Response to Rituximab Induction Is a Predictive Biomarker in Post-Transplant Lymphoproliferative Disorder (PTLD) and Allows Successful Treatment Stratification in an International Phase II Trial Including 152 Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 816-816 ◽  
Author(s):  
Ralf Ulrich Trappe ◽  
Daan Dierickx ◽  
Heiner Zimmermann ◽  
Franck Morschhauser ◽  
Peter Mollee ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Solid Organ ◽  
Transplant Recipients ◽  
Advisory Committees ◽  
Intention To Treat ◽  
Kaplan Meier ◽  
Treat Population

Abstract Background: The PTLD-1 trial has demonstrated the efficacy and safety of 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 + G-CSF in CD20-positive PTLD after solid organ transplantation. Median overall survival (OS) was 6.6 years, a clear improvement over the preceding rituximab monotherapy trials (2.4 years). However, response to rituximab induction predicted OS after completion of therapy. Based on the hypothesis that rituximab consolidation might be sufficient treatment for patients already in a complete response (CR) after rituximab induction, trial treatment was changed in 2007 through a protocol amendment introducing risk-stratified sequential treatment (RSST): rituximab consolidation for patients in CR after rituximab induction and R-CHOP-21 consolidation for all others. Methods: In this international, multicenter phase II trial (PTLD-1, 3rd amendment; NCT00590447), treatment-naïve adult solid organ transplant recipients diagnosed with CD20-positive PTLD were treated with rituximab (375 mg/m2 IV) on days 1, 8, 15 and 22. After restaging, patients in CR continued with four three-weekly courses of rituximab monotherapy while all others received 4 cycles of R-CHOP-21 + G-CSF. In case of disease progression during rituximab monotherapy R-CHOP was commenced immediately. The primary endpoint was treatment efficacy measured as response rates and response duration. Analysis was by intention to treat. This is the final analysis of 152 patients treated with RSST from 2007 to 2014 at centers in Germany (72), Belgium (36), France (24), Australia (7), Poland (7) and Italy (6) with a median follow-up of 4.5 years. The 70 patients treated with rituximab followed by CHOP-21 in the original PTLD-1 trial (median follow-up 5.1 years) served as a control population. Inclusion criteria and follow-up schedule were identical; there were no significant differences in the transplant- and lymphoma-related baseline factors listed below. Results: 115/152 patients were male. 69/152 were kidney, 40 liver, 18 lung, 15 heart, 5 heart/kidney, 3 kidney/pancreas and 2 heart/lung transplant recipients. Median age at diagnosis was 56 years. PTLD was late (> 1 year after transplantation) in 120/152 (79%) of patients. 67/145 (46%) PTLD were EBV-associated. 130/152 patients had monomorphic, 20 polymorphic and 2 early lesion PTLD. The overall response rate (ORR) was 111/126 (88%, CR: 88/126 [70%]). Median duration of remission (DR) was not reached; the 3-year Kaplan-Meier estimate was 82% (compared to 71% in PTLD-1). In the intention-to-treat population (152 patients), the median time to progression (TTP) was not reached either. The 3-year Kaplan-Meier estimate was 78% (69% in PTLD-1). Median OS by intention-to-treat was 6.6 years (95% CI 5.5 - 7.6) with a 3-year estimate of 70% in comparison to 61% in PTLD-1. There was no significant difference in ORR, DR, TTP or OS between EBV-positive and EBV-negative PTLD. On the other hand, response to 4 applications of rituximab was a highly significant predictor of OS, TTP and progression-free survival (PFS) despite treatment stratification (all p<0.001). 37/148 patients (25%) achieved CR with 4 cycles of rituximab and were allocated to rituximab consolidation. In this group, TTP in the intention-to-treat population was significantly longer than in the corresponding group in the PTLD-1 trial (37 patients versus 14 patients, p<0.05). In the 111 patients allocated to R-CHOP consolidation, ORR was 78/92 (85%) with 55/92 (60%) complete remissions (89% and 60%, respectively, in PTLD-1). Median TTP was not reached, the 3-year estimate was 73% (69% in PTLD-1). In patients refractory to rituximab induction, the CR rate was 22/38 (58%) with R-CHOP compared to 3/11 (27%) in PTLD-1 with CHOP (p=0.07); median PFS was 1.4 years versus 0.3 years in PTLD-1, p<0.05. The frequency of grade 3/4 leukopenia and infections was 63% and 34%, respectively. Treatment-related mortality occurred in 7%. Conclusions: This largest trial cohort in PTLD to date demonstrates for the first time that treatment stratification by response to rituximab induction is feasible, safe and effective. Rituximab consolidation in early rituximab responders results in significantly better disease control compared to CHOP consolidation. The addition of rituximab to CHOP chemotherapy improves outcome in patients refractory to rituximab monotherapy. Disclosures Trappe: Mundipharma: Research Funding; AbbVie: 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, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; CSL Behring: Research Funding, Speakers Bureau. Zimmermann:Roche: Honoraria; Celgene: Other: Travel support. Morschhauser:Genentech Inc./Roche: Other: Advisory boards. Mollee:Celgene: Honoraria, 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, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zaucha:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. Dührsen:Roche: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Hüttmann:Amgen: Research Funding; Roche: Research Funding. Salles:Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche and Gilead Sciences: Research Funding; Celgene Corporation; Roche: Speakers Bureau. Kliem:Astellas: Honoraria; Fresenius: Honoraria; Genzyme: Honoraria; Novartis: Honoraria; Roche: Honoraria; Raptor: Honoraria. Leblond:Janssen: Consultancy, Honoraria, Speakers Bureau; Mundipharma: Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau. Choquet:Janssen: Consultancy; Roche: Consultancy.

scholarly journals How Median Follow-up Time Informs Survival Outcomes: Lessons from a Trial of Acute Myeloid Patients Treated with Venetoclax and Azacitidine

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5897-5897
Author(s):  
Diana Abbott ◽  
Andrew Hammes ◽  
Jonathan A Gutman ◽  
Daniel A Pollyea ◽  
Clayton Smith
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Trial Data ◽  
Time To Event ◽  
Advisory Committees ◽  
Kaplan Meier ◽  
The Stability

Background: Follow-up time in clinical trials must leverage conflicting aims. To ensure patient safety, investigators often assess toxicity and efficacy endpoints at various times throughout a trial. Yet accurate analysis requires stable estimates of time-to-event outcomes, which can require longer follow-up than is observed in interim analyses. While median follow-up is routinely reported in clinical trials, the stability of time-to-event estimates and their relationship to follow-up times are rarely discussed. However, the potential follow-up of study participants who are censored in a clinical trial can impact time-to-event estimates (Betensky 2015). Methods: A clinical trial of venetoclax + azacitidine in 33 newly diagnosed older patients with AML was conducted at our institution and is described in detail elsewhere (Pollyea 2018). Trial data consisting of follow-up from January 2015 through February 2018 established promising results (overall response rate = 91%; median response duration, progression-free survival, and overall survival (OS) were not yet reached). Due to ongoing interest in median time-to-event patient outcomes that were not reached and thus could not be reported at the time of publication, the data have been re-analyzed on repeated occasions as follow-up has continued, with OS of particular interest. Median follow-up was calculated using the reverse Kaplan-Meier method. Median OS was calculated using Kaplan-Meier product limit estimates. Analysis of trial data has occurred at 6 different censoring time points: December 4, 2017; February 28, 2018; October 3, 2018; December 31, 2018; March 8, 2019; and May 20, 2019. Upper and lower limits of the Kaplan-Meier OS estimate were calculated to explore the stability of OS estimates over time (Betensky 2015). Analyses were performed using SAS version 9.4 (SAS Institute). Results: Median OS was not reached until analysis was conducted as of October 3, 2018. At this analysis the median OS (1130 days) exceeded the median follow-up time (867 days). This phenomenon also occurred for data censored on December 31, 2018, with the median OS (1130 days) also exceeding the median follow-up time (956 days). In the most recent two analyses of the data (March 8, 2019 and May 20, 2019), the median OS settled at a consistent value (880 days) that did not exceed the median follow-up times (1023 days and 1096 days, respectively). Exploration of the stability of OS estimates revealed that a single patient enrolled early in the study and died after 1130 days of follow-up skewed the median OS estimate upward. Conclusions: Interest in our clinical trial results motivated numerous follow-up analyses of our data. As such, we encountered a peculiar result in which median OS exceeded median follow-up. In investigating the stability of the OS K-M estimates, a single patient's study data was found to skew results in these instances. Removal of this patient's data in these instances (when the relationship between median follow-up and median OS suggest estimate instability) results in a median OS consistent with subsequent analyses at later censoring dates (880 days for the modified analysis). We therefore conclude that time-to-event estimate stability is informative and should be incorporated into survival analysis of clinical trial data. Disclosures Pollyea: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: 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; Diachii Sankyo: 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; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Efficacy and Safety of Ponatinib According to Prior Approved Tyrosine Kinase Inhibitor (TKI) Therapy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CP-CML): Results From the PACE Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3749-3749
Author(s):  
Dong-Wook Kim ◽  
Jorge E. Cortes ◽  
Javier Pinilla-Ibarz ◽  
Philipp le Coutre ◽  
Ronald Paquette ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rates ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Advisory Committees ◽  
Kaplan Meier ◽  
Previously Treated ◽  
Equity Ownership

Abstract Abstract 3749 Background: Ponatinib is a potent pan-BCR-ABL inhibitor that is active against native and mutated forms of BCR-ABL, including the uniformly TKI-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with CP-CML were evaluated in a pivotal phase 2, international, open-label clinical trial. Objectives: This prospectively defined analysis was performed to evaluate the impact that previous exposure to approved TKIs had on the efficacy and safety of ponatinib treatment among patients with CP-CML. Methods: The PACE trial enrolled 449 patients, including 270 patients with CP-CML. Enrolled patients were required to be resistant or intolerant (R/I) to dasatinib or nilotinib, or they had to have the T315I mutation at baseline. Patients with CP-CML were assigned to 1 of 2 cohorts: R/I (N=203) or T315I (N=64). Three patients were post-imatinib and did not have T315I at baseline; they were treated but not assigned to a cohort. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months after treatment initiation. The trial is ongoing. Data as of 23 July 2012 are reported, with a minimum follow-up of 9 months (median 12 [0.1 to 19] months). The efficacy and safety of ponatinib according to prior approved TKI therapy (imatinib, dasatinib, nilotinib) is presented for the total CP-CML (N=270) population. Results: The median age of CP-CML patients was 60 (18 to 94) years. Median time from initial diagnosis to start of ponatinib was 7 (0.5 to 27) years. Patients were heavily pretreated: 97% had received prior imatinib, 80% dasatinib, 68% nilotinib; 7% of patients had received 1 prior approved TKI, 40% 2 prior approved TKIs, 53% all 3 prior approved TKIs; 60% had received ≥3 prior approved/investigational TKIs. In patients previously treated with dasatinib or nilotinib (N=256), 84% had a history of resistance and 16% were purely intolerant to dasatinib or nilotinib. At the time of analysis, 66% of patients remained on study. The most common reasons for discontinuation were adverse events (AEs; 12%) and progressive disease (7%). Response rates according to the number of prior approved TKIs are shown in the table below. Patients receiving fewer prior approved TKIs had higher response rates. The difference in MCyR rate was statistically significant for patients previously treated with 1 vs. 3 approved TKIs (p=0.003) and for patients previously treated with 2 vs. 3 approved TKIs (p=0.011). Differences in MMR rates were not statistically significant. Of patients achieving MCyR, 98% of patients receiving 2 prior approved TKIs and 83% of patients receiving 3 prior approved TKIs were predicted (Kaplan-Meier) to remain in MCyR at 1 year. Of patients achieving MMR, 86% of patients receiving 2 prior approved TKIs and 80% of patients receiving 3 prior approved TKIs were predicted (Kaplan-Meier) to remain in MMR at 1 year. Kaplan-Meier estimates were not calculable for patients receiving 1 prior TKI. The most common treatment-related AEs according to number of prior approved TKIs (1, 2, 3, respectively) were thrombocytopenia (32%, 38%, 44%), rash (37%, 37%, 39%), dry skin (37%, 36%, 39%), abdominal pain (21%, 26%, 28%), and headache (26%, 28%, 19%). Rash, dry skin, abdominal pain, and headache were generally grade 1 or 2 in severity. Thrombocytopenia was typically reported early in treatment and was manageable with or without dose reductions and/or dose interruptions. Conclusions: Ponatinib has substantial activity in patients with CP-CML, with higher response rates and improved tolerability observed in patients receiving fewer prior approved TKIs. Data with a minimum follow-up of 12 months will be presented. Disclosures: Kim: Novartis, BMS, Pfizer, ARIAD, and Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis and Bristol Myers-Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:Novartis: 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. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Pfizer: Research Funding; BMS: Research Funding; Novartis: Consultancy, Research Funding; ARIAD: Research Funding.

scholarly journals Survival after Hematopoietic Stem Cell Transplantation in an Older, Fit Cohort of Patients with Advanced Myelodysplastic Syndromes: The MDS-TAO Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 972-972
Author(s):  
Gregory A. Abel ◽  
Haesook T. Kim ◽  
David P. Steensma ◽  
Richard M. Stone ◽  
Angel M. Cronin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Performance Status ◽  
Time Dependent ◽  
Ecog Performance Status ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Kaplan Meier ◽  
Baseline Characteristics

Abstract Background: The utility of reduced-intensity conditioning hematopoietic stem cell transplantation (RIC HSCT) for fit elderly patients with advanced myelodysplastic syndromes (MDS) is unclear. Methods: The MDS Transplant-Associated Outcomes Study, or "MDS-TAO," was a prospective longitudinal observational study at the Dana-Farber/Harvard Cancer Center designed to examine survival, quality of life, and other outcomes for RIC HSCT versus non-HSCT approaches for HSCT-eligible patients with advanced MDS ages 60 to 75. All patients who met eligibility criteria were approached in the leukemia or HSCT clinics; 96% agreed to enroll. Inclusion criteria included histologically-confirmed diagnosis of MDS or CMML, and (1) therapy-related disease or (2) Int-2/high IPSS (Greenberg, Blood, 1997), or (3) non-IPSS poor-risk cytogenetics (Haase, Blood, 2007), or (4) severe cytopenia/platelet or red cell transfusion-dependence. Exclusions were (1) comorbidities that in the judgment of the treating physician precluded HSCT eligibility (2) prior donor search and (3) patient unwillingness to consider HSCT. Considering time to transplant as a time-dependent variable, hazard ratio for ultimate HSCT was estimated using Cox regression analysis controlling for age, gender, ECOG performance status, IPSS, IPSS cytogenetic risk group, and year of consent. Landmark analyses at 5 months were conducted to present estimates of overall survival for patients who were alive for at least 5 months and received HSCT versus patients who did not (landmark cohort). Subgroup analyses (e.g., molecular characteristics) are also ongoing. Results: 290 patients were enrolled between May 2011 and May 2018; 24 had less than 1.5 months of follow up after consent and were excluded from this analysis. Of the remaining 266 patients, 143 were deceased at last follow up. Baseline characteristics are presented in the table. The median follow-up time among survivors was 31 months (range 1.9, 84). 102 patients received HSCT, of whom 45 subsequently died; of the 164 patients who have not undergone HSCT, 98 have died. The median time to HSCT among those transplanted (n=102) was 4.6 months. The median follow-up for patients alive and not yet transplanted (n=66) was 24 months (range 1.9, 82). Considering time to HSCT as a time-dependent variable (n=266), the hazard ratio for death in multivariable analysis was 0.63 (95% CI 0.42-0.96, p=0.03). Poor risk IPSS cytogenetic group was the only other factor associated with mortality, HR=1.86 (95% CI 1.15-3.00, p=0.006); age, gender, ECOG performance status, IPSS, and consent year were not. Five months was chosen for the landmark analysis given it was closest to the median time to HSCT. In the landmark cohort (N=229), HSCT patients were more likely to have Int-2/high IPSS at baseline (65% vs 35% for none, p=0.0003). No other baseline characteristics were different. Figure A shows Kaplan-Meier plots for the landmark cohort, comparing 54 who received HSCT ≤ 5 months versus 175 patients who did not receive a transplant within 5 months (log rank p=0.04). Figure B shows Kaplan-Meier plots for HSCT comparing 99 patients who received HSCT at any time during follow-up versus 130 patients who did not (log rank p=0.005). Conclusion: In this large cohort of fit elderly patients with advanced MDS, a treatment strategy that included HSCT was associated with better overall survival. Table Table. Disclosures Ho: Jazz Pharmaceuticals: Consultancy. DeAngelo:Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; Amgen: Consultancy; ARIAD: Consultancy, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Amgen: Consultancy; Shire: Honoraria; Takeda: Honoraria; BMS: Consultancy; Blueprint Medicines: Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; ARIAD: Consultancy, Research Funding; Pfizer Inc: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; BMS: Consultancy. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Multicenter Phase II Trial Addressing Lenalidomide Maintenance in Patients with Relapsed Diffuse Large B-Cell Lymphoma (rDLBCL) Who Are Not Eligible for Autologous Stem Cell Transplantation (ASCT): Efficacy and Safety Results after a Median Follow-up of Five Years

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1688-1688
Author(s):  
Andres JM Ferreri ◽  
Marianna Sassone ◽  
Francesco Zaja ◽  
Alessandro Re ◽  
Michele Spina ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Salvage Therapy ◽  
Research Funding ◽  
Progressive Disease ◽  
De Novo ◽  
Phase Ii Trial ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Observation Period

Abstract Background: Lenalidomide (LENA) maintenance is associated with significantly improved outcome in patients (pts) with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT. Preliminary results of a multicentre phase II trial (NCT00799513), reported after a median follow-up of 25 months, showed a 1-yr PFS of 70 ± 7% and a 1-yr OS of 81 ± 6%, with good tolerability (Ferreri AJM, et al. Lancet Haematol 2017). However, LENA was ongoing in 41% of pts at time of analysis, and late side effects and events after maintenance completion remained to be defined. Herein, we report efficacy and safety results of the trial after a median follow-up of 56 (range 27-100) months. Methods: HIV-neg pts (age ≥18 ys) with de novo or transformed DLBCL and relapsed disease responsive to conventional rituximab-containing salvage therapy were registered and treated with LENA 25 mg/day for 21 days out of 28, until lymphoma progression or unacceptable toxicity. A protocol amendment in 2015 allowed physicians to interrupt maintenance after a minimum duration of two years. Primary endpoint was 1-year PFS. Simon's two-stage optimal design was used. To demonstrate a 1-yr PFS improvement from 30% (P0) to 50% (P1), 47 pts (one-sided; α 5%; β 80%) were needed. Maintenance would be considered effective if ≥19 pts were progression-free survivors at 1 yr. Cell of origin was assessed by NanoString Technology (n=23) and Hans algorithm (n=39). Results: Between 3/2009 and 12/2015, we recruited 48 pts; 46 of them were assessable (median age 72 ys; range 34-86); 36 pts had de novo DLBCL, 10 had transformed DLBCL. All pts were previously treated with anthracycline- and rituximab-based combination, plus ASCT in 6 pts. Thirty-three pts were enrolled at 1st relapse; salvage therapy contained high doses of cytarabine or ifosfamide in two-thirds of cases, and response was complete in 26 pts and partial in 20. Most pts had unfavourable features: IPI ≥2 in 38 (83%) pts, advanced stage in 35 (76%), extranodal disease in 29 (63%), high LDH level in 21 (46%); 28 (61%) pts were older than 70 ys. Sixteen pts received ≥2 years of LENA (5 received >2 ys), 30 pts interrupted treatment due to progressive disease (PD; n= 17), toxicity (9) or pt refusal (4) (Table). LENA was well tolerated after an average of 18 courses/pt (range 3-82). With the exception of neutropenia, grade-4 toxicities occurred in <1% of courses. Infections were rare, and well controlled with oral antibiotics (grade 1-2 in 9 courses; grade 3 in 3). LENA dose reduction was indicated in 25 pts (transient in 21), and was due to neutropenia (13), rash (7), diarrhoea (3), or neurotoxicity (2). Three (6%) pts died of toxicity during maintenance (intestinal infarction, meningitis and sudden death) and two pts died due to myelodysplastic syndrome (Table). Grade 4-5 toxicity and SAEs were equally distributed according to maintenance duration (Table). At one year from trial registration, 31 pts were still progression free, which was significantly higher than the pre-determined efficacy threshold (n≥19). During the whole observation period, there were 24 events: progressive disease in 21 pts and death of toxicity in 3, with a 1-yr (primary endpoint) and 5-yr PFS of 67 ± 7% and 50 ± 7%, respectively. The duration of response to LENA was longer than response duration after the prior treatment line in 28 (61%) pts, and was twice as long in 21 (46%) of them. Twenty-six pts were disease-free at the last LENA course (Table), 22 of them remain relapse free after a median observation period from maintenance completion of 26 (8-92) months; 3 of the 4 relapses occurred in pts who received <1 yr of LENA (refusal or SAEs). The benefit of LENA was observed both in pts with de novo or transformed DLBCL. According to the Hans' algorithm, the 4-yr PFS was 50 ± 11% for GCB-DLBCL and 42 ± 11% for nonGCB-DLBCL (p= 0.58). Results using the Nanostring technique were consistent with the Hans' algorithm. Overall, 28 (61%) pts are alive, with a 1- and 5-yr OS of 80 ± 6% and 60 ± 8%, respectively. Conclusions: Long-term results of this trial soundly promotes the use of LENA maintenance in pts with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT. LENA was well tolerated in this elderly population, without higher toxicity rates in pts treated for ≥2 years, and with enhanced survival figures. These results warrant further investigation of immunomodulatory drugs as maintenance in these high-risk pts. Table. Table. Disclosures Ferreri: Celgene: Research Funding. Zaja:Abbvie: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria; Janssen: Honoraria; Sandoz: Honoraria. Di Rocco:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rusconi:Celgene: Research Funding.

scholarly journals Interim Analyses of Overall Survival (OS) from the TOURMALINE MM3 & MM4 Studies of Ixazomib Maintenance Following Primary Therapy in Multiple Myeloma (MM)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1656-1656
Author(s):  
Meletios A. Dimopoulos ◽  
S. Vincent Rajkumar ◽  
Sagar Lonial ◽  
Wee-Joo Chng ◽  
Shinsuke Iida ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Primary Therapy ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Interim Analyses ◽  
Kaplan Meier

Abstract Background: Two global, randomized, placebo (pbo)-controlled phase 3 studies of single-agent ixazomib (ixa) maintenance therapy are currently ongoing for newly diagnosed MM patients following primary therapy that included autologous stem cell transplantation (ASCT) (MM3, NCT02181413) or excluded ASCT (MM4, NCT02312258). Both trials have demonstrated statistically significant and clinically meaningful improvement in their primary endpoint of progression-free survival (PFS): for MM3, median 26.5 months (mos) ixa vs 21.3 mos pbo (hazard ratio [HR] 0.720, 95% confidence interval [CI] 0.582-0.890, P=0.002); for MM4, median 17.4 mos for ixa vs 9.4 mos for pbo (HR 0.659, 95% CI 0.542-0.801, P&lt;0.001). Data for the key secondary endpoint, OS, have not previously been published. Methods: Full methods have previously been reported (Dimopoulos, Lancet 2019; Dimopoulos, J Clin Oncol 2020). Eligible patients (MM3, N=656; MM4, N=706) were randomized 3:2 to receive maintenance therapy with single agent ixa or pbo for a maximum of approximately 24 mos (26 cycles, to the nearest complete cycle) or until progressive disease or unacceptable toxicity, whichever occurred first. Results: At the most recent data cut-off (MM3, 29 January 2021; MM4, 15 October 2020), with median follow up of 64 mos and 36 mos, respectively, 27% (MM3, 174/656) and 29% (MM4, 203/706) of the intention-to-treat (ITT) population had OS events. In MM3, the 5-year Kaplan-Meier estimate for OS was 74% for ixa and 73% for pbo, though the median OS had not yet been reached in either arm (HR 1.008, 95% CI 0.744-1.367, P=0.958; Figure). In MM4, the 5-year Kaplan-Meier OS estimate was 55% for ixa and 56% for pbo, though the median OS had also not yet been reached in either arm (HR 1.136, 95% CI 0.853-1.514, P=0.382; Figure). No new safety signals were identified, and the incidence of new primary malignancies in both studies was similar between ixa and pbo. Conclusions: These most current OS data for MM3 and MM4 have not demonstrated a statistically significant difference for the ixa or the pbo arm to date. After 64 mos of follow-up in MM3, the risk of OS does not differ between the study arms. After 36 mos of follow-up in MM4, the OS HR shows a trend that favors the pbo arm. Because interim analyses of OS may be overrepresented by deaths in patients who did not benefit from maintenance therapy, it is not known to what extent these results will be reflective of the ITT population at the time of the final analyses. As treatment options, including anti-CD38 mAb and other new mechanisms of action, for salvage therapies following progression continue to expand, OS is increasingly being confounded by subsequent therapies. Hence, demonstrating OS advantage for early line MM therapies is becoming increasingly challenging. OS data continue to be collected in these studies for later analyses. Figure 1 Figure 1. Disclosures Dimopoulos: Takeda: Honoraria; Amgen: Honoraria; Beigene: Honoraria; Janssen: Honoraria; BMS: Honoraria. Lonial: AMGEN: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Merck: Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Chng: Johnson and Johnson: Honoraria, Research Funding; BMS/Celgene: Honoraria, Research Funding; Takeda: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Iida: Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Glaxo SmithKlein: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding. Mateos: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Kumar: Takeda: Current Employment, Current holder of stock options in a privately-held company. Suryanarayan: Takeda: Current Employment. Vorog: Takeda: Current Employment. Fergus: Takeda: Current Employment. Labotka: Takeda: Current Employment. OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib as maintenance treatment for multiple myeloma following stem cell transplantation or induction therapy in newly diagnosed patients.

scholarly journals Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4619-4619
Author(s):  
Jee Yon Shin ◽  
Sung-Soo Park ◽  
Gi June Min ◽  
Silvia Park ◽  
Sung-Eun Lee ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Advisory Committees ◽  
Sibling Donor ◽  
Alternative Donor ◽  
Matched Sibling ◽  
Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4112-4112
Author(s):  
Charline Moulin ◽  
Romain Morizot ◽  
Thomas Remen ◽  
Hélène Augé ◽  
Florian Bouclet ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Intermediate Risk ◽  
Line Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Long Term Survivors ◽  
First Line Treatment

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

scholarly journals Outcome of Autologous Stem Cell Transplantation in Waldenström's Macroglobulinemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2149-2149
Author(s):  
Romil Patel ◽  
Neeraj Y Saini ◽  
Ankur Varma ◽  
Omar Hasan ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Advisory Committees ◽  
First Remission ◽  
Relapsed Disease

Abstract Introduction: The role of autologous hematopoietic stem cell transplantation (auto-HCT) in the management of patients with Waldenström Macroglobulinemia (WM), a rare, indolent lymphoma, has not been established. We had previously published our experience with auto-HCT in a small cohort of WM patients1. Here, we present an updated analysis of auto-HCT with a larger cohort of WM patients. Methods and study population: The study cohort was comprised of 29 patients who underwent high-dose chemotherapy and auto-HCT at MD Anderson Cancer Center (MDACC). The Kaplan-Meier method was used to create survival curves. Overall survival (OS) was defined as the duration from date of transplant to death or last date of follow-up in living patients. Progression-free survival (PFS) was defined as the duration from date of transplant to either progressive disease or death, whichever occurred first. Results: Median age at auto-HCT was 60 (range, 43-75 years). Eight patients (28%) had concurrent light chain amyloidosis (AL). Of the five patients who had MYD88 testing completed, 3 were positive for the MYD88 mutation. Additionally, of these 3 patients, 2 were also positive for CXCR4 mutation. Patients received a median of 2 lines (range 1-6) of therapy prior to auto-HCT; 3(10%) patients had primary refractory disease, 8(28%) were in first remission, and 18 (62%) had relapsed disease. Median time from transplant to last follow-up for the surviving patients was 5.3 years. Preparative regimens received by the patients were: Melphalan (n=20), BEAM-R (n=2), Busulfan/Melphalan (n=1), Cyclophosphomaide/Etoposide/total body irradiation (n=1), Thiotepa/Busulfan/Cyclophosphamide (n=1), and Carmustine/Thiotepa (n=1). Three patients further went on to receive allogeneic transplant either after relapse from auto-HCT or due to disease transformation to aggressive lymphoma. Twenty-eight patients achieved engraftment with a median time to neutrophil engraftment of 11 days (range, 10-15 days). One patient suffered primary graft failure due to progression of disease and died 84 days after transplant. Non-relapse mortality was 3.4% at 1 year. All patients were eligible for response evaluation. The median OS from diagnosis was 12.2 years. Overall response rate was 96%: complete response (n=8, 27.6%), very good partial response (n=5, 17.3%), partial response (n=15, 51.7%), and progressive disease (n=1, 3.4%). PFS and OS at 5 years were 43.3% and 62.9%, respectively. Median PFS and OS from auto-HCT were 4.1 and 7.3 years (Fig. 1A). The median OS from auto-HCT in first remission + primary refractory and relapsed disease was 8.2 years and 4.1 years, respectively.16 patients were alive at the time of censoring while 13 patients had died. Causes of death include relapsed disease (n=6), secondary malignancy (n=2), infection (n=1), chronic graft-versus-host disease (n=1), and unknown (n=3). 8 patients (28%) were positive for concurrent AL amyloidosis. The sites of amyloid involvement were kidneys (n=2), lungs (n=1), bone marrow (n=1), heart(n=1), lymph nodes(n=1), gastrointestinal tract (n=1) and subcutaneous fat aspirate(n=5). The median overall survival for patients with amyloid involvement (n=8) was 12 years. On univariate analyses, the number of chemotherapy regimens prior to transplant (≤ 2 vs >2 lines) was the strongest predictor of overall survival (p=0.03, HR 0.3, CI: 0.09-0.9, log-rank) and PFS (p=0.001, HR 0.24, CI: 0.07-0.85, log-rank). The median PFS in patients with ≤ 2 lines and > 2 lines of therapy was 71 months versus 19 months, respectively (Fig. 1B). Conclusion: Auto-HCT is safe and feasible in selected patients with WM, with a high response rate and durable remission even in patients with relapsed or refractory disease. References: Krina Patel et.al. Autologous Stem Cell Transplantation in Waldenstrom's Macroglobulinemia. Blood 2012 120:4533; Disclosures Thomas: Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Array Pharma: Research Funding; Amgen Inc: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Takeda: Consultancy; Celgene: Consultancy; Spectrum Pharma: Research Funding; Janssen: Consultancy; Kite Pharma: Consultancy; Sanofi-Aventis: Consultancy; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1589-1589
Author(s):  
Fabian Frontzek ◽  
Marita Ziepert ◽  
Maike Nickelsen ◽  
Bettina Altmann ◽  
Bertram Glass ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
High Dose ◽  
Advisory Committees ◽  
Scientific Advisory Board ◽  
Scientific Advisory

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

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

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-37
Author(s):  
Gavin Hui ◽  
Abdullah Ladha ◽  
Edna Cheung ◽  
Caroline Berube ◽  
Steven Coutre ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Gemtuzumab Ozogamicin ◽  
Intermediate Risk ◽  
Newly Diagnosed ◽  
Myeloablative Conditioning ◽  
Advisory Committees ◽  
Monosomy 7

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

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