Safety and Efficacy of Venetoclax-Based Treatment in Elderly CLL Patients: A Retrospective Study from the Filo Group

Abstract Median age at diagnosis of chronic lymphocytic leukemia is 72 years. However, only few patients over 80 years of age are included in clinical trials, even in those devoted to unfit patients. In order to evaluate both efficiency and safety of venetoclax in this category of patients, we conducted a multicentric retrospective study and collected data from 77 CLL patients from 19 FILO centers who started venetoclax after 80 years of age. Median age at venetoclax initiation was 86 years old (81-97). 63% of patients had a history of heart disease, 62% had renal failure (moderate 59% and severe 3%) and 29% had a history of severe infections. Despite their comorbidities and a CIRS greater than 6 in 70% of cases, their autonomy was preserved with a median performans status of 1 (0-4). In this comorbid geriatric population, pretherapeutic geriatric assessment was only performed in a single patient. The median number of prior therapies was 2 (0-6) with an exposure to a BCR inhibitor in 56% of cases. 11q and 17p deletion were found in 39% and 30% of cases respectively, 39% of patients had a complex karyotype and 30% harbored a TP53 mutation. However, in this real life population, these prognostic factors were only performed in half of patients. IGHV mutational status was only available in 11 patients, and 83% of them had unmutated IGHV. At the time of venetoclax initiation, the tumor lysis syndrome (TLS) risk was moderate in 57% of cases and high in 8% of cases. Venetoclax was administered as a single agent (42%) or in association with rituximab (58%). In total, half of the patients were hospitalized at each dose ramp-up, and only 3 patients were treated on outpatient basis. 82% of the cohort was able to reach the daily dose of 400mg. Half of the patients were included in a phone call monitoring program with oncology nurses to pre-emptively manage side effects and foster therapy adherence. The safety study reported 14% of TLS, with 2 discontinuations of treatment within the first month: one of which led to dialysis and the other to death. As in the previously published studies, 25% of patients had infectious complications, and grade 3 haematological and digestive toxicities were reported in 42% and 22% of cases, respectively. The reduction of the daily dose of venetoclax was necessary for 33%. Permanent discontinuation of venetoclax occurred in 40% of subjects, including 29% of early withdrawal (within the first 3 months). Main reasons for discontinuation were intolerance (21%), CLL progression (21%), death (21%) and scheduled treatment discontinuation (10%). The overall response rate was 86%, consisting of 49% of complete response (unconfirmed by bone marrow biopsy) and 37% of partial response. With a median follow-up of 21months, estimated progression free survival and overall survival were 29 and 38 months respectively. Prior exposure to a BCR inhibitor had no impact on progression free survival. To conclude, venetoclax has a manageable safety profile in elderly patients with comorbidities and can induce prolonged responses. Finally, if additional follow-up by oncology nurses seems to be more and more implemented, the pre-therapeutic onco-geriatric evaluation remains underexploited in this population. Disclosures Ferrant: AstraZeneca: Honoraria; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Other: Travel, Accommodations, Expenses. Feugier: Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria. Laribi: AstraZeneca: Other: Personal Fees; Le Mans Hospital: Research Funding; AbbVie: Other: Personal Fees, Research Funding; Jansen: Research Funding; Novartis: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees; Astellas Phama, Inc.: Other: Personal Fees; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding. Tchernonog: JANSSEN: Consultancy; ABBVIE: Consultancy; ASTRAZENECA: Consultancy. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Quinquenel: Abbvie: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria.

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Efficacy of Daratumumab, Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma Among Patients with 1 to 3 Prior Lines of Therapy Based on Previous Treatment Exposure: Updated Analysis of Pollux

Blood ◽

10.1182/blood.v128.22.489.489 ◽

2016 ◽

Vol 128 (22) ◽

pp. 489-489 ◽

Cited By ~ 13

Author(s):

Philippe Moreau ◽

Jonathan L. Kaufman ◽

Heather J. Sutherland ◽

Marc Lalancette ◽

Hila Magen ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Statistical Significance ◽

Previous Treatment ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Refractory Multiple Myeloma

Abstract Introduction: Daratumumab is an anti-CD38 IgGκ monoclonal antibody that has been combined successfully with lenalidomide and dexamethasone. The combination of daratumumab with lenalidomide and dexamethasone (DRd) has been compared with lenalidomide and dexamethasone alone (Rd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM) in a randomized phase 3 study (Dimopoulos MA, et al. N Engl J Med 2016; in press). In a pre-specified interim analysis, the DRd combination demonstrated significantly longer progression-free survival (PFS) in addition to deep and durable responses compared with the Rd arm. We performed subgroup analyses to further examine these efficacy data according to prior treatment exposure. Methods: Pts who received ≥1 prior line of therapy were randomized (1:1) to Rd (lenalidomide: 25 mg PO on Days 1-21 of each 28-day cycle; dexamethasone: 40 mg PO weekly) with or without daratumumab (16 mg/kg IV qw for 8 weeks, q2w for 16 weeks, then q4w until progression). The primary endpoint was PFS. Pts who were refractory to lenalidomide were not eligible. All analyses were performed in pts who received 1 to 3 prior lines of therapy. Results: Median follow-up was 13.5 months. Pts who were lenalidomide-naive prior to the start of study treatment (DRd, n=226; Rd, n=219) demonstrated significantly longer PFS with DRd vs Rd (median: not reached [NR] vs 18.4 months; HR, 0.36; 95% CI, 0.25-0.52; P<0.0001), with estimated 12-month PFS rates of 83.0% vs 59.9%, respectively. ORR was significantly higher with DRd vs Rd (96% vs 79%), with ≥VGPR rates of 76% vs 47% and ≥CR rates of 44% vs 21%, respectively (P<0.0001 for all). In the lenalidomide-exposed subgroup (DRd, n=46; Rd, n=45), median PFS was NR in both treatment groups (HR, 0.49; 95% CI, 0.22-1.12; P=0.0826); estimated 12-month PFS rates were 84.1% vs 63.1%, respectively. ORR was higher with DRd vs Rd but did not reach statistical significance (87% vs 71%; P=0.0729); however, rates of ≥VGPR (78% vs 38%; P=0.0001) and ≥CR (44% vs 12%; P=0.0011) were significantly improved with DRd vs Rd, respectively. For bortezomib-naive pts (DRd, n=44; Rd, n=45), PFS was significantly longer with DRd vs Rd (median: NR vs 15.8 months; HR, 0.34; 95% CI, 0.13-0.86; P=0.0170), with estimated 12-month PFS rates of 85.4% vs 69.2%, respectively. ORR was significantly higher with DRd vs Rd (98% vs 82%; P=0.0158), with trends toward increased rates of ≥VGPR (74% vs 55%; P=0.0544) and ≥CR (42% vs 23%; P=0.0576). In the bortezomib-exposed pts (DRd, n=228; Rd, n=219), median PFS was NR in DRd vs 18.4 months in Rd (HR, 0.35; 95% CI, 0.24-0.50 P<0.0001); estimated 12-month PFS rates were 82.8% vs 58.7%, respectively. Significant differences in ORR (93% vs 77%), rate of ≥VGPR (77% vs 43%) and rate of ≥CR (44% vs 19%) were observed with DRd vs Rd, respectively (P<0.0001 for all). Among bortezomib-refractory patients (DRd, n=54; Rd, n=49), the PFS benefit of DRd compared with Rd was maintained (median: NR vs 10.3 mo, respectively; HR, 0.46; 95% CI, 0.25-0.85; P=0.0117; Figure). The estimated 12-month PFS rates were 70.8% vs 44.4%, respectively. Similar to bortezomib-exposed pts, ORR (92% vs 68%; P=0.0024), rate of ≥VGPR (75% vs 36%; P=0.0001), and rate of ≥CR (46% vs 13%; P=0.0003) were all significantly higher with DRd vs Rd for bortezomib-refractory pts. Updated data will be presented at the meeting. Conclusions: Among pts who received 1 to 3 prior lines of therapy, significantly longer PFS and higher ORR were observed with DRd vs Rd among pts who previously received bortezomib or were refractory to bortezomib or were lenalidomide-naive. Higher rates of deeper responses were observed in pts who previously received lenalidomide or bortezomib. Follow-up is ongoing to assess PFS in pts who received 1 to 3 prior lines of therapy and previously received lenalidomide. These results further strengthen the significant benefit of combining daratumumab with Rd for RRMM. Figure Progression-free Survival in Bortezomib-refractory Patients who Received 1 to 3 Prior Lines of Therapy Figure. Progression-free Survival in Bortezomib-refractory Patients who Received 1 to 3 Prior Lines of Therapy Disclosures Moreau: Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Kaufman:Pharmacyclics: Consultancy; Incyte: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Sutherland:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Lalancette:Celgene: Honoraria; BMS: Honoraria. Iida:Celgene: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding. Prince:Janssen: Honoraria; Celgene: Honoraria. Cochrane:BMS: Other: Received sponsorship to attend international meetings; Novartis: Other: Received sponsorship to attend international meetings; Celgene: Other: Received sponsorship to attend international meetings; Takeda: Other: Received sponsorship to attend international meetings. Khokhar:Janssen: Employment. Guckert:Johnson & Johnson: Equity Ownership; Janssen: Employment. Qin:Janssen: Employment. Oriol:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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.

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Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy

Blood ◽

10.1182/blood.v122.21.509.509 ◽

2013 ◽

Vol 122 (21) ◽

pp. 509-509 ◽

Cited By ~ 56

Author(s):

Gilles Andre Salles ◽

John Francis Seymour ◽

Pierre Feugier ◽

Fritz Offner ◽

Armando Lopez-Guillermo ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Second Line ◽

Second Line Therapy ◽

Advisory Committees ◽

Free Survival ◽

Rituximab Maintenance ◽

Line Therapy

Abstract The intergroup PRIMA Phase III study was designed to investigate the potential benefit of 2-years of rituximab maintenance in patients with follicular lymphoma (FL) responding to one of three non-randomised first line immunochemotherapy treatments. The results of the final analysis with 36 months follow-up (Salles et al., Lancet 2011) demonstrated a significant reduction of the risk of progression or death with a hazard ratio (HR) of 0.55 in favour of patients randomized to rituximab maintenance. We present here the updated results with 3 additional years of follow-up. From December 2004 until April 2007, 1217 patients were enrolled from 223 centres and complete data were available for 1193 patients who had the following pre-induction treatment characteristics: median age 56 years [range 22–87]; 52% male; 90% Ann Arbor stage III-IV; 33% B symptoms; 56% bone marrow involvement; 4% ECOG performance status >1; 34% elevated LDH; 32% β2-microglobulin >3mg/L; FLIPI score 0-1 (21%), FLIPI 2 (36%), FLIPI 3-5 (43%). Most patients (75%) received R-CHOP induction (22% R-CVP, 3% R-FCM). Patients responding to induction therapy were stratified based on their immunochemotherapy regimen and response [CR/CRu versus PR] and randomized to observation or rituximab maintenance, 1 infusion (375 mg/m2) every 8 weeks for 2 years. A total of 1018 randomised patients were analyzed according to the ITT principle (513 observation / 505 rituximab maintenance). All initial pre-treatment characteristics were well balanced between arms and the response status at time of randomization was CR=39%; CRu=32% and PR=28% (others 1%). With a median follow-up of 73 months from randomization, 6-year progression free survival estimate was 42.7% (95% CI 38 – 46.9%) in the observation arm (284 events, median=48 months) and 59.2% (95% CI 54.7 – 63.7%) in the rituximab maintenance arm (194 events, median not reached), respectively (stratified Log-Rank, P<. 0001; HR = 0.58 ; 95% CI 0.48 - 0.69). In pre-planned analyses of patients subgroups categorized by age, sex, FLIPI score category, induction chemotherapy and response to induction, the effect of rituximab maintenance was examined and found to be consistent among these different subgroups. In a Cox regression multivariate analysis, rituximab maintenance (HR=0.57; P<.0001) as well as older age (HR=0.79; P=.015), female sex (HR=0.72; P=.0003) and low or intermediate FLIPI groups (HR=0.67; P<.0001) were all significant variables associated with superior progression free survival. A significant reduction in the risk of starting a new anti-lymphoma treatment (HR=0.63, 95% CI 0.52 - 0.76) or starting a new chemotherapy (HR=0.70, 95% CI 0.57 - 0.86) were also observed for rituximab maintenance. The rate of histological transformation did not appear to differ between the 2 treatment arms: in the observation arm, transformation was documented in 24 patients (114 cases with morphological documentation out of 278 progressions) versus 16 patients in the rituximab maintenance arm (80 out of 186) respectively. Overall response rate to second-line therapy was reported by investigators to be 180/227 (79%) in patients from the observation arm (CR/CRu=61%; PR=19%) versus 109/144 (76%) in patients from the rituximab maintenance arm (CR/CRu =51%; PR=22%) (P=NS). At the time of the data cut-off, overall survival (OS) remains favourable in both study arms: 58 patients (11.3%) have died in the observation arm (6-years OS estimate 88.7%) compared to 59 patients (11.7%) in the rituximab maintenance arm (6-year OS estimate 87,4%). Main causes documented for death in the observation and rituximab maintenance arm respectively were lymphoma (28 ; 28), other malignancy (19 ; 5) and infections (4 ; 7). No new significant safety data were captured with this additional follow-up period. In conclusion, with 3 additional years of follow-up, these data demonstrate a sustained and persistent benefit of 2 years of rituximab maintenance therapy after immunochemotherapy, resulting in improved progression free survival. No additional or unexpected long term toxicities were observed and second line therapy efficacy results did not significantly differ between the 2 study arms. Overall survival appears very favourable for these randomized patients. Disclosures: Salles: Roche: Consultancy, Honoraria, Research Funding. Seymour:Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau, Travel support Other; Genetech: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Feugier:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Offner:Lilly: Membership on an entity’s Board of Directors or advisory committees. Lopez-Guillermo:Roche: Membership on an entity’s Board of Directors or advisory committees. Belada:Roche: Consultancy. Catalano:Roche: Membership on an entity’s Board of Directors or advisory committees. Haioun:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Simpson:Janssen Research & Development: Honoraria. Leppa:Roche: Consultancy, Honoraria, Research Funding, Travel support Other. Soubeyran:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Hagenbeek:Takeda/Millennium: Consultancy. Casasnovas:ROCHE: Consultancy, Honoraria, Research Funding. Coiffier:Millennium Pharmaceuticals : Consultancy. Tilly:Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; Janssen: Honoraria; Amgen: Research Funding.

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Progression-Free Survival Outcomes By Response Status for Bortezomib, Melphalan, and Prednisone with or without Daratumumab in Newly Diagnosed Multiple Myeloma: Pooled Subgroup Analysis of Octans and Alcyone

Blood ◽

10.1182/blood-2021-148937 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1648-1648

Author(s):

Jianxiang Wang ◽

Weijun Fu ◽

Soo-Mee Bang ◽

Honghui Huang ◽

Kihyun Kim ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Publicly Traded ◽

Primary Analysis ◽

Advisory Committees ◽

Once Daily ◽

Free Survival ◽

Asian Patients

Abstract Introduction: Daratumumab is a human IgGκ monoclonal antibody that targets CD38 with a direct on-tumor and immunomodulatory mechanism of action. In the primary analysis (median follow-up, 16.5 months) of the global phase 3 ALCYONE trial, daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) significantly improved progression-free survival (PFS) versus VMP alone in patients with newly diagnosed multiple myeloma (NDMM) who were ineligible for transplant (median PFS, not reached vs 18.1 months; hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.38-0.65; P<0.001). In the primary analysis (median follow-up, 12.3 months) of the phase 3 OCTANS trial, D-VMP significantly prolonged PFS versus VMP in transplant-ineligible Asian patients with NDMM (median PFS, not reached vs 18.2 months; HR, 0.43; 95% CI, 0.24-0.77; P=0.0033). Here, we present a pooled subgroup analysis of PFS stratified by best response in Asian and global patients from the OCTANS and ALCYONE studies, respectively. Methods: Eligible patients in OCTANS and ALCYONE were ≥18 years of age, were diagnosed with NDMM, and were not eligible for autologous stem cell transplant due to age (≥65 years) or comorbidities. All patients received up to 9 cycles (42-days) of bortezomib (1.3 mg/m 2; subcutaneous) twice weekly on Weeks 1, 2, 4, and 5 of Cycle 1 and once weekly on Weeks 1, 2, 4, and 5 of Cycles 2 to 9; melphalan (9 mg/m 2; oral) once daily on Days 1 to 4 of each cycle; prednisone (60 mg/m 2; oral) once daily on Days 1 to 4 of each cycle. For patients in the D-VMP group, daratumumab (16 mg/kg, intravenous) was administered once weekly in Cycle 1, once every 3 weeks in Cycles 2 to 9, and once every 4 weeks thereafter until disease progression or unacceptable toxicity. Response over time (at 6, 12, 18, 24, 54 weeks) and disease progression were assessed by a validated computer algorithm in accordance with the IMWG criteria. Minimal residual disease (MRD) negativity (10 -5) was assessed by multi-parameter flow cytometry in OCTANS and by next-generation sequencing in ALCYONE. Results: In the OCTANS study, 220 Asian patients were randomized (D-VMP, n=146; VMP, n=74); in the ALCYONE study, 706 global patients were randomized (D-VMP, n=350; VMP, n=356). Median age in OCTANS was 69 (range, 57-84) years and 71 (range 40-93) years in ALCYONE. Patients were pooled from both studies (D-VMP, n=496; VMP, n=430). D-VMP increased the rate of complete response or better (≥CR; 10.2% vs 5.6%) and the rate of very good partial response or better (≥VGPR; 58.5% vs 38.1%) versus VMP after 18 weeks of treatment (Figure A). Responses deepened over time among patients in both the D-VMP and VMP groups, as shown by the ≥CR rate (D-VMP, 38.8%; VMP, 21.6%) and the ≥VGPR rate (D-VMP, 74.0%; VMP, 50.7%) at 54 weeks. At a median follow-up of 12.3 months for OCTANS and 16.5 months for ALCYONE, among patients who achieved a VGPR (D-VMP: n=145 [29.2%]; VMP: n=109 [25.3%]), the median PFS was not reached in the D-VMP group versus 19.9 months in the VMP group (HR, 0.61; 95% CI, 0.36-1.00; P=0.0499; Figure B). All patients who achieved ≥CR with or without MRD negativity (10 -5) demonstrated prolonged PFS, regardless of treatment (≥CR: HR, 1.54; 95% CI, 0.65-3.65; P=0.3210; ≥CR+MRD negativity: HR, 0.67; 95% CI, 0.13-3.40; P=0.6225; Figure B); however, more patients treated with D-VMP achieved this level of response (≥CR: D-VMP , n=212 [42.7%]; VMP, n=100 [23.3%]; ≥CR+MRD negativity: D-VMP, n=116 [23.4%]; VMP, n=27 [6.3%]; Figure B). Conclusion: In a pooled analysis of OCTANS and ALCYONE, more patients with transplant-ineligible NDMM achieved deeper responses with D-VMP versus VMP. More patients treated with D-VMP achieved ≥CR with or without MRD negativity compared with those treated with VMP alone, leading to prolonged PFS regardless of treatment. These results support the use of daratumumab in addition to VMP in transplant-ineligible Asian patients with NDMM. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding. Kim: BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Li: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Chim: Janssen, Takeda & Amgen: Other: received sponsorship for overseas meetings. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria; Clínica Universidad de Navarra: Current Employment. Liberati: abbvie, amgen, archigen, beigene, BMS, celgene, DR REDDY'S LABORATORIES SPA, fibrogen, glaxo, Janssen, Karyopharm, Morphosys, Novartis, Onconova, Oncopeptides ab, Roche, Sanophi, Secura Bio, Takeda, Verastem,: Research Funding. Takamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; SRL: Consultancy; Adaptive Biotechnologies, Eisai: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Dimopoulos: BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Wroblewski: Janssen: Current Employment, Current equity holder in publicly-traded company. Carson: Janssen: Current Employment. Qi: Janssen: Current Employment, Current equity holder in publicly-traded company. Wang: Janssen: Current Employment. Song: Janssen: Current Employment. Jia: Janssen: Current Employment. Yang: Janssen: Current Employment, Current equity holder in publicly-traded company. Liu: Janssen: Ended employment in the past 24 months. Li: Janssen: Current Employment. Zhang: Janssen: Current Employment.

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Presence of Chip-Mutated Autologous Hematopoietic Cells in Mobilized Peripheral Blood Products Is Associated with Shorter Progression-Free Survival after Autologous Transplants for Multiple Myeloma

Blood ◽

10.1182/blood-2019-127335 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 515-515

Author(s):

Ehsan Malek ◽

Petra Martin ◽

Paolo F Caimi ◽

Benjamin K. Tomlinson ◽

Michael Caldwell ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Progression Free Survival ◽

Hematopoietic Cell ◽

Advisory Committees ◽

Free Survival ◽

Whole Exome ◽

High Risk Disease

Multiple Myeloma (MM) remains a cancer of terminally-differentiated plasma cells that reside predominantly within the bone marrow. Malignant plasma cells are nurtured by a permissive microenvironment that favors tumor progression, drug resistance and disease relapse. Recurrent somatic mutations in hematopoietic stem cells, the source of major components in bone marrow niche, lead to age-associated clonal hematopoiesis of indetermined potential (CHIP) and has been associated with inferior survivals among individuals without malignant hematologic disorders. It is possible that these mutations in non-MM cells would affect remission time after transplant. We performed whole exome sequencing to identify CHIP-associated mutations within the autograft utilized to rescue hematopoiesis after high dose melphalan and autologous hematopoietic cell transplant (HCT). We then correlated the presence of CHIP with the outcome of MM patients (pts) following autologous HCT. Methods. MM pts (N=101) that underwent HCT between 2006 and 2017 were studied. DNA was extracted from 1 ml of cryopreserved mobilized hematopoietic cell product. Targeted sequencing was then performed using Tempus xE whole exome platform (Tempus, Chicago, IL) with variable allele frequency (VAF) ≥0.1. Progression-free survival (PFS) and overall survival (OS) were defined as the time from transplantation until event of interest, with censoring at time of last follow up. Cox regression was used for time-to-event outcomes; hazard ratios (HR) and 95% confidence intervals (CI) were reported. P-values were two-sided and those <0.05 were considered statistically significant. Results. The median age was 60.1 years at the time of HCT. 58 pts were male and 43 female; 29 pts were African-American, 1 Asian/Indian and 71 were Caucasian. Seventy five (75%) and 42 (43%) pts had prior exposure to lenalidomide or cyclophosphamide, respectively. Thirty two pts (32%) underwent hematopoietic cell mobilization with GCS-F and plerixafor, 38 pts (38%) with cyclophosphamide and 31 pts (31%) with GCS-F alone. Forty seven pts (47%) had at least one CHIP-associated mutation. The median number of CD34+ yield in the first day was 6.7 x 10e6/kg for pts with CHIP mutations and 5.64 x 10e6/kg for pts without any CHIP mutation (p = 0.4). The presence or absence of CHIP mutations did not impact the yield of CD34+ stem cells collected (Fig. 1). The majority of mutations were either missense variants or mRNA splicing variations (Fig. 2), most commonly SF3B1, ASXL1, TET2 and ASXL2. CHIP mutations were associated with increased age (p= 0.021), but there was no association with prior history of previous cancer, smoking, cytogenetically-defined high risk disease, pre-HCT hemoglobin level or red blood cell mean corpuscular volume. There was also no significant difference between the transplant course between the two groups in terms of neutrophil and platelet engraftment or length of hospital stay. Median follow up was 32 months. During follow up 3 pts develop MDS/AML (2 pts in the CHIP group and one in no CHIP group). Coronary artery disease was the cause of death in one patient in CHIP cohort versus none in the CHIP negative cohort. Myeloma progression was the major cause of death in CHIP and No CHIP cohorts (66% vs. 60%, p=0.48). Median PFS was 19 months in CHIP cohort vs. 39 months in No CHIP group (HR: 0.62, 95% CI: 0.51-0.92, p= 0.001). Median OS has not been reached in the No CHIP group while it was 56 months in CHIP group (HR: 0.78, 95% CI: 0.62-1.04, P=0.09). In multivariate analysis, presence of CHIP remained a significant predictor of worse PFS after adjusting for age, maintenance therapy, high risk disease, performance status, triplet vs. doublet pre-SCT therapy, melphalan dose and MM genetic risk. (Table 2). Conclusion: Here we showed high frequency of large clonal hematopoiesis clones (i.e., VAF ≥0.1) in autograft of MM pts. The presence of this mutations does not impact stem cell yield or transplant course, however it impacts PFS independent of age and other unfavorable factors. Our data highlights high frequency of SF3B1; the role of this mutant in modulating apoptotic factors in myeloma microenvironment should be investigated. Disclosures Malek: Celgene: Consultancy; Amgen: Speakers Bureau; Adaptive: Consultancy; Janssen: Speakers Bureau; Medpacto: Research Funding; Sanofi: Consultancy; Takeda: Consultancy. Caimi:ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Fate Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Caldwell:Tempus Inc.: Employment.

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Comparison of Patient Outcomes with Two Different Formulations of Melphalan As Conditioning Chemotherapy for Autologous Stem Cell Transplantation in Multiple Myeloma

Blood ◽

10.1182/blood-2020-141105 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-1

Author(s):

Filiz Yucebay ◽

Ashleigh Keiter ◽

Qiuhong Zhao ◽

Alison Neal ◽

Nita Williams ◽

...

Keyword(s):

Board Of Directors ◽

Propylene Glycol ◽

Research Funding ◽

Transfusion Requirement ◽

Progression Free Survival ◽

High Dose ◽

Advisory Committees ◽

Free Survival ◽

High Dose Melphalan

Introduction: High-dose melphalan is the standard conditioning chemotherapy for autologous stem cell transplantation (ASCT) in multiple myeloma (MM). However, patients experience several side effects and toxicities from high-dose melphalan. In 2016, United States Food and Drug Administration approved Evomela, a propylene glycol-free formulation of melphalan, as conditioning chemotherapy for ASCT in MM. This was based on its bioequivalence to the standard propylene-glycol solubilized melphalan formulation (Alkeran) in a phase 2 study. Evomela has the advantages of improved solubility, stability, bioavailability and being free of propylene glycol that is associated with organ dysfunction. Methods: We conducted a retrospective study of patients who received ASCT with high dose chemotherapy using alkeran (n=255) or evomela (n=259) at our institution to compare their outcomes such as side effects, duration of cytopenias, transfusion requirements, length of hospital stay, readmission within 30 days and progression-free survival (PFS) post-SCT. Clinical and demographic characteristics were compared between two treatment regimens using the Chi-square test for categorical variables and the Wilcoxon rank sum test for the continuous variables. Overall survival (OS) was calculated from the date of transplant to death, censoring the alive patients at their last follow up date. Progression-free survival (PFS) was calculated from the date of transplant to date of relapse or death, whichever occurred first, censoring at the last follow-up if no relapse or death. OS and PFS estimates were calculated using the Kaplan-Meier method and compared using the log-rank test. Results: The baseline patient characteristics such as age, ISS stage, comorbidity index and number of prior lines of therapy prior to ASCT were similar between the two groups. (See table 1). Mucositis was seen in 77.2% of the patients who received Alkeran compared to 69.5% who received Evomela (p=<0.001). Incidence of febrile neutropenia was 65.9% in the Alkeran group and 49.4% in the Evomela group (p=0.0002). Chemotherapy-induced nausea and vomiting were reported in 98.8% and 93.4% of the patients in the Alkeran and Evomela groups respectively (p=0.001). Rates of diarrhea and clostridium difficile infection were similar with the two drugs. Time to neutrophil engraftment was the same in both the groups while duration of thrombocytopenia (platelets <20k) was slightly longer in the Evomela group (6 days in alkeran and 8 days in evomela group, p=<0.001). Red cell transfusion requirement was higher with the use of Alkeran compared to Evomela (42.3% vs 21.8%, p=0.001) while platelet transfusion was the same. There was no difference in the duration of hospital stay between the two groups. However, rate of readmission within 30 days of discharge was higher in patients who got Evomela compared to Alkeran (9.4% versus 17.4%, p=0.008). Day +100 serological response (very good partial response or better), PFS post-SCT and OS were similar in both groups. (Figure 1). Conclusion: We conclude that use of Evomela is associated with a better side-effect profile and transfusion requirement while having similar outcomes as Alkeran. Disclosures Yucebay: Janssen: Membership on an entity's Board of Directors or advisory committees; BioXCell: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Membership on an entity's Board of Directors or advisory committees. Chaudhry:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Efebera:Takeda: Honoraria, Speakers Bureau; Pharmacyclics: Research Funding; Celgene: Research Funding; Ohio State University: Current Employment. Bumma:Amgen: Speakers Bureau; Sanofi: Speakers Bureau. Khan:Amgen: Consultancy; Janssen: Consultancy. Devarakonda:Janssen: Consultancy.

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Interim or End of Treatment FGD-PET Complete Response Does Not Have Adequate Predictive Value in Mature T/NK Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.1813.1813 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1813-1813

Author(s):

Tatyana Feldman ◽

Larysa Sanchez ◽

Patrick Toth ◽

David Panush ◽

Lori A Leslie ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Predictive Value ◽

Research Funding ◽

Nk Cell ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Significant Difference

Abstract Introduction: Cure rate of Mature T/NK cell lymphoma (TCL) is rather low and multiple trials are being conducted to improve frontline therapy outcomes. Consolidation with autologous stem cell transplant is becoming widely used as a mean of improving survival (SCT). Based on data from several retrospective trials, pts who achieve CR may not benefit from consolidative SCT. There is no data available on the role of PET-CR as defined by using Deauville criteria (which became standard in response assessment of NHL (The Lugano Classification 2014)). We performed retrospective analysis of 59 pts with TCL examining the correlation between PFS/OS and iPET and eotPET. Methods: 59 pts newly diagnosed pts with TCL treated between 2008-2016 for whom interim and eotPET scan were available. It was our routine practice to obtain baseline, interim (after 3 cycles of chemotherapy) and eotPET. Pathology slides of outside cases were centrally evaluated by a hematopathologist to confirm diagnosis. Baseline, interim and eotPET were centrally reviewed by a nuclear medicine radiologist blinded to clinical outcomes who assigned Deauville score (DS) to every PET. Responses were recorded according to the Lugano classification 2014. Descriptive statistics and Kaplan Meier method was used to calculate the Progression-free survival (PFS) and Overall survival (OS), two-sided Log-rank test was used to compare OS and PFS between PET groups. Results: Detailed demographic is presented in Table1. Median age at diagnosis is 59, sixty two percent males, 37% female; ALCL 34%, PTCLnos 22%, AITL 19%, and ATLL 10%; most of pts were advanced stage. Most common chemotherapy regimens used were CHOP/CHOEP, HCVAD, and CODOX, SMILE. Median follow up time for the entire cohort was 22.7mo. Forty nine percent of pts progressed and 29% of pts died during follow up. Cause of death for majority of pts was disease progression. Following Deauville scores were assigned on iPET and eotPET respectively: DS1 in 37% and 39%, DS2 in 30% and 35%, DS3 in 15% and 6%, DS4 in 9% and 4%, DS5 in 9% and 16%. We analyzed mPFS and mOS for PET-CR using DS1-2 or DS1-3 to define it. Sixty seven percent and 82% were considered in PET-CR on iPET based on DS 1-2 and DS 1-3 respectively. PET-CR went up to 77% and 83% respectively on eotPET. For final analysis, DS1-2 was used to define PET-CR as no statistically significant difference in mPFS and mOS was noted between DS1-2 and DS1-3. With median follow up of 22.7mo, two-year mPFS and mOS for the cohort were 50% and 74% respectively. Two- year mPFS for iPET-CR and eotPET-CR were 62%. Two-year mOS for iPET-CR and eotPET-CR were 86%% and 83%. Two-year mPFS for iPET-PR and eotPET-PR were 37% and 67%. Two-year mOS for iPET-PR and eotPET-PR were 70% and 100 % (not statistically significant difference with PET-CR mPFS and mOS). None of the pts with PD on iPET were alive at two year. Two-year mOS for eotPET-SD and eotPET-PD are 40%. Negative predictive value of iPET and eotPET is 61%, positive predictive value is 65% and 72% respectively. Conclusion: While PET-SD and PD is quite predictive of poor survivorship, significant number of PET-CR pts will relapse. Even though PET-CR rate to frontline therapy is high, it does not translate into durable responses for significant number of pts with TCL. Thus, PET-CR is not a sensitive enough measure to be considered as a predictor of long-term remission in TCL. It is important to develop response assessment tools which will correlate better with long term survivorship of TCL patients. Figure 1 Overall survival stratified on PET response Figure 1. Overall survival stratified on PET response Figure 2 Progression free survival stratified on PET response Figure 2. Progression free survival stratified on PET response Disclosures Feldman: Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Skarbnik:Pharmacyclics: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Mato:Theradex: Research Funding; TG Therapeutics: Research Funding; ProNAi: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma: Research Funding; Abbvie: Research Funding; TG Therapeutics: Consultancy; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy; Abbvie: Consultancy. Chow:Seattle Genetics: Speakers Bureau. Protomastro:COTA: Employment. Leslie:Celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau. Goy:Acerta: 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, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Excellent Outcomes at 3 Years with Nilotinib 800 Mg Daily In Early Chronic Phase, Ph+ Chronic Myeloid Leukemia (CML): Results of a Phase 2 GIMEMA CML WP Clinical Trial

Blood ◽

10.1182/blood.v116.21.359.359 ◽

2010 ◽

Vol 116 (21) ◽

pp. 359-359 ◽

Cited By ~ 12

Author(s):

Gianantonio Rosti ◽

Fausto Castagnetti ◽

Gabriele Gugliotta ◽

Massimo Breccia ◽

Luciano Levato ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Chronic Phase ◽

Molecular Response ◽

Phase 2 ◽

Advisory Committees ◽

Free Survival ◽

Daily Dose ◽

Cumulative Rate

Abstract Abstract 359 Background: Nilotinib is a potent and selective inhibitor of BCR-ABL. In the phase 3 ENESTnd trial, nilotinib demonstrated superior efficacy to imatinib with higher and faster molecular responses. With a median follow-up of 18.5 months (ASCO/EHA 2010), the rates of progression to accelerated or blast phase (AP/BC) were 0.7% and 0.4% with nilotinib 300 mg and 400 mg BID, respectively, and significantly lower in comparison to imatinib (4.2% P = .006 and .003, respectively). Based on the results of the ENESTnd trial, nilotinib has been approved (FDA) for the frontline treatment of Ph+ CML. With imatinib 400 mg (IRIS trial), the rate of any event and the rate of progression to AP/BC were higher during the first 3 years on treatment (15.6% and 6.1%, respectively). Consequently, a confirmation of the durability of nilotinib responses at 3 years is extremely important. Aims: To evaluate responses (either cytogenetic and molecular) and to investigate outcomes of patients treated for 3-years with nilotinib 400 mg BID as frontline therapy. Outcomes evaluated include Overall Survival (OS), Progression-Free Survival (PFS), Failure-Free Survival (FFS) and Event-Free Survival (EFS). Method: A multicentre phase 2 trial (nilotinib 400 mg BID) was conducted by the GIMEMA CML Working Party (ClinicalTrials.gov.NCT00481052). The median follow-up is currently 30 months (3 years by November 2010). Definitions: Major Molecular Response (MMR): BCR-ABL/ABL ratio < 0,1% IS; Complete Molecular Response (CMR): undetectable transcript levels and nested PCR negative; failures: no CHR at 3 months, no CgR at 6 months, no PCgR at 1 year, no CCgR at 18 months, loss CHR or CCgR, progression and death (according to the revised European LeukemiaNet recommendations); events: failures and treatment discontinuation for any reason. All the analysis has been made according to the intention-to-treat principle. Result: 73 patients have been enrolled; median age 51 years (range 18–83); 45% low, 41% intermediate and 14% high Sokal risk. The cumulative CCgR rate (primary endpoint) at 12 months was 100%. CCgR at each milestone: 78% at 3 months, 96% at 6, 12 and 18 months, 92% at 24 months. The cumulative rate of MMR was 96%, while the rates of MMR at 3, 6, 12, 18 and 24 months were 52%, 66%, 85%, 81% and 82%, respectively. The cumulative rate of CMR was 41%, while the rates of CMR at 12 and 24 months were 7% and 12%, respectively. None of the patients who achieved a MMR progressed to AP/BC. Only one patient progressed at 6 months to AP/BC: a 63 years old female with a high Sokal risk disease in CCgR at 3 months, who developed a T315I mutation. During the first 12 months, the mean daily dose was 600–800 mg, 400–599 mg, and less than 400 mg in 74%, 18% and 8% of patients, respectively. The nilotinib last daily dose was as follows: 800 mg in 48 (71%) patients, 400 mg in 19 (28%) patients and 200 mg in 1 (1%) patient. Adverse events (AEs) were mostly grade 1 or 2 and manageable with appropriate dose adaptations. Two patients (3%) showed a prolongation of the QTcF above 450 msec (none above 50 msec). Four events lead to permanent discontinuation of nilotinib: 3 patients discontinued after 9, 15 and 27 months on treatment for recurrent episodes of amylase and/or lipase increase (no pancreatitis) and 1 patient after 25 months due to atrial fibrillation, unrelated to study drug. Three of them are currently on imatinib second-line and 1 on dasatinib third-line. Overall, 5 events have been recorded so far (1 progression to AB/BC and 4 permanent discontinuation of nilotinib due to AEs). At 30 months the OS, PFS and FFS are 99% and the EFS is 92%. Conclusion: The rate of failures was very low during the first 3 years. Responses remain stable. The very high rates of responses achieved during the first 12 months on treatment are being translated into optimal outcome for most of the patients. Acknowledgments: European LeukemiaNet, COFIN, Bologna University, BolognAIL Disclosures: Rosti: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau. Castagnetti:Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Gugliotta:Novartis: Honoraria. Saglio:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martinelli:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; pfizer: Consultancy. Baccarani:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; Wyeth: Consultancy, Research Funding.

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Updated Efficacy Including Genetic and Clinical Subgroup Analysis and Overall Safety in the Phase 3 RESONATETM Trial of Ibrutinib Versus Ofatumumab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Blood ◽

10.1182/blood.v124.21.3331.3331 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3331-3331 ◽

Cited By ~ 14

Author(s):

Jennifer R. Brown ◽

Peter Hillmen ◽

Susan O'Brien ◽

Jaqueline C. Barrientos ◽

Nishitha Reddy ◽

...

Keyword(s):

Board Of Directors ◽

Interim Analysis ◽

Research Funding ◽

Single Agent ◽

Progression Free Survival ◽

Phase 3 ◽

Advisory Committees ◽

Free Survival ◽

Prior Therapy

Abstract Introduction: The role of various prognostic factors in CLL/SLL is not yet fully understood, including the implications of new genetic markers associated with high risk. Ibrutinib (Imbruvica®), a first-in-class Bruton’s tyrosine kinase inhibitor, is a once-daily single agent approved by the US FDA for CLL patients (pts) who have received ≥ 1 prior therapy, and for pts with 17p deletion CLL. We report updated efficacy results for the phase 3 RESONATETM(PCYC-1112) study of ibrutinib (ibr) vs ofatumumab (ofa), relative to genetic features and prior treatment exposure, and provide updated adverse event (AE) data. Methods: Pts received 420 mg oral ibr daily until disease progression or unacceptable toxicity or IV ofa for up to 24 weeks. Primary endpoint was IRC-assessed PFS with secondary endpoints OS and IRC ORR (Byrd et al, NEJM 2014). At interim analysis, with median follow-up of 9.4 months, the Independent Data Monitoring Committee recommended pts in the ofa arm be provided access to ibr. Additional endpoints including investigator-assessed efficacy, investigation of potential predictive biomarkers, and safety with longer follow-up are reported. Results: The 391 pts were randomized to ibr (n=195) or ofa (n=196). Median age was 67 years, with 40% ≥70 years, 57% Rai stage III/IV disease. Median number of prior therapies was 3 (ibr) vs 2 (ofa) with 23% having 1, 28% with 2, and 49% ≥ 3 prior therapies. Approximately 32% had del(17p) and 32% (122/381) del(11q). 72 of 300 pts had complex cytogenetics (≥3 abnormalities) and 68% (181/266) unmutated IGHV. With outcome analyses pending, preliminary analysis revealed that 19% of pts had NOTCH1, 23% SF3B1, 36% TP53, and 1% MYD88 gene mutations at baseline. With median follow-up of 16 months, investigator-assessed PFS was significantly longer for ibr vs ofa (median NR vs 8.1 months, [HR 0.106, 95%CI 0.073-0.153, P<0.0001]) (figure). OS was significantly better for ibr vs ofa, with 18-month OS rates of 85% and 78% respectively, despite 120 pts (61%) randomized to ofa who crossed over to ibr and were censored at that time. Higher number of prior therapies (≥3) and 11q deletion were associated with significantly lower 12-month PFS rate for ofa (P=0.001) but not for ibr (P=0.14) and (P=0.13), respectively. The best ORR as assessed by investigator for ibr vs ofa was 90% vs 25% (P<0.0001), including 8% of pts on ibr achieving PR with lymphocytosis and 6% with CR/CRi. Compared with ofa, ibr improved 12-month PFS (table) and ORR regardless of baseline genetics, complex cytogenetics, or number of prior therapies (P<0.001 for ibr vs ofa for all comparisons). Of pts receiving ibr, those who received only 1 prior therapy had better efficacy outcomes than those who received ibr in later lines (12-month PFS of 94% vs 82% [P=0.01]); responses were achieved in 100% vs 88% (P=0.04), of these pts, respectively. No significant difference in 12-month PFS was observed in ibr-treated patients with or without del(17p) or for those who developed lymphocytosis compared to those without lymphocytosis. Median treatment duration was longer for ibr vs ofa (16 vs 5 months). The most common cumulative AEs for ibr, displayed here by maximum grade, were consistent with those reported at interim analysis including diarrhea (37% grade [G]1, 10% G2, 4% G3), fatigue (18% G1, 12% G2, 3% G3), and nausea (24% G1, 6% G2, 2% G3). The most frequent grade 3/4 AEs for ibr included neutropenia (18%), pneumonia (9%), thrombocytopenia (6%), anemia (6%) and hypertension (6%). Atrial fibrillation of any grade occurred in 7% of ibr-treated pts. 47 pts (24%) discontinued ibr; 17 (9%) for progressive disease, 13 (7%) for AEs, 10 (5%) deaths, 3 (2%) pt decision, including 2 pts going to commercial ibr, and 4 (2%) investigator decision, including 1 (1%) for SCT. 76% of pts randomized to ibr continue treatment on study. Conclusions: Ibr significantly improved investigator-assessed PFS, OS, and ORR relative to ofa in pts with CLL/SLL who had received ≥ 1 prior therapy. The updated results are consistent with previously published phase 2 single-agent results (Byrd et al. NEJM 2013). Pts in the ibr arm treated in the second line experienced better outcomes than those salvaged in later lines of therapy. These results provide further evidence of ibrutinib’s robust clinical activity in CLL pts regardless of high-risk baseline genetics or number of prior therapies. Figure 1 Progression-Free Survival Figure 1. Progression-Free Survival Table. Investigator-assessed Efficacy Outcomes Table. Investigator-assessed Efficacy Outcomes Disclosures Brown: Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Barrientos:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mulligan:Roche, Abbvie: Consultancy, Honoraria. Jaeger:Janssen Cilag: Honoraria. Barr:Pharmacyclics: Research Funding. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Kipps:Pharmacyclics: Research Funding. Cymbalista:Janssen, Roche, GSK, Gilead, Mundipharma: Honoraria. Delgado:Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria. Montillo:Janssen: Honoraria. Burger:Pharmacyclics: Consultancy, Honoraria, Research Funding. Chung:Pharmacyclics: Employment. Lin:Pharmacyclics: Employment. Gau:Pharmacyclics: Employment. Chang:Pharmacyclics: Employment. McGreivy:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Byrd:Pharmacyclics: Research Funding.

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Updated Analysis of Overall Survival in Randomized Phase III Study of Idelalisib in Combination with Bendamustine and Rituximab in Patients with Relapsed/Refractory CLL

Blood ◽

10.1182/blood.v128.22.231.231 ◽

2016 ◽

Vol 128 (22) ◽

pp. 231-231 ◽

Cited By ~ 3

Author(s):

Andrew D. Zelenetz ◽

Jennifer R. Brown ◽

Julio Delgado ◽

Herbert Eradat ◽

Paolo Ghia ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Opportunistic Infections ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Prior Therapy ◽

Equity Ownership

Abstract Introduction: Therapies able to improve overall survival in patients with relapsed/refractory (RR) CLL are needed. We have previously reported that idelalisib (IDELA), a selective PI3K delta inhibitor, administered in combination withbendamustine/rituximab (BR) improves progression-free survival compared with BR alone after a medianfollowup of 12 months. This study (NCT01569295) was unblinded by the independent data monitoring committee at first interim analysis for efficacy. We now present updated data on overall survival (OS). Methods: Between June 2012 and August 2014, 416 patients (pts) with RR CLL were enrolled in the study across 19 countries. The current analysis data cutoff date of May 2016 represents a median follow-up of 21 months. Progression-free survival based on independent review committee assessment was the primary endpoint of this study, with OS as a secondary endpoint. All pts had completed study treatment with BR. Key eligibility criteria included pts with RR CLL requiring therapy, having received previous purine analog or bendamustine (ineligible if refractory to bendamustine); and anti-CD20 antibody; relapsing or progressing within 36 months of the completion of the last therapy. Patients were randomized to BR for 6 cycles Q 28 days (B = 70 mg/m2 D1, D2 of each cycle; R = 375 mg/m2 C1 and 500 mg/m2 C2-6) and IDELA 150 mg BID or placebo (administered until IRC-confirmed PD), death, intolerable toxicity, or withdrawal of consent. Stratification was based on presence/absence ofdel(17p) and/or p53 mutation (mut), immunoglobulin heavy chain variable region (IGHV) mutated/unmutated (analysis performed by a central lab), and disease status refractory (CLL progression <6 months from completion of prior therapy) vs relapsed (CLL progression ≥6 months from completion of prior therapy). Crossover was not permitted at the time of PD or unblinding. Results: The ITT population reflects 207/209 pts in the IDELA + BR/BR + placebo arm: 76% male; 42% ≥65 years; Rai stage III/IV 46%; median time since completion of last prior therapy 16 months; pts with high-risk features (del[17p]/p53mut 32.9%, unmutated IGHV 83.2%, refractory 29.8%); median number of prior therapies: 2 (range 1-13); and median follow-up 21 months. All pts have completed study treatment with BR. A total of 65 pts remain on study treatment: 64 on IDELA monotherapy and 1 pt on placebo. Overall by ITT and IRC, 260/416 pts (IDELA/placebo 95/165) have met the primary endpoint of PD or death. Median OS (mo) of IDELA + BR vs BR + placebo was not reached vs 41 (HR = 0.67; p value 0.036; 95% CI 0.47, 0.96) (Figure 1). The safety findings were similar to what we previously reported: Serious AEs occurred in 147 (71%)/94 (5%) IDELA/placebo arms, respectively. The commonly occurring SAEs by system organ class were infections and infestations (41%/23%) and by MEDRA-preferred terms febrile neutropenia 43 (21%)/10 (5%) and pneumonia 35 (17%)/16 (8%) in the IDELA/placebo arms respectively. The total number of pts with opportunistic infections (Pneumocystis jirovecii pneumonia [PJP]/cytomegalovirus [CMV]) in the IDELA arm was 5/13 vs 0/3 in the placebo arm. Conclusion: IDELA in combination with BR is superior to BR alone with regard to OS in RR CLL. The improvement in OS was observed across risk categories. Opportunistic infections (PJP, CMV) and SAEs were more frequent in the IDELA vs placebo arm. Results of IDELA-containing regimens may be further improved with implementation of adequate PJP prophylaxis and CMV monitoring measures. This regimen represents an important new option for pts with RR CLL. Figure 1. Kaplan-MeierCurve: Overall Survival. Figure 1. Kaplan-MeierCurve: Overall Survival. Disclosures Zelenetz: Gilead Sciences: Research Funding. Brown:Celgene: Consultancy; Sun BioPharma: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Gilead Sciences: Consultancy; Janssen: Consultancy; Infinity: Consultancy; Abbvie: Consultancy. Delgado:Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; GSK/Novartis: Honoraria; Abbvie: Consultancy. Eradat:Genentech: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria. Ghia:Adaptive: Consultancy; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Jurczak:Celltrion, Inc: Research Funding; Acerta: Research Funding; Gilead Sciences: Research Funding; Bayer: Research Funding; Janssen: Research Funding. Loscertales:Roche: Honoraria, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees. MacDonald:Gilead Sciences: Speakers Bureau. Morschhauser:Celgene: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Honoraria. De la Serna:Abbvie: Consultancy; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Speakers Bureau. Shadman:Pharmacyclics: Honoraria, Research Funding. Pocock:Gilead Sciences: Other: Sponsorship to attend the EHA 2016 Meeting; Janssen: Speakers Bureau; Takeda: Honoraria. Adewoye:Gilead Sciences: Employment, Equity Ownership. Kim:Gilead Sciences: Employment, Equity Ownership. Simpson:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Stilgenbauer:Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding.

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ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽

10.1182/blood-2019-128198 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1565-1565 ◽

Cited By ~ 1

Author(s):

Patrizia Mondello ◽

Irene Dogliotti ◽

Jan-Paul Bohn ◽

Federica Cavallo ◽

Simone Ferrero ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advanced Stage ◽

Advisory Committees ◽

Free Survival ◽

High Risk Patients ◽

Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with >90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= <0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS <3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, 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 Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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