Early Death in Patients with Disseminated Intravascular Coagulation during Induction Therapy for Acute Promyelocytic Leukemia: A Nationwide Analysis

Background: Real-world data studies showed poorer outcomes in patients with acute promyelocytic leukemia (APL) than randomized controlled trials, because elderly patients were excluded in such trials. Reportedly, the main cause of death was severe bleeding due to disseminated intravascular coagulation (DIC) during induction therapy for APL. The management of DIC was therefore crucially important especially in elderly patients. This study aimed to clarify factors associated with in-hospital death in all patients, and elderly patients with DIC during induction therapy for APL. Study Design and Methods: We retrospectively identified 1,463 patients with newly diagnosed APL who received induction therapy including all-trans retinoic acid (ATRA) between July 2007 and March 2018 from a nationwide inpatient database in Japan. In-hospital death was evaluated with multivariable logistic regression models in all patients, and in ≥60 year-old patients. Anticoagulants included recombinant human soluble thrombomodulin, delteparin (low molecular weight heparin), danaparoid sodium, gabexate mesilate, and nafamostat mesilate which were administered within three days from admission. Patients who died within three days from the admission were excluded from the study to avoid immortal time bias. Results: We identified a total of 1,138 (78%) patients who developed DIC. We excluded 23 patients who died within three days from the admission. The remaining 1,115 patients were analyzed. During hospitalization, 172 (15%) patients died at a median of 13 days (interquartile range: 7-30). Compared with younger patients (20 to 39 years old), elderly patients were significantly associated with higher in-hospital mortality (60 to 79 years old: odds ratio 5.58 [95% confidence interval 3.05-10.22], 80 years or older: 13.51 [6.07-30.08]). Patients who received ATRA monotherapy had significantly higher incidence of in-hospital death (2.48 [1.54-4.01]). Delayed initiation of ATRA was significantly associated with higher mortality (1.60 [1.11-2.30]). A total of 699 patients (63%) received anticoagulant therapies, but none of these were significantly associated with lower mortality. Use of multiple anticoagulants was significantly associated with higher in-hospital mortality (2.47 [1.16-5.26]). Subgroup analyses in patients ≥60 years old were then conducted. During hospitalization, 122 of 416 (29%) patients died at a median of 13 days (interquartile range: 7-29). Both late initiation of conventional chemotherapy and no conventional chemotherapy were significantly associated with higher in-hospital mortality (1.88 [1.01-3.49], 3.25 [1.74-6.06], respectively). Use of recombinant human soluble thrombomodulin and use of multiple anticoagulants were significantly associated with higher mortality (1.91 [1.09-3.35], 2.64 [1.01-6.90], respectively). Conclusions: Elderly patients who developed DIC during induction therapy for APL were significantly associated with higher in-hospital mortality. Immediate initiation of ATRA and early initiation of conventional chemotherapy may have contributed to preferable outcomes. Disclosures Matsuda: Kyowa Kirin: Speakers Bureau. Jo:Tsumura: Other: Belongs to joint program with Tsumura, Research Funding. Toyama:Bristol-Myers Squibb: Speakers Bureau; Eisai: Speakers Bureau; Kyowa Kirin: Speakers Bureau; Celgene: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Chugai Pharmaceutical,: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau. Kurokawa:Ono: Research Funding, Speakers Bureau; Jansen Pharmaceutical: Speakers Bureau; Teijin: Research Funding; Eisai: Research Funding, Speakers Bureau; Shire Plc: Speakers Bureau; Nippon Shinyaku: Research Funding, Speakers Bureau; MSD: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy, Research Funding, Speakers Bureau; Sanwa-Kagaku: Consultancy; Pfizer: Research Funding; Otsuka: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Bioverativ Japan: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau.

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Practice Patterns and Real-Life Outcomes for Patients with Acute Promyelocytic Leukemia

Blood ◽

10.1182/blood-2020-136983 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 21-22

Author(s):

Jan Philipp Bewersdorf ◽

Stephanie Prozora ◽

Rong Wang ◽

Nikolai A. Podoltsev ◽

Rory M. Shallis ◽

...

Keyword(s):

Logistic Regression ◽

Mortality Rate ◽

Board Of Directors ◽

Acute Promyelocytic Leukemia ◽

Research Funding ◽

Primary Outcome ◽

Promyelocytic Leukemia ◽

Early Mortality ◽

Hospital Death ◽

Advisory Committees

Background: Despite a potential for cure, a large proportion of patients with acute promyelocytic leukemia (APL) succumb early to hemorrhagic and thrombotic complications. Prompt initiation of all-trans retinoic acid (ATRA) has been associated with improved outcomes. However, little is known about the patterns of care and clinical outcomes of patients with APL in the United States (US) outside of the controlled trial setting. Method s : We identified APL patients (pts) included in the Vizient Clinical Database/Resource Manager (CDB/RM™), which includes patient demographics, hospital characteristics, charge-level medication usage, procedures and mortality data from over 100 academic health centers and affiliated hospitals. Initial inpatient encounters of adult APL pts (≥18 years) during 2014-2015 (most recent years available) were identified by ICD-10 code (C92.40; C92.42) or ICD-9 codes for acute myeloid leukemia (AML; 250.00, 205.02) plus receipt of ATRA for ≥3 days as monotherapy, or in combination with arsenic trioxide (ATO) or an anthracycline. The 3-day minimum ATRA requirement is intended to exclude AML patients who may have therapy initiated while awaiting diagnostic confirmation. Pts were excluded if information on discharge disposition or medication administration were missing or if patients had an ICD-9/10 code consistent with relapsed AML/APL. Primary outcome was a composite of in-hospital death or discharge to hospice. Pearson's Chi-square test was used to compare categorical variables in bivariate analysis. Multivariable logistic regression was used to examine associations between patient, hospital, and treatment characteristics with the primary outcome. We lacked information on laboratory test results needed to assess the impact of treatment on clinical outcomes. Results: We identified 486 pts treated at 76 hospitals. Patient demographic, treatment and hospital characteristics are shown in Table 1. Median length of stay was 30 days (interquartile range [IQR]: 22-36 days). Pts received a median of 26 days of ATRA (IQR: 12-34 days). The majority of pts was treated with ATRA + ATO (240 pts; 49.4%) or ATRA + anthracycline (146 pts; 30.0%), which are the standard of care for lower- and higher-risk APL, respectively. Forty-two pts (9.3%) received ATRA monotherapy and 58 (11.9%) were treated with ATRA + ATO + anthracycline. Forty-eight pts (9.9%) required endotracheal intubation. Overall, 54 (11.1%) pts experienced our composite adverse outcome of in-hospital death or transfer to hospice (45 pts [9.3%] died in the hospital; 9 pts [1.9%] were discharged to hospice). Among 45 pts who died in the hospital, median time to death was 17 days (IQR: 5-24 days) with 31.1% of deaths occurring during the first 7 days of hospitalization. Half of the pts (n=18; 50%) who died in the ATRA monotherapy group died within 5 days of admission. In bivariate analyses, age ≥66 years (22.9% vs. 7.9%; p<0.001), endotracheal intubation (64.6% vs. 5.3%; p<0.001), and ATRA monotherapy (42.9% vs. 8.1%; p<0.001) were associated with an increased risk of poor outcome (i.e. inpatient death or discharge to hospice). Similar results were obtained from the multivariable logistic regression model (Table 2). Discussion: A substantial proportion (11%) of adults treated for APL in this large inpatient dataset died or were discharged to hospice. This likely underestimates the full mortality rate of APL, because our APL case definition excluded pts who received <3 days of ATRA therapy, which may have been due to early mortality. Age≥66 years, receipt of ATRA monotherapy or ATRA + anthracycline was associated with higher odds of adverse outcomes. The higher mortality with ATRA + anthracycline compared to ATRA + ATO is likely due to an inherently higher disease risk, but the database lacked laboratory results (e.g. white blood cell count) needed to confirm that hypothesis. Early complications related to coagulopathy or differentiation syndrome that precluded co-administration of ATO or anthracycline could be a potential explanation for the high early mortality rate in pts receiving ATRA monotherapy. Disclosures Wang: Celgene/BMS: Research Funding. Podoltsev:Kartos Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Incyte: Consultancy, Honoraria; Sunesis Pharmaceuticals: Research Funding; Samus Therapeutics: Research Funding; Genentech: Research Funding; AI Therapeutics: Research Funding; Boehringer Ingelheim: Research Funding; CTI biopharma: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Bristol-Myers Squib: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Arog Pharmaceuticals: Research Funding; Blueprint Medicines: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding. Huntington:Genentech: Consultancy; DTRM: Research Funding; Astrazeneca: Honoraria; Bayer: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Novartis: Consultancy; AbbVie: Consultancy; Pharmacyclics: Honoraria; TG Therapeutics: Research Funding. Neparidze:Janssen: Research Funding; GlaxoSmithKline: Research Funding; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Diagnostic committee member ; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Ma:BMS: Consultancy; Celgene/BMS: Research Funding. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Zeidan:Acceleron: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; CCITLA: Other; Leukemia and Lymphoma Society: Other; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Astex: Research Funding; MedImmune/Astrazeneca: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; ADC Therapeutics: Research Funding; Taiho: Consultancy, Honoraria; Aprea: Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Davidoff:Celgene: Research Funding; Amgen: Consultancy; AbbVie: Consultancy.

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Phase I Study of Ixazomib with Conventional Chemotherapy in the Treatment of Acute Myeloid Leukemia in Older Adults

Blood ◽

10.1182/blood-2020-140584 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-8

Author(s):

Philip C. Amrein ◽

Eyal C. Attar ◽

Geoffrey Fell ◽

Traci M. Blonquist ◽

Andrew M. Brunner ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Remission Rate ◽

Conventional Chemotherapy ◽

Advisory Committees ◽

Secondary Aml ◽

Grade 3 ◽

Acute Myeloid

Introduction: Outcomes for acute myeloid leukemia (AML) among older patients has remained largely unchanged for decades. Long-term survival for patients aged >60 years is poor (median survival 10.5 months). Targeting the proteasome in AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition in preclinical models, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). AML cell lines are susceptible to synergistic cytotoxicity when bortezomib, a proteasome inhibitor, is combined with daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although grade 2 sensory neurotoxicity was noted in approximately 12% of treated patients. A newer generation proteasome inhibitor, ixazomib, is less frequently associated with neurotoxicity, and, therefore, was selected for combination with conventional chemotherapy in this phase I trial. The primary objective of this study was to determine the maximum tolerated dose (MTD) of ixazomib in combination with conventional induction and consolidation chemotherapy for AML. Herein are the initial results of this trial. Methods: Adults >60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. There were 2 phases in this study. In the first phase (A), the induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3, and ixazomib was provided orally at the cohort dose, Days 2, 5, 9, and 12. Consolidaton or transplant was at the discretion of the treating physician in phase A. In the second phase (B), induction was the same as that with the determined MTD of ixazomib. All patients were to be treated with the following consolidation: cytarabine at 2 g/m2/day, days 1-5 with ixazomib on days 2, 5, 9, and 12 at the cohort dose for consolidation. A standard 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction (phase A) and subsequently in consolidation (phase B). The determined MTD of ixazomib in the first portion (A) of the trial was used during induction in the second portion (B), which sought to determine the MTD for ixazomib during consolidation. Secondary objectives included rate of complete remission, disease-free survival, and overall survival (OS). Results: Thirty-six patients have been enrolled on study, and 28 have completed dose levels A-1 through A-3 and B1 through B-2. Full information on cohort B-3 has not yet been obtained, hence, this report covers the experience with the initial 28 patients, cohorts A-1 through B-2. There were 12 (43%) patients among the 28 with secondary AML, either with prior hematologic malignancy or therapy-related AML. Nineteen patients (68%) were male, and the median age was 68 years (range 61-80 years). There have been no grade 5 toxicities due to study drug. Three patients died early due to leukemia, 2 of which were replaced for assessment of the MTD. Nearly all the grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 4 platelet count decrease extending beyond Day 42). There has been no grade 3 or 4 neurotoxicity with ixazomib to date. Among the 28 patients in the first 5 cohorts, 22 achieved complete remissions (CR) and 2 achieved CRi, for a composite remission rate (CCR) of 86%. Among the 12 patients with secondary AML 8 achieved CR and 2 achieved CRi, for a CCR of 83%. The median OS for the 28 patients has not been reached (graph). The 18-month OS estimate was 65% [90% CI, 50-85%]. Conclusions: The highest dose level (3 mg) of ixazomib planned for induction in this trial has been reached safely. For consolidation there have been no serious safety issues in the first 2 cohorts with a dose up to 2.3 mg, apart from 1 DLT in the form of delayed platelet count recovery. The recommended phase 2 dose of ixazomib for induction is 3 mg. Accrual to cohort B-3 is ongoing. Notably, to date, no grade 3 or 4 neurotoxicity has been encountered. The remission rate in this older adult population with the addition of ixazomib to standard chemotherapy appears favorable. Figure Disclosures Amrein: Amgen: Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding. Attar:Aprea Therapeutics: Current Employment. Brunner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Hobbs:Constellation: Honoraria, Research Funding; Novartis: Honoraria; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding; Jazz: Honoraria; Celgene/BMS: Honoraria. Neuberg:Celgene: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Fathi:Blueprint: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kura Oncology: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy; Newlink Genetics: Consultancy; Forty Seven: Consultancy; Trovagene: Consultancy; Kite: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Amphivena: Consultancy; PTC Therapeutics: Consultancy; Agios: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz: Consultancy. OffLabel Disclosure: Ixazomib is FDA approved for multiple myeloma. We are using it in this trial for acute myeloid leukemia.

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Impact of DNMT3a Status on Post Induction NPM1 MRD Predictive Value on Survival in Elderly AML Patients Treated Intensively

Blood ◽

10.1182/blood-2020-141890 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-8

Author(s):

Maël Heiblig ◽

Hélène Labussière ◽

Marie Virginie Larcher ◽

Gaelle Fossard ◽

Marie Balsat ◽

...

Keyword(s):

Elderly Patients ◽

Board Of Directors ◽

Predictive Value ◽

Scoring System ◽

Research Funding ◽

Risk Group ◽

Advisory Committees ◽

Post Induction ◽

Mutational Status ◽

Elderly Aml

Minimal residual disease is now a powerfull surrogate marker to assess response to chemotherapy in acute myeloid leukemia (AML). In younger adults, NPM1 MRD has recently demonstrated to be a favorable predictive marker for EFS and OS independently of fms-like tyrosine kinase-3 internal tandem duplications (FLT3-ITD) status. However, there is very few datas regarding predictive value of NPM1 MRD in elderly patients treated with intensive chemotherapy. Moreover, numerous studies have suggested the negative impact of DNMT3a mutation in NPM1 AML patients, especially in those with concurrent FLT3-ITD mutation. In this study, we aimed to investigate the impact of DNMT3a status on post induction NPM1 MRD1 predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1 mutated AML in two French institutions (Lyon, Lille) were analyzed retrospectively. Median age of the entire cohort was 66.1 years old (range 60-78.2). An FLT3-ITD mutation was evidenced in 52 of 138 patients (37.6%) with a median FLT3-ITD AR of 0.53 (range, 0.05-3). With a median follow-up of 19.61 months (0.07-128.4), the overall CR rate was 89.9% with no influence of DNMT3a or FLT3 mutational status on the probability of CR. In this elderly cohort of NPM1mut patients, a 4log reduction of NPM1 bone marrow (BM) MRD1 was associated with better outcome (median OS: NR vs 13.4 months, HR=0.35, p<0.01)(Figure A). Overall, DNMT3 status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. However, only 9/44 (20.4%) FLT3-ITD patients reached ≥ 4log MRD1 reduction whereas 38/80 FLT3wt (47.5%) were good molecular responders (p<0.001). FLT3-ITD mutated patients who achieved a 4log reduction had a superior outcome compared to those who did not (HR=0.34; 95% CI, 0.16 to 0.70; P <0.001). Similarly, NPM1mut FLT3wt patients with a 4log reduction in NPM1 BM-MRD1 had a longer OS (3-year OS, 68.1%; 95% CI, 48.8 to 82.9) than those without good molecular response (3-year OS, 46.5%; 95% CI, 30.2 to 61.7)(Figure B). DNMT3a negative patients who achieved a 4log reduction had a superior outcome to those who did not reached at least a 4log reduction (HR=0.23; 95% CI, 0.07 to 0.72; P <0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and leukemia free survival (LFS) in DNMT3amut patients. DNMT3amut patients has a very poor LFS which was even worst in poor NPM1 MRD1 responders compared to those who reached at least 4log reduction (median LFS: 8.3 months vs 17.4 months, HR = 0.48, 95% CI, 0.25-0.91, p=0.023)(Figure C). In multivariate analysis, only DNMT3a mutational status and a 4-log reduction in NPM1 BM-MRD were significantly associated with survival. Based on these results, we identified among NPM1 positive patients 3 groups with distinct prognosis, based on FLT3-ITD, DNMT3a status and NPM1 BM-MRD post induction response (NPM1 scoring system)(Figure D). When compared to ELN 2017 intermediate risk group (AUC=0.695), NPM1 scoring system (NPM1 SS) was more accurate for OS prediction in patients within intermediate (AUC=0.833) and unfavorable (AUC=0.863) NPM1 SS risk group. However, there was no significant difference in AUC between NPM1 SS favorable and ELN 2017 favorable risk group. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3a also identify a subgroup of patients at very high risk of relapase, despite good molecular responses. As hematopoietic stem cell transplantation (HSCT) might improve OS in elderly patients, DNMT3a positive AML elderly patients should be considered for HSCT or post induction maintenance strategies, even within the favorable ELN risk group. Figure Disclosures Sujobert: Gilead/Kyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding.

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Increased Idarubicin Dosage during Consolidation Therapy for Adult Acute Myeloid Leukemia Improves Leukemia-Free Survival

Blood ◽

10.1182/blood.v128.22.338.338 ◽

2016 ◽

Vol 128 (22) ◽

pp. 338-338

Author(s):

Bradstock Kenneth ◽

Emma Link ◽

Juliana Di Iulio ◽

Jeff Szer ◽

Paula Marlton ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Board Of Directors ◽

Induction Therapy ◽

Myeloid Leukemia ◽

Research Funding ◽

Consolidation Therapy ◽

Advisory Committees ◽

Free Survival ◽

Acute Myeloid

Abstract Background: Anthracylines are one of the major classes of drugs active against acute myeloid leukemia (AML). Increased doses of daunorubicin during induction therapy for AML have been shown to improve remission rates and survival. The ALLG used idarubicin in induction therapy at a dose of 9 mg/m2 x 3 days (total dose 27 mg/m2) in combination with high-dose cytarabine and etoposide (Blood 2005, 105:481), but showed that a total idarubicin dose of 36 mg/m2 was too toxic in this context (Leukemia 2001, 15:1331). In order to further improve outcomes in adult AML by anthracycline dose escalation, we conducted a phase 3 trial comparing standard to an increased idarubicin dose during consolidation therapy. Methods: Patients achieving complete remission after 1 or 2 cycles of intensive induction therapy (idarubicin 9 mg/m2 daily x3, cytarabine 3 g/m2 twice daily on days 1,3,5 and 7, and etoposide 75 mg/m2 daily x7; ICE protocol) were randomized to receive 2 cycles of consolidation therapy with cytarabine 100 mg/m2 per day for 5 days, etoposide 75 mg/m2 for 5 days, and idarubicin 9mg/m2 daily for either 2 or 3 days (standard and intensive arms respectively). No further protocol therapy was given. The primary endpoint was leukemia-free survival from randomization to consolidation therapy (LFS) with overall survival (OS) as secondary endpoint. Results: A total of 422 patients with AML (excluding cases with CBF rearrangements or APL) aged 16 to 60 years were enrolled between 2003-10, with 345 (82%) achieving complete remission, and 293 being randomized to standard (n=146) or intensive (n=147) consolidation arms. The median age was 45 years in both arms (range 16- 60), and both groups were balanced for intermediate versus unfavorable karyotypes and for frequency of mutations involving FLT3-ITD and NPM1 genes. Of the randomized patients, 120 in the standard arm (82%) and 95 in the intensive arm (65%) received the second consolidation cycle (p<0.001). The median total dose of idarubicin received in the 2 consolidation courses was 36 mg/m2 (range 17-45), or 99% (47-125%) of the protocol dose in the standard arm, versus 53 mg/m2 (18-73), or 98% (33-136%) of the protocol dose in the intensive arm. The durations of grades 3-4 neutropenia and thrombocytopenia were significantly longer in the intensive arm, but there were no differences in grade 3 or 4 non-hematological toxicities. There were no non-relapse deaths during consolidation on the standard arm and 2 in the intensive (0% vs 1%; p =0.50). Subsequently, 41 patients in the standard arm and 37 in the intensive arm underwent elective allogeneic BMT during first remission. On intention to-treat analysis uncensored for transplant and with a median follow-up time of 5.3 years (range 0.6 - 9.9), there was improvement in LFS in the intensive arm compared with the standard arm (3 year LFS 47% (95% CI 40-56%) versus 35% (28-44%); HR 0.74 (95% CI 0.55-0.99); p=0.045) (Figure 1). The 3 year OS for the intensive arm was 61% (95% CI 54-70%) and 50% (95% CI 43-59%) for the standard arm; HR 0.75 (95% CI 0.54-1.05); p=0.092). Although adverse cytogenetics, presence of FLT3-ITD mutation, and absence of NPM1 mutation were all associated with poorer outcomes, there was no evidence of a benefit of intensive consolidation being confined to specific cytogenetic or gene mutation sub-groups. Conclusion: We conclude that in adult patients in complete remission after intensive induction chemotherapy an increased dose of idarubicin delivered during consolidation therapy results in improved LFS, without increased non-hematologic toxicity. Figure 1. Figure 1. Disclosures Szer: Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees. Marlton:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: 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, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wei:Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Abbvie: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Cartwright:ROCHE: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roberts:Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Mills:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Meeting attendance sponsorship. Gill:Janssen: Membership on an entity's Board of Directors or advisory committees. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: 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, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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First Analysis of an International Double-Blind Randomized Phase III Study of Lenalidomide Maintenance in Elderly Patients with DLBCL Treated with R-CHOP in First Line, the Remarc Study from Lysa

Blood ◽

10.1182/blood.v128.22.471.471 ◽

2016 ◽

Vol 128 (22) ◽

pp. 471-471 ◽

Cited By ~ 8

Author(s):

Catherine Thieblemont ◽

Hervé Tilly ◽

Maria Gomez da Silva ◽

Rene-Olivier Casasnovas ◽

Christophe Fruchart ◽

...

Keyword(s):

Elderly Patients ◽

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Phase Iii ◽

First Line ◽

Advisory Committees ◽

Double Blind

Abstract Background. R-CHOP is the standard first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). However 30% of patients will relapse and 70% of relapsed patients will die within 2 years of diagnosis. The REMARC study (clinicalTrials.gov NCT01122472) is an international, multicenter, double-blind, randomized, placebo controlled, phase III trial that assessed the benefit of lenalidomide (LEN) maintenance after response to R-CHOP in patients aged 60 to 80 years with untreated DLBCL, FL3b or transformed lymphoma. Patients achieving CR or PR at the end of 6 or 8 cycles of R-CHOP21 or R-CHOP14 were stratified by CR/PR status and country and randomized 1:1 to receive 2 years of LEN maintenance (25 mg/day for 21 of every 28 days) or placebo (PBO). The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints were safety, PR to CR conversion rate, and overall survival (OS). Diagnosis was retrospectively centrally reviewed. In patients with adequate samples, GCB/nonGCB profile was assessed by the Hans algorithm and GCB/ABC/unclassified profile was assessed using NanoString gene expression profiling technology. Methods. From 05/2009 to 05/2014, 784 patients were enrolled either before R-CHOP (n= 437) or after completion of 6 or 8 cycles of R-CHOP (n= 347). At the end of R-CHOP therapy, 650 patients were randomized to maintenance, either in CR (n= 495) or in PR (n= 152). Central review found that 3 patients were randomized in SD or PD, all in LEN arm. At time of diagnosis, median age was 68 y (range 58-80), 43.5% were older than 70 y, and 56% were male. aaIPI was low in 38.5% and high in 57.5% of patients (missing data 4%). COO analyses are ongoing for both Hans algorithm and NanoString technology. Results. With a median follow-up of 40 months, median PFS (according to independent centralized radiology review) was not reached in the LEN group versus 68 months in the PBO group (hazard ratio favoring the LEN group, 0.708 (95% CI 0.537-0.932; p=0.0135))(See Figure). In the LEN group, 18 patients (21%) converted from PR to CR during maintenance compared to 13 patients (14%) in the PBO group. Immature overall survival data did not show any benefit for LEN arm, a lack of difference not attributable to an excess of lymphoma relapse, secondary cancer or safety problems in LEN arm. Deaths generally occurred off study drug (median time from last dose of study drug to death was 277 days (range 20, 1291) in LEN arm and 334 (41, 1594) in control arm. During maintenance, the most common observed grade 3 or 4 AEs were neutropenia (56% vs. 22%), rash (5% vs. 1%), infections (8% vs. 6%), and thrombocytopenia (2.5% vs. 0.6%) in LEN and PBO arms, respectively. Dose adjustments were necessary in 72% of the LEN patients and 42% of PBO patients. 59% of patients stopped LEN and 40% stopped PBO for toxicity (p<0.001). Median number of cycles was 15 in LEN and 25 in PBO (p<0.001). Secondary primary malignancies occurred in 33 patients receiving LEN and in 42 patients on PBO. Conclusion. This analysis of the REMARC study shows that 2 years of LEN maintenance in patients responding to R-CHOP significantly improved PFS (primary endpoint) without an early significant impact on OS. The COO analysis is currently ongoing. This is the first report finding that using an immunomodulatory agent as maintenance therapy prolongs PFS for patients with DLBCL after first line treatment with R-CHOP. Figure 1. Progression-free survival of elderly patients with diffuse large B-cell lymphoma in response to R-CHOP treated in maintenance with either lenalidomide or placebo Figure 1 Figure 1. Disclosures Thieblemont: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Bayer healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gomez da Silva:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; ROche: Consultancy, Membership on an entity's Board of Directors or advisory committees; takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Haioun:Sandoz: 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; 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cabecadas:celgene: Consultancy, Honoraria. Salles:Gilead: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mundipharma: Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Coiffier:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Analysis of Long-Term Survival in Multiple Myeloma Patients after First-Line Autologous Stem Cell Transplantation: Impact of Clinical Risk Factors and Duration of Response

Blood ◽

10.1182/blood.v128.22.4649.4649 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4649-4649

Author(s):

Nicola Lehners ◽

Natalia Becker ◽

Axel Benner ◽

Maria Pritsch ◽

Elias Karl Mai ◽

...

Keyword(s):

Maintenance Therapy ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Conditional Survival ◽

First Line ◽

Advisory Committees ◽

Term Survival ◽

Long Term Survival

Abstract Background: In the last decade, the introduction of novel agents into multiple myeloma (MM) therapy has significantly improved response rates and enabled long-term survival in a subset of patients. Yet, clinical characteristics of these long-term survivors as well as the exact impact of depth and sustainment of response still remain a matter of debate. Methods: MM patients treated at our center with high-dose melphalan supported by autologous stem cell transplantation (ASCT) as part of their first-line therapy between June 1992 and July 2014 were retrospectively analyzed. Response assessment was performed 100 days after ASCT according to EBMT criteria, since 2008 response according to IMWG criteria was also available. Overall survival (OS) and progression-free survival (PFS) were calculated from day of first ASCT. Additionally, landmark analyses regarding OS were performed at 1, 2, 3, and 5 years after ASCT. Impact of variables on PFS and OS were analyzed using multivariate Cox regression models. Furthermore, in order to assess evolution of prognosis over time, the conditional survival CS(t|s), which expresses the conditional probability of surviving further t years, was calculated as the ratio of two Kaplan-Meier estimates Ŝ(t) with . Results: 865 patients were included in this analysis, median age was 57.0 years (range 24-74), 509 were male. New agents based induction therapy was administered in 358 patients, 258 patients underwent tandem ASCT. Following ASCT, 386 patients received maintenance therapy, mainly with interferon or thalidomide. 75 patients proceeded to allogeneic transplantation and were censored at that time. Median PFS was 2.1 years, median OS was 6.4 years. Analysis of clinical influence factors revealed novel agent based induction therapy (p<0.01), maintenance therapy (p<0.01) and achievement of complete response (CR) (p=0.01) to be significantly associated with prolonged PFS, while older age (p=0.01) and thrombocytes at diagnosis < 150/nl (p=0.02) were identified as risk factors; a negative trend was seen for ISS stage 3 (p=0.067). With regard to OS, novel agent based induction therapy (p<0.01), maintenance therapy (p<0.01) and duration of time to progression (p<0.01) showed a highly significant positive impact, older age (p<0.01) and renal insufficiency at diagnosis (p=0.048) exerted a negative influence. To assess the importance of duration of response, landmark analyses were performed at 1, 2, 3, and 5 years after ASCT evaluating OS of patients with sustained CR, sustained inferior responses (non-CR), lost CR and lost non-CR at these respective time points. Remarkably, sustainment of any response showed a highly significant impact on survival at each of these time points (p<0.01) with no discernable difference between sustained CR and sustained non-CR patients. Landmark analysis at 1 year is shown in Figure 1. Administration of maintenance therapy independently improved outcome (p<0.01). Conditional survival regarding the probability to survive further three years CS(3|s) was calculated starting from the time of first ASCT stratified for the different response cohorts (see Figure 2). No significant differences could be found between patients with complete and partial response. In contrast, patients with progressive disease (PD) at day 100 after ASCT had a much lower probability of surviving the following three years after ASCT compared to patients responding to ASCT. However, those patients with PD that did survive the first year after ASCT, achieved a similar conditional three-year survival to that of patients responding initially. Conclusions: In this large retrospective study, sustainment of response after first-line ASCT was revealed as a major impact factor for OS independent of the depth of response. Administration of maintenance therapy further improved outcome, supporting the hypothesis that interventions prolonging responses achieved after ASCT are essential to reach long-term survival. Figure 1 OS of patients with sustained vs not-sustained responses at 1-year landmark analysis. Figure 1. OS of patients with sustained vs not-sustained responses at 1-year landmark analysis. Figure 2 3-year-conditional survival CS(3|s) after ASCT stratified for responses achieved. Figure 2. 3-year-conditional survival CS(3|s) after ASCT stratified for responses achieved. Figure 3 Figure 3. Disclosures Hillengass: Amgen: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Research Funding; Sanofi: Research Funding. Goldschmidt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Raab:Amgen: Consultancy, Research Funding; BMS: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Research Funding.

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Impact of Early Progression on Long Term Outcomes Among Myeloma Patients Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVD) Induction Therapy

Blood ◽

10.1182/blood-2018-99-120314 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3302-3302

Author(s):

Ajay K Nooka ◽

Jonathan L Kaufman ◽

Charise Gleason ◽

Nisha Joseph ◽

Craig C Hofmeister ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Long Term Outcomes ◽

Advisory Committees ◽

Term Survival ◽

Risk Status ◽

Early Progression

Abstract Background: The incorporation of modern day induction regimens, autotransplant and continuous maintenance has resulted in better long-term outcomes for myeloma patients. Experience and trials demonstrated that by prolonging 1st progression-free survival (PFS1) and pushing the relapse farther, we can gain the OS advantage (McCarthy et al NEJM 2012). Unfortunately, a subgroup of patients fail to exploit this advantage, either due to their disease biology or due to inadequate therapy and suffer early progression (inferior PFS1) that impacts their long term outcomes. First, we evaluated the predictors of early progression to highlight the modifiable factors that can prevent progression. Next, we quantified the impact of shorter PFS1 (<36 months) on the long-term survival (OS). Methods: Of the 1000 consecutive newly diagnosed myeloma patients treated with homogenous induction therapy (RVD) induction therapy per Richardson et al (Blood 2010) from July 2005 until August 2016, 230 patients progressed within the first 36 months while 96 patients progressed beyond the 36-month mark, at the time of analysis. Median follow up duration was 38 months. Demographic and outcomes data for the pts were collected from myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: Median age of the pts is 60 years (range 29-78). 29% of the patients are above the age of 66. M/F 54%/46%; W/AA 60%/32%; ISS III 27% were other patient characteristics. Cytogenetic abnormalities of significance: t(11;14): 13.5%, t(4;14): 7.8%, t(14;16): 5% del 17p: 16%, complex cytogenetics: 29% and high-risk status was conferred to 44% of the patients. 83% of patients underwent an autotransplant and median time to transplant was 6 (2-50) months. 68% of patients received maintenance therapy. Response rates are summarized in Fig 1. The median PFS for early and non-early progressors were 32 months (95% confidence interval (CI), 30.293-33.707) and 101 months (95% CI, 77.14-124.86) months, respectively (P<0.001). The median overall survival (OS) for early progressors was 94 months, and non-early progressors was not reached. (Fig 2). Among the predictors of early relapse, presence of high-risk status, ISS stage 3, inability to achieve ≥VGPR after transplant, non-receipt of transplant and/or maintenance were independent predictors of early progression on the multivariate analysis as illustrated in Table 1. Conclusions: Even with the effective use of the 3-drug induction regimen, these functionally high-risk patients that are early progressors have truncated long term survival. Our analysis advocates for using transplant, deepening the responses with modern drugs such as monoclonal antibodies to achieve ≥VGPR after transplant and intense maintenance strategies to prevent relapse. Disclosures Nooka: Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kaufman:Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Roche: Consultancy; Janssen: Consultancy; BMS: Consultancy. Hofmeister:Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Heffner:ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. Lonial:Amgen: Research Funding.

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Induction Therapy with Everolimus in Combination with DHAP (Dexamethasone, High-Dose AraC, Cisplatinum) in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma: A Randomized, Placebo-Controlled Phase I/II Trial (HD-R3i)

Blood ◽

10.1182/blood-2018-99-117291 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2912-2912 ◽

Cited By ~ 1

Author(s):

Bastian von Tresckow ◽

Andreas Hüttmann ◽

Vladan Vucinic ◽

Horst Mueller ◽

Annette Plütschow ◽

...

Keyword(s):

Placebo Group ◽

Phase I ◽

Board Of Directors ◽

Phase Ii ◽

Induction Therapy ◽

Research Funding ◽

High Dose ◽

Classical Hodgkin Lymphoma ◽

Advisory Committees ◽

Support Research

Abstract Introduction: Induction chemotherapy followed by BEAM high dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplant (PBSC transplant) is standard of care for transplant-eligible patients with relapsed or refractory classical Hodgkin lymphoma (rrHL). However, approx. 50% of patients relapse and therefore, this strategy must be improved. As response to induction therapy is predictive of the outcome after HDCT, this trial aimed at improving the response to induction therapy by adding oral everolimus to time-intensified standard DHAP (Ever-DHAP). Methods: We included patients with histologically confirmed rrHL aged 18-60 years in this phase I/II trial. Dosage of everolimus was pre-determined in the phase I part with 10 mg/day given parallel to DHAP for 14 days within each of two cycles. The phase II part started as a randomized controlled trial comparing 50 patients in the everolimus group to 50 patients in a placebo group. The primary endpoint of the phase II part was the CT-based complete remission (CR-) rate after two cycles of Ever-DHAP. This CR-rate would be expected to be ≥ 40% if adding everolimus was effective. Secondary efficacy endpoints of the trial were PET-based CR-rate after two cycles of induction, progression-free and overall survival. Secondary feasibility endpoints were time to recovery, CTC-based adverse events, duration of induction therapy, discontinuation rates and the rates of successful PBSC collection. The trial was registered at ClinicalTrials.gov with ID NCT01453504. Results: From 7/2014 to 3/2018 we recruited a total of 59 patients in the phase II part. Because of poor recruitment the placebo group was closed in 9/2015 after 9 patients were randomized. These patients are analyzed in a descriptive way only. Of 50 patients in the everolimus group two were not evaluable because of retracting consent and not starting therapy; three additional patients discontinued Ever-DHAP because of toxicity. PBSC collection was successful in 37/39 documented patients receiving Ever-DHAP (95%). After two cycles of therapy we observed a CT-based CR in 12/45 patients of the everolimus group (27%) and in 2/9 patients of the placebo group (22%). A PET-based CR was achieved by 19/38 patients of the everolimus group (50%) and by 4/5 patients of the placebo group. In the everolimus group two patients had refractory disease (4%) and two died (4%), 3 and 4 months after starting but not related to Ever-DHAP. Final results and additional analyses will be presented. Conclusions: Adding everolimus to time-intensified DHAP is feasible, however, the Ever-DHAP regimen failed to show an improved efficacy. Disclosures von Tresckow: Novartis: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; MSD: Honoraria, Other: Travel support, Research Funding. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Viardot:Amgen: Consultancy; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Gilead Kite: Consultancy, Honoraria. Topp:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding. Borchmann:Novartis: Consultancy, Honoraria.

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Liposomal Formulation of Vincristine Allows for Doubling the Dose Compared to Conventional Vincristine: Results of the First Futility Analysis of the OPTIMAL>60 Study of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)

Blood ◽

10.1182/blood.v124.21.4420.4420 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4420-4420

Author(s):

Sascha Duecker ◽

Viola Poeschel ◽

Anne Wolf ◽

Gerhard Held ◽

Niels Murawski ◽

...

Keyword(s):

Elderly Patients ◽

Board Of Directors ◽

Cumulative Dose ◽

Research Funding ◽

Study Group ◽

High Grade ◽

Advisory Committees ◽

Non Hodgkin Lymphoma ◽

Lymphoma Study Group ◽

Median Cumulative Dose

Abstract Background: Cumulative neurotoxicity is a major issue and dose limiting factor of vincristine in the treatment of diffuse large B-cell-lymphoma (DLBCL) and other malignancies, especially in elderly patients. In the RICOVER-60 trial of the German High Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) [Pfreundschuh et al., Lancet Oncol. 2008] only 59% of patients received full-dose vincristine at cycle 6, 22% of patients received no vincristine at cycle 6 and 36% at cycle 8 due to the neurotoxicity of the drug. Thus, vincristine-induced polyneuropathy is a long-term toxicity that heavily affects the quality of life of successfully treated elderly patients with lymphoma, because of slow and often incomplete recovery. Moreover, retrospective analyses suggest that dose reductions of vincristine lead to a considerable loss of efficacy [Fisher et al., Am J Med. 1977; De VV et al., Cancer Res. 1987]. Since preclinical and clinical studies suggest a high activity and excellent tolerability of liposomale vincristine, a randomized comparison of the two formulations is warranted. Methods: In the OPTIMAL>60 study elderly patients with DLBCL (61- to 80 years-old, ECOG 0-4, IPI 1 [age>60] with bulk, or IPI 2-5) are randomized to receive eight 2-week applications or an optimized schedule of 12 application of rituximab in combination with 6 cycles of CHOP-14. In a 2x2 factorial design, patients receive a second randomization into conventional vincristine (1.4 mg/m2, capped at 2 mg) or liposomal vincristine (2mg/m2, uncapped). One secondary endpoint of the OPTIMAL>60 trial of the DSHNHL is the determination of the median dose of either conventional or liposomal vincristine, that can be given to patients applying identical dose reduction rules. Neurotoxicity was determined as polyneuropathy according to the Common Terminology Criteria for Adverse Events (CTCAE v. 4.03). Results: In this planned futility analysis of the OPTIMAL>60 trial, we investigated the cumulative dose of liposomal (VLIP, Marqibo®) and conventional vincristine (VCR) and the neurotoxic effect of the first 105 patients. Fifty-three patients received VCR and 52 patients VLIP. In comparing the median cumulative dose received for each group. The median cumulative dose of VLIP group (10.09mg/m2) was nearly double the median cumulative dose of VCR group (5.42mg/m2) (p<0.001). Since identical dose reduction rules were applied, we expected equal neurotoxic effects with VLIP and VCR, which was indeed the case. Before initiation of therapy 100% of patients receiving VCR showed PNP grade 0 while 15.2% of patients in the VLIP-group showed PNP grade 1 (84.8% grade 0) which was significantly worse (p=0.018). After cycles 1 and 2 the median grade of polyneuropathy was 0 in both groups, which increased to a median toxicity of grade 1 after cycles 3, 4, 5 and 6. The maximum grades of polyneuropathy observed in both groups were not significantly different (p=0.865). In the VLIP group no liposomal vincristine was administered in 18 patients (34.62%) , in the VCR arm group no vincristine in 14 patients (26.42%) in at least one cycle of therapy (p=0.361). Due to polyneuropathy no VLIP was given in 16 patients (30.77%), no VCR in 12 patients (22.64%) for the minimum of one cycle of therapy (p=0.346). Conclusions: With nearly twice the dose of VLIP achieved in elderly patients treated in the OPTIMAL>60 study, the preset goals were met and the study will continue as planned. A total recruitment of 864 patients is necessary to demonstrate whether the double dose of VLIP will translate into a significantly improved outcome in 3-year PFS (HR 0.68 or 9% with an alpha=5% and a power of 80%). Acknowledgment: This study was supported by Spectrum, Amgen and Roche. Disclosures Viardot: Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Travel support Other; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel support, Travel support Other; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Travel support Other. Pfreundschuh:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Research Funding.

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Functional Cure, Defined As PFS of More Than 7 Years, Is Achieved in 9% of Myeloma Patients in the Era of Conventional Chemotherapy and of First-Generation Novel Anti-Myeloma Agents; A Single-Center Experience over 20-Year Period

Blood ◽

10.1182/blood-2018-99-113108 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1968-1968

Author(s):

Evangelos Terpos ◽

Maria Roussou ◽

Ioannis Ntanasis-Stathopoulos ◽

Nikolaos Kanellias ◽

Despina Fotiou ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

First Generation ◽

Steering Committee ◽

First Line ◽

Conventional Chemotherapy ◽

Advisory Committees ◽

First Line Therapy ◽

Line Therapy ◽

Travel Grant

Abstract Advances in the management of multiple myeloma (MM) led to a significant prolongation of overall survival (OS), mainly of the younger patients; almost 10% of them experience more than 10-year OS. Although long progression-free survival (PFS) correlates with extended OS, there is very limited information for the characteristics of patients who manage to be progression-free for a long period after first-line therapy. The aim of this analysis was to evaluate the characteristics of patients who achieved at least 7-year of PFS after frontline therapy and compare them with those of all other patients who were treated in a single center during the same time period. Between January 1994 and December 2010, 406 consecutive newly diagnosed MM patients received first line therapy in the Department of Clinical Therapeutics (Athens, Greece). All patients had symptomatic disease, based on the IMWG criteria of that period (at least one CRAB symptom to start anti-myeloma therapy). Thirty-six (8.8%; 23M/13F) patients achieved a PFS of at least 7 years (long PFS group) after frontline treatment. The median PFS of these 36 patients is 10 years, while the other patients had a median PFS of 22 months. Long PFS patients were younger (median age 56 vs 68 years; p<0.001), had bigger body surface area (median: 1.85 m2 vs. 1.76 m2; p=0.013) and lower ECOG performance status (score 0-1: 71% vs 52%; p=0.014) compared to all others. Long PFS patients had higher hemoglobin (11.4 g/dl vs 10.2 g/dl; p=0.001), higher platelet count (278 vs 224 x109/l; p<0.001) and higher creatinine clearance (CrCl, based on the MDRD formula: 88 vs 67 ml/min; p<0.001; no patient in the long PFS group presented with CrCl <45 ml/min at diagnosis). There was no difference between the two groups regarding percentage of patients with high LDH, presence of osteolysis, type of myeloma (IgG vs IgA vs others), levels of serum and/or urine M-protein, and percentage of plasma cell infiltration in the bone marrow. However, more patients in the long PFS group had ISS-1 or ISS-2 disease (86% vs 61%; p=0.002) and normal pattern of marrow infiltration in the MRI of the spine and pelvis (24% vs 15%; p=0.035). Regarding chromosome abnormalities at diagnosis, no patient in the long PFS group had high-risk cytogenetics (defined as presence of del17p, t(4;14) or t(14;16) vs 32% in all other patients. All patients received either conventional chemotherapy (CC) or first-generation novel anti-myeloma agent (bortezomib (B), thalidomide (T) or lenalidomide (R)-based regimens as frontline therapy. There was no difference between the two groups regarding CC versus novel agent-based induction treatment. Out of 36 long-term PFS patients, 11 (30%) received CC, 8 (22%) B-based, 8 (22%) RD, 6 (17%) T-based, and 3 (8%) VTD; 10 (28%) patients received first-line therapy participating in a clinical trial. Long PFS patients had received more often autologous stem cell transplantation (ASCT, 61% vs 23%; p=0.001) as part of first line therapy; therefore, more long PFS patients had also received consolidation and/or maintenance (50% vs 15%; p=0.001). Higher proportion of patients achieved at least VGPR (74% vs 41%) or at least CR (32% vs 18%) in the long PFS group. We performed next generation flow cytometry in 23 patients of the long PFS group to evaluate minimal residual disease (MRD) and 14 (61%) of them were MRD (-) at the level of the 10-6. The probability of achieving long PFS (≥7 years) for patients who managed to be progression-free at 2, 3 and 4 years was 11.6%, 13.2% and 15.3%, respectively. In the multivariate analysis, only younger age was associated with probability for long PFS (p<0.001). The median OS of the whole group of patients was 5 years; in the long-PFS group median OS has not been reached yet while in all other patients the median OS was 4.3 years. In conclusion, our study in an unselected group of patients, the majority of whom did not participate in clinical trials, showed that 9% of patients with newly diagnosed myeloma experience prolonged PFS of more than 7 years (median: 10 years) even in the era of CC or first-generation novel agents. These patients have low risk disease, mainly of ISS-1 or -2, no high-risk cytogenetics, no or mild renal impairment, and achieve deep responses after ASCT. These patients may be considered as "functionally" cured. The incorporation of novel treatment approaches may lead to a significant improvement in the probability of achievement of this "functionally" cured status. Disclosures Terpos: Novartis: Consultancy; BMS: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding. Kastritis:Prothena: 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; Takeda: 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. Dimopoulos:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria.

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