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

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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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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Safety and Clinical Activity of Atezolizumab (Anti-PDL1) in Combination with Obinutuzumab in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood.v126.23.5104.5104 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5104-5104 ◽

Cited By ~ 10

Author(s):

Brian G. Till ◽

Steven I. Park ◽

Leslie L. Popplewell ◽

Andre Goy ◽

Elicia Penuel ◽

...

Keyword(s):

Monoclonal Antibody ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Clinical Activity ◽

Cell Transplant ◽

Advisory Committees ◽

Grade 3

Abstract Introduction: Despite modern chemo-immunotherapy regimens, the outcomes for patients with relapsed or refractory diffuse-large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) remain poor, and more effective therapies are sorely needed. Immune checkpoint inhibitors (anti-PDL1 or anti-PD-1) represent a novel class of therapeutics with great promise. Atezolizumab (MPDL3280A) is a fully humanized IgG1 monoclonal antibody that blocks the interaction between PD-L1 and its receptors PD-1 and B7.1, thereby preventing inhibition of T-cell activity. Clinical activity of atezolizumab has been seen in multiple tumor types, including NHL as monotherapy. Increased PD-L1 expression has been reported in DLBCL and FL on tumor cells, stromal cells and tumor-infiltrating immune cellsand may represent a mechanism of tumor escape from immune surveillance. Obinutuzumab is a next generation anti-CD20 monoclonal antibody with enhanced ADCC activity. The combination of atezolizumab and obinutuzumab has the potential to activate both innate and adaptive immunity to enhance anti-tumor responses in lymphoma. Methods: This multi-center, open-label, Phase Ib (NCT02220842) study is evaluating atezolizumab in combination with obinutuzumab in patients with relapsed or refractory DLBCL or FL. Primary endpoints were safety and tolerability, with secondary endpoints of PK and clinical activity. Key eligibility criteria included measurable disease and treatment with ≥ 1 prior chemo-immunotherapy regimen. Previous autologous stem cell transplant was allowed, but not allogeneic stem cell transplant. During cycle 1, patients received obinutuzumab alone on days 1 (100 mg), 2 (900 mg), 8 and 15 (1000 mg). From cycles 2-8, atezolizumab (1200 mg) and obinutuzumab (1000 mg) were administered on day 1 every 3 weeks. This was followed by atezolizumab consolidation (1200 mg q3 weeks) for an additional 6 months. ORR was assessed by IWG NHL criteria (Cheson et al, J Clin Oncol 2007). Pre-treatment biopsies and on-treatment samples are being collected to determine PD-L1 expression and other biomarkers of response and resistance. Results: As of July 28, 2015, all 6 patients (2 male, 4 female) evaluable for safety have completed at least 4 cycles of therapy. Median age was 68.5 years (range, 58-81 years). Three patients had FL, and 3 patients had DLBCL. The median number of prior therapies was 4 (range, 2-6). All patients have received at least one prior rituximab-containing chemo-immunotherapy regimen. One patient with DLBCL had received a prior autologous stem cell transplant, as well as CD19 CAR T-cell therapy. The median disease burden at baseline was 2717.4 mm2 (range, 990-7247 mm2). The median duration of therapy was 118 days (range, 64-212 days). One dose-limiting toxicity (Grade 3 thrombocytopenia) was observed. Three patients experienced 1 treatment-emergent Grade 3 AE each (thrombocytopenia, ileus, intestinal obstruction). No Grade ≥ 3 infusion-related reactions, Grade 4 or 5 AEs, treatment related deaths or discontinuations due to study treatment have been seen. Responses for 5 patients who have completed the first disease assessment time point are available. Preliminary efficacy evaluation (CT scan) after 4 cycles (3 months) of therapy are as follows: 2 PRs (up to 68.6% reduction; 1 pt with DLBCL and 1 pt with FL), 2 SDs and 1 PD. Three of 4 patients, experiencing SD or better have ongoing clinical benefit. Expansion cohorts in FL and DLBCL are currently enrolling, and updated safety and efficacy data will be presented. Biomarker data will also be discussed. Conclusions: Preliminary results indicate that the combination of atezolizumab and obinutuzumab appears well tolerated with early evidence of activity in patients with heavily pretreated relapsed or refractory DLBCL and FL. Disclosures Till: Roche-Genentech: Research Funding. Park:TEVA: Research Funding; Seattle Genetics: Research Funding; Jannsenn: Other: Travel. Goy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/JNJ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Penuel:Genentech, Inc.: Employment. Venstrom:Genentech: Employment. Liu:Genentech: Employment. Fingerle-Rowson:F.Hoffmann-LaRoche: Employment. Byon:Genentech: Employment. Woodard:Genentech: Employment.

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The Effect of Maintenance Therapy Following Salvage Autologous Stem Cell Transplant in Multiple Myeloma Patients

Blood ◽

10.1182/blood-2018-99-111379 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3439-3439

Author(s):

Brandon B. Wang ◽

Mark A. Fiala ◽

Mark A. Schroeder ◽

Tanya Wildes ◽

Armin Ghobadi ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Advisory Committees ◽

The Impact

Abstract Background: In the current era, autologous stem cell transplant (ASCT) remains an effective form of treatment for patients diagnosed with multiple myeloma (MM), but it is not curative and a relapse is inevitable. A second, or salvage, ASCT provides better outcomes than conventional chemotherapy but it is infrequently used. Maintenance therapy after initial ASCT has been adopted as the standard in the US; however, there is limited data on the effects of maintenance therapy following salvage ASCT and the benefits are still unclear. Methods: We performed retrospective chart review of all patients with MM who received a second, salvage ASCT at time of first relapse at Washington University in St. Louis from 2008 to 2016. We identified two cohorts of patients, those who received maintenance therapy following salvage ASCT and those who did not. Patients who received maintenance therapy post-initial ASCT were excluded as the objective of this study was to determine the impact of maintenance post-salvage ASCT and maintenance post-initial ASCT may confound the results. Results: Sixty-five patients (who underwent second/salvage ASCT) were identified. Three were excluded from the analysis-two had treatment-related mortality following salvage ASCT and one received maintenance other than a proteasome inhibitor (PI) or an immunomodulatory drug (IMID). The maintenance cohort consisted of 31 patients, with 68% (n = 21) males and 32% (n = 10) females; the median age at salvage ASCT was 61 years (range 38-73). The no-maintenance cohort consisted of 31 patients as well with 45% (n = 14) males and 55% (n = 17) females. Their median age at salvage ASCT was 62 years (range 44-74). The characteristics of the two cohorts are summarized in Table 1. Most patients received PIs and/or IMIDs as part of their induction regimens prior to initial ASCT. All received melphalan conditioning. The response to treatment was similar between the two cohorts, with respective CR rates of 68% (n = 21) and 77% (n = 24) and median progression-free survival (PFS) of 46 months compared to 33 months. Following relapse, 16% (n = 5) of patients in the no-maintenance cohort proceeded directly to salvage ASCT without re-induction. All other patients received re-induction, mostly with PIs and/or IMIDs, with a median of 4 cycles for the maintenance cohort and 2 cycles for the no-maintenance cohort. For conditioning prior to salvage ASCT, 4 patients received Velcade-BEAM conditioning as part of a prospective trial at our site (NCT01653418); 3 from the maintenance cohort and 1 from the no-maintenance cohort. The rest received melphalan conditioning. Both cohorts had a CR rate of 52% (n = 16) post-salvage ASCT. Maintenance therapy after salvage ASCT consisted of lenalidomide (74%, n = 23), bortezomib (23%, n = 7), or pomalidomide (3%, n = 1). Three of the patients on bortezomib were originally started on lenalidomide but were switched due to intolerance. At time of data collection, the median follow-up was 49 months (range 9-105) for the maintenance cohort and 61 months (range 19-113) for the no-maintenance cohort. 45% (n = 14) of patients in the maintenance cohort and 90% (n = 28) of the no-maintenance cohort had relapsed. In the maintenance cohort, PFS following salvage ASCT was similar to what was observed following initial ASCT. The median estimated PFS post-salvage ASCT was 53 months (95% CI 42-64) compared to 46 months post initial ASCT (p = 0.144). Conversely, in the no-maintenance cohort PFS following salvage was only about 60% that of initial ASCT (21 months [95% CI 18-24]; compared to 33 months; p = 0.002). Conclusion: These results suggest that maintenance following salvage ASCT is associated with improved outcomes. Although patients who received maintenance post-initial ASCT were excluded, the benefits of maintenance post-salvage ASCT may extend to them as well. Ongoing prospective clinical trials will further clarify these benefits. Disclosures Schroeder: Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wildes:Janssen: Research Funding. Vij:Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: 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, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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

Blood ◽

10.1182/blood-2021-149297 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4833-4833

Author(s):

Mateo Mejia Saldarriaga ◽

Yassine Tahri ◽

Sangmin Lee ◽

Zhengming Chen ◽

Tsiporah B. Shore ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Cell Transplant ◽

Allogeneic Stem Cell Transplant ◽

Advisory Committees ◽

Post Transplant ◽

Idh Mutations

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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Elotuzumab As Post-Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Myeloma

Blood ◽

10.1182/blood-2019-129504 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3141-3141 ◽

Cited By ~ 2

Author(s):

Nikhita Gadi ◽

Linda Schmidt ◽

Jaeil Ahn ◽

Tianmin Wu ◽

Scott D. Rowley ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Advisory Committees ◽

Ultra High Risk ◽

Equity Ownership ◽

Baseline Characteristics

Introduction: Patients (pts) with high-risk multiple myeloma (HRMM) experience early disease progression post autologous stem cell transplant (ASCT). The median progression free survival (PFS) for HRMM pts undergoing ASCT with lenalidomide (len) maintenance ranges between 27 and 42 months in high risk pts and 22 months in ultra-high risk, defined by two or more adverse cytogenetic abnormalities such as: gain(1q), t(4;14), t(14;16),t(14;20), or del(17p)( Chakraborty et al, Leukemia,2018 and Jackson et al, Lancet, 2018). Elotuzumab, a humanized IgG kappa monoclonal antibody against SLAM-F7 (CS-1), is approved in combination with len and dexamethasone (ERd) in pts with relapsed MM (Dimopoulus et al, BJH, 2017). It directly activates natural killer (NK) cells and mediates myeloma cell death by antibody-dependent cell mediated cytoxicity. We hypothesized that administration of ERd as post-ASCT consolidation will enhance an immune-competent phenotype, by restoring NK cells and effector T-cell populations at a time of maximal disease de-bulking, and will ultimately improve outcomes among pts with HRMM. Methods: Thirty-one HRMM patients who achieved stable disease or better were treated beginning at 30-90 days post ASCT with ERd (29/31 pts) or elotuzumab/pomalidomide )/dex (EPd) (2/31 pts) between September 2016 and February 2019. With institutional review board approval, electronic medical records were reviewed for baseline characteristics, treatment history, adverse events (AE) while on therapy as defined by common terminology criteria for adverse events (CTCAE), and survival outcomes. Treatment with ERd or EPd was administered for 4 consecutive 28-day cycles per standard dosing regimens with a tapering or discontinuation of corticosteroids per investigator discretion with cycles 3 and 4. HRMM was defined by any of the following: ISS or Revised-ISS stage 3, CD-138 selected FISH with del 17p, 1q21 gain, t(4;14), t(14;16), and t(14;20), cytogenetics with 13q del or complex karyotype, and/or high-risk gene expression profile score. Ultra-HR pts were defined by having both del 13q and 1q21 gain by FISH based on recent unpublished COMPASS data. Minimal residual disease (MRD) was evaluated upon achievement of very good partial remission or complete remission using 10-color multiparametric flow cytometry. PFS was measured using the log-rank test. Response criteria was defined per International Myeloma Working Group criteria. Results: Baseline characteristics of all 31 patients are shown in Table 1. Thirty-four percent were ISS-3, 71% (22/31 pts) had high-risk FISH, of which 19% were ultra-high risk (6/22 pts). Seven pts (22.6%) underwent tandem-ASCT pre-consolidation. Of the 8 pts who had GEP testing, 2 (25%) were high risk. Best response to treatment by cycle is depicted in Table 2. Consolidative ERd/EPd deepened response compared to post-ASCT with 71.4% vs 19.4% achieving stringent complete remission (sCR). Post-consolidation, 19.3% vs 12.9%, pre-consolidation, achieved MRD negativity. With a median follow-up of 24.8 months, median PFS was 31.4 months (Figure 1). There was no significant association between median PFS and variables such as tandem ASCT and ultra-HR using multivariate cox regression. Although all pts experienced at least one AE while on therapy, only 1 patient (3.22%) experienced a grade 3 AE. Hematologic AEs included: anemia (48%), neutropenia (45%), and thrombocytopenia (52%), while the most common non-hematologic AEs included: fatigue (32%), malaise (23%), and back pain (19%). One patient experienced a serious AE (SAE) which was PCP pneumonia requiring hospitalization, resulting in early discontinuation from therapy. There was no treatment-related mortality. Conclusion: ERd or EPd as 4 months of fixed duration consolidation therapy post-ASCT resulted in a median PFS of 31.4 months amongst pts with HRMM, similar to or perhaps surpassing historical reports of HRMM pts receiving lenalidomide maintenance until progression. This therapy may offer comparable, if not superior, outcomes while having the advantage of allowing for significant time without therapy and perhaps improving quality of life and financial toxicity. This study is limited due to its retrospective nature. Larger prospective studies evaluating fixed duration ERd/EPd in HRMM patients post ASCT should be conducted. Disclosures Rowley: Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Goldberg:COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership. Siegel:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Biran:Bristol Meyers Squibb: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Merck: Research Funding.

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Phase II Study Of The Combination Of MLN 9708 With Lenalidomide As Maintenance Therapy Post Autologous Stem Cell Transplant In Patients With Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.1983.1983 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1983-1983 ◽

Cited By ~ 1

Author(s):

Jatin J. Shah ◽

Veera Baladandayuthapani ◽

Donna M. Weber ◽

Sheeba K. Thomas ◽

Raymond Alexanian ◽

...

Keyword(s):

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Phase Ii Study ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Newly Diagnosed ◽

Time To Progression ◽

Advisory Committees

Abstract Background The role of lenalidomide for maintenance after myeloblative therapy and autologous stem cell transplant (ASCT) has been established based on the CALBG 100104 and IFM 2005-02 experience. Continuous low dose lenalidomide demonstrated a significant benefit in progression free survival (PFS), time to progression (TTP) in both trials and the CALBG trial also demonstrated a benefit in early overall survival. The benefit in PFS with lenalidomide is preserved in patients with high risk cytogenetics and in complete remission after ASCT. Proteaseome inhibitors (PI) have been studied after ASCT in a hybrid consolidation/maintenance model with a predefined course of bortezomib-based therapy, which was well tolerated and led to a significant improvement in response rates and in PFS. However long term proteasome inhibitor maintenance therapy has been limited by the route of administration. The combination of PIs and immunomodulatory agents (IMiDs) have a strong preclinical rationale, and their activity has been confirmed with high response rates in various combinations in both newly diagnosed and relapsed/refractory myeloma. MLN9708, an oral PI, may be more convenient as an oral therapy to be studied in the maintenance setting. Here we report preliminary data from a pilot study of the combination of MLN9708 and lenalidomide as maintenance therapy post ASCT. Methods This is a single arm phase II study with the primary objective to establish the safety and efficacy (PFS) of MLN 9708 (Ixazomib) and lenalidomide in the maintenance setting post ASCT. The secondary objectives were to evaluate the incidence of secondary primary malignancy, the best response rate (sCR/nCR/VGPR/PR), time to progression and time to next therapy. Patients must have undergone ASCT with melphalan as a preparative regimen within 12 months of initiation of induction for newly diagnosed myeloma. Patients started maintenance therapy 60-180 days post ASCT. Treatment consisted of 28 day cycles of oral MLN9708 4 mg on days 1, 8, 15, and oral lenalidomide 10 mg daily on days 1-28 with a dose increase to 15 mg after 3 months if tolerating well. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria. Results A total of 16 patients have been enrolled with a median age of 60 years (range 51-74); 12/16 patients were male. 6 patients had ISS stage 1, 2 patients had stage II, 5 patients had stage III, and 3 had an unknown stage. 14 of the patients remain on trial, 2 patients have discontinued maintenance therapy. 1 patient with high risk disease, including del17p, del 13 discontinued due to rapidly progressive disease during cycle 2; 1 patient discontineud due to hospitalization for bilateral pneumonia. 3 patients had a treatment related SAE including 2 patients with PNA, 1 pt with G2 dehydration requiring hospitalization. 5 patients required a dose reduction in MLN9708 or lenalidomide due to G3/4 thrombocytopenia (n=2); dose delays for thrombocytopenia/neutropenia (n=3); one patient also had concurrent grade 3 rash. Hematologic toxicity included 3/16 patients with G3/4 thrombocytopenia, 9/16 with G1/2 thrombocytopenia, 5/16 patients with G3 neutropenia and 6/16 patients with G1/2 neutropenia. G3/4 drug-related non-hematologic AEs occurring in >1/16 of patients were limited to 2 patients with G3 creatinine elevation (in the setting of hospitalization for pneumonia). Additional non-hematologic G1/2 events included 9/16 patients with nausea, 5/16 with diarrhea, 9/16 with constipation, 4/16 with emesis, 6/16 patients with G1 rash; 1 pt with worsening of baseline G1 neuropathy. Conclusions The combination of MLN9708 and lenalidomide as maintenance therapy post ASCT for NDMM is a well-tolerated combination. 14/16 patients remain on study with only 1 patient discontinuing due to toxicity (pneumonia). The preliminary experience demonstrates the combination is safe, feasible and well tolerated with minimal toxicity and no unexpected toxicity. Disclosures: Shah: Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Off Label Use: This abstract describes bortezomib + rituximab as 1st line induction therapy for patients with Waldenstrom macroglobulinemia. Thomas:Millenium: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Wang:Onyx: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Qazilbash:Otsuka Pharmaceuticals: Research Funding. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: 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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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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