis of sequential BMF data from patients with MF in an open-label Phase I/II study to evaluate the long-term effects of orally administered fedratinib (TED12015; NCT00724334). Methods Patients with intermediate or high-risk MF (Mayo Prognostic Scoring System) received fedratinib therapy in consecutive cycles (1 cycle = 28 days) as long as they derived clinical benefit. Bone marrow trephine biopsies were performed at baseline and after every 6 cycles. Hematoxylin and eosin, reticulin, and Masson's trichrome staining of core biopsy slides were used to grade BMF on a scale from 0 to 3 using the 2008 WHO MF grading criteria. BMF was graded independently in a blinded fashion by 3 hematopathologists. BMF grades were established as long as at least 2 of the 3 pathologists agreed independently. Changes in BMF grade from baseline were categorized as improvement (≥1 grade reduction), stabilization (no change), or worsening (≥1 grade increase). Results Of the 43 patients enrolled in the TED12015 study, the median fedratinib dose received was 473 (range 144–683) mg/day and median treatment duration was 32.3 (range 7–61) cycles. Bone marrow biopsies at baseline and at least one other time point were available for 21/43 (49%) patients, whose baseline characteristics were: median age 61 years (range 43–85); 57% male; 38% high-risk MF by WHO 2008 criteria (Leukemia 2008; 22:14); and 90% JAK2V617F positive. A consensus grade was achieved for 96% of the samples. At baseline, 2, 10, and 9 patients had grade 1, 2, and 3 BMF, respectively. Changes in BMF grade from baseline are shown in the figure. BMF improvement with 1 grade reduction was observed in 8/18 (44%) patients at Cycle 6. By Cycle 30, 4/9 (44%) evaluable patients had BMF improvement, including 2 patients with improvement by 2 grades and 2 patients with improvement by 1 grade. Of patients with Grade 3 BMF at baseline, 6/9 (67%) exhibited 1 grade improvement at Cycle 6. Two patients had 2 grades of BMF reduction from baseline during treatment (grade 3 to 1, and grade 2 to 0, both at Cycle 12), and the latter achieved a complete clinical remission at Cycle 30 assessed by IWG-MRT response criteria. The two patients who experienced complete reversal of BMF to grade 0 (one from grade 2 and one from grade 1) had normalization of not only hemoglobin level but also white blood cell and platelet counts at Cycle 18. Conclusions These exploratory analyses suggest that a proportion of patients treated long-term with fedratinib demonstrate stable or improved BMF. The disease modifying impact of fedratinib on BMF changes will be further assessed in a randomized, placebo-controlled Phase III clinical trial (JAKARTA; NCT01437787). This study was sponsored by Sanofi. Disclosures: Jamieson: J&J, Roche: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Hasserjian:Sanofi, Inc: Consultancy. Gotlib:Sanofi: Travel to EHA 2012, Travel to EHA 2012 Other; Sanofi: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Thiele:AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Consultancy; Novartis, Shire: Research Funding; AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Honoraria. Rodig:Ventana/Roche Inc.: Research Funding; Daiichi-Sankyo/Arqule Inc., Ventana/Roche Inc., Shape Pharmaceuticals Inc.: Consultancy. Patki:Sanofi: Employment. Wu:Sanofi: Employment. Wu:Sanofi: Employment. Pozdnyakova:Sanofi: Honoraria; Sanofi: Consultancy.

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A Phase I/II Study of Lenalidomide Plus Obinutuzumab in Relapsed Indolent Lymphoma

Blood ◽

10.1182/blood-2019-131045 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 348-348 ◽

Cited By ~ 6

Author(s):

Nathan H Fowler ◽

Loretta J. Nastoupil ◽

Collin Chin ◽

Paolo Strati ◽

Fredrick B. Hagemeister ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Marginal Zone ◽

Advisory Board ◽

Indolent Lymphoma ◽

Advisory Committees ◽

Grade 3

Background: Patients with advanced indolent non-Hodgkin lymphoma (iNHL) can develop chemoresistance and most relapse following standard therapy. Although multiple treatment options exist, most are associated with short remission or intolerable side effects. Lenalidomide activates NK cells ± T cells and leads to in vivo expansion of immune effector cells in NHL models. The combination of rituximab and lenalidomide (R2) in relapsed iNHL is highly active and was recently approved. Obinutuzumab is a glycosylated type II anti-CD20 molecule with enhanced affinity for the FcγRIIIa receptors leading to improved ADCC. The primary objective of this phase I/II study was to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide and obinutuzumab in relapsed indolent lymphoma. Methods: Patients with relapsed small lymphocytic lymphoma (SLL), marginal zone, and follicular lymphoma (gr 1-3a) were eligible. Patients enrolled in three predefined dose cohorts of lenalidomide (10mg,15mg, 20mg) given on days 2-22 of a 28 day cycle. Obinutuzumab was given at a fixed dose (1000mg) IV on days 1,8,15 and 22 of cycle 1 and day 1 of subsequent cycles for 6 cycles. The combination was given for up to 12 cycles in responding pts. Antihistamines were given in pts who developed rash. Prophylactic growth factor was not allowed. In the absence of progression or toxicity, single agent obinutuzumab was continued every 2 months for maximum of 30 months on study. Traditional 3+3 dose escalation was used with dose limiting toxicities (DLT) assessed during cycle 1. Once the MTD was established, 60 additional patients were enrolled in the phase II portion of the study. Adverse events were graded using CTCAE version 4.03. Results: 66 pts were enrolled between May 2014 until March 2019, and all are eligible for safety and response assessment. No DLTs were observed in dose escalation, and 60 pts were enrolled in the phase II portion of the study at 20mg of lenalidomide daily. Histologies included follicular lymphoma (FL) n=57, marginal zone n=4, SLL n=5. The median age was 64 (36-81), with 2 (1-5) median prior lines of treatment. For 53% of pts, the combination represented the third or greater line of treatment. The overall response (OR) rate for all pts was 98% with 72% attaining a complete response (CR). Eighteen pts (27%) had a partial response, and stable disease was noted in 1 (2%). At a median follow up of 17 months, 14 pts have progressed, with an estimated 24mo progression-free survival (PFS) of 73% (57-83% 95% CI). The estimated 24 mo PFS for ≥ third line pts was 63%. Twenty five pts (38%) remain on treatment and 95% remain alive at last follow up. The most common grade ≥ 3 non-hematologic toxicities included fatigue (5 pts), rash (4 pts), and cough (3 pts). Grade ≥3 neutropenia and thrombocytopenia occurred in 11 (17%) and 7 (11%) pts respectively. Two pts stopped treatment due to adverse events, including 1 transient bradycardia and 1 grade 3 fatigue. Conclusion: The combination of 20 mg of lenalidomide and 1000mg obinutuzumab is safe and effective in patients with relapsed indolent lymphoma. Adverse events appeared similar to our prior experience with lenalidomide and rituximab and were generally well tolerated. Overall response rates were high, with many pts achieving prolonged remission, including pts who had relapsed after 2 or more lines of prior therapy. Validation studies in the frontline and salvage setting are ongoing. Disclosures Fowler: Celgene: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; TG Therapeutics: 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. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; MorphoSys: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Neelapu:Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding; Cellectis: Research Funding; Novartis: Consultancy; BMS: Research Funding; Karus: Research Funding; Acerta: Research Funding; Poseida: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Celgene: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Allogene: Consultancy; Pfizer: Consultancy; Cell Medica: Consultancy.

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Front-Line Treatment with Obinutuzumab ± Chlorambucil for Chronic Lymphocytic Leukemia in Real-World Clinical Practice: Results of a Multinational, Multicenter Study By Eric and Icllsg

Blood ◽

10.1182/blood-2019-122309 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1766-1766

Author(s):

Yair Herishanu ◽

Adir Shaulov ◽

Riva Fineman ◽

Sandra Bašić-Kinda ◽

Ariel Aviv ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Entire Cohort ◽

Real World Setting ◽

High Risk Disease ◽

Frontline Treatment

Chronic lymphocytic leukemia (CLL) occurs in older individuals with a median age at diagnosis of 72 years. In recent years, there has been considerable progress in the frontline therapy of elderly/physically unfit patients with CLL. The German CLL11 trial showed that addition of obinutuzumab to chlorambucil (G-Clb) prolongs progression free survival (PFS) and overall survival (OS) compared to chlorambucil alone or in combination with rituximab. More recently, obinutuzumab together with ibrutinib or venetoclax were shown to be superior to G-Clb with regard to PFS, but there was no advantage in terms of OS. In this retrospective, multinational and multicenter co-operative study the European Research Initiative on CLL (ERIC) and the Israeli CLL Study Group (ICLLSG) evaluated the efficacy of frontline treatment with G-Clb in patients with CLL, in a "real-world" setting. Our analysis excluded CLL patients with documented del(17p) or TP53 mutations since they are no longer treated with chemotherapy. Results: A total of 437 treatment-naïve patients with CLL from 51 medical centers located in 13 countries were included. The median age of this patient population was 75.9 years; 59.7% were men, median CIRS total score was 8 and estimated creatinine clearance 61.1 mL/min. Seventy four patients had Binet stage A (17.2%), 167 (38.8%) stage B and 190 (44.1%) stage C. Results of FISH and IGHV mutational status were available for 332 and 115 patients, respectively. High-risk cytogenetics, del(11q) was documented in 18.7% patients and IGHV-unmutated gene in 64.4%. The vast majority of patients were treated with G-Clb (N=408) and the rest with obinutuzumab monotherapy (G-monotherapy, N=29). The clinical overall response was 86.5%, including clinical complete and partial responses in 41.6% and 45.8% of cases, respectively. The median observation time was 14.1 months (m) and the median PFS of the entire cohort was 27.6m (95% CI, 24.2-31.0). The PFS for G-Clb was significantly better than G-monotherapy (P=0.001; HR=0.38, 95% CI: 0.22-0.67), being the 2-year PFS estimates 61.8% and 52.8%, respectively. The median PFS was significantly shorter for patients with del(11q) (19.2m) compared to those with normal FISH (not reached, P<0.001), del(13q) (29.9m, P<0.001) and trisomy12 (not reached, P=0.027). Patients with IGHV-unmutated had a trend for shorter PFS compared to those with IGHV-mutated gene (median PFS 25.3m vs. not reached, respectively. p=0.06). In a multivariate analysis, older age, high risk-disease, lymph nodes >5cm, G-monotherapy, reduced cumulative dose of obinutuzumab and status less than CR, were independently associated with shorter PFS. Seventy patients (16%) received a second-line treatment. The median OS for the entire cohort has not been reached yet and 2-year OS estimate is 88%. In conclusion, in a "real-world" setting, frontline treatment with G-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were observed in patients with high-risk disease [del(11q) and/or IGHV-unmutated] and those treated with G-monotherapy. Thus, even today in the era of novel drugs, G-Clb can be considered a legitimate frontline treatment in unfit CLL patients with low-risk disease [non-del(11q) and IGHV-mutated]. Disclosures Herishanu: Roche: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Simkovic:Roche: Honoraria; University Hospital Hradec Kralove: Employment; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria. Mauro:Gilead: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Coscia:Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Research Funding. Scarfo:AstraZeneca: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Tedeschi:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria. Gimeno Vázquez:JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Assouline:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Levato:Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria. Rigolin:Gilead: Speakers Bureau; Gilead: Research Funding; AbbVie: Speakers Bureau. Loscertales:Janssen: Honoraria; Roche: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Gilead: Honoraria. Ghia:Dynamo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Gilead: Consultancy, Honoraria, Research Funding.

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A Systematic Review and a Survey Both Reveal Wide Heterogeneity across Trials and Investigators on Time-to-Event Endpoints Definitions in Marginal Zone Lymphoma

Blood ◽

10.1182/blood-2021-150603 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4502-4502

Author(s):

Côme Bommier ◽

Emanuele Zucca ◽

Catherine Thieblemont ◽

Jérôme Lambert

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Marginal Zone ◽

Phase 1 ◽

Marginal Zone Lymphoma ◽

Time To Event ◽

Phase 3 ◽

Advisory Committees ◽

Free Survival ◽

Secondary Endpoints

Abstract Background: Marginal zone lymphoma (MZL) is an indolent and heterogeneous B-cell lymphoma. Because of its very indolent course, many time-to-endpoints are used across MZL trials without clear consensus on their definitions. Our aim was to carry out a description of the endpoints used in trials involving MZL patients and to point out the different definitions of time-to-event (TTE) endpoints, both in the literature and among the MZL experts. Methods: We searched over the last 35 years via PubMed, The Cochrane Library, clinicaltrials.gov and clinicaltrialsregister.eu for published and registered clinical trials using the keyword "marginal zone lymphoma". We excluded studies focusing on pediatric populations, cutaneous MZL and on use of allogenic stem cell transplant. Endpoints were reviewed and definitions were analyzed. Afterwards, an online questionnaire was sent to a panel of leading international experts involved in the conduct of lymphoma clinical trials. Experts were selected for their commitment in published phase 2/phase 3 indolent lymphoma trials or for their membership in international lymphoma study groups (International Extranodal Lymphoma Study Group, Lymphoma Research Foundation). The questionnaire proposed 12 criteria to define Progression-free survival (PFS), Event-free survival (EFS), Time to failure (TTF), and Time to next treatment (TTNT). Results: 1192 references were identified by the initial screening. Among the 309 included references (111 published, 198 registered), 213 (69%) were phase 2, 65 (21%) phase 1/2 and 31 (10%) phase 3 trials. The majority of them were open-label (n=295, 95%) non-randomized (n=256, 83%) trials, included all subtypes of MZLs (n=239, 77%), and also non-MZL patients (n=232, 75%). Among phase 1/2 and 2 trials, Overall/complete response rate (ORR/CRR) was the most used primary endpoint (n=196, 70.5%), followed by PFS (n=28, 10.1%); in phase 3 trials PFS was the most used primary endpoint (n=18, 58.1%; ORR/CRR n=6, 19.4%, p<0.001). Overall, the most frequent secondary endpoints were overall survival (OS, n=153, 50%), PFS (n=142, 46%) and ORR/CRR (n=116, 38%). Distribution of endpoints was similar when considering trials with only MZL patients. Time-to-event endpoints definitions were inconsistent across published trials, with up to 9 different definitions of EFS and TTF, and 4 different definitions of Duration of response. A total of 60 MZL experts from 16 different countries (Europe 66%, Northern America 26%, Asia 4%, Oceania 2%, Southern America 2%) took the questionnaire. Forty-nine (82%) of them were clinicians hematologists, and the other were oncologists, radiologists, nuclear medicine physicians, or radiotherapists. Eighty percent and 75% of them had already been primary investigator or coinvestigator in a prospective clinical trial including either MZL-only patients or MZL patients merged with other lymphoma patients, respectively. Among the experts' answers, a total of 23 different definitions of PFS were retrieved, 44 of EFS, 38 of TTF and TTNT. The main divergences concerned the consideration as event of: the add-on of a new therapy and the non-lymphoma related death for PFS; the treatment discontinuation due to adverse events and the add-on of a new therapy for EFS and TTF; the progression of the disease for TTNT. Conclusion: Trials involving MZL patients showed marked heterogeneity both in the choice and definitions of primary and secondary endpoints, thus hampering comparability between trials. This heterogeneity was confirmed through a survey among leading international MZL experts. If PFS and TTNT definitions have been well established by the Food Drug Administration and the European Medicines Agency, a consensus shall be pursued on EFS and TTF definitions within the MZL community. Disclosures Zucca: AstraZeneca: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: 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; Merck: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biomedicine: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Gilead, Kite: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Support. Thieblemont: Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Takeda: 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, Other: Travel, Accommodations, Expenses ; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses .

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Phase 2 Study of Zanubrutinib (BGB-3111) in Patients with Relapsed/Refractory Marginal Zone Lymphoma

Blood ◽

10.1182/blood-2019-122629 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5256-5256 ◽

Cited By ~ 1

Author(s):

Stephen Opat ◽

Robert Marcus ◽

Craig A. Portell ◽

William Reed ◽

Chris Tankersley ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Marginal Zone ◽

Marginal Zone Lymphoma ◽

Phase 2 ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration, and adhesion. Inhibition of BTK has emerged as a strategy for targeting B-cell malignancies including marginal zone lymphoma (MZL). Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. Increased specificity may minimize toxicities reported with ibrutinib potentially due to off-target inhibition such as diarrhea, thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue (Coutre et al. Blood Advances 2019). In non-clinical studies, zanubrutinib has been shown to be highly potent, selective, bioavailable, and irreversible, with potentially advantageous pharmacokinetic and pharmacodynamic properties. Complete and sustained BTK occupancy has been observed with zanubrutinib treatment in both peripheral blood mononuclear cells and in lymph nodes (Tam et al. Blood 2019). Based on drug-drug interaction studies and population PK analyses (internal data), zanubrutinib may be co-administered with strong or moderate CYP3A4 inhibitors at a reduced dose, proton pump inhibitors, vitamin K antagonists, as well as direct oral anticoagulants. Zanubrutinib does not prolong the QT interval. Pooled clinical data from 6 zanubrutinib monotherapy trials including 682 patients with either non-Hodgkin lymphoma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia suggests that zanubrutinib has been generally well tolerated amongst patients with B-cell malignancies (Tam et al. EHA 2019). This data further showed that some toxicities often associated with BTK inhibitors were infrequent with zanubrutinib, including 1.9% atrial fibrillation/flutter (0.6% grade ≥3), 2.5% major hemorrhage (2.1% grade ≥3), 10.9% fatigue (0.7% grade ≥3), 18.0% rash (0.1% grade ≥3), 18.3% thrombocytopenia (6.6% grade ≥3), and 19.4% diarrhea (0.9% grade ≥3). Early clinical data from a phase 1 study demonstrated responses in 7 of 9 patients with relapsed/refractory (R/R) MZL treated with zanubrutinib (Tam et al. ASH 2017); the remaining 2 patients had stable disease indicating an encouraging rate of overall disease control. Study Design and Methods: This ongoing global phase 2, single-arm, open-label study (MAGNOLIA; NCT03846427) is examining zanubrutinib monotherapy in patients with R/R MZL who have received 1 or more prior lines of systemic therapy (Figure). Eligible patients must have histologically confirmed diagnosis of MZL including splenic, nodal, and extranodal subtypes, have received prior anti-CD20 antibody therapy, and have measurable disease. Patients must have documented clinical need for therapy as well as adequate marrow and organ function. Patients are treated with oral zanubrutinib at 160 mg twice daily until progressive disease, unacceptable toxicity, or withdrawal of consent. The primary efficacy endpoint is ORR according to the Lugano Classification (Cheson et al. J Clin Oncol. 2014) measured by computed tomography and bone marrow assessment data as determined by an independent review committee (IRC). A 2-sided Clopper-Pearson 95% CI for ORR will be calculated. Key secondary endpoints include ORR by investigator assessment, time to and duration of response, time to treatment discontinuation, progression-free survival (all determined by IRC and investigator assessments), overall survival, safety, and patient-reported outcomes. All patients are tested for the MYD88 mutation at study entry. Recruitment is ongoing. Disclosures Opat: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Epizyme: Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Novartis: Consultancy. Marcus:Gilead: Consultancy; Roche: Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Other: Travel, Accommodations, Expenses; Roche-Genentech: Honoraria. Portell:Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; Acerta/AstraZeneca: Research Funding; Kite: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Bayer: Consultancy; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Research Funding; Pharmacyclics: Consultancy. Reed:BeiGene: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Tankersley:BeiGene: Employment, Equity Ownership. Huang:BeiGene: Employment, Equity Ownership. Trotman:Pharmacyclics: Research Funding; Roche: Research Funding; BeiGene: Research Funding; Janssen: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US

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Causes of Death in Non-Follicular Indolent B-Cell Lymphoma in the Rituximab Era

Blood ◽

10.1182/blood-2020-139814 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Aung M Tun ◽

Raphael Mwangi ◽

Brian K. Link ◽

Andrew L. Feldman ◽

Matthew J. Maurer ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Board Of Directors ◽

Cause Of Death ◽

Research Funding ◽

Marginal Zone ◽

B Cell Lymphoma ◽

Marginal Zone Lymphoma ◽

Advisory Committees ◽

Common Cause

Background: Indolent B-cell lymphomas are a group of neoplastic disorders that account for approximately one-third of non-Hodgkin lymphomas in the Western world. They are clinically indolent but pathologically diverse and generally composed of follicular lymphoma (FL), extranodal marginal zone lymphoma (EMZL), lymphoplasmacytic lymphoma (LPL), nodal marginal zone lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), and small lymphocytic lymphoma. The overall prognosis is favorable in most patients, but others can have a more aggressive disease with associated progression, relapse, or histologic transformation. We have previously reported that the most common cause of death in FL was lymphoma. Here we report on the cause of death (COD), in other non-follicular indolent B-cell lymphomas (NFIBL) during the first decade of the rituximab era. Methods: Participants were from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). From 2002 -2015, MER offered enrollment to all patients with newly diagnosed lymphoma who were US residents and age >18 years. Patients were treated per physician choice and followed prospectively. An event was defined as progression or relapse, initiation of 2nd line therapy, or death from any cause. EFS24 was defined using event-free survival at 24 months from diagnosis. Overall survival was defined as the time from diagnosis until death due to any cause. Overall survival from EFS24 was defined as time from event defining date (achieving EFS24 or early event). For decendents, copies of the death certificate or medical records associated with death were reviewed. Cumulative incidence estimates of the cause of death in NFIBL were calculated as competing risks utilizing the cuminc function from the cmprsk package in R version 3.6.2. COD was categorized as a result of lymphoma (progression or therapy-related) vs. other causes vs. unknown/missing. Results: 820 patients with newly diagnosed NFIBL were enrolled in this study. The subtypes included extranodal marginal zone (EMZL, N = 362), unclassifiable low-grade B-cell lymphoma (LGBCL-U, N = 202), lymphoplasmacytic lymphoma (LPL, N = 92), nodal marginal zone lymphoma (NMZL, N = 80), and splenic marginal zone lymphoma (SMZL, N = 84). The median age at diagnosis was 63 years (range 18-92), and 50.5% were male. Baseline clinicopathologic characteristics showed that the LDH was abnormal in 19.3%, hemoglobin was abnormal in 33.8%, and 62.8% had stage III-IV disease. The IPI score was 0-1 in 51%, 2 in 36.6%, 3 in 10.6%, and 4-5 in 1.8%. At a median follow-up of 83 months (range 0-193), 172 (21%) patients had died, and the primary cause of death was non-lymphoma related in 87 (50.6%), lymphoma related 48 (27.9%), and unknown in 37 (21.5%). When examining all subtypes combined, the 10-year estimate for lymphoma related death was 7% (95% CI: 5.2-9.5) which was lower than the rate of non-lymphoma related death (10 years estimate 14%, 95% CI: 11.3-17.4), Figure 1A, Table 1. The 10-year estimate of lymphoma related death varied by subtype, ranging from 2.7% in EMZL to 16.3% in LPL (table 1), while non-lymphoma related death at 10 years ranged from 10.2% in EMZL to 22.5% in SMZL; only in LPL was the lymphoma related rate higher than the non-lymphoma. Patients who failed to achieve EFS24 from diagnosis had significantly higher rates of lymphoma related death (18% at 10 years from failure, 95% CI: 11.7-29.1, Figure 1B) compared to patients who achieved EFS24 (3.9% at 10 years from achieving EFS24, 95% CI: 2.3-6.8, Figure 1C). Rates were similar by EFS24 for non-lymphoma related death (14.5%, 95% CI: 11.0-19.0 vs. 11.2, 95% CI: 6.3-19.7). Figure 1B-C. Conclusion: The most common cause of death in NFIBL at 10 years was unrelated to lymphoma, in contrast to our previous data in follicular lymphoma which showed lymphoma as the most common cause of death at 10 years. However, similar to follicular lymphoma, patients with NFIBL who failed to achieve EFS24 to frontline therapy had significantly increased risk of lymphoma related death. Further research into the cause of death in NFIBL is warranted. Disclosures Maurer: Celgene / BMS: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Witzig:Celgene: Consultancy, Research Funding; MorphSys: Consultancy; AbbVie: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy. Novak:Celgene/BMS: Research Funding. Farooq:Kite, a Gilead Company: Honoraria. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding.

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Outcomes and Toxicities of Ibrutinib in Marginal Zone Lymphoma: A Retrospective Cohort Study at a Single Institution

Blood ◽

10.1182/blood-2019-128556 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5250-5250

Author(s):

David M. Weiner ◽

Nathaniel D. Robinson ◽

Steven M. Bair ◽

Hatcher J. Ballard ◽

Mitchell E. Hughes ◽

...

Keyword(s):

Clinical Trial ◽

Tyrosine Kinase ◽

Board Of Directors ◽

Research Funding ◽

Marginal Zone ◽

Response Rate ◽

Marginal Zone Lymphoma ◽

Advisory Committees ◽

Bruton's Tyrosine Kinase ◽

Anti Cd20

Background: Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor that was recently approved by the FDA for treatment of patients (pts) with relapsed/refractory marginal zone lymphoma (MZL) who have already received one or more anti-CD20 containing treatment regimens and require systemic therapy. Approval was based on a clinical trial in 60 pts that showed durable responses and a median progression-free survival (PFS) of 14.2 months (mos) (Noy et al., Blood 2017). Since pts outside clinical trials may have different disease and demographic characteristics, our study investigates the safety and efficacy of ibrutinib when implemented in a non-trial setting. Materials and Methods: This is a retrospective analysis of MZL pts who received ibrutinib monotherapy as part of their treatment at the University of Pennsylvania. Subjects were identified by a database search for any MZL pts prescribed ibrutinib. Primary endpoints were PFS and overall survival (OS) since initiation of ibrutinib. Secondary endpoints were overall response rate (OR) and complete response rate (CR), adverse events, and reasons for discontinuation. The first patient was treated on April 10, 2014, and the data cutoff was July 1, 2019. Analyses were performed using STATA 15.0 software. Results: There were 28 pts included in this study with a median age of 69 years (range 36-90) and median ECOG performance status at diagnosis of 0 (range 0-2). All pts had advanced disease (all stage III/IV & 68% with bone marrow involvement). The distribution of MZL subtypes was 43% extranodal, 25% nodal, and 32% splenic. Most pts (89%) had received one or more treatments prior to ibrutinib (32% received first-line rituximab only). The median number of previous therapies was 2 (range 0-5), and 43% of pts were refractory to the previous line of therapy. A minority of pts (11%) received rituximab or another anti-CD20 antibody concurrently with ibrutinib. Pts started ibrutinib a median of 56 mos after their initial diagnosis (range 0.5-221 mos) with a median duration of therapy of 7 mos (range 0.7-62 mos). The median starting dose was 420 mg daily (range 70-560 mg daily). In 26 pts with response data available, the OR was 73% with CR 15%. The 12-mo PFS and OS were 77% and 87% respectively (see Figures 1 & 2, median PFS and OS not yet reached). PFS and OS at median follow-up were 55% and 69% respectively. There was no significant difference in response or survival rates among MZL subtypes. Pts who received rituximab only prior to ibrutinib had an OR of 86% compared to 69% in those with more than one previous therapy (Χ2 = 0.73, p = 0.39). Ibrutinib was discontinued in 43% of pts after a median of 2.9 mos (range 0.7-13.7 mos) due to disease progression (50%), intolerance (42%), or other reasons (8%). Most (67%) pts subsequently received other therapies. All pts who stopped due to toxicity were responding at the time of discontinuation. Ibrutinib was also temporarily held or dose-reduced in 46% of pts due to toxicity (77%), preparation for surgery (15%), or drug interactions (8%). One patient experienced acute rebound of symptoms until ibrutinib was restarted. Most commonly reported toxicities are summarized in Table 1. Grade 3 toxicities included pneumonia (7%), sepsis (4%), hemorrhage (4%), arthralgia (4%), fatigue (4%), URI (4%), and hepatitis (4%). Toxicities responsible for cessation of treatment were arthralgia, hepatitis, thyroiditis, and hemorrhage. There were no reported treatment-related deaths. Conclusion: To our knowledge, this is the first study to report the efficacy and safety of ibrutinib in a large cohort of MZL pts treated outside of a clinical trial. We found that the therapy was well-tolerated and observed response rates that compared favorably to those shown in the prospective clinical trial. Disclosures Hughes: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Acerta Pharna/HOPA: Research Funding. Dwivedy Nasta:47 (Forty Seven): Research Funding; Rafael: Research Funding; Millenium/Takeda: Research Funding; Debiopharm: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Roche: Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding. Barta:Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria. Chong:Novartis: Consultancy; Merck: Research Funding; Tessa: Consultancy. Schuster:Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria; Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. OffLabel Disclosure: This paper looked at the effectiveness of ibrutinib, a Bruton's tyrosine kinase inhibitor, in treating patients with marginal zone lymphoma (MZL). Ibrutinib is FDA approved for MZL patients who have received at least one anti-CD20 containing therapy and now require systemic treatment. Some patients in the study had not previously received an anti-CD20-based therapy and received ibrutinib off-label.

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Multicenter Analysis of Treatment and Outcomes for Patient with TP53 Mutated AML in the Era of Novel Therapies; Significant Impact of Allogeneic Stem Cell Transplantation on Survival

Blood ◽

10.1182/blood-2021-147639 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 797-797

Author(s):

Talha Badar ◽

Mark R. Litzow ◽

Rory M. Shallis ◽

Jan Philipp Bewersdorf ◽

Antoine Saliba ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Advisory Board ◽

Novel Therapies ◽

Advisory Committees ◽

Tp53 Mutations

Abstract Background: TP53 mutations occur in 10-20% of patients with AML, constitute high-risk disease as per ELN criteria, and confer poorer prognosis. Venetoclax combination therapies and CPX-351 were recently approved for AML treatment and lead to improved outcomes in subsets of high-risk AML, however the most effective approach for treatment of TP53-mutated (m) AML remains unclear. In this study we explored the clinical outcome of TP53m AML patients treated over the last 8 years as novel therapies have been introduced to our therapeutic armamentarium. Methods: We conducted a multicenter observational study in collaboration with 4 U.S. academic centers and analyzed clinical characteristics and outcome of 174 TP53m AML patients diagnosed between March 2013 and February 2021. Mutation analysis was performed on bone marrow specimens using 42, 49, 199, or 400 gene targeted next generation sequencing (NGS) panels. Patients with an initial diagnosis of AML were divided into 4 groups (GP) based on the progressive use of novel therapies in clinical trials and their approvals as AML induction therapy during different time periods: 2013-2017 (GP1, n= 37), 2018-2019 (GP2, n= 53), 2019-2020 (GP3, n= 48) and 2020-2021 (GP4, n= 36) to analyze difference in outcome. Results: Baseline characteristics were not significantly different across different GP, as shown in Table 1. Median age of patients was 68 (range [R], 18-83), 65 (R, 29-88), 69 (R, 37-90) and 70 (R, 51-97) years in GP1-4, respectively (p=0.40). The percentage of patients with de novo AML/secondary AML/therapy-related AML in GP1-4 was 40/40/20, 36/29/24, 37.5/37.5/25 and 28/52/20, respectively (p=0.82). The proportion of patients with complex cytogenetics (CG) was 92%, 89%, 96% and 94% in GP1-4, respectively (p=0.54). The median TP53m variant allele frequency (VAF) was 48% (range [R], 5-94), 42% (R, 5-91), 45% (R, 10-94) and 60% (R, 8-82) in GP1-4, respectively (p=0.38). Four (11%), 13 (24.5%), 10 (21%) and 9 (25%) patients had multiple TP53 mutations in GP1-4, respectively (p=0.33). The proportion of patients who received 3+7 (30%, 16%, 6% & 8%; p=0.01), HMA only (11%, 18%, 2% & 8%; p=0.06), venetoclax-based (2.5%, 12%, 48%, & 61%; p <0.01) and CPX-351 induction (16%, 40%, 28% & 5%; p<0.001) were varied in GP1-4, respectively. The rate of CR/CRi was 22%, 26%, 28% and 18% in GP1-4, respectively (p=0.63). Treatment related mortality during induction was observed in 3%, 7%, 10% and 17% of patients in GP1-4, respectively (p=0.18). Overall, 28 (16%) patients received allogeneic hematopoietic stem cell transplantation (alloHCT) after induction/consolidation: 22%, 15%, 17% and 11% in GP1-4, respectively (p=0.67). In subset analysis, there was no difference in the rate of CR/CRi with venetoclax-based regimens vs. others (39% vs 61%, p=0.18) or with CPX-351 vs. others (25% vs 75%, p=0.84). The median progression-free survival was 7.7, 7.0, 5.1 and 6.6 months in GP1-4, respectively (p=0.60, Fig 1A). The median overall survival (OS) was 9.4, 6.1, 4.0 and 8.0 months in GP1-4, respectively (p=0.29, Fig 1B). In univariate analysis for OS, achievement of CR/CRi (p<0.001) and alloHCT in CR1 (p<0.001) associated with favorable outcome, whereas complex CG (p=0.01) and primary refractory disease (p<0.001) associated with poor outcome. Multiple TP53 mutations (p=0.73), concurrent ASXL1m (p=0.86), extra-medullary disease (p=0.92), ≥ 3 non-TP53m mutations (p=0.72), TP53m VAF ≥ 40% vs. < 40% (p=0.25), induction with CPX-351 vs. others (p=0.59) or venetoclax-based regimen vs. others (p=0.14) did not show significance for favorable or poor OS in univariate analysis. In multivariable analysis, alloHCT in CR1 (hazard ratio [HR]=0.28, 95% CI: 0.15-0.53; p=0.001) retained an association with favorable OS and complex CG (HR 4.23, 95%CI: 1.79-10.0; p=0.001) retained an association with dismal OS. Conclusion: We present the largest experience with TP53m AML patients analyzed by NGS. Although outcomes were almost universally dismal, alloHCT appears to improve the long-term survival in a subset of these patients. Effective therapies are warranted to successfully bridge patients to alloHCT and to prolong survival for transplant ineligible patients. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Goldberg: Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; Arog: Research Funding; DAVA Oncology: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah: BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Foran: revolution medicine: Honoraria; gamida: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; takeda: Research Funding; kura: Research Funding; h3bioscience: Research Funding; OncLive: Honoraria; servier: Honoraria; aptose: Research Funding; actinium: Research Funding; abbvie: Research Funding; trillium: Research Funding; sanofi aventis: Honoraria; certara: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

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Primary Plasma Cell Leukemia Outcomes Remain Dismal Despite Novel Agents and Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2019-127049 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 266-266

Author(s):

Sagar Patel ◽

Saulius K. Girnius ◽

Binod Dhakal ◽

Lohith Gowda ◽

Raphael Fraser ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Plasma Cell ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Disease Status ◽

Cell Leukemia ◽

Advisory Committees ◽

Primary Plasma Cell Leukemia ◽

Equity Ownership

Background Primary plasma cell leukemia (pPCL) is a rare plasma cell neoplasm with a high mortality rate. There have been improvements in multiple myeloma (MM) outcomes with novel induction agents and use of hematopoietic cell transplantation (HCT) with maintenance, but similar progress has not been reported for pPCL. We examined the outcomes of pPCL patients receiving novel agents with autologous (autoHCT) or allogeneic (alloHCT) approaches as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) in the modern era. Methods From 2008 to 2015, 348 pPCL pts underwent HCT (N = 277 - autoHCT and 71 - alloHCT) with 45% and 48% having research level data available, respectively. Cumulative incidences of non-relapse mortality (NRM) and relapse/progression (REL), and probability of progression-free survival (PFS) and overall survival (OS) were calculated. Cox multivariate regression was used to model survival after autoHCT only. Median follow-up in autoHCT and alloHCT was 48 and 60 months, respectively. Results AutoHCT Cohort Median age was 60 years and 93% received HCT within 12 months of diagnosis with 76% after a single line of induction (Table 1). 35% had high risk cytogenetics. 23% received bortezomib, doxorubicin, cisplatin, cyclophosphamide, and etoposide (VDPACE). Moreover, 40% received bortezomib (BTZ) and immunomodulatory drug (IMIID)-based triplets. Disease status at HCT was VGPR or better in 47%. 27% received maintenance therapy. At 4 years post-HCT, NRM was 7% (4-11%), REL 76% (69-82%), PFS 17% (13-23%), and OS 28% (22-35%) (Figures 1A, 2A, 2B). Disease status ≥VGPR at HCT and Karnofsky Performance Score >90 significantly predicted superior OS in multivariate analysis. AlloHCT Cohort Median age was 53 years and 89% received HCT within 12 months of diagnosis (Table 1). 61% received a single alloHCT, while 39% used auto-alloHCT tandem approach. 42% had high-risk cytogenetics. 61% received total body irradiation with 44% receiving myeloablative conditioning. Use of VDPACE was higher at 41% in this cohort. VGPR status at HCT was similar (48%), while maintenance was used less often (12%). Grade II-IV acute GVHD occurred in 30% and chronic GVHD in 45%. At four years post-HCT, NRM was 12% (5-21%), REL 69% (56-81%), PFS 19% (10-31%), and OS 31% (19-44%) (Figures 1A, 1B, 2A, 2B). There were no differences in outcomes based on type of HCT. A comparison of post-HCT outcomes of CIBMTR pPCL patients from 1995 to 2006 showed that PFS and OS outcomes are inferior despite lower NRM in this modern cohort (Mahindra et al. Leukemia. 2012). In addition, analysis of SEER (1995-2009) and CIBMTR databases showed that use of HCT increased from 12% (7-21%) in 1995 to 46% (34-64%) in 2009. Conclusion More newly diagnosed pPCL patients are receiving modern induction regimens translating into a higher proportion receiving HCT, but without significant further benefit post-HCT. Post-HCT relapse remains the biggest challenge and further survival in pPCL will likely need a combination of targeted and cell therapy approaches. This study provides a benchmark for future HCT studies for pPCL. Disclosures Girnius: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dhakal:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria. Shah:University of California, San Francisco: Employment; Indapta Therapeutics: Equity Ownership; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: 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; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Qazilbash:Amgen: Consultancy, Other: Advisory Board; Bioclinical: Consultancy; Autolus: Consultancy; Genzyme: Other: Speaker. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria.

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Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

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