scholarly journals Optimal Therapy for Relapsed AL Amyloidosis Post Autologous Stem Cell Transplant

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3171-3171
Author(s):  
M Hasib Sidiqi ◽  
Abdullah S. S. Al Saleh ◽  
Iuliana Vaxman ◽  
Angela Dispenzieri ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
Autologous Stem Cell Transplant ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Free Survival ◽  
Treatment Regimens ◽  
2Nd Generation

Introduction: There is a paucity of randomized trials to guide therapy for relapsed AL amyloidosis with treatment regimens generally extrapolated from experience in multiple myeloma. Methods: We conducted a retrospective review of patients who relapsed after receiving autologous stem cell transplant at Mayo Clinic. Patients treated for first relapse between January 2004 and December 2018 were included. Results: Three hundred and twenty-one patients were seen for relapsed AL amyloidosis post ASCT during the study period. Baseline characteristics were typical for a cohort with AL amyloidosis and are listed in Table1. 39% received therapy prior to transplant, conditioning in the majority (75%) was melphalan 200mg/m2. The median progression free survival from transplant (PFS1) was 30.7 months. Of the 321 patients 294 received treatment for relapsed disease. We categorized treatment regimens according to commonly used combinations and drug classes to further analyze outcomes. 34 patients were excluded from this analysis as they either proceeded directly to second ASCT (n=10) or received an atypical regimen not commonly considered for AL amyloidosis (n=24). Five categories of therapy regimens were identified, thalidomide based (n=110), melphalan plus steroids (n=31), 2nd generation immunomodulatory (IMiD) drug +/- alkylator (n=76), proteasome inhibitor (PI) +/- alkylator (n=116), PI plus IMiD (n=16), or daratumumab based (n=9). Disease and treatment characteristics for patients treated with these regimens are listed in Table 2. Patients treated with thalidomide had the shortest PFS1 (17.7 months) but PFS1 was similar for those treated with melphalan plus steroids, PI+IMiD and 2nd generation IMiDs (25.5, 24.3 and 25.6 months respectively). Patients treated with a PI +/- alkylator and daratumumab based regimen had the longest PFS1 (36.7 and 41.9 months respectively). The median duration of therapy was longer in patients treated with a 2nd generation IMiD or daratumumab based regimen (10.2, 12, 6.1, 5.5, 6.2 and 5.9 months for Dara based, 2nd generation IMiD, PI+/- alkylator, PI+IMiD, melphalan plus steroids and thalidomide based respectively). Hematologic response rate was lowest in those treated with melphalan plus steroids or thalidomide based regimens (44% and 55% respectively) and highest for patients treated with a PI+/- alkylator, (Figure 1). Progression free survival from relapsed therapy (PFS2) was longest amongst patients treated with daratumumab based regimens, PI +/- alkylator and 2nd generation IMiDs (not reached, 29.9 and 26.7 months respectively), Figure 2A. Overall survival from time of relapsed therapy favored patients treated with daratumumab based regimens, 2nd generation IMiDs and PI +/- alkylator, Figure 2b). Conclusion: A second generation IMiD based regimen or PI +/- alkylator produce high response rates and prolonged progression free and overall survival for relapsed AL amyloidosis. Patients treated with daratumumab based regimens and those treated with a PI plus IMiD also appear to do well, although numbers were low in our study. Patients treated with melphalan plus steroids or thalidomide based combinations have inferior outcomes and these regimens should be avoided. Disclosures Dispenzieri: Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Kapoor:Glaxo Smith Kline: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Janssen: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Gertz:Medscape: Consultancy, Speakers Bureau; Prothena Biosciences Inc: Consultancy; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Appellis: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; Annexon: Consultancy. OffLabel Disclosure: Daratumumab off label use for AL amyloidosis.

Practice Patterns of Re-Initiation of Therapy at Time of Relapse or Progression Post- Autologous Stem Cell Transplant (ASCT) Among Patients with AL Amyloidosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3444-3444 ◽  
Author(s):  
Yi L. Hwa ◽  
Rahma Warsame ◽  
Morie A. Gertz ◽  
Francis K Buadi ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Practice Patterns ◽  
Autologous Stem Cell Transplant ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Second Line ◽  
Second Line Therapy ◽  
Advisory Committees ◽  
Line Therapy

Abstract Background: Among patients with immunoglobulin light chain (AL) amyloidosis, there is little consensus on when reinstitution of chemotherapy should occur (Milani and Dispenzieri, International Society of Amyloidosis 2016). AL amyloidosis patients who are treated with high dose chemotherapy followed by autologous stem cell transplant (ASCT) are a relatively low-risk and homogenous population, making them an ideal group to study practice patterns. Methods: We conducted a retrospective study to evaluate the patterns of relapse or progression and the timing of re-initiation of therapy among 146 patients who were initially treated with ASCT at Mayo Clinic between 1996 and 2009 and who received second-line therapy between 7/9/1997 and 4/12/2012. Results: The median time from ASCT to second-line therapy was 23.6 months and the median follow up post ASCT was 57.5 months. The indications for second-line treatment were: 1) both hematologic and organ progression 24.7% (36 patients); 2) organ progression only 41.1% (60); 3) hematologic relapse only 34.2% (50). The median dFLC at the time of starting second-line therapy was 10.5 mg/dL (1.6 - 59.5 mg/dL), which was 44.9% (13.8-167.2%) of dFLC level at diagnosis. Increase in proteinuria by > 50% from nadir (that was also at least 1g/24 hours, i.e. renal progression) was present in 35.8%. Increase in NT proBNP by >30% from nadir and minimum of 300 pg/mL was present in 48.9% of patients. The respective 4 years overall survival rates from the time of ASCT were 87.8%, 63.9%, and 56.7% (p=0.0016) for patients who had hematologic relapse, organ progression only and both organ and hematologic progression. Comparisons of laboratory markers at diagnosis, nadir of post ASCT and initiation of second-line therapy are listed in the table. Conclusions: Our study investigated the patterns of relapse / progression following upfront ASCT. This provides some insights on practice patterns of when physicians re-initiate therapy. Table Table. Disclosures Gertz: NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Novartis: Research Funding; Prothena Therapeutics: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria; Ionis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Annexon Biosciences: Research Funding. Kumar:Millennium: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; Kesios: Consultancy. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Celgene: Research Funding; Jannsen: Research Funding; pfizer: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Prolonged Progression-Free Survival Is Possible in Patients with Diffuse Large B-Cell Lymphoma Receiving > 1 Salvage Therapies before Autologous Stem Cell Transplant

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5825-5825
Author(s):  
Abigail G Kettle ◽  
Jeffrey Switchenko ◽  
Oscar Calzada ◽  
Anh Thuy Phan ◽  
Monique Farone ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Board Of Directors ◽  
Salvage Therapy ◽  
Research Funding ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Salvage Treatment ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Free Survival

Abstract Introduction While 50-60% of patients with diffuse large B-cell lymphoma (DLBCL) are cured with initial chemoimmunotherapy such as R-CHOP, many patients will relapse and require additional therapy. Historically, autologous stem cell transplant (ASCT) has been utilized in chemo-sensitive patients with relapsed DLBCL although the role of ASCT in patients who require > 1 salvage treatment to achieve remission is less defined due to concerns about the likelihood of long-term remission in that population. We evaluated the outcome of ASCT in patients who required >1 salvage therapy. Methods We included all patients undergoing ASCT for relapsed/refractory DLBCL at our site between 2005-2016 who received > 1 salvage treatment before transplant, with radiation therapy considered a salvage treatment if given after relapse but before ASCT. We collected demographic, clinical, laboratory and pathologic data on all patients. We defined progression-free survival (PFS) as time from ASCT to date of progression or death from any cause and overall survival (OS) as time from ASCT to date of death from any cause. Living patients were censored at the time of their last follow up. Univariate Cox proportional hazards models of PFS and OS were fit and Kaplan-Meier plots were developed to estimate the impact of variables of interest on survival. Results Out of 259 patients undergoing ASCT for DLBCL, 43 received > 1 salvage treatment, the median age was 51 years and 23 patients were male. Twenty patients had stage III/IV disease at diagnosis. The median time to relapse from the time of diagnosis was 9.3 months, and 42% of patients experienced a relapse > 12 months after diagnosis. Twenty-six patients (60%) received radiation as one of their salvage therapies, 25 patients (58%) received R-ICE as their first salvage therapy and 10 (23%) patients received R-ICE as their second salvage treatment. All patients received either 2 (n=39) or 3 (n=4) salvage therapies before ASCT, and the response to the initial salvage therapy received was CR in 4 patients, PR in 14 patients, SD in 1 patient, and PD in 14 patients, with initial response to salvage therapy missing in 10 patients. The median PFS for all patients was 15.9 months and the median OS was 57.2 months (Figure 1a). Receipt of radiation and having disease sensitive to treatment at the time of ASCT were the only factors associated with prolonged PFS and OS. Median PFS has not been achieved in patients who received radiation while patients who did not receive radiation had a median PFS of 4.2 months (HR = 0.36, p = 0.014; Figure 1b). Patients who had a chemo sensitive disease status at transplant had a median PFS of 22.6 months; however, patients with refractory disease at transplant only achieved a median PFS of 3.6 months (HR = 0.30, p=0.008). Remaining factors including conditioning regimen, time to relapse, and number of salvage therapies were not significantly associated with PFS or OS. Conclusions ASCT can result in prolonged PFS/OS in patients requiring > 1 salvage therapy especially in the case of sensitive disease. Radiation as an additional line of therapy is associated with improved PFS/OS, suggesting this can be included to induce remission in patients who fail to achieve CR with initial salvage treatment. While uncommon, patients with chemo-refractory disease can also have durable survival and should not be excluded from transplant. Figure 1a Progression-free survival for all patients with DLBCL receiving > 1 salvage therapy. Figure 1a. Progression-free survival for all patients with DLBCL receiving > 1 salvage therapy. Figure 1b Progression-free survival for all patients with DLBCL receiving > 1 salvage therapy based on receipt of radiation therapy. Figure 1b. Progression-free survival for all patients with DLBCL receiving > 1 salvage therapy based on receipt of radiation therapy. Disclosures Calzada: Seattle Genetics: Research Funding. Flowers:Spectrum, Janssen, Infinity, AbbVie, Acerta, Pharmacyclics, TG Therapeutics: Research Funding; Celgene Corporation: Consultancy, Honoraria; Optum Rx, Seattle Genetics, Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Seattle Genetics: Research Funding. Cohen:Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1884-1884 ◽  
Author(s):  
Alfred Chung ◽  
Gregory P. Kaufman ◽  
Surbhi Sidana ◽  
David Iberri ◽  
Erik Eckhert ◽  
...  
Keyword(s):  
Disease Progression ◽  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Control Group ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Free Interval ◽  
Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: 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, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

Long-Term Efficacy and Safety (27 months) of the Biosimilar CT-P10 in Patients with Low Tumor Burden Follicular Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Larry W Kwak ◽  
Juan Manuel Sancho ◽  
Seok-Goo Cho ◽  
Hideyuki Nakazawa ◽  
Junji Suzumiya ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
Time To Progression ◽  
Advisory Committees ◽  
Free Survival ◽  
Travel Costs ◽  
Single Transition ◽  
Second Year

We assessed long-term safety and efficacy of CT-P10 and rituximab in patients with newly diagnosed low-tumour-burden follicular lymphoma (LTBFL), and following a single transition from rituximab to CT-P10. This double-blind, parallel-group, active-controlled phase 3 trial randomized patients with CD20+ LTBFL to receive CT-P10 or US-sourced rituximab (375 mg/m2 intravenous). Induction therapy (weekly for 4 cycles) was followed by a 2-year maintenance period for patients achieving disease control (CR, CRu, PR and SD). During the maintenance, CT-P10 or rituximab were administered every 8 weeks (6 cycles) in the first year and additional CT-P10 was administered every 8 weeks (6 cycles) in the second year. Secondary endpoints (reported here) were overall response rate during the study period, progression-free survival, time-to-progression, and overall survival. Safety and immunogenicity were also evaluated over the study period. Between Nov 9, 2015 and Jan 4, 2018, 258 patients were randomised (130 CT-P10; 128 rituximab). Over the study period, 115 (88%; CT-P10) and 111 (87%; rituximab) patients achieved overall response. At a median follow-up of 29·2 months (IQR: 26·1-33·7), median progression-free survival, time-to-progression, and overall survival were not estimable. The KM estimates (95% CI) for OS at 36 months were 98% (93-99) and 97% (89-99) in the CT-P10 and rituximab groups, respectively. Corresponding values for PFS were 80% (70-87) and 68% (54-79), while results for TTP were 82% (72-88) and 68% (54-79) in the CT-P10 and rituximab groups, respectively. (Figure A. OS; Figure B. PFS and Figure C. TTP) Over the study period, 114 (88%) and 104 (81%) patients in the CT-P10 and rituximab groups, respectively, experienced at least one treatment-emergent adverse event (TEAE) and 14 (11%) patients in each group experienced TE-serious adverse events (TESAEs). There were no unexpected safety findings observed during the second year of the maintenance period after single transition from rituximab to CT-P10. Figure 1 Disclosures Kwak: Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Xeme Biopharma/Theratest: Other: equity; CJ Healthcare: Consultancy; Sellas Life Sciences Grp: Consultancy; Enzychem Life Sciences: Membership on an entity's Board of Directors or advisory committees; Antigenics: Other: equity; InnoLifes, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pepromene Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc.: Consultancy. Sancho:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gelgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: 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. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Menne:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Speakers Bureau; Novartis: Honoraria, Other: Travel costs, Speakers Bureau; Pfizer: Honoraria, Other: Travel costs, Speakers Bureau; Celgene: Honoraria, Other: Travel grants; Roche: Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Astra Zeneca: Research Funding; Takeda: Honoraria, Speakers Bureau. Jurczak:Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; Acerta: Research Funding; Bayer: Research Funding; Janssen: Research Funding; MeiPharma: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Trneny:Gilead: Consultancy, Honoraria, Other: Travel Expenses; Janssen: Consultancy, Honoraria, Other: Travel Expenses; Roche: Consultancy, Honoraria, Other: Travel Expenses; MorphoSys: Consultancy, Honoraria; Celgene: Consultancy; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb Company: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel Expenses. Ogura:Cellgene: Honoraria; Chugai: Honoraria; Denovo Biopharma: Membership on an entity's Board of Directors or advisory committees; MejiSeika Pharma: Membership on an entity's Board of Directors or advisory committees; Mundi Pharma: Membership on an entity's Board of Directors or advisory committees; SymBio: Membership on an entity's Board of Directors or advisory committees; TevaTakeda: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Membership on an entity's Board of Directors or advisory committees. Kim:Pfizer: Research Funding; Donga: Research Funding; Mundipharma: Research Funding; F. Hoffmann-La Roche: Research Funding; Kyowa Kirn: Research Funding; Celltrion: Research Funding; JJ: Research Funding. Lee:Celltrion, Inc.: Current Employment. Kim:Celltrion, Inc.: Current Employment. Ahn:Celltrion, Inc.: Current Employment. Buske:Roche, Janssen, Bayer, MSD: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Roche, Janssen, AbbVie, Pfizer, Celltrion: Honoraria, Speakers Bureau. OffLabel Disclosure: Rituximab monotherapy to LTBFL patients

Progressive but Previously Untreated CLL Patients with Greater Array CGH Complexity Exhibit A Less Durable Response to Chemoimmunotherapy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2406-2406
Author(s):  
Neil E. Kay ◽  
Jeanette Eckel Passow ◽  
Esteban Braggio ◽  
Scott Van Wier ◽  
Tait Shanafelt ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Board Of Directors ◽  
Copy Number ◽  
Research Funding ◽  
Progression Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Genomic Complexity ◽  
Duration Of Response ◽  
Gains And Losses

Abstract Abstract 2406 The outcome for a given CLL patient is difficult to predict. While there are promising models, they require collation of multiple clinical and laboratory parameters, and it remains to be seen whether they will apply to typical CLL patients in the community. To further dissect out explanations for this dramatic clinical heterogeneity, we sought to understand genomic complexity of clonal B-cells as a possible explanation of clinical variability with specific application to genomic complexity as a predictor of therapeutic response and clinical outcome in CLL. Thus we wished to identified global gains and losses of genetic material in order to define copy-number abnormalities (CNA) in 48 clinically progressive CLL patients who were about to be treated on a chemoimmunotherapy protocol. This protocol was previously reported by us (Blood. 109:2007) and had an induction phase with pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2) and rituximab (375 mg/m2) given every 3 weeks for 6 cycles and then responding patients were followed ever three months until relapse. In order to estimate CNA, we employed array-based comparative genomic hybridization (aCGH) using a one-million oligonucleotide probe array format on the leukemic B-cells from the 48 patients entering this trial. In those same patients, the aCGH data were compared to a) FISH detecxtable data using a panel for the common recurring genetic defects seen in CLL and b) to their clinical outcome on this trial. With aCGH we found that 288 CNA were identified (median of 4 per patient; range 0–32) of which 215 were deletions and 73 were gains. The aCGH method identified most of the FISH detected abnormalities with a complete concordance for 17p13.1- deletion (17p-) between aCGH and FISH. We also identified chromosomal gain or loss in ≥6% of the patients on chromosomes 3, 8, 9, 10, 11, 12, 13, 14 and 17. We found that CLL patients with ≥15 CNA had a significantly worse progression free survival (PFS) than patients with <15 CNA (p=0.004)(figure). Patients with ≥15 CNA also had a shorter duration of response than those with <15 CNA (p=0.0726). Of interest, more complex genomic features were found both in patients with a 17p13.1 deletion and in more favorable genetic subtypes such as 13q14.1. Thus, for 5 patients with >15 CNAs the following FISH patterns were seen: +12/13q14.1-x1/13q14.1 -x2, 13q14.1 ×1 (n=2), and 17p13.1 (n=2). In addition, a 17p- by FISH was positively associated with the number of CNA and total deletion size. The odds of having an overall response decreased by 28% (95% CI: 5–55%; p=0.015) with each additional CNA for the 17p13.1- patients. In addition to defining genomic complexity as the total number of CNA for each patient, we also defined complexity as the sum of the lengths of all interstitial chromosomal gains and losses. When defined as the total size of chromosomal gains or losses, genomic complexity was significantly associated with 17p13.1 and worse overall clinical response. In summary, this analysis utilized the global assessment of copy number abnormalities using a high-resolution aCGH platform for clinically progressive CLL patients prior to initiation of their treatment. One outcome was that we found higher genomic complexity was associated with shorter progression-free survival, reduced duration of response and predicted a poor response to treatment. In addition since we did find genomic complexity in more traditionally favorable FISH categories, such as 13q14.1 type defects, this may explain why some of the latter patients do not fare as well as might be expected even with aggressive chemoimmunotherapy approaches. This study adds information on the association between inferior trial response and increasing genetic complexity as CLL progresses. Disclosures: Off Label Use: Pentostatin. Kipps: GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding; Memgen: Research Funding; Igenica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Research Funding; Abbott Laboratories: Research Funding.

Tandem Autologous Hematopoietic Stem Cell Transplants (AuHCT) with or without Maintenance Therapy (auto-auto) Versus Single AuHCT Followed by HLA Matched Sibling Non- Myeloablative Allogeneic HCT (auto-allo) for Patients with Standard Risk (SR) Multiple Myeloma (MM): Results From the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 41-41 ◽  
Author(s):  
Amrita Krishnan ◽  
Marcelo C Pasquini ◽  
Marian Ewell ◽  
Edward A. Stadtmauer ◽  
Edwin P Alyea ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Disease Progression ◽  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
Response Rates ◽  
Advisory Committees ◽  
Free Survival ◽  
Allogeneic Hct ◽  
Matched Sibling

Abstract Abstract 41 AuHCT improves survival in patients with MM, but disease relapse and progression remain a challenge. Both tandem AuHCT and post transplant maintenance therapy improve progression-free survival (PFS). Alternatively, allogeneic HCT has the potential to reduce disease progression through a graft-versus-myeloma effect. Use of nonmyeloablative conditioning regimens allows the latter approach to be used with reduced treatment-related mortality (TRM). BMT CTN 0102 was a multicenter phase III trial that biologically assigned patients with MM to auto-auto using melphalan 200mg/m2 (MEL 200) conditioning or an auto-allo approach using MEL 200 followed by alloHCT with 2 Gy total body irradiation. Graft-versus-disease (GVHD) prophylaxis was cyclosporine and mycophenolate mofetil. The primary endpoint was 3-year progression free survival (PFS). Between December 2003 and March 2007, 710 patients from 43 US centers were enrolled. Patients were assigned to the auto-allo arm based on availability of an HLA-matched sibling donor at time of enrollment. Patients in the auto-auto arm were further randomized to thalidomide and dexamethasone (Thal-Dex) for 1 year or observation (obs). Among 625 patients with SR MM (absence of chromosome 13 deletion by metaphase karyotyping and β-2 microglobulin ≤ 4mg/L), 436 were assigned to auto-auto (217 Thal-Dex, 219 obs) and 189 to auto-allo. Compliance with Thal-Dex was poor, with 84% of patients not completing prescribed therapy. PFS and overall survival (OS) between the Thal-Dex and obs cohorts were equal and these arms were pooled for the primary analysis. The auto-auto and auto-allo groups differed in age (median 55y vs. 52y, p =0.01) and time between first and second transplants (median 98d vs 105d, p =0.02), but were otherwise balanced. Complete and near complete (CR+nCR) response rates at study entry were 24% for both groups. Three-year PFS was 46% and 43% (p=0.67) and 3-year OS was 80% and 77 % (p=0.19) for the auto-auto and auto-allo groups, respectively. Corresponding probabilities for 3-year progression/relapse were 50% and 46% (p=0.8) and for 3-year TRM were 4% and 11% (p=0.04). Among auto-allo patients, probabilities of grade III-IV acute and chronic GVHD were 9% and 47%, respectively. Eighty-two percent of patients in each arm received the assigned second transplant. Among 522 patients who received their second transplant, 3-year PFS was 47% and 44% (p=0.89) with auto-auto and auto-allo, respectively. Disease response rates at day 56 after second HCT were: 50% very good partial response (VGPR) or better and 40% CR+nCR in the auto-auto group; and 49% (VGPR or better, p=0.8) and 48% (CR+nCR,p=0.12) in the auto-allo group. In conclusion, there were no differences in 3-year PFS and OS between patients receiving auto-auto or auto-allo. Potential benefits of graft-versus-myeloma to reduce disease progression or relapse were offset by increased TRM. Thal-Dex maintenance did not improve PFS or OS, likely due to poor tolerability of this regimen. At 3 years, the auto-allo approach for SR MM had no added benefit compared to tandem AuHCT. Disclosures: Krishnan: Celgene: Speakers Bureau. Stadtmauer:Celgene: Speakers Bureau. Comenzo:Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Elan Pharmaceuticals: Consultancy; Genzyme: Research Funding; Celgene: Research Funding; Ortho: Research Funding. Hari:Celgene: Research Funding. Qazilbash:Celgene: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Giralt:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

Phase 1 Study of the Novel Kinesin Spindle Protein Inhibitor ARRY-520 + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4082-4082 ◽  
Author(s):  
Jatin J. Shah ◽  
Donna M. Weber ◽  
Sheeba K. Thomas ◽  
Raymond Alexanian ◽  
Michael Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Single Agent ◽  
Autologous Stem Cell Transplant ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Kinesin Spindle Protein

Abstract Abstract 4082 Background: ARRY-520, a novel kinesin spindle protein (KSP) inhibitor, has been studied as a single agent and in combination with dexamethasone, and demonstrated promising clinical activity in patients with bortezomib- and lenalidomide-refractory multiple myeloma (MM). Carfilzomib, a novel irreversible proteasome inhibitor (PI), has also demonstrated single agent activity in relapsed and refractory MM, and recently received regulatory approval for this indication. Preclinical data support the presence of synergy with the combination of a PI and a KSP inhibitor via the latter's ability to down-regulate Mcl-1, supporting our hypothesis that the combination of carfilzomib and ARRY-520 (Car-ARRY) would be highly active in relapsed and/or refractory myeloma. We therefore aimed to combine these two agents for the first time, and here report the initial findings from the phase I dose-escalation in patients with relapsed and/or refractory MM. Methods: The primary objective was to determine the maximum tolerated dose (MTD) and the safety/tolerability of the Car-ARRY combination. Secondary objectives were to determine efficacy as measured by the overall response rate, time to progression, progression free survival and time to next therapy. Patients had to have myeloma that was relapsed and/or refractory, be ineligible for autologous stem cell transplant, bortezomib refractory/intolerant, and prior lenalidomide exposure. ARRY-520 was administered intravenously over 1 hour on days 1, 2, 15 and 16, while carfilzomib was administered intravenously over 30 minutes on days 1, 2, 8, 9, 15 and 16 on a 28 day cycle. All patients received growth factor support with filgrastim. Dose-escalation used a standard 3+3 schema proceeded based on dose-limiting toxicities (DLTs) during cycle 1, with planned escalation of the dose of ARRY-520. Dose level 1 was ARRY-520 0.75 mg/m2, and carfilzomib was dosed at 20 mg/m2 for cycle 1 on days 1 and 2 and all subsequent dose were at 27 mg/m2. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria. Results: To date, 8 patients have been enrolled in the ongoing dose escalation phase. The median age was 66 (range 47–80), 6/8 were males, and the median number of prior therapies was 4 (range 2–10). 7/8 patients had undergone prior autologous stem cell transplant, and all patients were bortezomib refractory or intolerant. In the first cohort, 3 patients were enrolled and no dole limiting toxicity (DLT) was observed. During the second cohort, ARRY-520 was escalated to 1 mg/m2 with carfilzomib at 20/27 mg/m2, and among the first 3 patients, one patient suffered a DLT in the form of an admission for influenza pneumonia with non-neutropenic fever. Expansion of cohort 2 is currently underway. Among the 6 patients who completed the first cycle of therapy, 5 remain on study. In the first cohort, one patient remains on study with 6 cycles and achieved a near complete remission, 1 patient achieved stable disease, and 1 patient suffered disease progression after first cycle. In the second cohort, all three patients who completed the first cycle have stable disease and remain on trial. In the first 6 toxicity-evaluable patients who have completed one cycle, grade (G) 3 events included one each of pneumonia, diarrhea, and hyperglycemia. There was limited hematologic toxicity with 4/6 patients with G1/2 thrombocytopenia, 3/6 patients with G1/2 anemia, and 1/6 patient with G1/2 neutropenia. Additional G1/2 non-hematologic toxicity included 3/6 patients with diarrhea, 3/6 patients with dyspnea, 3/6 patients with transient elevations in creatinine and 3/6 patients with aspartate aminotransferase elevations. An MTD has not been established and enrollment is ongoing in cohort 2 with carfilzomib at 20/27mg/m2 and ARRY-520 at 1.0 mg/m2. Conclusions: The combination of ARRY-520 and carfilzomib is well tolerated with limited hematologic toxicity and a manageable side effect profile. Notably, in this patient population, with patients who have bortezomib refractory/intolerant myeloma, the combination has demonstrated early signals of activity. Updated safety and efficacy data for all patients will be presented at the meeting. Disclosures: Shah: Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: This presentation will include information about Arry-520 which is not yet approved for use in patients with multiple myeloma. Wang:Pharmacyclic: Research Funding; onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hilder:Array BioPharma: Employment. Orlowski:onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; array biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Characteristics Of Multiple Myeloma Patients With 6-Year Or Longer Progression-Free Survival After a Single Autologous Transplant

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3366-3366 ◽  
Author(s):  
Kehinde U.A. Adekola ◽  
Qaiser Bashir ◽  
Nina Shah ◽  
Sai Ravi Pingali ◽  
Simrit Parmar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Progression Free Survival ◽  
High Dose ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Free Survival ◽  
Autologous Transplant ◽  
Preparative Regimen

Background High dose chemotherapy followed by an autologous stem cell transplant (auto-HCT) is considered standard of care in patients with newly diagnosed multiple myeloma (MM). In a recent randomized trial, median progression free survival (PFS) after auto-HCT, with or without maintenance therapy was 46 and 27 months, respectively (McCarthy P et al. NEJM 2012). However, about 15% of patients are reported to have much longer PFS (Pineda-Roman M et al. Cancer 2008). Here we tried to identify the factors that may predict a long PFS after auto-HCT. Methods We performed a retrospective chart review of patients who received an auto-HCT for MM between January 2000 and March 2007. A total of 1135 patients underwent an auto-HCT during this period, and 194 patients (17%) had a minimum PFS of 72 months or longer after a single auto-HCT. The primary objective was to determine the variables associated with a long PFS and overall survival (OS). Results Patient characteristics and outcomes are shown in the attached Table. The median age at auto-HCT was 56 years, and the median time from diagnosis to auto-HCT was 7.5 months. Twenty-three (13%) patients had ≥ 10% plasma cells in the bone marrow at auto-HCT and only 9 patients (4.8%) had high-risk cytogenetic abnormalities. One-hundred and fifty (77%) patients received induction therapy containing either an immunomodulatory (IMiD) agent or a proteasome inhibitor (PI). At the time of the auto-HSCT, only 13 (6.7%) patients were in CR and 38 (19.6%) were CR or VGPR after induction therapy (Table). One-hundred and sixty three (84%) patients received mephalan alone as conditioning regimen. Eighty-one (42%) patients received post auto-HCT maintenance. Eighty (41%) patients achieved a CR, while 104 (54%) achieved CR + VGPR after auto-HCT. Six patients (3.1%) developed a second primary malignancy post- autologous transplant. After a median follow-up of 95.4 months, median PFS was 97.3 months and median OS has not been reached. The 10-year PFS and OS were 41% and 73% respectively. Use of melphalan alone as preparative regimen was associated with a longer PFS and OS (p=0.004 and 0.004, respectively). Achievement of CR after auto-HCT was associated with a longer PFS only (p=0.001), and the use of IMiD or a PI as induction was associated with a longer OS (p=0.01). Conclusion Approximately 17% patients achieved a median PFS of 6 years or longer after a single auto-HCT. The long PFS in this cohort may be associated with younger age, low incidence of HR cytogenetics, use of an IMiD or PI as induction therapy, relatively low disease burden at auto-HCT, transplant from the year 2000 onwards, achievement of CR in >40% and the use of melphalan alone as preparative regimen. Disclosures: Shah: Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Qazilbash:Celgene: Membership on an entity’s Board of Directors or advisory committees.

Efficacy of Melflufen, a Peptidase Targeted Therapy, and Dexamethasone in an Ongoing Open-Label Phase 2a Study in Patients with Relapsed and Relapsed-Refractory Multiple Myeloma (RRMM) Including an Initial Report on Progression Free Survival

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3029-3029
Author(s):  
Peter M. Voorhees ◽  
Valeria Magarotto ◽  
Pieter Sonneveld ◽  
Torben Plesner ◽  
Ulf-Henrik Mellqvist ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
Study Drug ◽  
Progression Free Survival ◽  
Hematologic Toxicity ◽  
Advisory Committees ◽  
Free Survival

Abstract Background: Melflufen is a highly potent anti-angiogenic compound that triggers rapid, robust and irreversible DNA damage and exerts its cytotoxicity through alkylation of DNA. The lipophilicity of melflufen leads to rapid and extensive distribution into tissues and cells where it binds directly to DNA or is readily metabolized by intracellular peptidases into hydrophilic alkylating metabolites. With targeted delivery of alkylating metabolites to tumor cells in vitro (such as multiple myeloma that are rich in activating peptidase), melflufen exerts a 20-100 fold higher anti-tumor potency and produces a 20 fold higher intracellular concentration of alkylating moieties compared with melphalan. Methods: Melflufen is evaluated in combination with dexamethasone (dex) 40 mg weekly in an ongoing Phase 1/2a study. RRMM patients with measurable disease and at least 2 prior lines of therapy are eligible (NCT01897714). Phase 1 established the maximum tolerated dose (MTD) of melflufen to be 40 mg every 3 weeks in combination with low dose dex. The primary objective of Phase 2a is the overall response rate and safety of the MTD in a total of 55 patients. Response was investigator assessed at the end of each cycle by IMWG criteria. Here we present the Phase 2 data as of 14 July 2015 data-cut. Results: Thirty-one patients were dosed at the MTD. The median time from initial diagnosis to first dose of melflufen was 6 years (1-15). The median number of prior therapies was 4 (2-9). 97% of patients were exposed to immunomodulatory drugs (IMiDs), 90% to proteasome inhibitors (PIs), 77% to melphalan, and 71% had received prior autologous stem cell transplant. 58% were double refractory (IMiDs and PIs) and 42% were triple refractory (IMiDs, PIs and alkylators). In total, 121 doses of melflufen have been given (1-11 cycles). Median treatment duration was 13 weeks with 9 patients still ongoing. One patient completed therapy as planned, 15 patients discontinued due to AEs (48%) and 6 due to progression (19%). Twenty-three patients were evaluable for response (protocol defined as ≥2 doses of melflufen with baseline and follow-up response assessments). One patient achieved a very good partial response and 10 patients achieved partial response (PR) (1 unconfirmed, still ongoing) for an overall response rate (ORR) of 48%. Three additional patients achieved minimal response (MR) for a clinical benefit rate (CBR) of 61%. Time to clinical benefit and response was rapid with 93% of patients achieving ≥ MR after 1-3 cycles and 64% achieving PR after only 1-3 cycles. Eight patients maintained stable disease and 1 patient had early progressive disease. Similar ORRs were seen in PI-refractory (43%), IMiD-refractory (40%), alkylator-refractory (62%), double-refractory (38%) and triple-refractory (50%) patients. The median progression free survival (PFS) is currently at 7.6 months (95% confidence interval: 3.4 - ∞) based on 14 events in 30 patients. The most frequent adverse events (AE), all grades, occurring in >10% of patients, regardless of relationship to study drug were thrombocytopenia (94%), anemia (84%), neutropenia (61%), leukopenia (42%), pyrexia (36%), asthenia (32%), fatigue and nausea (26%), bone pain (19%), cough, diarrhea, dyspnea, mucosal inflammation and upper respiratory infection (16%) and constipation and epistaxis (13%). Treatment-related Grade 3 or 4 AEs were reported in 27 patients (87%). Those occurring in >5% of patients were thrombocytopenia (68%), neutropenia (55%), anemia (42%), leukopenia (32%) and febrile neutropenia, fatigue, pyrexia, asthenia and hyperglycemia each occurred in 6% of patients. Serious AEs occurred in 9 patients (29%), but were only assessed as related to study drug in 5 patients (16%) including 3 febrile neutropenia, 1 fever and 1 pneumonia. Cycle length has recently been increased to 28 days to improve tolerability with respect to hematologic toxicity. Conclusion: Melflufen has promising activity in heavily pretreated RRMM patients where conventional therapies have failed. The current ORR is 48% and CBR is 61%. Similar results were seen across patient populations regardless of refractory status. The median PFS is encouraging at 7.6 months. Hematologic toxicity was common, but non-hematologic AEs were infrequent. Updated results will be presented at the meeting. Disclosures Voorhees: Millennium/Takeda and Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Array BioPharma, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Janssen, Celgene, GlaxoSmithKline,Onyx Pharmaceuticals and Oncopeptides: Consultancy, Research Funding. Sonneveld:Janssen: Speakers Bureau; Takeda: Research Funding; Celgene and Onyx: Research Funding, Speakers Bureau. Plesner:Roche and Novartis: Research Funding; Janssen and Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees. Mellqvist:Celgene, Amgen, Mundipharma and Novartis: Honoraria. Byrne:Oncopeptides: Consultancy. Harmenberg:Oncopeptides: Consultancy. Nordstrom:Oncopeptides: Employment. Palumbo:Amgen: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Array BioPharma: Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Sanofi-Aventis: Honoraria. Richardson:Oncopeptides, Celgene and Takeda: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3747-3747
Author(s):  
Charlotte Doublet ◽  
Marie-Sarah Dilhuydy ◽  
Emmanuelle Ferrant ◽  
Pierre Feugier ◽  
Alexandra Fayault ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
Oncology Nurses ◽  
Advisory Committees ◽  
Free Survival ◽  
Daily Dose ◽  
History Of

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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