Impact of Peri-Transplant Molecular Mutations on Outcomes of AML Patients Undergoing Fludarabine/Melphalan Conditioned Allogeneic Stem Cell Transplant

Abstract Introduction: Acute myeloid leukemia (AML) is heterogenous disease with a range of cytogenetic and molecular changes. Several molecular mutations identified in AML patients at diagnosis have prognostic implications and play important roles in guiding induction and consolidative treatment decisions. The prognostic impact of mutations peri allogeneic stem cell transplant are less well characterized. In this study, we examine the significance of pre and by D100 Post-transplant mutation status in AML patients underwent Fludarabine/Melphalan conditioned reduced intensity allogeneic stem cell transplant (SCT). Methods: AML patients who are in morphologic complete remission (CR1 or greater) with available molecular mutation at diagnosis, within 6 weeks prior to allogeneic SCT, and by 100 days post-transplant were included. Variables analyzed included baseline demographics, clinical variables (CIBMTR disease risk index (DRI), type of transplant, ELN risk, performance status) and 23 recurring molecular mutations. Analysis was also performed by grouping mutations into six pre-defined gene groups based on gene function (Table 2). Multivariable cox regression analysis was adjusted for age, gender, DRI and molecular mutation. Backward selection method was used to select the best combination of genes that is associated with overall survival (OS) and relapse-free survival (RFS). Results : A total of 142 AML patients with molecular genetic data available from 2014 to June, 2020 at Weill Cornell Medicine/New York Presbyterian Hospital were analyzed. Clinical characteristics of the patients are summarized in Table 1. The median age was 58 years (range 20 -78). Total of 261 mutations were detectable at diagnosis (Table 3). Prior to allo SCT and by D100, the detectable mutations were 87 and 40 respectively, which represent 56 and 26 patients. High-dose chemotherapy was less effective on clearing DNMT3A, ASXL1, TET2 (DAT) or IDH mutations, resulting in over-representation of DAT and IDH mutations prior to transplant. With a median follow-up time of 25 months, the median overall survival for the group was 40.8 months. The presence of mutations in TP53 at diagnosis was associated with worse OS by both univariate (HR 3.67, p=0.0030, CI 1.56-8.68) and multivariate analysis (HR 4.75, p=0.0014, CI 1.82-12.39) with median OS reduced from 49.3 to 19.3 months (p=0.002). High CIBMTR DRI (HR 0.17, p=0.0018, CI 0.05-0.51) predicted reduced OS and RFS, and Age >60 at diagnosis was associated with worse OS (HR 1.7 CI 1.04-3, p 0.03). Presence of any molecular mutation prior to transplant did not impact OS or RFS. For patients with any persistent mutations by D100 post-transplant, both OS ( HR 2.04, p 0.027, CI 1.08-3.8) and RFS (HR 1.99, p 0.025, CI 1.09-3.6,) were reduced in the univariate analysis, but not on multivariate analysis (HR 1.88, p 0.5, CI 0.99-3.49). Analysis based on six mutational groups (table 2) did not show any difference in their OS or RFS. However, worse RFS was independently associated with persistent IDH1 (HR 3.8, p 0.004, CI 1.07-56,), TET2 (HR 3.9, P 0.04, CI 1.04-14.1), and FLT3-ITD (HR 4.5, p 0.01, CI 1.7-52). Worse OS was independently associated with persistent TET2 (HR 3.9, p 0.013, CI 1.04-14.1), with a trend towards worse OS for IDH1, FLT3-ITD, with a trend towards worsening OS and RFS for ASXL1 (OS HR 7.4, p 0.06, CI 0.86 -63; RFS HR 4.9, p 0.06, CI 0.9-26) and DNMT3A (OS HR 2.3, p 0.12, CI 0.86-6.9; RFS 2.9, p 0.08, CI 0.98-8). Association with worse clinical outcomes remained significant after multivariate analysis for TET2 (both OS HR 3.98 p 0.041, CI1.07- 32 and RFS HR 5.8, p 0.032, CI 1.1- 29), IDH1 (RFS HR 8.02, p 0.049, CI 1.02 - 65) and FLT3-ITD (RFS HR 11.4, p0.010, CI 2.2- 80). Conclusions: Presence of TP53 mutations was associated with worse OS. Presence of pre-transplant mutation did not impact RFS or OS. Persistent presence of mutations in TET2, IDH1 and FLT3-ITD after Fludarabine/melphalan conditioning regimen allogeneic SCT were associated with shorter RFS and OS (in the case of TET2) independent of CIBMTR DRI. This analysis supports association of adverse outcomes in AML patients with selected persistent mutations by D100 post-transplant in reduced intensity transplant setting. Post-transplant strategies that can further eliminate persistent mutations should be investigated in prospective studies. Figure 1 Figure 1. Disclosures Lee: Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: 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; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Desai: Kura Oncology: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Takeda: Consultancy; Janssen R&D: Research Funding; Astex: Research Funding. Ritchie: Protaganist: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; NS Pharma: Research Funding; Abbvie: Consultancy, Honoraria; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Roboz: MEI Pharma - IDMC Chair: Consultancy; Daiichi Sankyo: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Bristol Myers Squibb: Consultancy; Glaxo SmithKline: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Mesoblast: Consultancy; Blueprint Medicines: Consultancy; Jasper Therapeutics: Consultancy; AbbVie: Consultancy; Actinium: Consultancy; Agios: Consultancy; Amgen: Consultancy; Astex: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Janssen: Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy.

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Comparison of Cyclophosphamide/Total Body Irradiation (Cy/TBI) and Etoposide/Total Body Irradiation (Etop/TBI) Conditioned Allogeneic Stem Cell Transplant (alloHSCT) for Adult Acute Lymphoblastic Leukaemia (ALL), Data from an Australian Tertiary Care Centre

Blood ◽

10.1182/blood.v126.23.5543.5543 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5543-5543 ◽

Cited By ~ 1

Author(s):

Anish Puliyayil Nair ◽

Shaun Fleming ◽

Sharon Avery ◽

David J. Curtis ◽

Sushrut S. Patil ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Board Of Directors ◽

Total Body Irradiation ◽

Research Funding ◽

Stem Cell Transplant ◽

Cell Transplant ◽

Allogeneic Stem Cell Transplant ◽

Advisory Committees ◽

Total Body

Abstract Background/Aim: Despite recent advances in the management of ALL, alloHSCT remains standard of care for younger adults with high-risk features. The optimum conditioning regimen for adults is not yet established. There is evidence for usage of Etoposide or higher-dose TBI in advanced disease transplants for ALL in a mixture of adult and paediatric patients (Marks et al, Biol BMT, 2006) We undertook a retrospective analysis of adult ALL patients who underwent allogeneic stem cell transplantation at our centre to find out factors influencing outcome and early treatment related complications. We also compared between Cyclophosphosphamide and Total Body Irradiation (Cy/TBI) and Etoposide and Total Body Irradiation (Etop/TBI). Method: Patients were identified from a transplant database search from January 2000 to May 2015 at the Alfred Hospital Melbourne, Australia. Decision to transplant the patients were based on high risk factors such as adverse cytogenetics (Ph+, MLL, complex karyotype), high presenting WBC count, delayed blast clearance with induction treatment and relapsed and refractory disease. Patients were compared based on transplant conditioning, disease factors and analysed for disease outcomes and complications. We also stratified the patients based on EBMT risk score and investigated the applicability of the score to predict outcome. High EBMT score was defined as >3. Results: 69 patients identified (34 Cy/TBI, 35 Etop/TBI) with median age of 33 years (range 17 - 59 years). Age was comparable for each group (Cy/TBI 35 years, Etop/TBI 31 years, p=0.84). 52 patients were males. The diagnoses were B ALL(49),T ALL(15), Bilineage Leukemia(1) and ambiguous lineage leukemia(1). 27 sibling and 42 non-sibling transplants, similar proportion for each conditioning (p=0.14). T-cell depletion with antithymocytic globulin used in 43 cases (all non-sibling and 1 sibling). High EBMT scores seen in 22 patients, with significantly higher numbers in Cy/TBI group (47% vs. 17%, p=0.01). 43 transplants done in CR1, 8 in CR2 and 18 in active-disease. There were significantly higher non-CR transplants in the Cy/TBI group (55% vs. 20%,p=0.003). Stem cell source was bone marrow in 10 patients (6 in CyTBI, 4 in Etop/TBI, p=0.5). 18 patients developed grade 3-4 acute GVHD and 13 of them were from Etop/TBI group (p=0.09). 28 patients developed extensive chronic GVHD and 20 of them received Etop/TBI conditioning(p=0.006). TRM was similar in both groups (38% vs. 31%, p=0.62). TRM was lower in patients transplanted in CR1 versus non-CR1 (25% vs. 50%, p=0.04). Median overall survival (OS) was 263 days in the Cy/TBI group versus not reached in the Etop/TBI group (p=0.08). In patients transplanted in CR1, OS was similar (NR, p=0.59) with a predicted 3-year OS of 77% and 62% in Cy/TBI and Etop/TBI groups respectively. OS was superior in CR1 transplants compared to the rest (NR vs 174 days, p<0.001). There was no difference in outcome between sibling and matched unrelated transplants (p=0.12). Patients with a high EBMT score had inferior OS (99 days vs NR, p<0.001) and TRM (63% vs 21%, p<0.001). Discussion: Outcomes for allogeneic stem cell transplant are similar for Cy/TBI and Etop/TBI for transplants performed in first remission, with equivalent outcomes for sibling and unrelated donor transplants. The rates of chronic graft vs. host disease are higher in Etop/TBI conditioned transplants. The EBMT score was highly predictive of outcome in ALL transplants, with high transplant related and disease related mortality. While long-term survivors are seen with Etop/TBI conditioning in non-CR1 transplants, the outcome in this patient group are very poor, highlighting the need for better prediction of relapse risk to aid appropriate patient selection for allografts in CR1. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Wei: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.

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Does Presence of Persistent Molecular Mutations Matter in AML Patients Undergoing Allogeneic Stem Cell Transplant?

Blood ◽

10.1182/blood-2018-99-119946 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2172-2172 ◽

Cited By ~ 1

Author(s):

Sangmin Lee ◽

Jingmei Hsu ◽

Yassine Tahri ◽

Zhengming Chen ◽

Tsiporah B. Shore ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Research Funding ◽

Stem Cell Transplant ◽

Mutation Testing ◽

Molecular Testing ◽

Prognostic Impact ◽

Cell Transplant ◽

Allogeneic Stem Cell Transplant ◽

Post Transplant

Abstract Introduction: Mutations at diagnosis in acute myeloid leukemia (AML) patients have prognostic implications. For AML patients undergoing allogeneic stem cell transplant (SCT), the prognostic impact of molecular mutations pre-transplant and immediately post-transplant are less well characterized. Here we examine the mutation status of AML patients at different time points in relation to allogeneic SCT and their implications in relapse and survival. Methods: AML patients who underwent allogeneic SCT after achieving complete remission with available molecular mutation testing at diagnosis, prior to transplant (within 4 weeks), and 28 days post-transplant were included in the analysis. Multivariable cox regression analysis was adjusted for age, gender, CIBMTR disease risk index (DRI), type of transplant, and genetic mutation. Backward selection method was used to select the best combination of genes that is associated with OS and relapse-free survival (RFS). Results: A total of 110 AML patients with molecular genetic data available from 2014 to2018 at Weill Cornell Medicine were included in the analysis. Clinical characteristics of the patients are summarized in Table 1. The median age was 58 years (20-77). Twenty-three molecular mutations analyzed at baseline, pre-transplant, and at 28 days are listed in Table 2. With a median follow-up time of 31.6 month, the median overall survival for the cohort was 37.1 months. Eighty-one patients had molecular testing at diagnosis. The presence of mutations in TP53 at diagnosis was associated with worse OS by both univariate (HR 3.67, p=0.0030, CI 1.56-8.68) and multivariate analysis (HR 4.75, p=0.0014, CI 1.82-12.39) with median OS reduced from 49.3 to 19.3 months (p=0.002). High CIBMTR DRI (HR 0.17, p=0.0018, CI 0.05-0.51) predicted reduced RFS, but not OS on multivariate analysis. Seventy-seven patients had molecular testing prior to transplant and 27 patients had persistent mutations (Table 2). The presence of mutations in ETV6 and FLT3-ITD were independently associated with worse RFS ((HR 49.7, p=0.001, CI 5.0-528) & (HR 36.4, p<0.0001, CI 6.6-200)) and OS ((HR 38.31, p=0.0035, CI 3.31-443.37) & (HR 10.57, p=0.0038, CI 2.14-52.27)). The presence of NRAS mutations was associated with worse RFS (HR 105, p=0.0004, CI 8.1-1350), but not OS. Mutations in TP53 were associated with worse RFS (HR 70.97, p=0.0026 CI 4.44-1135) and OS on univariate (HR 9.82, p=0.0327, CI 1.21-79.82), but not on multivariate analysis. At 28 days post-transplant, only 9 of the 84 patients had persistent mutations. Persistence of FLT3-ITD conferred worse RFS and OS in both univariate ((HR 11.92, p=0.0218, CI 1.43-98.98) & (HR 25.16, p=0.0052, CI 2.62, 241.92)) and multivariate ((HR 18.13, p=0.0089, CI 2.07-158.86) & (HR 35.47, p=0.0028, CI 3.41-368.81)) analysis. Conclusions: Persistent presence of mutations in ETV6 and FLT3-ITD prior to stem cell transplant were associated with shorter RFS and OS independent of CIBMTR DRI. Persistent mutations in NRAS and CBL prior to stem cell transplant were associated with poor RFS and OS respectively. This analysis further supports association of adverse outcomes in AML patients with selected persistent mutations prior to stem cell transplant. Utility of serial mutation testing prior to transplant should be further investigated in prospective studies. Disclosures Lee: AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Ritchie:NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Desai:Argenx: Consultancy; Cellerant Inc: Consultancy. Roboz:Eisai: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy; Roche/Genentech: Consultancy; Aphivena Therapeutics: Consultancy; Eisai: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Argenx: Consultancy; Novartis: Consultancy; Janssen Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Orsenix: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Cellectis: Research Funding; Celltrion: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Argenx: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Sandoz: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Otsuka: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy.

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Increased Early Mortality after Fludarabine and Melphalan Conditioning with Peripheral Blood Grafts in Haploidentical SCT with Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood-2019-129872 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4496-4496 ◽

Cited By ~ 1

Author(s):

Luke Eastburg ◽

David A. Russler-Germain ◽

Ramzi Abboud ◽

Peter Westervelt ◽

John F. DiPersio ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Early Mortality ◽

Cell Transplant ◽

Advisory Committees ◽

Post Transplant ◽

Equity Ownership

The use of post-transplant cyclophosphamide (PTCy) in the context of haploidentical stem cell transplant (haplo-SCT) has led to drastically reduced rates of Graft-vs-Host (GvH) disease through selective depletion of highly allo-reactive donor T-cells. Early trials utilized a reduced-intensity Flu/Cy/TBI preparative regimen and bone marrow grafts; however, relapse rates remained relatively high (Luznik et al. BBMT. 2008). This led to the increased use of myeloablative (MA) regimens for haplo-SCT, which have been associated with decreased relapse rates (Bashey et al. J Clin Oncol. 2013). Most studies have used a MA total body irradiation (TBI) based regimen for haplo-SCT. Preparative regimens using fludarabine and melphalan (FluMel), with or without thiotepa, ATG, and/or low dose TBI have also been reported using bone marrow grafts. Reports on the safety and toxicity of FluMel in the haplo-SCT setting with PTCy and peripheral blood stem cell (PBSC) grafts are lacking. In this two-center retrospective analysis, the safety/toxicity of FluMel as conditioning for haplo-SCT was evaluated. We report increased early mortality and toxicity using standard FluMel conditioning and PBSC grafts for patients undergoing haplo-SCT with PTCy. 38 patients at the University of Rochester Medical Center and the Washington University School of Medicine underwent haplo-SCT with FluMel conditioning and PBSC grafts between 2015-2019. Outcomes were measured by retrospective chart review through July 2019. 34 patients (89.5%) received FluMel(140 mg/m2). Two patients received FluMel(100 mg/m2) and two patients received FluMel(140 mg/m2) + ATG. The median age at time of haplo-SCT was 60 years (range 21-73). 20 patients were transplanted for AML, eight for MDS, two for PMF, two for NHL, and five for other malignancies. The median Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score was 4 (≥3 indicates high risk). 11 patients had a history of prior stem cell transplant, and 16 patients had active disease prior to their haplo-SCT. Seven patients had sex mismatch with their stem cell donor. Median donor age was 42 (range 21-71). 20 patient deaths occurred by July 2019 with a median follow up of 244 days for surviving patients. Nine patients died before day +100 (D100, "early mortality"), with a D100 non-relapse mortality (NRM) rate of 24%. Median overall and relapse free survival (OS and RFS, respectively) were 197 days (95% CI 142-not reached) and 180 days (95% CI 141-not reached), respectively, for the entire cohort. The 1 year OS and NRM were 29% and 50%. The incidence of grades 2-4cytokine release syndrome (CRS) was 66%, and 52% of these patients were treated with tocilizumab. CRS was strongly associated with early mortality, with D100 NRM of 36% in patients with grade 2-4 CRS compared to 0% in those with grade 0-1. The incidence of acute kidney injury (AKI) was 64% in patients with grade 2-4 CRS, and 8% in those without (p < 0.001). 28% of patients with AKI required dialysis. Grade 2-4 CRS was seen in 54% of patients in remission prior to haplo-SCT and in 92% of those with active disease (p = 0.02). Of the 9 patients with early mortality, 89% had AKI, 44% needed dialysis, and 100% had grade 2-4 CRS, compared to 31%, 10%, and 55% in those without early mortality (p = 0.002, p = 0.02, p = 0.01). Early mortality was not significantly associated with age, HCT-CI score, second transplant, disease status at transplant, total dose of melphalan, volume overload/diuretic use, or post-transplant infection. In conclusion, we observed a very high rate of NRM with FluMel conditioning and PBSC grafts for haplo-SCT with PTCy. The pattern of toxicity was strongly associated with grade 2-4 CRS, AKI, and need for dialysis. These complications may be mediated by excessive inflammation in the context of allo-reactive donor T-cell over-activation. Consistent with this, multiple groups have shown that FluMel conditioning in haplo-SCT is safe when using bone marrow or T-cell depleted grafts. Based on our institutional experiences, we would discourage the use of FluMel as conditioning for haplo-SCT with PTCy with T-cell replete PBSC grafts. Alternative regimens or variations on melphalan-based regimens, such as fractionated melphalan dosing or inclusion of TBI may improve outcomes but further study and randomized controlled trials are needed. This study is limited in its retrospective design and sample size. Figure Disclosures DiPersio: WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Karyopharm Therapeutics: Consultancy; Magenta Therapeutics: Equity Ownership; Celgene: Consultancy; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Amphivena Therapeutics: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau; Macrogenics: Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees. Liesveld:Onconova: Other: Data safety monitoring board; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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Impact of Wait Times for Autologous Stem Cell Transplantation in Patients with Aggressive Non-Hodgkin Lymphoma, a Subset Analysis of the Canadian Cancer Trials Group (CCTG) LY.12 Clinical Trial

Blood ◽

10.1182/blood.v128.22.690.690 ◽

2016 ◽

Vol 128 (22) ◽

pp. 690-690

Author(s):

Tanya Skamene ◽

Wenyu Jiang ◽

Ralph M. Meyer ◽

Michael Crump ◽

John Kuruvilla ◽

...

Keyword(s):

Clinical Trial ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Wait Time ◽

Salvage Chemotherapy ◽

Cell Transplant ◽

Advisory Committees ◽

Stem Cell Collection

Abstract Background: High dose chemotherapy followed by autologous stem cell transplant (ASCT) is the standard curative option for patients with relapsed or refractory, chemosensitive, aggressive non-Hodgkin lymphoma (NHL). The optimal timing for ASCT following salvage chemotherapy is not known. Cancer Care Ontario (CCO)-the cancer agency for Ontario, Canada's largest province-treatment guidelines recommend that no more than 91 days should elapse from the first day of salvage chemotherapy to stem cell transplant. We evaluated the impact of time to stem cell transplant in the context of the international CCTG LY.12 phase 3 clinical trial. Methods: Patients with relapsed or refractory (R/R) aggressive NHL were randomly assigned to gemcitabine, cisplatin and dexamethasone (GDP) or dexamethasone, cytarabine, cisplatin (DHAP), with or without rituximab, followed by ASCT [Crump JCO 2014]. Time interval definitions were based on CCO guidelines: Total Wait Time (TWT) as the number of days from the first day of salvage chemotherapy to day of ASCT; Apheresis Wait Time (AWT) as the number of days from the first day of salvage to the first day of stem cell collection; Stem cell transplant Wait Time (SWT) as the number of days from the last day of stem cell collection to the day of ASCT. Patients were considered to have experienced a delay in TWT, AWT or SWT if the time intervals exceeded 91, 70 and 21 days respectively. Overall survival (OS) and event-free survival (EFS) from transplant date were compared between patients who met and exceeded TWT targets using a Cox proportional hazards model. A linear regression model was applied to analyze TWT as a continuous variable. Univariate and multivariate analyses were performed to estimate the adjusted hazard ratio (HR) for TWT for the following co-variables: age ≤60, performance status 0/1, disease stage (I/II), presence of ≤1 extranodal sites, and response after cycle 2 (complete response, CR; complete response, unconfirmed, CRu; partial response, PR). Results: Of 619 patients enrolled on LY.12, 307 (47%) had sufficient response to salvage chemotherapy and adequate stem cell collection to complete ASCT on protocol. Among these, median age was 54.6 years, 64% were male and 94% had a performance status of 0 or 1. International Prognostic Index (IPI) score at relapse was 0-1 in 45%, 2 in 31% and ≥3 in 24%. The majority of patients had poor risk disease at study entry; 58% had a best response of stable disease (SD) or progressive disease (PD) to primary therapy, or initial duration of response < 1 year. Following up to 2 cycles of salvage chemotherapy, 75/307 (24%) achieved CR/CRu, 142/307 (46%) achieved PR, 89/307 (29%) had SD. One patient had missing data. The median TWT for the total transplanted population was 91 days (range 50-217). Median AWT and SWT were 63 (range 0-151) and 26 (range 6-146) days, respectively. Fifty percent of patients exceeded TWT target of 91 days; 32% and 57% of patients exceeded AWT and SWT targets. There was no difference in median OS (HR 0.96, 95% CI 0.66-1.39, p=0.81) or EFS (HR 1.13, 95% CI 0.82-1.55, p=0.46) between patients who exceeded and met TWT targets. The 4-year OS for patients who met and exceeded TWT was 62% and 64%, respectively. The 4-year EFS for patients who met and exceeded TWT was 43% and 50%, respectively. When analyzed as a continuous variable, TWT did not affect OS (HR 0.99) or EFS (HR 0.99). Comparison of the quartiles with shortest and longest TWT demonstrated HR 0.72 (95% CI 0.42-1.26, p=0.25) for overall survival and 0.69 (95% CI 0.44-1.09, p=0.11) for EFS. Comparison of the 10th and 90th percentiles for TWT demonstrated HR 0.67 (95% CI 0.28-1.59, p=0.36) for overall survival and 0.71 (95% CI 0.35-1.44, p=0.34) for EFS. Only the presence of ≤1 extranodal sites of disease was found to be predictive of OS in the transplanted population on univariate and multivariate analysis (adjusted HR 0.51, p=0.005). The median TWT was longer for the 31 patients transplanted at Italian centers, compared to 266 transplanted at Canadian centers (median TWT 90 vs. 118 days, t < 0.0001). Conclusion: In this exploratory analysis, limited to patients who completed transplant on the LY.12 clinical trial, we did not find evidence that those meeting current CCO ASCT wait time targets had superior outcomes compared with those who did not. Table. Table. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Kuruvilla: BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck: Honoraria; Roche Canada: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria. Luminari:Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Takeda: Other: Travel, Accomodations, Expenses; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Hay:Amgen: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Kite Pharmaceuticals: Research Funding.

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Comparative Analysis of Immune Reconstitution in HIV-Positive Recipients of Allogeneic and Autologous Stem Cell Transplant on the BMT CTN 0903/AMC-080 and BMT CTN 0803/AMC-071 Trials

Blood ◽

10.1182/blood-2019-129488 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4525-4525

Author(s):

Polina Shindiapina ◽

Maciej Pietrzak ◽

Michal Seweryn ◽

Eric McLaughlin ◽

Xiaoli Zhang ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Immune Cell ◽

Cell Transplant ◽

Advisory Committees ◽

Time Points ◽

The Difference

Introduction. Our previous flow cytometry-based comparison of HIV(+) and HIV(-) autologous hematopoietic stem cell transplant (auto-HSCT) recipient immunomes at 56, 180 and 365 days post-transplant to each other and to healthy controls (HCs) showed that both sets of auto-HSCT recipient immunomes approached HCs over time, but retained significant differences. HIV(+), but not HIV(-), auto-AHCT recipients retained pro-inflammatory features consistent with chronic HIV infection. Here, we report the results of a quantitative and functional analysis of immune reconstitution in HIV(+) patients treated with allogeneic hematopoietic stem cell transplant (allo-HSCT), in comparison with HIV(+) auto-HSCT recipients and HCs. Methods. Blood samples were collected for analysis at days 56, 180 and 365 post-transplant from HIV(+) transplant recipients and at 1 time point from HCs. Whole blood analysis was performed by five-color flow cytometry across 100 immune marker combinations. Comparisons were made between HIV(+) allo-HSCT recipients (n=17, acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, Hodgkin and non-Hodgkin lymphoma that received myeloablative or reduced intensity conditioning on the BMT-CTN-0903/AMC-080 trial), HIV(+) auto-HSCT recipients (n=36, aggressive B cell non-Hodgkin lymphoma or Hodgkin lymphoma that received myeloablative conditioning on the BMT-CTN-0803/AMC-071 trial) and 71 HCs. Unsupervised principal component analysis (PCA) examined differences in immune cell proportions, identified by flow cytometry across 100 cell subsets at each time point. Wilcoxon rank-sum tests compared median absolute counts and median proportions of cell subsets. An independent feature importance score analysis (FIS) identified contributions of immune cell populations expressing specific immune marker combinations to the differences between HIV(+) auto-HSCT recipients, HIV(+) allo-HSCT recipients and HCs. Functional responsiveness of HIV(+) allo-HSCT recipients' T cells to stimulation with CD3- and CD28-directed antibodies, NK cells to stimulation with IL-12 and IL-18 and monocytes to stimulation with lipopolysaccharide (LPS) was assessed in a preliminary mass cytometry on peripheral blood mononuclear cells isolated at the same time points (n=2) and compared to HCs (n=2). Results. PCA showed that immunomes of HIV(+) allo-HSCT recipients and HIV(+) auto-HSCT recipients clustered together with each other, but away from HCs at all time points throughout the post-transplant year. FIS identified: 1) 13 cell subsets that defined the difference between HIV(+) allo-HSCT recipients (all visits) and HCs, and 2) 11 immune cell subsets that defined the difference between HIV(+) auto-HSCT recipients (all visits) and HCs; in both of these comparisons, activated CD3+/HLA-DR+ T cells had the greatest impact on the difference between HIV(+) and HC immunomes. At 1 year, both HIV(+) transplant recipient cohorts had higher absolute numbers of activated T cells, effector T cells and CD8+ T cells than HCs (Wilcoxon rank-sum test, p<0.0031). HIV(+) autologous and allogeneic HSCT recipients also had lower numbers of CD4+ T cells, naïve T cells and activated NK cells compared to HCs (p<0.0031). FIS also identified 20 immune cell subsets that defined the difference between HIV(+) autologous and allogeneic HSCT recipients immunomes at 1 year, with CD8+/CD27- effector T cell subset exerting the highest impact on the difference. Preliminary functional mass cytometry analysis of 2 HIV(+) allo-HSCT recipients and 2 HCs showed that: 1) IFNʏ production by CD8+ T cells was increased above that of HCs at all time points. 2) Expanded populations of CD4+/T-bet+ cytotoxic cells expressing granzyme B and perforin, and CD8+ cytotoxic T cells expressing granzyme B and perforin, persisted in HIV(+) allo-HSCT recipients at all time points, but not in HCs. 3) NK cells retained an ability to produce IFNʏ in response to stimulation with IL-12 and IL-18 in HIV(+) allo-SCT recipients. 4) Monocytes showed an enhanced production of TNFα in response to stimulation with LPS in HIV(+) allo-HSCT recipients compared to HCs at 1 year post-HSCT. Conclusion. Chronic HIV infection confers the pro-inflammatory immune features on the phenotypic and functional profiling of the T lymphocyte immunome of stem cell transplant recipients, irrespective of allogeneic or autologous stem cell donor source. Disclosures Devine: Bristol Myers: Other: Grant for monitoring support & travel support; Kiadis Pharma: Other: Protocol development (via institution); Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Noy:Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Hofmeister:Celgene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Navarro:Atara Biotherapeutics: Employment, Equity Ownership. Behbehani:Fluidigm corporation: Other: Travel funding. Lozanski:Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding; Genentec: Research Funding. Baiocchi:Prelude: Consultancy.

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Impact of Novel Agents on the Outcomes of Patients with Classic Hodgkin Lymphoma That Relapsed after Autologous Stem Cell Transplant

Blood ◽

10.1182/blood-2021-154038 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1373-1373

Author(s):

Aung M Tun ◽

Yucai Wang ◽

Aasiya Matin ◽

David J. Inwards ◽

Patrick B. Johnston ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Advisory Board ◽

Novel Agents ◽

Survival Outcomes ◽

Cell Transplant ◽

Advisory Committees ◽

Scientific Advisory

Abstract Introduction: Novel therapeutic agents such as immune checkpoint inhibitor (ICI) and brentuximab vedotin (BV) are active in classic Hodgkin lymphoma (cHL), including in patients that relapse after autologous stem cell transplant (ASCT). However, optimal management strategy is unclear for patients with relapsed or refractory (RR) cHL post-ASCT. The aim of the study is to determine the impact of novel agents relative to conventional therapy and allogeneic stem cell transplant (allo-SCT) on survival outcomes of patients with cHL who relapsed after ASCT. Methods: Patients with RR cHL who underwent ASCT between 06/1993 and 10/2017 at 3 Mayo Clinic sites were included. Clinical characteristics, treatment information, and outcome data were abstracted. For patients who relapsed after ASCT, the post-relapse progression free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox proportional hazards models. Statistical analyses were done in JMP v15.2.1 and EZR v1.54. Results: A total of 332 patients with RR cHL who underwent salvage therapy and ASCT were identified. After a median post-ASCT follow-up of 8.6 years (range 6.8-9.7), 136 (41%) patients had a relapse or disease progression after ASCT. Patient characteristics of the 136 cases are summarized in the Table. The median age at post-ASCT relapse was 34 years (range 20-73), and 77 (57%) were male. 59 (43%) relapsed within 6 months and 77 (57%) relapsed after 6 months following ASCT. 59 (45%) had an extranodal site involvement at relapse. 14 (10%) had therapy with ICI or BV as salvage therapy prior to ASCT or maintenance therapy post-ASCT. The median post-relapse PFS and OS was 0.8 (95% CI 0.6-1.1) and 3.2 years (95% CI 2.2-5.5) years, respectively. Compared to patients who relapse after 6 months, patients who relapsed within 6 months of ASCT had worse post-relapse PFS (median 0.5 [0.3-0.7] vs 1.3 [0.9-1.9] years, p=0.0003) and OS (median 1.3 [0.5-2.2] vs 6.4 [3.7-10.4] years, p=0.0003). Extranodal site involvement at relapse was not associated with post-relapse PFS (median 0.7 [0.5-1.2] vs 0.9 [0.6-1.3] years, p=0.28) but was associated with worse post-relapse OS (median 2.7 [1.5-4.2] vs 6.4 [2.6-NA] years, p=0.006). Prior therapy with ICI or BV was not associated with post-relapse PFS (median 0.6 [0.3-NA] vs 0.8 [0.6-1.1] year, p=0.8) and OS (median NR [1.0-NA] vs 3.2 [2.2-5.5] years, p=0.5). After post-ASCT relapse, the median lines of subsequent therapy were 2 (range 1-12). For first post-ASCT salvage therapy, novel agents (ICI or BV), compared to other therapies, were associated with superior post-relapse PFS (median 1.7 [0.7-3.6] vs 0.7 [0.5-1.0] years, p=0.004) and OS (median 7.6 [4.7-NA] vs 3.2 [2.2-5.6], p=0.02). Allo-SCT following first post-ASCT relapse (n=9) was not associated with improvement in post-relapse PFS (median 2.2 years [0.3-NA] vs 0.8 [0.6-1.1] years, p=0.1) or OS (median NR [0.5-NA] vs 5.1 [3.2-7.3] years, p=0.7). Patients who received ICI or BV at any point post-ASCT relapse had significantly better post-relapse OS (median 7.6 [4.3-16.7] vs 2.2 [1.4-3.7] years, p=0.004) compared to those who never received any novel agent (Figure 1A). In contrast, allo-SCT at any point post-ASCT relapse (n=27) did not improve post-relapse OS (median 5.6 [2.7-NA] vs 4.7 [2.7-7.3] years, p=0.3) (Figure 1B). In multivariate Cox regression models adjusted for age and sex, exposure to ICI and/or BV was associated with superior post-relapse OS (HR 0.5, 95% CI 0.3-0.8, p=0.007); however, allo-SCT was not associated with improvement in post-relapse OS (HR 0.8, 95% CI 0.4-1.5, p=0.5). Conclusions: Patients relapsing within 6 months of ASCT and those with extranodal involvement at relapse had inferior OS after post-ASCT relapse. Prior therapy with novel agents did not impact post-relapse survival outcomes. In the setting of post-ASCT relapse, novel therapeutic agents significantly improved survival outcomes while allo-SCT did not. Future multicenter studies are needed to explore the role of novel agents and allo-SCT in patients with RR cHL post-ASCT relapse. Figure 1 Figure 1. Disclosures Wang: Eli Lilly: Membership on an entity's Board of Directors or advisory committees; InnoCare: Research Funding; MorphoSys: Research Funding; Genentech: Research Funding; Novartis: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Paludo: Karyopharm: Research Funding. Tun: Gossamer Bio, Acrotech: Consultancy; Mundipharma, Celgene, BMS, Acrotech, TG therapeutics, Curis, DTRM: Research Funding. Cerhan: Regeneron Genetics Center: Other: Research Collaboration; Genentech: Research Funding; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; NanoString: Research Funding. Habermann: Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Incyte: Other: Scientific Advisory Board; Seagen: Other: Data Monitoring Committee; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Nowakowski: Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, NanoString Technologies, MorphoSys: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding.

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Prognostic Impact of CD3 Count in Apheresis Collection in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplant

Blood ◽

10.1182/blood-2021-151439 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3774-3774

Author(s):

Marcella Kaddoura ◽

Morie A. Gertz ◽

David Dingli ◽

Francis K. Buadi ◽

Martha Q. Lacy ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Prognostic Impact ◽

Cell Transplant ◽

Immune Competence ◽

Advisory Committees ◽

Stem Cell Collection

Abstract Background: The use of immunotherapeutic agents in multiple myeloma (MM) has shown improvements in clinical outcomes, emphasizing the role the host immune system plays in disease control. In recognition of this relationship, efforts aimed at identifying biomarkers of immune surveillance in MM have identified prognostic value in the peripheral absolute lymphocyte (ALC) and absolute monocyte (AMC) counts at various stages of disease and following autologous stem cell transplant (ASCT), with lower ALC and AMC serving as a surrogate for immune dysregulation and correlating with inferior progression free (PFS) and overall survival (OS). With ASCT remaining the standard of care in the treatment of MM, we sought to examine whether CD3 content of the apheresis product during stem cell collection could be used as a biomarker for immune competence and whether it influences outcomes. Methods: A retrospective study was conducted on 1086 MM patients who underwent stem cell (CD34) collection with available CD3 data and subsequent ASCT at our institution. We recorded the total absolute CD3 and CD34 cell count upon completion of mobilization, with a higher CD3 count serving as a surrogate for immune competence. In addition to investigating the absolute CD3 count, we calculated the CD3/CD34 ratio given variation in the CD34 goals. Patients were dichotomized based on whether their absolute CD3 and CD3/CD34 ratio values were above or below medians. A Kaplan-Meier model was used to compare median PFS and OS between groups. A cox proportional hazards model was used to determine its prognostic impact, adjusting for ISS stage 3, high risk FISH, achievement of CR near day 100, and maintenance therapy received post-ASCT. Results: The median length of follow-up from date of ASCT for the entire cohort (N=1086) was 34.1 months (range: 0.26-157 months) and the median time from stem cell collection to ASCT was 9 days (range: 3-3143 days). The most common mobilizing regimen was Neupogen and plerixafor (N=425, 39%) and 694 (64%) patients received ASCT in the first line setting. The median absolute total CD3 count was 4.3 x 10^6/kg (range: 0.1-21.9) with 542 patients above and 544 patients at or below the median. The median absolute total CD34 count was 8.53 x 10^6/kg (range: 0.2-37.0) and median CD3/CD34 ratio was 0.50 (range: 0.01-15), with 536 patients above and 550 patients at or below the median ratio. The median PFS among patients with a CD3 count > 4.25 x 10^6/kg was 23.1 vs. 16.9 months among patients with CD3 count ≤ 4.25 x 10^6/kg (p<0.0001) and median OS was 65.3 months vs. 41.6 months (p<0.0001), respectively. A similar trend was observed when dividing patients based on CD3/CD34 ratio, with median PFS of 22.4 vs. 17.5 months (p=.0003) and median OS of 61.5 vs. 45.7 months (p=.0001), both favoring the cohort with a CD3/CD34 ratio > 0.5 (Figure 1). The prognostic value among patients with a CD3/CD34 ratio > 0.5 was retained after adjusting for ISS stage III, high risk FISH features, and use of maintenance therapy as follows: PFS HR: 0.73 (95% CI: 0.62-0.86; p=0.0002); OS 0.71 (95% CI: 0.59-0.88; p=0.001). Conclusions: Our study demonstrates that patients who have higher CD3 content in their apheresis product have better PFS and OS following ASCT. These findings reveal a possible role for using absolute CD3 and CD3/CD34 ratios in the apheresis product as a surrogate marker for immune competence and in predicting clinical outcomes. Figure 1 Figure 1. Disclosures Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Ionis Pharmaceuticals: Other: Advisory Board. Dingli: GSK: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Alexion: Consultancy; Apellis: Consultancy; Novartis: Research Funding. Dispenzieri: Takeda: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Sanofi: Research Funding; Takeda: Research Funding; Ichnos Sciences: Research Funding; Glaxo SmithKline: Research Funding; Regeneron Pharmaceuticals: Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding. Kumar: Novartis: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; BMS: Consultancy, Research Funding; Oncopeptides: Consultancy; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

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Bortezomib Maintenance (BM) Versus Consolidation (BC) Following Aggressive Immunochemotherapy and Autologous Stem Cell Transplant (ASCT) for Untreated Mantle Cell Lymphoma (MCL): CALGB (Alliance) 50403

Blood ◽

10.1182/blood.v126.23.337.337 ◽

2015 ◽

Vol 126 (23) ◽

pp. 337-337 ◽

Cited By ~ 20

Author(s):

Lawrence D. Kaplan ◽

Sin-Ho Jung ◽

Wendy Stock ◽

Nancy L. Bartlett ◽

Brandelyn Pitcher ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Post Treatment ◽

Study Entry ◽

Patient Specific ◽

Cell Transplant ◽

Advisory Committees ◽

Post Transplant ◽

Equity Ownership

Abstract Introduction: Aggressive chemo-immunotherapy followed by peripheral blood stem cell autografting (ASCT) in CALGB 59909 achieved a median progression-free survival (PFS) in MCL of 5 years (Damon et al JCO, 2009), but late recurrences occurred. Bortezomib has a 33% response rate in relapsed/refractory MCL. Using the CALGB 59909 treatment backbone, we evaluated tolerability and efÞcacy of adding post-transplant BC or BM in a randomized phase II trial. Methods: The primary endpoint was PFS estimated from study entry for each treatment arm. Induction therapy was with 2-3 cycles of augmented R-CHOP (2000 mg/m2 cyclophosphamide) and methotrexate (300 mg/m2) followed by high-dose cytarabine/etoposide/rituximab(R)/Þlgrastim (EAR) stem cell mobilization and cyclophosphamide/carmustine/etoposide (CBV) ASCT. After 2 doses of post-transplant R, patients were randomized to BC (1.3 mg/ m2 days 1, 4, 8, 11 of a 3 week cycle for 4 cycles) or BM (1.6 mg/m2 weekly 4 of 8 weeks for 18 months) beginning at approximately day 90. Minimal residual disease (MRD) was analyzed using patient-specific PCR probes for the bcl-1 / IgH junction or the IgH CDR3 region. Results: 151 patients were enrolled at 14 sites and 147 received treatment. Median age was 59 (29-69); stage II (2.7%), III (12%), IV (86%); MIPI low (52.4%), int. (30.6%), high (17%); blastoid histology (14%); bone marrow involvement (81%). 118 (88%) underwent ASCT and 102 (68%) were randomized. Most withdrawals (45) were for progression (10) or adverse events (AEs) (19) including 4 treatment-related deaths. Following randomization, 34 (65%) completed BM and 33 (66%) completed BC. Withdrawal for AEs occurred in 14 (28%) of BC and 7 (13%) of BM patients (p = 0.088), most for cytopenias or peripheral neuropathy. Median follow-up was 5.5 years from registration. Median PFS was significantly greater than the null hypothesis (4 years) for both BM and BC (1-sided test of exponential parameter p < 0.001). The 5-year PFS estimates from study entry in the BM and BC arms were 70% (55-81%) and 69% (54-80%), respectively. Progression occurred in 17 BM (12 post-treatment) and 19 BC patients (all post-treatment). Five-year PFS from time of transplantation in CALGB studies 50403 (n=118) and 59909 (n=66) was 72.7% (63-80%) and 51.5% (36.7-62%), respectively (log rank p=0 0006) favoring the 50403 trial which differed from 59909 only by the addition of post-transplant bortezomib. MRD results were available in 47 patients. Five-year PFS from study entry was 93% if MRD-negative (n=15) and 51% if MRD-positive (n=32) following induction chemo-immunotherapy (log rank p=.003) (See figure). Conclusions: Induction chemotherapy followed by ASCT and either BC or BM was efficacious and tolerable, although BC was associated with more withdrawals for toxicity. The comparison between studies 50403 and 59909 suggests a PFS benefit from the addition of BC or BM. MRD-negativity following induction chemo-immunotherapy is highly associated with improved PFS and could provide an important tool for designing future trials. Figure 1. Figure 1. Disclosures Off Label Use: Post-autotransplant use of bortezomib . Bartlett:Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy; Janssen: Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Research Funding; ImaginAB: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Medimmune: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Byrd:Acerta Pharma BV: Research Funding. Blum:cephalon: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding. Hurd:Procter and Gamble: Equity Ownership; Medtronic: Equity Ownership; Pfizer: Equity Ownership; Merck: Equity Ownership; Bristol Myers Squib: Equity Ownership. Czuczman:MorphoSys: Consultancy; Cellgene: Employment; Immunogen: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees. Leonard:Weill Cornell Medical College: Employment; Genentech: Consultancy; Medimmune: Consultancy; AstraZeneca: Consultancy; Spectrum: Consultancy; Boehringer Ingelheim: Consultancy; Vertex: Consultancy; ProNAI: Consultancy; Biotest: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Mirati Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy. Cheson:AstraZeneca: Consultancy; Astellas: Consultancy; Ascenta: Research Funding; Spectrum: Consultancy; Teva: Research Funding; MedImmune: Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

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Risk-Adapted Melphalan and Stem Cell Transplant for Systemic Light Chain Amyloidosis: A Single Institution Experience.

Blood ◽

10.1182/blood.v120.21.3109.3109 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3109-3109 ◽

Cited By ~ 2

Author(s):

Heather Landau ◽

Daniel E Fein ◽

Hani Hassoun ◽

Christina Bello ◽

Joanne F Chou ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Stem Cell Transplant ◽

Novel Agents ◽

Cell Transplant ◽

Advisory Committees ◽

Related Mortality

Abstract Abstract 3109 Background: High dose melphalan (MEL) is a standard treatment for eligible patients with AL, a disease in which hematologic response is a key determinant of survival. With the advent of novel agents the role of stem cell transplant (SCT) for patients with AL is being questioned, especially given safety concerns. Yet with appropriate patient selection and the use of risk-adapted SCT (RA-SCT), treatment-related mortality (TRM) improved.(Br J Haem 2007;139:224; Bone Marrow Transplantation 2011; 46:970) Moreover, beginning in 2002, we showed in 2 consecutive phase II trials that following RA-SCT patients can safely receive consolidation with thalidomide and dexamethasone (TD) or bortezomib and D (BD), with the goal of improving hematologic response thereby extending overall survival (OS).(Br J Haem 2007;139:224; Amyloid 2010;17:80a) Consolidation was administered for patients achieving less than a complete response (CR). We now describe the outcomes of all patients with AL who underwent RA-SCT at Memorial Sloan-Kettering Cancer Center (MSKCC) since the year 2000. Methods: We performed a retrospective study to assess the OS of all patients who underwent SCT for a diagnosis of AL confirmed at MSKCC. Patients who had >2 major organs involved, NYHA class III or greater CHF, critical arrhythmias or cardiac syncope were ineligible for SCT. OS was calculated from transplant to date of death or last follow up. Median survival was estimated by Kaplan Meier methods. Log-rank test was used to determine whether survival functions differed by covariates of interest. Cumulative incidence function was used to estimate the incidence of cause-specific mortality. Results: A total of 151 patients underwent RA-SCT between February 2000 and June 2011; three lost to follow-up are excluded from this analysis. Of the remaining 148 patients 21%, 52% and 34% received RA-SCT at 100, 140 and 200mg/m2 of melphalan respectively based on age, renal function and cardiac involvement.(Blood 2002; 99: 4276) Five patients died within 100 days of SCT (TRM 3.4%). At a median follow up of 6.7 years, the median OS for all patients is 11.1 years (95% CI, 7.32 - not reached-NR) (Figure 1), and for patients who received MEL 100, 140 or 200 is 4.4 (95% CI, 2.7 – 6.3), NR and 11 years (95% CI, 8.2 – NR) respectively (P = <0.01). Cumulative incidence of disease related mortality at 2 years is 5.5%, and subsequently the rate of death from other causes exceeds that due to AL (Figure 2). Conclusions: RA-SCT for appropriately selected patients is safe and is associated with excellent long-term survival. Consolidation with novel agents may improve survival following RA-SCT and likely accounts for the similar OS seen in patients who received MEL 140 and 200. In the era of novel agents available for post-SCT consolidation, RA-SCT is an effective and important initial treatment for patients with AL. Disclosures: Landau: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding. Hassoun:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Giralt:Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Comenzo:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Outcomes after Autologous Stem Cell Transplant in Patients with Relapsed Multiple Myeloma

Blood ◽

10.1182/blood-2020-137091 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-12

Author(s):

Christopher Lemieux ◽

Juliana Craig ◽

David Iberri ◽

Sally Arai ◽

Laura J. Johnston ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Private Company ◽

Advisory Committees ◽

First Relapse ◽

Support Research

Introduction: Given similar overall survival (OS) seen in patients receiving delayed vs. early autologous stem cell transplant (ASCT) in multiple myeloma (MM), some patients are electing to proceed with transplant at relapse instead of with upfront therapy. However, there is limited data in the era of novel therapies on expected disease control and outcomes in MM when ASCT is done for relapsed disease. The objective of this single-center retrospective study was to evaluate the outcomes of ASCT in patients with relapsed MM. Methods: Between January 1, 2010, and November 31, 2019, 168 consecutive patients with relapsed MM received ASCT at our center and constitute the study cohort. Progression free survival (PFS) was estimated from start of therapy at relapse until progression or death. PFS-PRIOR represents PFS of the immediate prior line of therapy before current relapse for which ASCT was pursued. OS was estimated from start of therapy at relapse and also from diagnosis until death. Results: Of the 168 patients, the majority underwent transplant in first relapse (69%, n=116) and the majority had not received a prior transplant (80%, n=135). Baseline and treatment characteristics of the cohort are shown in Table 1. High-risk cytogenetics were seen in 27% and ISS stage III disease in 15%. Median PFS-PRIOR was 20 months (range 2-228). The induction regimen used before ASCT included a doublet in 32%, a triplet in 56%, a quadruplet in 1.5% and a chemotherapy-based regimen in 9% of patients. Stem cell collection was done after relapse in 72% of the cohort. Conditioning regimen included melphalan 200 mg/m2 in 90% patients, including melphalan 200 mg/m2+BCNU in 55%. Median time to neutrophil and platelet engraftment was 11 and 16 days, respectively. Response after ASCT was very good partial response or better in 82% (n=124) of patients. Maintenance therapy was given in 35% (n=56) of patients after ASCT, with 73% patients receiving IMiD maintenance and a median duration of maintenance of 7 months (range 1-41). Survival: Median follow-up of this cohort was 61 months. Median PFS from start of treatment was 28 months. Median OS from start of treatment was 69 months and from diagnosis was 118 months. Two patients (1%) died within the first 3 months of complications related to transplant. As expected, patients who received ASCT at first relapse had a longer PFS of 33 months compared to 22 months when the transplant was done at second or later relapse, p=0.003 (Fig. 1A). OS from treatment start in patients undergoing transplant at first relapse was 82 months and those undergoing ASCT at second or later relapse was 45 months, p=0.004 (Fig. 1B). However, there was no difference in OS from diagnosis in these two groups (118 vs 134 months, p=0.97). Subgroup analysis was done in patients undergoing transplant at first relapse. Patients who had a PFS-PRIOR of ≥36 months had OS of 91 months compared to 62 months for those who experienced a shorter PFS-PRIOR, p=0.03. PFS in the subgroup of patients without prior ASCT undergoing transplant in first relapse (N=96) was 30 months. Multivariate Cox proportional hazards analysis was done for PFS and OS incorporating the following covariates: high risk cytogenetics, Karnofsky performance status (KPS), relapse number, PFS-PRIOR ≥36 months, response at ASCT, and use of maintenance. ASCT in first relapse was associated with better PFS with a hazard ratio (HR) of 0.63 (95% CI 0.42-0.94, p=0.03) and OS (HR 0.59, 95% CI 0.35-0.99, p=0.04). Achieving a PFS-PRIOR of ≥36 months was associated with improved PFS (HR 0.62, 95% CI 0.39-0.99, p=0.04) and OS (HR 0.41, 95% CI 0.21-0.82, p=0.01). Better KPS was also associated with longer PFS (HR 0.61, 95% CI 0.41-0.91, p=0.01) and OS (HR 0.52, 95% CI 0.31-0.86, p=0.01). Progressive disease at transplant was, as expected, associated with worse PFS (HR 3.28, 95% CI 1.89-5.70, p<0.001) and OS (HR 2.70, 95% CI 1.39-5.22, p=0.003). Conclusions: This study provides comprehensive data on expected outcomes and prognostic factors amongst patients with MM undergoing ASCT at relapse, with median PFS and OS being 28 and 69 months in a cohort where only a third of patients received maintenance therapy. Disease response at transplant, PFS-PRIOR and KPS were prognostic for survival. These data can serve as a guide when counseling patients undergoing ASCT for relapsed MM and also serve as benchmark in designing clinical trials of transplant and comparative novel therapies for relapsed MM. Disclosures Muffly: Amgen: Consultancy; Adaptive: Research Funding; Servier: Research Funding. Shiraz:Kite, a Gilead Company: Research Funding; ORCA BioSystems: Research Funding. Liedtke:Adaptive: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; 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; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees. Rezvani:Pharmacyclics: Research Funding. Meyer:Orca Bio: Research Funding. Shizuru:Jasper Therapeutics, Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Negrin:Biosource: Current equity holder in private company; Magenta Therapeutics: Consultancy, Current equity holder in publicly-traded company; BioEclipse Therapeutics: Current equity holder in private company; UpToDate: Honoraria; KUUR Therapeutics: Consultancy; Amgen: Consultancy. Miklos:Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding. Sidana:Janssen: Consultancy.

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