Assessment of Clinical Differences Between Starting Antimyeloma Treatment at Biological Relapse or at Clinical Relapse: Preliminary Results of an Observational Prospective Registry

Abstract Introduction: In recent years, the multiple myeloma (MM) treatment (Tx) landscape has evolved considerably, with the approval of effective novel agents, such as immunomodulatory drugs (thalidomide, lenalidomide, and most recently, pomalidomide) and proteasome inhibitors (bortezomib and carfilzomib; Chng et al, Leukemia, 2014). However, most patients relapse and patterns of relapse in MM can be heterogeneous (Alegre et al, Haematologica, 2002). Tx rescue for MM relapse should begin at symptomatic clinical relapse (clinR) and probably earlier at asymptomatic biological relapse (BR; specifically when significant paraprotein relapse), according to the International Myeloma Workshop Consensus Panel (Rajkumar et al, Blood, 2011). In the case of asymptomatic BR/progression, rescue Tx could be delayed in a subset of pts (Fernández de Larrea et al, Bone Marrow Transplant, 2014), particularly when M-component and hemoglobin levels are stable. Progressive increases of M-spike blood and/or urine could lead to rescue Tx, even in the absence of clinical symptoms, to avoid complications (ie, renal failure, plasmacytomas, bone lesions; Castelli et al, Clin Med Insights Oncol, 2013). This Spanish registry (EPA-MMBR) is an observational prospective study to describe MM relapse patterns, comparing the impact of Tx decisions (starting Tx at BR vs delaying Tx until clinR). We present the updated preliminary results of this study. Methods: MM pts in (or prior to) first or second BR who had achieved ≥ PR since their last Tx were included. Bi-monthly evaluations were performed. Forty-one Spanish sites are participating after approval from their independent ethics committees, with 410 pts expected to be included. The main objective was to assess time to progression (TTP) from BR in both groups (pts who started Tx at the onset of asymptomatic BR vs pts who started Tx at clinR). Secondary objectives included demographic, clinical, and Tx characteristics; median time from BR to clinR; and response rates. Here we present the results of 138 pts with baseline data (48.4%) of a total of 285 registered. Results: In the cohort evaluated (n = 138), mean age was 67.9 years, and 50.7% were male. MM types were IgG Κ (43.5%), IgG λ (22.1%), IgA Κ (16%), and IgA λ (7.6%). Prognostic stage at diagnosis according to the International Staging System (ISS) was II (32.6%) followed by I and III (22.7% each) and data not available (22%). Pts' cytogenetic risk included standard risk (20.8%), high risk (8.5%), and no cytogenetic alterations (32.3%). More than half of pts (51.5%) had received autologous stem cell transplant, 13.2% consolidation and 21.1% maintenance. After first-line Tx, pts had achieved sCR (16.0%), CR (33.6%), VGPR (28.8%), or PR (21.6%). Pts with BR had a median time from diagnosis to BR of 2.66 years. Tx was delayed until clinR in 51.2% of pts, and 48.8% had started Tx at BR (73.3% of whom had significant paraprotein relapse; Figure); there were no relevant differences in demographic and clinical characteristics between the 2 groups. Median time to BR was 31.97 months. Median time from BR to clinR was 105.0 days. Among pts who started Tx at BR, most pts received lenalidomide-based Tx (75% at first relapse and 70.6% at second relapse). At the time of the analysis, only 3 pts had disease progression (1 in each group). In pts who started Tx at BR, first-line Tx after diagnosis was mainly bortezomib-based (73.3%). sCR was achieved in 20.0% of pts, CR in 33.3%, PR in 26.7%, and VGPR in 20.0%. Since the beginning of the study, Tx was prescribed in 54 pts (39.1%). Since only 3 pts had progressed, further follow-up data, particularly in terms of TTP and survival, are needed to identify differences between these 2 strategies. Conclusions: To our knowledge, this is the first prospective study in MM that evaluates the effects of starting Tx at BR vs starting Tx at clinR. In this updated cohort, we find that almost half of pts started Tx at BR (48.8%). We also found that a higher percentage of pts started Tx at BR with significant paraprotein relapse (73.3%), which seems to be a clear factor guiding Tx decision for the physician. Further follow-up and a complete study are needed to identify the differences between these 2 strategies and to define patients who could benefit from early Tx. Figure 1. Percentage of pts who started Tx at clinR, BR, or significant paraprotein relapse (n = 138). Figure 1. Percentage of pts who started Tx at clinR, BR, or significant paraprotein relapse (n = 138). Disclosures Gironella: Celgene Corporation: Consultancy, Honoraria. Fernández de Larrea:Celgene Corporation: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Lahuerta:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cabañas:Amgen: Membership on an entity's Board of Directors or advisory committees. Lostaunau:Celgene SLU: Employment. Vilanova:Celgene SLU: Employment. Alegre:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

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Observational Prospective Registry for the Assessment of the Clinical Impact of Starting Anti-Myeloma Treatment at Biological Relapse

Blood ◽

10.1182/blood.v124.21.4765.4765 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4765-4765

Author(s):

Adrian Alegre ◽

Merche Gironella ◽

Juan Miguel Bergua ◽

Esther Gonzalez ◽

Fernando Escalante ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Marrow Transplant ◽

Clinical Relapse ◽

First Line ◽

Advisory Committees ◽

Free Survival

Abstract Introduction: Despite the great medical advances associated with the introduction of thalidomide, bortezomib (BORT), and lenalidomide (LEN) for the treatment of multiple myeloma (MM), it remains an incurable disease. Most patients (pts) show disease progression, consistent with the clinical evolution of MM, and only a low percentage achieve long-term responses and extended progression-free survival (PFS). The heterogeneous nature of MM in both the clinical and biological setting is reflected in the heterogeneity of MM relapses. The International Myeloma Workshop Consensus Panel (Rajkumar, Blood 2011) states that treatment (Tx) shall begin either at clinical relapse with symptoms (clinR), or in the event of asymptomatic relapse with significant paraprotein relapse, biological relapse (BR). The purpose of this Spanish registry is to describe MM relapse patterns comparing the impact of Tx decisions in pts who meet the criteria for biological relapse (BR) according to IMWG criteria with those in whom Tx was delayed until clinical relapse (clinR). Here, the preliminary results of this study are presented. Methods: MM pts in (or previous to) first or second BR who have achieved ≥ PR since their last Tx are eligible for inclusion in this observational prospective registry at the time BR is detected. Evaluations performed at least bi-monthly are mandatory. A total of 41 Spanish sites participated in the registry following approval from their independent ethics committees, with 410 pts expected to be included, without physician’s decision of prescribing Tx affecting the inclusion. The main objective of the registry is to assess the time to progression (TTP) from the start of anti-MM Tx at the onset of asymptomatic BR vs. the start of Tx at the time of clinR. Secondary objectives are to describe demographics of BR; to assess the median time elapsing from BR to clinR; to assess overall response rate (ORR), event-free survival (EFS), PFS, overall survival (OS) at BR and at clinR (if appropriate); to asses safety and quality of life (QoL) using 2 validated questionnaires (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and QLQ-MY24); to document the tolerability profile of the Tx; and to describe the use of associated resources. Here, we summarize baseline characteristics and preliminary results from 83 pts (out of 126 registered pts) who had basal data in the registry at the time of this report. Results: Overall, 79% of pts presented with a BR and 21% were in a bi-monthly watchful waiting follow up. The mean age of pts was 67 years, 53% were female, 57% were in first relapse, 43% and 27% had an ECOG performance status (PS) of 0 and 1, respectively, while the ECOG PS was unknown in 30% of pts at the time of this report. In total, 30% of pts had ISS stage I, 26% had ISS stage II, and 22% had ISS stage III, while ISS stage data were not available or unknown for 12% and 10% of pts, respectively. MM types were IgG Κ (37% of pts), IgG λ (23%), IgA Κ (13%), IgA λ (9%), and type was unknown in 17% of pts. 28% of IgG/IgA MM types were Bence-Jones. Cytogenetic risk assessments were available in 66% of pts. Among those pts with a BR, 51% received active Tx without waiting for a ClinR. First-line Tx was BORT-based in 70% of pts. Overall, 55% of pts had undergone autologous stem cell transplantation, 15% had received consolidation Tx and 34% had received maintenance Tx. After first-line Tx, 17% of pts achieved a stringent complete response (sCR), 31% achieved a CR, 24% achieved a very good partial response (VGPR), and 10% achieved a PR. The median time to BR was 24.53 months. Most (63%) pts who registered after second relapse received LEN-based Tx. Conclusions: To our knowledge, this is the first prospective study in MM to evaluate BR as well as the effects of Tx based on the decision to start Tx at BR vs. clinR. In this preliminary cohort, the physicians’ decision to start active Tx at BR, before the onset of clinR in 50% of cases, was noteworthy. Further follow-up is needed to identify the differences between these two strategies. Updated clinical results will be presented at the meeting. MM-BR Study, Spanish Myeloma Group-GEM/PETHEMA Bibliography Alegre A, et al. Haematologica. 2002;87:609-14. Brioli A, et al. Blood. 2014;123:3414-9. Fernández de Larrea C, et al. Bone Marrow Transplant. 2014;49:223-7. Lenhoff S, et al. Haematologica. 2006;91:1228-33. Rajkumar SV, et al. Blood. 2011;117:4691-5. Zamarin D, et al. Bone Marrow Transplant. 2013;48:419-24. Disclosures Alegre: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lahuerta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ruiz:Celgene: Celgene Stock options as part of the employee's compensation plan Other, Employment. Vilanova:Celgene: Contracted by Celgene Other.

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The Outcome of Treatment-Free Remission after First-Line Nilotinib or Dasatinib in Chronic Phase Chronic Myeloid Leukemia Patients Is Different

Blood ◽

10.1182/blood-2021-146722 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2552-2552

Author(s):

Franck E. Nicolini ◽

Vincent Alcazer ◽

Stephanie Dulucq ◽

Sandrine Hayette ◽

Jean-Michel Cayuela ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Chronic Phase ◽

Median Dose ◽

First Line ◽

Advisory Committees ◽

French Group ◽

Treatment Free Remission ◽

The Impact

Abstract Aims: The absolute number of chronic phase CML patients (pts) reaching the treatment-free remission (TFR) criteria has been substantially increased by the use of second-generation TKI (TKI2), initiated since diagnosis, comparing to Imatinib first-line. However, the relative rate of unsuccessful TFR (i. e. pts loosing their MMR after TKI2 cessation) still remains around 50% at 2 years and beyond, whatever the TKI2 was. The aim of this study is to analyse the rate of successful TFR in pts receiving Nilotinib (Nilo) or Dasatinib (Dasa) first-line obtaining the appropriate criteria. Methods: Observational retrospective study in 3 reference centers of the French group of CML lead between 2010 and 2021. Eligible pts were CP CML pts initiating either Nilo 300 mg BID or Dasa 100 mg daily since diagnosis, until cessation for sustained MR4.5 (i.e. ≥2 years on ≥4 datapoints). Data were retrospectively collected according to the national regulations with pts' information. All pts were assessed and followed according to ELN recommendations 2009, 2013 and 2020 along treatment and to the recommendations from the French group of CML (D. Rea et al., Cancer 2018) for TFR. In this regard, the TKI2 was resumed in case of loss of MMR. All BCR-ABL1 assessments were performed in the 3 reference laboratories, standardised and expressed in % (IS) with ≥32,000 copies of ABL1 as control. All patients were harbouring major BCR-ABL1 transcripts. The primary endpoint was the survival without loss of MMR after TKI2 cessation. The secondary endpoints were the kinetics of MMR loss, and the identification of factors influencing MMR loss. Results: Seventy-two pts were reported (47 Nilo, 25 Dasa) with 57% females with a median age at diagnosis of 48 (36.75-61.25) years. The median follow-up since diagnosis was 9.26 (3.75-13.75) years (8.8 for Nilo and 9.47 for Dasa p=ns) and after TKI2 cessation 3.94 (0.7-8.8) years (3.92 for Nilo and 3.90 for Dasa p=ns). Sokal scores were 42% Low, 41% Intermediate, 17% High in Nilo and 39% L, 25% I and 35% H in Dasa pts (p=ns). ELTS scores were 50% L, 22% I, 9.5% H (18.5% Uk) in Nilo and 46.5% L, 28.5% I and 3.5% H (21.5% Uk) in Dasa pts (p=0.95). Five (9%) pts harboured ACA at diagnosis in the Nilo group and 2 (7%) in the Dasa group (p=1.00). The median time from TKI2 initiation to sustained MR4.5 was 19 (3.12-36) months in the Nilo group and 16 (6.3-39) months in the Dasa group (p=0.644). The duration of sustained MR4.5 until cessation was 3.04 (1.5-9.3) years for Nilo and 2.65 (1.11-7.95) for Dasa (p=0.96). The median dosing of Nilo was 600 (300-800) mg daily and 80 (20-100) mg at TKI2 cessation. None of these patients switched to another TKI during the follow-up. TKI2 cessation occurred after 60.5 (43-74.5) months in the Nilo group and 68 (39-90) months in the Dasa group (p=0.581). Thirty-seven pts out of 47 (79%) were BCR-ABL1 undetectable at Nilo cessation 18/25 (72%) at Dasa cessation (p=0.60). At M3 after discontinuation, 58% of pts remained undetectable after Nilo cessation and 30.4% after Dasa cessation (p=0.05).The median survival of pts without loss of MMR was not reached in the Nilo group, and was 14 (4.73-NR) months in the Dasa group, (p=0.042) as analysed by the KM method (Figure 1.). Two patients died (1 Nilo, 1 Dasa) from competing events (solid tumours) after unsuccessful TFR. Twenty-eight pts (14 Dasa, 14 Nilo) restarted their TKI2 after MMR loss and all regained ≥ MMR after 3 months of Dasa at a median dose of 75 (40-100) mg daily and all except one (who regained MMR at M12) after resumption of Nilo at a median dose of 350 (300-600) mg daily. Univariate analysis identified pts with H+I Sokal (as compared to low) as an unfavourable factor for successful TKI2 cessation [HR=0.35 (0.15-0.83), p=0.017] and type of TKI2 (Nilo as reference vs Dasa) was discriminant [HR=2.1 (1.01-4.35), p=0.047]. Multivariate analysis identified the type of TKI2 as a significant factor impacting on TFR outcome [HR 2.11 (0.97-4.55], p=0.05]. Conclusions: As it is likely that no prospective head-to-head comparison will be performed in this setting, on this limited series of pts, we conclude that the outcome of TFR seems to be different according to the TKI2 used since diagnosis, suggesting the impact of distinct biological variables modified by the type of TKI2 on the long run (such as immunological system, BM micro-environment, others) on TFR outcome. Figure 1 Figure 1. Disclosures Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Etienne: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Overview of Primary and Secondary Myelofibrosis in Young Adults: Genomic Characteristics, Treatment Strategies and Outcomes

Blood ◽

10.1182/blood-2019-123536 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4177-4177

Author(s):

Andrew T Kuykendall ◽

Chetasi Talati ◽

Kendra L. Sweet ◽

Eric Padron ◽

David A Sallman ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Treatment Strategies ◽

Cell Transplant ◽

Advisory Committees ◽

Treatment History ◽

Secondary Myelofibrosis

Introduction: Primary and secondary myelofibrosis (MF) [i.e. occurring after a prior diagnosis of polycythemia vera [PV] or essential thrombocythemia (ET)] are myeloid malignancies often diagnosed in the 6th and 7th decade of life. In the rare occurrence that younger patients receive this diagnosis, prognostic recommendations are poorly extrapolated and optimal treatment strategies are unclear. Prior studies assessing young MF patients have suggested a more indolent course for this cohort. Here we aim to analyze our experience with young MF patients in terms of genetic makeup, treatment history, and outcomes. Methods: We assessed a database of primary and secondary MF patients who presented to our center between 1/2000 and 6/2019. We identified patients who were 50 years or younger at the time of MF diagnosis. Clinical and genetic features along with treatment history and outcomes were analyzed. Kaplan-Meier method was used for survival analysis. Patients surviving at 240 months after diagnosis were censored at that time. Results: Among 599 MF patients, 63 (11%) were ≤50 at the time of diagnosis. Median age at diagnosis was 43.6 years (yr). Median time from diagnosis to first presentation to our institution was 4.2 months (mo) (range 0-35 yr). Thirty-eight (60%) and 44 (70%) were seen within 1 and 5 years of diagnosis, respectively. Females accounted for 62% (n = 39) of patients. Forty-five (71%) patients had primary MF, 4 (6%) had post-PV MF and 13 (21%) post-ET MF. Median follow-up for the cohort was 94.9 mo. Among 62 patients in whom IPSS at diagnosis could be calculated, 20 (32%) were low, 27 (44%) intermediate-1, 12 (19%) intermediate-2, and 3 (5%) high-risk. JAK2 mutation was detected in 22/60 (37%), CALR in 21/44 (48%), MPL in 0/49 (0%). One patient was triple-negative. Extended targeted gene sequencing was performed in 42/63 patients during their clinical course. Sequencing occurred at a median time of 2.6 yr after diagnosis (range 0-35 yr). Genes most commonly mutated were ASXL1 (12%), TET2 (12%), EZH2 (10%), and DNMT3A (10%). No mutations involving SRSF2, U2AF1, ZRSR2, or SF3B1 were seen. Thirteen patients did not receive active treatment during follow-up. Among those receiving treatment, median time to first treatment was 9.4 mo (range 0-331 mo). The most common initial treatments were erythropoiesis-stimulating agents (ESAs) (14%), hydroxyurea (28%), and ruxolitinib (22%). In total, 29 (46%) received ruxolitinib with median time to ruxolitinib treatment of 27.2 mo. Median duration of ruxolitinib treatment was 44.5 mo. Fourteen patients underwent allogeneic hematopoietic stem cell transplant (AHCT) at a median of 57.4 mo after diagnosis (range 6-123 mo). Transformation to acute myeloid leukemia (AML) occurred in 5 patients at a median time of 99 mo (range 51-178 mo) after diagnosis. Median overall survival (OS) was not reached. Five and 10-year OS estimated at 93% and 77%, respectively. No difference was seen in OS for patients with primary and secondary MF (p = 0.40). Conclusions: Primary and secondary MF are rarely diagnosed in patients ≤ 50 years old. In this cohort, patients are often CALR mutant, have lower-risk disease, and lack splicing mutations. Initial treatment strategies are varied, but favor cytoreductive approaches. The prognosis in these patients is favorable, but high-risk mutations can occur and progression to AML occurs in a minority of patients. AHCT remains a curative option; however, optimal timing for transplant is not clear. Figure Disclosures Kuykendall: Celgene: Honoraria; Janssen: Consultancy; Abbvie: Honoraria; Incyte: Honoraria, Speakers Bureau. Talati:Astellas: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Agios: Honoraria; Pfizer: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Honoraria. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding. Komrokji:JAZZ: Consultancy; Agios: Consultancy; celgene: Consultancy; pfizer: Consultancy; Incyte: Consultancy; Novartis: Speakers Bureau; DSI: Consultancy; JAZZ: Speakers Bureau.

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Ibrutinib Plus Obinutuzumab and Venetoclax in Relapsed/Refractory Mantle Cells Lymphoma Patients, Results of the OASIS Phase I Clinical Trial

Blood ◽

10.1182/blood-2018-99-113777 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4158-4158 ◽

Cited By ~ 5

Author(s):

Steven Le Gouill ◽

Franck Morschhauser ◽

Krimo Bouabdallah ◽

Guillaume Cartron ◽

Rene-Olivier Casasnovas ◽

...

Keyword(s):

Drug Resistance ◽

Phase I ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Primary Objective ◽

Clinical Relapse ◽

Advisory Committees ◽

Grade 3

Abstract Background. Mantle Cell Lymphoma (MCL) drug resistance are highly dependent on B-cell-receptor signaling, Bcl-2 and the microenvironment. Ibrutinib inhibits both tumor cell proliferation and binding to the microenvironment. Venetoclax is a Bcl-2 inhibitor and Bcl-2 family members like Mcl-1 and Bcl-xL confers resistance to Venetoclax and are upregulated by the tumor microenvironment but downregulated by Ibrutinib (Touzeau, 2011, Chiron, 2015). Ibrutinib plus venetoclax has recently demonstrated high efficacy in relapsed/refractory (R/R) MCL (Tam et al NEJM 2018). Preclinical investigations show that microenvironment-dependent long-term expansion and drug resistance to venetoclax are counteracted by obinutuzumab (type II glycoengineered humanized anti-CD20 antibody) and obinutuzumab/venetoclax/ibrutinib is highly active against primary MCL cells. (Chiron Blood 2016). All together these findings gave the rational to investigate Obinutuzumab/Ibrutinib (step A) and Obinutuzumab/Venetoclax/Ibrutinib (step B) combinations. The OAsIs trial (NCT02558816) has been designed to assess the safety, tolerability and efficacy of these two combos in R/R MCL. DLTs were assessed during the first 2 months (step A) and 3 months (step B) of treatment. Methods: Oasis is a multicenter, non-randomized, phase I study. Step A evaluates the safety of obinutuzumab (1000mg IV C1D1, 8,15, C2-6 D1 and every 2 months until C24) plus Ibrutinib (560mg/d until progression) (n=9). Step B primary objective is to determine the MTD of obinutuzumab/venetoclax/ibrutinib. Venetoclax is administered from C2 (C2W1 100mg/d, C2W2 200mg/d, C2W3 400mg/d and C2W4-C6: 400, 600 or 800mg/d). A continual reassessment method is used to allocate venetoclax doses (3 patients-pts- per dose-level). Enrolment in step A and B for R/R MCL started in November 2015 and October 2016, respectively. Results. Step A (Obinutuzumab/Ibrutinib) (n=9). Median age at inclusion was 64y (range 58-82) and median lines of treatment prior to inclusion is 1 (1-4), including ASCT in 7 patients and allo-SCT in one case. Median time from diagnosis to C1D1 is 46.5m (18.4-103). Two pts presented with blastoid variant. One of nine step A patients presented TP53 mutation. Median time from diagnosis to C1D1 is 46.5m (18.5-103). During the first 3 months of treatment, there was no clinically relevant non-hematological grade 3-4 AEs. Eight grade 3-4 hematological AEs were reported in 4 pts (lymphopenia 4 ; neutropenia 4 ; thrombocytopenia 1). One patient progressed at end of C2 and died few weeks later while 7 (87%) were in CR according to Lugano criteria at end of C6. MRD status was assessed by ASO qPCR targeted to clonal immunoglobulin rearrangements in 6 /9 step A pts (one progressed before C6, data missing = 2). Of these, 4 were MRD negative in both blood and bone marrow after C6 (one remained MRD pos with no clinical relapse and underwent allo-SCT, one was not evaluated in BM). At the 12 months time point, the 3 evaluated pts remained MRD negative. With a median follow-up of 23,5m (8,9-31.6), 8 pts are alive (6 completed the 2y treatment program and are in CR). Step B (Obinutuzumab/ Ibrutinib/Venetoclax; Ven 400mg (n=3); at Ven=600mg (n=3) and Ven=800mg (n=6)). Median age at inclusion is 64.5y (range 45-74). Median lines of treatment prior inclusion is 2 (1-3), including ASCT in 8 patients. Five pts presented with blastoid MCL. TP53 status was assessed in 3/10 pts (2 ongoing). Of these 10, 3 presented TP53 mutations. Median time from diagnosis to C1D1 is 50.2m (12.8-123). The median follow-up for living pts (n=8) is 6.5m (2.5-15). During the first three months of treatment, there was no clinically relevant non-hematological grade 3-4 AEs. Twenty-nine grade 3-4 hematological AEs were reported in 7 pts (febrile neutropenia 1, neutropenia 4 ; thombopenia 4, anemia 2 and lymphopenia 3). At end of C2 , 3 achieved CR, 5 PR and 4 pts had PD. Among 9 pts assessed after C6, 5 patients were in CR (MRD analysis ongoing) Conclusion. No DLT has been reported in both step A and B. Both combinations are well tolerated and provide high disease control including CR at the molecular level. Oasis step C (obinutuzumab/venetoclax/ibrutinib) for untreated MCL pts is now open for inclusion since July 2018. Disclosures Le Gouill: Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria. Morschhauser:BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cartron:Sanofi: Honoraria; Janssen: Honoraria; Gilead Sciences: Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Gastinne:Millennium/Takeda: Honoraria. Davies:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; ADC-Therapeutics: Research Funding; Janssen: Honoraria; Karyopharma: Membership on an entity's Board of Directors or advisory committees. Herbaux:Gilead Sciences, Inc.: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Rule:Kite: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Ibrutinib for Relapsed Mantle Cell Lymphoma after Standard First Line Therapy and ASCT Is Efficacious but Does Not Overcome the Impact of POD24 - a Retrospective Study from the LWP-EBMT

Blood ◽

10.1182/blood-2019-123442 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 701-701

Author(s):

Claire Burney ◽

Stephen Robinson ◽

Ariane Boumendil ◽

Hervé Finel ◽

Irma Khvedelidze ◽

...

Keyword(s):

Board Of Directors ◽

Inclusion Criteria ◽

First Line ◽

Advisory Committees ◽

First Line Therapy ◽

Line Therapy ◽

Mantle Cell ◽

Duration Of Response ◽

The Impact

Introduction Standard first line treatment for mantle cell lymphoma (MCL) in fit patients is induction with cytarabine containing chemo-immunotherapy and a consolidative autologous stem cell transplant (ASCT). Responses are excellent but there is a continuous pattern of relapse. Progression within 24 months (POD24) of standard first line therapy including ASCT has been shown to predict poorer outcomes, which may be ameliorated by alloSCT. Ibrutinib, a Bruton's Tyrosine Kinase inhibitor, is an effective therapy for relapsed MCL. However, there is a paucity of published data of ibrutinib's efficacy in patients treated at relapse after standard first line treatment with ASCT and very little regarding the impact of POD24 on outcomes after ibrutinib and outcomes of subsequent alloSCT. Methods This was a retrospective analysis of the EBMT registry. The inclusion criteria were: patients with MCL ≥18 years old, 1st line therapy containing cytarabine and rituximab, ASCT in first CR/PR between 2009 and 2016 and received ibrutinib for 1st relapse after ASCT. POD24 was defined as progressive disease in less than 24 months after ASCT. Results 66 patients met the inclusion criteria (Table 1) relapsing at a median of 25 months (range 15-33) post ASCT. Thirty-two patients progressed in less than 24 months after ASCT. Ibrutinib was started at a median of 30 days after relapse (range 10-54). Overall response rate (ORR) was 74% [32 (48%) achieving CR and 18 (27%) PR]. The median duration of response was 10.1 months (available for 28 patients). There were no significant differences in the duration of response to ibrutinib for patients with POD24 (median: 10.4 months, IQR 4.0-15.4) compared to POD after 24 months or more (POD≥24) [(median 9.8 months, IQR 6.5-20.7) p=0.9]. Relapse after/during ibrutinib occurred in 21 patients (33%) at a median of 12 months (range 1-34). 13 of those patients were on ibrutinib at the time of relapse and the remaining 8 after ibrutinib had been stopped for a SCT or because of toxicity. Ibrutinib therapy continues at last follow-up in 23 (35%) patients. Ibrutinib was stopped for the following reasons: 16 patients subsequent SCT, 13 relapse, 5 toxicity (cytopenia, infection, tachycardia, hepatitis and poor tolerance, 1 case each), 9 other/unknown reasons. Second SCT was undertaken in 23 patients (22 alloSCT, 1 ASCT), 16 of whom were in CR/PR after only ibrutinib at the time of relapse. For alloSCT recipients, the donor was MUD in 11, MSD in 5 and mismatch related in 6. The majority (n=19) had reduced intensity conditioning. 50% of the patients developed acute GvHD and 50% chronic GvHD (3 extensive). With a median follow up of 17 months post alloSCT, 18 (63%) are in remission. There were no significant differences in PFS (p=0.173) or OS (p=0.336) post alloSCT for patients with POD24 and POD≥24. At last follow up (median follow-up of 22 months after starting ibrutinib), 35 (71%) patients were in CR and 4 (8%) in PR. 17 patients have died; the most common reason was MCL (14 patients), 2 deaths were secondary to alloSCT toxicity and in 1 case the cause of death was unknown. 2-year OS after starting ibrutinib was 72% (69% for alloSCT patients) and 2-year PFS 62%. PFS after starting ibrutinib was significantly better for patients with POD≥24 compared to those with POD24 (72% vs. 53% at 2 years post ASCT, p=0.017) and this translated to an OS benefit (80% vs. 68% at 2 years post ASCT, p=0.019) (figures 1 and 2). Conclusion Ibrutinib therapy did not overcome the poor outcome for patients with POD24 after first line therapy and although there was a high ORR to ibrutinib the median duration of response is only 10.1 months. AlloSCT should therefore be undertaken if possible, in our retrospective cohort of patients it appeared to overcome the poor prognosis of POD24 patients. Disclosures Hunter: Jazz pharamceuticals: Honoraria, Other: speaker fees, Meeting attendance support; Novartis: Honoraria, Other: speaker fees; celegene: Other: Meeting attendance support. Peggs:Autolus: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Speakers Bureau. Foà:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees. Pillai:Celgene: Honoraria. Mufti:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Evolving Unmet Need in Patients Refractory to Lenalidomide: Overview of the Clinical Trials in Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2020-142642 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 22-23

Author(s):

Maria-Victoria Mateos ◽

Rohan Medhekar ◽

Istvan Majer ◽

Mehmet Turgut

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Literature Review ◽

Board Of Directors ◽

Unmet Need ◽

Publicly Traded ◽

First Line ◽

Advisory Committees ◽

Line Of Therapy

Introduction: The majority of newly diagnosed multiple myeloma (NDMM) patients are currently treated with lenalidomide-based regimens as their first line of therapy. This trend is likely to continue in the coming years. Typically, lenalidomide is administered until disease progression and has significantly contributed to better outcomes in these patients. However, most patients relapse, and prognosis worsens with each relapse. The choice of optimal treatment for patients who relapse while receiving lenalidomide as first line of therapy is unclear. Moreau et al (Blood Cancer J. 9, 38 [2019]) concluded that there is limited data on approved combinations for treating these patients and are restricted by the low number of lenalidomide-refractory patients enrolled in the pivotal trials. Results from the ongoing clinical trials of the combination of carfilzomib and anti-CD38 antibodies were not available at the time of the Moreau et al publication. The aim of this targeted literature review was to include this new data and to summarize currently available evidence on progression-free survival (PFS) for the treatment of RRMM patients who progressed on lenalidomide-based regimens. Methods: A targeted literature review was conducted to identify registrational clinical trials in patients with RRMM reporting PFS outcomes. PubMed, congress proceedings, and product labels were searched between Jan 2014 to July 2020. In addition to PFS, demographic, disease characteristics and treatment history were extracted for the trial populations to contextualize potential variations in study outcomes. The regimens studied in these trials were classified as lenalidomide-based, proteasome inhibitor (PI)-based and pomalidomide-based. Number of prior lines of therapy, prior exposure and refractoriness to lenalidomide and bortezomib were reported. Results: Twelve registrational trials were identified based on the search criteria (Table 1). Most pivotal trials assessing lenalidomide-based regimens (POLLUX, ELOQUENT-II, TOURMALINE-MM1) except the ASPIRE trial excluded patients who were refractory to lenalidomide. Trials evaluating PI-based regimens (e.g., CANDOR) or pomalidomide-based regimens (e.g., OPTIMISMM) included these patients, with more recent studies enrolling a larger proportion. Percentage of lenalidomide-exposed (and lenalidomide refractory) ranged from 40% (32%) in CANDOR to 98% (90%) in ELOQUENT III. These studies also enrolled a larger proportion of patients who were bortezomib-exposed, although most of these patients were at first relapse, with the exception of ELOQUENT III and ICARIA where most patients were at third relapse. Among lenalidomide-refractory patients, the median-PFS (mPFS) observed for the pomalidomide-based regimens ranged from 9.5 to 10.1 months and that observed for PI-based regimens ranged from 4.9 to 25.7 months. PFS in the lenalidomide-refractory subgroup was considerably shorter than in the ITT population. The mPFS for patients receiving carfilzomib/daratumumab/dexamethasone (KDd; CANDOR) and isatuximab/carfilzomib/dexamethasone (IsaKd; IKEMA) was not reached at median follow-up of 16.9 and 20.7 months respectively. While the mPFS for (KDd) for lenalidomide-refractory patients in CANDOR trial was not yet reached at median follow up of 16.9 months; the mPFS of 25.7 months for KDd in the MMY-1001 trial appears to be the longest among the assessed regimens. Conclusion: Patients refractory to lenalidomide have shorter PFS and represent a population with high unmet need. This targeted literature review suggests that the PI-based KDd regimen provides longer PFS compared to other lenalidomide-sparing regimens in lenalidomide-refractory populations. Heterogeneity across trial populations may limit the comparability of these treatments. Disclosures Mateos: Regeneron: 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; Celgene: 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; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; GlaxoSmithKline: Consultancy. Medhekar:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Majer:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company.

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Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

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Routine Use of Gemtuzumab Ozogamicin in 7+3-Based Inductions for All "Non-Adverse" Risk AML

Blood ◽

10.1182/blood-2020-142691 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Gavin Hui ◽

Abdullah Ladha ◽

Edna Cheung ◽

Caroline Berube ◽

Steven Coutre ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Gemtuzumab Ozogamicin ◽

Intermediate Risk ◽

Newly Diagnosed ◽

Myeloablative Conditioning ◽

Advisory Committees ◽

Monosomy 7

Introduction: The addition of gemtuzumab ozogamicin (GO) to 7+3 chemotherapy for newly diagnosed acute myeloid leukemia (AML) has been shown to significantly improve event-free survival (EFS) for cytogenetically favorable-risk AML, with marginal benefit for intermediate-risk AML, and no benefit for cytogenetically adverse-risk AML. Of note, with the exception of mutated FLT3-ITD, little is known about the impact of GO in ELN 2017-defined genotypically adverse-risk AML, and a recent randomized trial found no EFS benefit for 7+3+GO in patients (pts) with genotypically favorable-risk, NPM1-mutated AML. Since 2017, our institution incorporated GO into 7+3-based inductions for all "non-adverse" risk AML pts, as defined by wild-type FLT3 and no abnormalities on rapid FISH analysis for del(5q)/monosomy 5, del(7q)/monosomy 7, and del(20q). We report our experience treating all pts with "non-adverse" risk AML-as defined by this algorithm-with 7+3+GO. Methods: An institutional database was queried in order to identify all pts ≥18 years old who received 7+3-based chemotherapy for newly diagnosed AML between 2017 and 2020; pts who received the FDA-approved fractionated dose of GO were included in the analysis. Data collection included demographic variables, karyotype/FISH, targeted PCR analyses, and multigene NGS panels for AML-related mutations including, but not limited to, mutations in FLT3, NPM1, CEBPA, TP53, RUNX1, and ASXL1. Outcome data included response to induction, relapse, and death, as well as hematopoietic cell transplant (HCT) rates, conditioning regimens, and post-transplant complications. Results: Between January 2017 and July 2020, 96 pts received 7+3-based induction at our institution. Of these, 29 (30%) received 7+3 in combination with GO. Median age at diagnosis was 46 years (range 23-66), with 17 (59%) males. Sixteen (55%) pts had ELN favorable-risk AML (5 [31%] by cytogenetics and 11 [69%] by genotype), 6 (21%) pts had ELN intermediate-risk AML, and 7 (24%) pts had ELN adverse-risk AML (4 [57%] by cytogenetics and 3 [43%] by genotype). Median time from diagnosis to start of induction was 4 days (range 0-43). For cytogenetically adverse-risk pts, median time from diagnostic bone marrow biopsy to receipt of adverse karyotype results was 8 days (7-14). Median time from start of induction to receipt of multigene NGS results for all pts was 15 days (3-32). Overall, 22 (76%) pts achieved remission. All genotypically adverse-risk pts (1 with mutated TP53 and 2 with mutated RUNX1) were refractory to induction, while 3 of 4 (75%) cytogenetically adverse-risk pts (1 with t(6;9), 1 with monosomy 7, and 2 with 11q23 abnormalities) achieved remission. Eight of the 29 (28%) pts proceeded to HCT, including 4 adverse-risk pts. Of the adverse-risk pts, all received myeloablative conditioning prior to HCT and 3 (75%) developed veno-occlusive disease (VOD), with 2 (50%) requiring defibrotide therapy. In favorable/intermediate-risk pts, 4 (18%) proceeded to HCT (2 intermediate-risk pts in first remission and 2 favorable-risk pts in second remission). Of these, 2 (50%) received myeloablative conditioning and 1 (25%) developed VOD. At last follow-up, 23 of 29 pts (79%) remained alive, with a median overall survival not reached (range 1-29 months) and a median EFS of 20 months (9-31). The percentage of ELN favorable-, intermediate-, and adverse-risk pts who remained event-free at last follow-up was 75%, 33%, and 43%, respectively. Discussion: This single-center, retrospective cohort describes the outcomes of pts with "non-adverse" risk AML who received induction chemotherapy with 7+3+GO according to a pre-defined algorithm. Using this algorithm, 30% of all pts receiving 7+3-based inductions received GO. Of these, nearly 25% were ultimately found to have adverse-risk AML as defined by ELN 2017 criteria, largely driven by long turn-around times for karyotyping and NGS multigene panel results. No patient with genotypically adverse-risk AML by ELN criteria responded to induction chemotherapy, and 75% of cytogenetically adverse-risk pts who proceeded to HCT developed VOD. Routine use of 7+3+GO induction outside of the context of cytogenetically favorable-risk AML remains controversial, and further study is needed to define the role of GO, particularly for pts with ELN genotypically adverse-risk AML. Table Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: 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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The Introduction of Novel Agents Improves Outcomes of Young Patients with Myeloma (MM) Treated with Autologous Stem Cell Transplant (ASCT)

Blood ◽

10.1182/blood.v116.21.1348.1348 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1348-1348

Author(s):

Radovan Saso ◽

Kevin D Boyd ◽

Kabir Mohammed ◽

Ping Wu ◽

Jennifer Treleaven ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Survival Rates ◽

Young Patients ◽

Novel Agents ◽

Cell Transplant ◽

Advisory Committees ◽

Younger Patients ◽

Response To Chemotherapy ◽

The Impact

Abstract Abstract 1348 Background: There has been an improvement in the population based survival of patients with MM in the UK (Office of National Statistics), however, because of the way the data is collected it is uncertain what has happened to the outcome of younger patients. High dose melphalan with ASCT has formed an integral part of the treatment of younger patients with myeloma for more than 20 years. During this time the context within which this treatment has been delivered has changed. Peripheral blood stem cell harvesting has replaced bone marrow harvesting, and importantly, novel agents have become available at induction and at relapse. It is not known how these changes have affected patient outcome. We analysed the survival of patients undergoing ASCT for MM in a single referral centre over an 18 year period to assess the impact of these changes. Patients: 1291 patients with myeloma were registered on the Royal Marsden Hospital Database in the period between 1981–2009, of which 875 patients underwent autologous transplantation. Bone marrow transplant (BMT) was performed in 191 patient, while 684 patients had peripheral blood stem cell transplant (SCT). Prognostic Factors: The following factors were found to be associated with improved overall survival (OS) in univariate analysis: Salmon Durie Stage A vs Stage B (p<0.004), ISS Stage I vs II vs III (p<0.001), response to chemotherapy CR vs PR vs Other (p<0.007), Platelets >130 vs <130 × 109/L (p<0.001), Hb >10 vs <10 g/dl (p<0.001), Calcium <10 vs >10mg/dl, Albumin >35 vs <35g/L (p<0.034), B-2M >3.5 vs <3.5 mg/l (p<0.001), IgG vs IgA vs BJ (p<0.038). Variables significant in multivariate testing were: Response to chemotherapy CR vs <CR (HR 1.4; 95% CI 1.0–2.0), Platelets >130 (HR 0.52; 95% CI 0.3–0.9), Calcium (HR1.7; 95% CI 1.2–2.5) and B2M (HR2.1; 95% CI 1.5–2.9). These variables were significantly associated with OS in the overall dataset, and in the subgroup of younger patients under the age of 60. Response and Survival: The overall response (OR) rate following induction chemotherapy was 84%, including 22% complete responses (CR). Following autologous SCT, CR rates improved to 42%, with an OR of 91%. Analysis of actuarial survival for the whole group of patients who had SCT showed that young patients had significantly longer survival (Median survival: <60yrs vs. >60yrs; 8.7yrs vs 6.2yrs, p<0.009). In order to assess the impact of the introduction of new therapeutic agents in, we defined groups of patients treated in five year periods: 1991–1996, 1997–2003, 2004–2009. 5 year OS was unchanged when comparing the first two cohorts. However, the cohort of patients treated from 2004–2009 were associated with significant improvement in 5 year survival rates, from 61% for the earlier quinquennia to 82% for those treated in 2004-9 (p<0.001). We also assessed the impact of the introduction of SCT compared to BMT. SCT entered routine use at this centre in 2002, and patient outcomes did not improve from 2002–2004. The improved survival after 2004 is therefore unlikely to be due to the introduction of SCT. Summary: We found that patient survival following ASCT did not change significantly during the period 1991–2004. However, since 2004 survival rates have improved significantly, and the group that benefitted most were patients under the age of 60. This time period corresponds to the incorporation of novel agents such as thalidomide, bortezomib and lenalidomide into induction and relapse regimens, and suggests that novel agents have significantly improved the outcome of younger patients with myeloma in the context of treatment with ASCT. Disclosures: Boyd: celgene: Honoraria. Davies:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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