Outcomes of Allogeneic Hematopoietic Cell Transplantation in Adults with Ph-like ALL

Abstract Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) represents 20% of newly diagnosed adults with B cell ALL (B-ALL), with increased frequency in adults with Hispanic ethnicity. Ph-like ALL harbors a diverse range of genetic alterations with CRLF2-rearrangement/overexpression (CRLF2r) being the most common one. When treated with chemotherapy, Ph-like ALL is associated with inferior response, high relapse rate, and low overall survival (OS). Allogenic hematopoietic cell transplantation (alloHCT) is a well-established curative modality for adults with high-risk ALL. Considering that Ph-like ALL is a high-risk leukemia subtype, it is appealing to recommend alloHCT consolidation routinely for this entity in adults. However, large datasets describing alloHCT outcomes in patients with Ph-like ALL is lacking. In this study, we retrospectively analyzed archived DNA samples from 125 consecutive adult patients with Ph-negative ALL who underwent alloHCT in complete remission (CR) at our center between 2006 and 2020. Classification of Ph-like versus non-Ph-like was performed according to WHO 2017 classification using accumulative results from RNAseq, conventional cytogenetics, FISH, and whole genome array studies. A proprietary RNA sequencing assay covering 1,188 genomic regions from 235 genes was designed to detect all the clinically significant fusions and expressions for Ph-like ALLs. In addition, an algorithm employing the RNAseq data was developed to further aid in classification of Ph-like ALL. Boruta feature selection (R package "Boruta" version 7.0.0) was used to identify the most informative genes for prediction with an out-of-bag error of 9.62%. The following 24 genes were identified: CCND2, SOX11, PAX5, DENND3, RARA, MME, ID4, SH3BP5, HOXA9, CA6, MUC4, CYB5R2, CD97, EPOR, IL2RA, RAB29, PDGFRA, MLLT4, RHOA, JAK2, DNM2, ASXL1, BCL2A1, and KDR. The results were used to predict Ph-like status by a Random Forest model (R package "randomForest" version 4.6-14) that generates a probability/similarity score of Ph gene expression profile (Ph score). The testing samples with Ph score over 50% and without other subtype-defining lesions are defined as Ph-like. We identified Ph-like genetic alterations in 66 (53%) patients, of whom 42 (66%) were carrying CRLF2r and 24 (36%) were non-CRLF2r. Compared to non-Ph-like ALL (n=59), Ph-like ALL patients were younger (42 vs 36 years old, p=0.022), more frequently Hispanic (56% vs 83%, p=0.003), less frequently carried high-risk cytogenetics (39% vs 9%, p<0.001), more frequently induced with pediatric-inspired regimens (25% vs 61%, p=0.003) and more likely required >1 regimen to achieve their first complete remission (CR1; 30% vs 55%, p=0.025). However, we did not detect any significant difference between the two groups in disease status (CR1 vs. CD2/3; p=0.81) or minimal residual disease clearance at the time of HCT (negative vs. positive; p=0.17), donor type (match related/unrelated vs mismatch vs haplo vs cord blood; p=0.88), conditioning regimen intensity (myeloablative vs non-myeloablative/ reduced intensity; p=0.59), GVHD prophylaxis (tacrolimus/sirolimus-based vs PTCy-based; p=0.84), Karnofsky Performance Status (KPS; p=0.24) or HCT comorbidity index (0 vs 1-2 vs >2; p=0.42). With the median follow-up of 3.2 years, we observed similar 3-years leukemia-free survival (LFS) (40% vs 47%; p=0.95), OS (44% vs 54%; p=0.96), relapse rate (33% vs 34%; p=0.96) and non-relapse mortality (NRM) (27% vs 19%; p=0.92) between non-Ph-like and Ph-like ALL patients, respectively. (Figure) In multivariable analysis, disease status at the time of HCT (HR=2.63, 95% CI: 1.57-4.41; p<0.001), donor type (p=0.049) and KPS (HR=2.22, 95% CI: 1.05-4.69; p=0.038) influenced OS. LFS was significantly influenced by disease status (HR=2.35, 95% CI: 1.45-3.80); p<0.001) and conditioning regimen intensity (HR=1.84, 95% CI: 1.11-3.04; p=0.017). Relapse rate was associated with disease status (HR=2.06, 95%CI: 1.11-3.84; p=0.23) and conditioning regimen intensity (HR=1.97, 95% CI: 1.03-3.75; p=0.40). Only KPS (HR=6.56, 95% CI: 2.48-17.36; P<0.001) was associated with NRM. In conclusion, our data suggest that alloHCT consolidation results in favorable outcomes in adult patients with Ph-like ALL with comparable outcomes to non-Ph-like ALL. Our data support utilization of alloHCT for adults with Ph-like ALL in CR. Figure 1 Figure 1. Disclosures Al Malki: Neximmune: Consultancy; Rigel Pharma: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Hansa Biopharma: Consultancy; CareDx: Consultancy. Khaled: Omeros: Honoraria; Alexion: Honoraria, Speakers Bureau; Janssen: Current Employment; Astellas: Honoraria; Jazz: Honoraria. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Aribi: Seagen: Consultancy. Mei: BMS: Research Funding; Epizyme: Research Funding; TG Therapeutics: Research Funding; EUSA: Honoraria; Janssen: Honoraria; Morphosys: Research Funding; Beigene: Research Funding. Koller: Novartis: Consultancy. Artz: Radiology Partners: Other: Spouse has equity interest in Radiology Partners, a private radiology physician practice. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Marcucci: Abbvie: Other: Speaker and advisory scientific board meetings; Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Pullarkat: AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Amgen, Dova, and Novartis: Consultancy, Honoraria.

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Primary Plasma Cell Leukemia Outcomes Remain Dismal Despite Novel Agents and Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2019-127049 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 266-266

Author(s):

Sagar Patel ◽

Saulius K. Girnius ◽

Binod Dhakal ◽

Lohith Gowda ◽

Raphael Fraser ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Plasma Cell ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Disease Status ◽

Cell Leukemia ◽

Advisory Committees ◽

Primary Plasma Cell Leukemia ◽

Equity Ownership

Background Primary plasma cell leukemia (pPCL) is a rare plasma cell neoplasm with a high mortality rate. There have been improvements in multiple myeloma (MM) outcomes with novel induction agents and use of hematopoietic cell transplantation (HCT) with maintenance, but similar progress has not been reported for pPCL. We examined the outcomes of pPCL patients receiving novel agents with autologous (autoHCT) or allogeneic (alloHCT) approaches as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) in the modern era. Methods From 2008 to 2015, 348 pPCL pts underwent HCT (N = 277 - autoHCT and 71 - alloHCT) with 45% and 48% having research level data available, respectively. Cumulative incidences of non-relapse mortality (NRM) and relapse/progression (REL), and probability of progression-free survival (PFS) and overall survival (OS) were calculated. Cox multivariate regression was used to model survival after autoHCT only. Median follow-up in autoHCT and alloHCT was 48 and 60 months, respectively. Results AutoHCT Cohort Median age was 60 years and 93% received HCT within 12 months of diagnosis with 76% after a single line of induction (Table 1). 35% had high risk cytogenetics. 23% received bortezomib, doxorubicin, cisplatin, cyclophosphamide, and etoposide (VDPACE). Moreover, 40% received bortezomib (BTZ) and immunomodulatory drug (IMIID)-based triplets. Disease status at HCT was VGPR or better in 47%. 27% received maintenance therapy. At 4 years post-HCT, NRM was 7% (4-11%), REL 76% (69-82%), PFS 17% (13-23%), and OS 28% (22-35%) (Figures 1A, 2A, 2B). Disease status ≥VGPR at HCT and Karnofsky Performance Score >90 significantly predicted superior OS in multivariate analysis. AlloHCT Cohort Median age was 53 years and 89% received HCT within 12 months of diagnosis (Table 1). 61% received a single alloHCT, while 39% used auto-alloHCT tandem approach. 42% had high-risk cytogenetics. 61% received total body irradiation with 44% receiving myeloablative conditioning. Use of VDPACE was higher at 41% in this cohort. VGPR status at HCT was similar (48%), while maintenance was used less often (12%). Grade II-IV acute GVHD occurred in 30% and chronic GVHD in 45%. At four years post-HCT, NRM was 12% (5-21%), REL 69% (56-81%), PFS 19% (10-31%), and OS 31% (19-44%) (Figures 1A, 1B, 2A, 2B). There were no differences in outcomes based on type of HCT. A comparison of post-HCT outcomes of CIBMTR pPCL patients from 1995 to 2006 showed that PFS and OS outcomes are inferior despite lower NRM in this modern cohort (Mahindra et al. Leukemia. 2012). In addition, analysis of SEER (1995-2009) and CIBMTR databases showed that use of HCT increased from 12% (7-21%) in 1995 to 46% (34-64%) in 2009. Conclusion More newly diagnosed pPCL patients are receiving modern induction regimens translating into a higher proportion receiving HCT, but without significant further benefit post-HCT. Post-HCT relapse remains the biggest challenge and further survival in pPCL will likely need a combination of targeted and cell therapy approaches. This study provides a benchmark for future HCT studies for pPCL. Disclosures Girnius: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dhakal:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria. Shah:University of California, San Francisco: Employment; Indapta Therapeutics: Equity Ownership; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Qazilbash:Amgen: Consultancy, Other: Advisory Board; Bioclinical: Consultancy; Autolus: Consultancy; Genzyme: Other: Speaker. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria.

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Outcomes of Hematopoietic Cell Transplantation in Acute Promyelocytic Leukemia - a Single Institution Experience

Blood ◽

10.1182/blood-2019-128985 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5739-5739

Author(s):

Hamza Hashmi ◽

Jeffrey Lancet ◽

Asmita Mishra ◽

Kendra L. Sweet ◽

Rami S. Komrokji ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Conditioning Regimen ◽

Disease Status ◽

Promyelocytic Leukemia ◽

Single Institution ◽

Advisory Committees ◽

Total Body

BACKGROUND: Outcomes of patients with acute promyelocytic leukemia (APL) have improved; however, a number of patients, particularly those with high-risk APL, still relapse despite all-trans-retinoic acid (ATRA) and arsenic-based therapies. We present single institution outcomes of autologous (auto) and allogenic (allo) hematopoietic cell transplantation (HCT) in patients with relapsed APL. PATIENTS AND METHODS: We retrospectively reviewed outcomes in patients with relapsed APL who underwent either auto- or allo- HCT at Moffitt Cancer Center from 1990 to 2018 utilizing the clinical data obtained from BMT Research & Analysis Information Network (BRAIN). Survival data were analyzed using Kaplan-Meier estimates. RESULTS: Autologous HCT Cohort: A total of 15 received auto-HCT with a median age at HCT of 39 (range, 21-60) years. Disease status at HCT were first complete remission (CR1) in 5 (33%) and CR2 in 10 (67%). Majority of patients (13/15, 87%) received busulfan/cyclophosphamide (Bu/Cy) conditioning and remaining (2/15, 13%) Bu/Cy/etoposide. All (n=15) patients received peripheral blood (PB) stem cell grafts. Median time to neutrophil engraftment was 11 (range, 10-14) days and platelet recovery was 14 (range 9-44) days. The median progression-free survival (PFS) for auto HCT was 12.9 (95% confidence interval (CI): 1.2-24.8) months. With a median follow up of 45.1 months for surviving patients, overall survival (OS) for auto HCT was 12.9 (95%CI: 0-27.8) years. At the time analysis, 8 patients were relapse-free. Allogeneic HCT Cohort: A total of 10 patients received allo HCT with a median age of 46 (range, 22-56) years at HCT. Disease status at allo HCT was CR2 in 2, CR3 in 6, and two had refractory disease. Two patients had prior auto HCT. Donor type was HLA-identical sibling=5; one antigen-mismatched sibling=1; HLA-matched unrelated donor=3; related haploidentical=1. Seven patients received peripheral blood graft and 3 received bone marrow graft. Conditioning regimen intensity was myeloablative in 7 (fludarabine/busulfan +/- anti-thymocyte globulin=3; Bu/Cy=3; cyclophosphamide/total body irradiation=1), and reduced intensity in 3 (fludarabine/melphalan=2; fludarabine/cyclophosphamide/total body irradiation=1). Seven patients received tacrolimus-based graft-versus-host disease (GVHD) prophylaxis. Median time of neutrophil engraftment was 15 (range, 12-22) days, and platelet engraftment was 22 (range, 15-28) days. The median PFS for allo HCT was 11.9 (95%CI: 2.1-21.6) months. With a median follow up of 48.2 months for surviving patients, median OS for allo HCT was 12.4 (95%CI: 4.8-19.9) months. At the time of analysis 4 patients were relapse-free. CONCLUSIONS: In our single center analysis, auto HCT for APL resulted in a durable remission and prolonged survival. Outcomes after allo HCT were suboptimal primarily due to their heavily pretreated condition and chemotherapy resistant disease. Further research on novel conditioning regimen and relapse prevention is needed to improve the outcomes of allo HCT in APL. Figure Disclosures Lancet: Jazz Pharmaceuticals: Consultancy; Agios Pharmaceuticals: Consultancy; Daiichi-Sankyo: Consultancy; Pfizer: Consultancy. Sweet:Pfizer: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Stemline: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Speakers Bureau; Novartis: Speakers Bureau; Agios: Consultancy; JAZZ: Consultancy; Incyte: Consultancy; pfizer: Consultancy; DSI: Consultancy; celgene: Consultancy. Bejanyan:Kiadis Pharma: Other: advisory board. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding.

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Phase I/I Clinical Trial for the Evaluation of Bortezomib within the Reduced Intensity Conditioning Regimen (RIC) and Post-Allogeneic Transplantation As Gvhd Prophylaxis Among High-Risk Myeloma Patients. EudraCT: 2005–004858-27

Blood ◽

10.1182/blood.v118.21.3025.3025 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3025-3025

Author(s):

Jose Antonio Perez-Simón ◽

Teresa Caballero-Velazquez ◽

Cristina Encinas ◽

Cristina Castilla-Llorente ◽

Rodrigo Martino ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Conditioning Regimen ◽

Disease Status ◽

Allogeneic Transplantation ◽

Reduced Intensity Conditioning ◽

Advisory Committees ◽

Gvhd Prophylaxis ◽

Reduced Intensity Conditioning Regimen ◽

Reduced Intensity

Abstract Abstract 3025 Introduction: Although allogeneic stem cell transplantation (allo-SCT) is the only curative treatment for MM, it is associated to a high morbility and mortality. Moreover, relapses are common after allo-RIC. Accordingly, new strategies are required to reduce both the risk of relapse and the toxicity of the procedure. As we have previously demonstrated, Bz induces a selective depletion of alloreactive T-cells and has immunomodulatory properties which might be of potential benefit for GVHD control. The primary end point of this study was to evaluate the efficacy of allo-RIC in terms of response when Bz was added as part of a reduced intensity conditioning prior to allo-SCT. Secondary end points included incidence of GVHD and analysis of the toxicity of the procedure when Bz is also administered post-infussion as part of the GVHD prophylaxis. Method: Prior to allo-RIC, patients received two cycles of Bz plus dexamethasone. Conditioning consisted of fludarabine (30 mg/m2 intravenously on days -9 to -5) and melphalan (70 mg/m2 intravenously on days -4, -3) plus Bz 1, 3mg/m2 on day - 11 and -2. GVHD prophylaxis included cyclosporine (CsA) and methotrexate for the first 9 patients and CsA plus MTX and Bz on days +3 and +7 for the remaining 7 patients. From day +50 post allo-RIC 7 cycles of Bz (+1, +8, +15) were administered, the first two cycles every 28 days and the rest every 56. Results: 16 patients from the Twenty-one initially enrolled, were evaluable. All 16 patients had received at least 2 lines of therapy including autologous-SCT. Disease status was CR or nCR in 4 patients, 9 had PR and the remaining 3 patients had relapsed / progressive disease. 15 patients maintained or improved status at transplant including all × patients with active disease at transplant. Eight patients (50%) relapsed, four with extramedullary involvement. No patient developed grade 4 aGVHD.Grades 2–3 aGVHD occurred in 6 patients (37%). Interestingly, two out of the nine (29%) patients who received Bz on days +3 and 7 developed grades 2–3 acute GVHD as compared to four of the nine (44%) who did not receive it. In terms of toxicity, one patient did not achieve platelet engraftment and 2 patients developed peripheral neuropathy requiring treatment withdrawal. 8 patients died, four of them due to relapse (MRT: 25%). With a median follow-up of 457 days overall survival was 46%. Conclusions: The current trial is the first evaluating the efficacy and safety of Bz as part of a reduced intensity conditioning regimen among patients with high risk MM undergoing allogeneic transplantation. Regarding the efficacy of the procedure all but one patient improved disease status post-alloRIC although relapse rate was still high in this heavily pretreated population. In addition, Bz post-alloSCT is well tolerated and may decrease the incidence of GVHD. Disclosures: Perez-Simón: Janssen-Cilag: Patents & Royalties. Off Label Use: This study evaluates the efficacy of Bortezomib as part of a reduced intensity conditioning regimen among patients with high risk MM undergoing allogeneic transplantation. Rosiñol:Celgene: Honoraria; Janssen: Honoraria. San Miguel:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

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Busulfan, Cyclophosphamide and Melphalan As Conditioning Regimen for Pediatric Patients with AML in 1st or 2nd CR: A Retrospective Analysis from the AIEOP HSCT Registry

Blood ◽

10.1182/blood-2018-99-111805 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2106-2106

Author(s):

Annalisa Ruggeri ◽

Marco Zecca ◽

Franca Fagioli ◽

Adriana Balduzzi ◽

Mattia Algeri ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Board Of Directors ◽

Pediatric Patients ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Status ◽

Unrelated Donor ◽

Advisory Committees ◽

Donor Type

Abstract Allogeneic stem cell transplantation (HSCT) is largely adopted as post-remissional therapy in children with acute myeloid leukemia (AML) in first complete remission (CR1) but with high-risk characteristics (including high-risk cytogenetics or high levels of minimal residual disease at the end of induction therapy) or to rescue patients reaching CR2 after a previous relapse. Busulfan-based regimens represent the standard of care for these patients in association with alkylating agents. One of the most frequent drugs combination used in Europe in pediatric patients is Busulfan, Cyclophosphamide and Melphan (BuCyMel), which provide a potent anti-leukemic effect, despite remarkable extramedullary toxicities, especially in adolescents. We aimed at analyzing the results of children with AML receiving BuCyMel and reported to the AIEOP registry from 2008 to 2015. A total of 182 patients were reported by 15 transplant centers. Median age at HSCT was 9 years (range 0.3-18); 100 patients (55%) were male. Disease status at HSCT was CR1 in 159 (88%) patients and CR2 in the remaining 23 (12%). All patients received the same myeloablative conditioning regimen with BuCyMel and GVHD prophylaxis was mainly based on calcineurin inhibitors, with the addition of methotrexate in unrelated donors recipients. In vivo T-cell depletion/modulation with ATG was used in 90 cases (49.5%). In almost all cases, pharmacokinetics monitoring of Busulfan was performed, with the drug dosage adjusted according to the systemic exposure evaluated after the first dose. Donor type was an HLA-matched family donor (MFD) in 82 (45%) patients and an unrelated donor (UD) in 100 (55%); 154 (85%) patients received bone marrow (BM) as stem cell source, while the remaining patients (15%) were transplanted with peripheral blood stem cells (PBSCs). Median follow up for surviving patients was 39 months (range 1-111). All patients achieved neutrophil engraftment. The cumulative incidence (CI) of grade II-IV and grade III-IV aGVHD was 35% (95%CI 28-42) and 11% (95% CI 7-16), respectively. The CI of aGVHD was not different according to the type of donor, being 37% (95%CI 28-50) and 32% (95%CI 24-46) in MFD and UD, respectively (p=0.38). The CI of chronic GVHD at 3 years was 17% (95%CI 12-24), while that of extensive cGVHD was 6% (95%CI 3-10). No difference was found in the CI of CGVHD according to the donor employed (MFD 15% and UD 19%, p=0.49). Overall, the CI of relapse and non-relapse mortality (NRM) at 3 years was 18% (95%CI 12-26) and 15% (95%CI 10-22), respectively. The CI of relapse and NRM was significantly different according to age at HSCT (using 12 years as cut-off): (Relapse age<12y: 21% (95%CI 15-32) and age>12y: 11% (95%CI 3-32), (p=0.003); NRM age<12y: 10% (95%CI 5-20) and age>12y: 24% (95%CI 15-37), (p=0.005). According to disease status at HSCT the CI of relapse and NRM were as follows: Relapse: CR1: 18% (95%CI 18-26), CR2 15% (95%CI 5-41) p=0.90) and NRM CR1: 14% (95%CI 9-21), CR2 19% (95%CI 8-46) p=0.38). Also, there was no difference in relapse and NRM by donor type, relapse: MFD 16% (95%CI 9-28), UD 19% (95%CI 11-32) p=0.38) NRM: MFD 19% (95%CI 11-34), UD 11% (95%CI 7-20) p=0.62). Causes of deaths were disease recurrence (39%), infections (27%), and GVHD (12%). Three- years overall survival (OS) and disease-free survival (DFS) were 74% (95%CI 67-81) and 68% (95%CI 60-70). DFS was 70% (95%CI 60-77) and 67% (95%CI 47-87) for patients transplanted in CR1 and CR2 respectively, (p=0.39); and was 70% (95%CI 59-81) and 65% (95%CI 53-78), p=0.77, for UD and MFD HSCT recipients, respectively. In conclusion, our results confirm the efficacy of BuCyMel in preventing relapse in a large series of pediatric patients affected by AML in CR1 and CR2. Adolescents represent a population of more fragile patients at risk of developing transplant-related fatalities. Optimization of toxicity profile and supportive care could further improve outcomes. Prospective randomized clinical trials are warranted to assess the best conditioning regimen for children and adolescents with AML. Disclosures Zecca: Chimerix: Honoraria. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Utilizing Organ-Sparing Marrow Irradiation to Condition Patients Prior to Allogeneic Hematopoietic Cell Transplant with High-Risk Hematologic Malignancies: Results of a Pilot Study

Blood ◽

10.1182/blood-2021-150948 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2856-2856

Author(s):

Sumithira Vasu ◽

Meghan Kromer ◽

Qiuhong Zhao ◽

Hannah Choe ◽

Karilyn Larkin ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Cell Transplant ◽

Advisory Committees ◽

High Incidence ◽

Grade Ii

Abstract Background: Total body irradiation (TBI) has long been incorporated as part of the conditioning regimen prior to hematopoietic stem cell transplant (HSCT). While the myeloablative TBI conditioning is associated with a lower relapse rate in high risk diseases such as Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Acute Lymphoblastic Leukemia (ALL), it is also associated with substantial toxicities, and increased NRM so use of this regimen is limited to young patients with excellent performance status. In this study, we used a linac-based volumetric modulated arc therapy (VMAT) technique to deliver standard myeloablative radiation to high risk body sites while sparing radiation sensitive organs (Organ Sparing Marrow Targeted Irradiation, OSMI). We hypothesized that this technique would be feasible and safe in patients who are older or who have higher transplant specific comorbidity index (HCT-CI), typically ineligible for standard TBI conditioning. Methods: This is a single-arm prospective study. Patients from age 18-75 with high risk AML, MDS or ALL were eligible. There are 3 cohorts: (1) age 18-50 with HCT-CI of 3/4; (2) age 51-65 with HCT-CI of ≤ 3; and (3) age 66-75 with HCT-CI of ≤ 2. Patients receive OSMI to a total dose of 1200 cGy delivered twice daily for 6 fractions for a total of 7200 cGy. Clinical tumor volume includes total skeletal bone marrow and any sanctuary or high-risk areas. Graft-versus-host disease (GVHD) prophylaxis originally was tacrolimus and methotrexate. Given high incidence of bacterial infections related to mucositis, prophylaxis was changed to tacrolimus and sirolimus without methotrexate. All patients received Keratinocyte growth factor for prevention of mucositis. The primary objective was to assess feasibility and tolerability of OSMI based HSCT as defined by transplant-related mortality (TRM) at day 30 (D30) as well as rate of grade II/III organ toxicity (defined by Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 days. Results: Patient demographics for the 24 patients are shown in Table 1. Median age of recipients was 56.5 years. No graft failures were observed. The most common grade II or III Bearman toxicities include mucositis (grade 2: n=4), and diarrhea (grade 2: n=4). Clinical outcomes are shown in Figure 2. With a median follow-up of 3.3 years, overall survival (OS) and relapse-free survival (RFS) at 2 years was 78% and 74% respectively. Among the 5 patients who were not in complete remission at the time of transplant, 2-year OS and RFS rate was 40%. Incidence of Grades II-IV acute GVHD was 79% and Grades III-IV GVHD was 30%. Relapse incidence was 4% at 2 years. Incidence of Thrombotic microangiopathy by day 100 (TMA) as defined by Jodele's criteria was 17%. Incidence of chronic GVHD was 45% and severe chronic GVHD was 16%. One year non-relapse mortality was 22%, likely due to higher incidence of GVHD. Conclusions: Selected patients who are older or with higher HCT-CI, who are typically not candidates for standard TBI conditioning, were able to receive a radiation-based myeloablative conditioning regimen with 2 year overall survival rates of 78%. We observed a high incidence of TMA, possibly related to use of tacrolimus and sirolimus as GVHD prophylaxis, and a high incidence of Grade II-IV acute GVHD. Low incidence of relapse was observed. OSMI-based conditioning was feasible in this cohort with median age of 56 years and was associated with low rates of relapse and favorable 2 year overall survival. Figure 1 Figure 1. Disclosures Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Jaglowski: Novartis: Consultancy, Research Funding; Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. de Lima: Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding.

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Efficacy of Venetoclax Combination Therapy with Hypomethylating Agents in Patients with Relapsed Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2019-129514 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5089-5089 ◽

Cited By ~ 1

Author(s):

Varun Mittal ◽

Mimi Lo ◽

Lloyd E. Damon ◽

Karin L. Gaensler ◽

Thomas G. Martin ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Hypomethylating Agents ◽

Advisory Committees ◽

Allogeneic Hct ◽

Acute Myeloid

Introduction: Venetoclax (VEN), a selective BCL-2 inhibitor, in combination with hypomethylating agents (HMA) has high efficacy in treatment-naïve elderly patients with acute myeloid leukemia (AML). The role for VEN in patients with relapsed/refractory (R/R) AML, myelodysplastic syndrome (MDS), or other myeloproliferative neoplasms remains incompletely defined. In particular, the efficacy of VEN+HMA has not been studied systematically in patients who experience AML relapse following allogeneic hematopoietic cell transplantation (HCT). Method: All patients treated with VEN+HMA (azacitidine or decitabine) for R/R de novo or secondary AML or progressive MDS following allogeneic HCT were identified and reviewed retrospectively. All included AML patients had overt clinical relapse with ≥ 5% bone marrow blasts or extramedullary disease biopsy proven to be AML. Patients were included in this analysis if they received at least 14 days of VEN therapy. Results: Eleven patients with median age 66 (range 25-75) were treated for R/R AML post-allogeneic HCT. Transplant characteristics included use of reduced intensity conditioning in 10/11 (91%), matched sibling donors in 5/11 (45%), matched unrelated donors in 5/11 (45%), and cord blood in 1/11 patients. The median time from HCT to relapse/disease progression was 7 months (range 3-36). Two patients had extramedullary relapse only, and the remainder had marrow involvement. Eight patients (73%) received azacitidine and 3 (27%) received decitabine in combination with VEN. All but two patients (82%) had prior HMA exposure and most received VEN+HMA as initial post-transplant salvage therapy (64%). Only one patient received donor lymphocyte infusion in conjunction with VEN+HMA therapy, and none proceeded to a second allotransplant. Nine patients (82%) experienced an objective response, which included 4 CR/CRi (36%) and 5 PR/SD (45%). In patients with CR/CRi, three patients had adverse risk cytogenetics and one had a favorable risk profile at diagnosis consisting of normal cytogenetics with an isolated NPM1 mutation. All patients who failed to remit with VEN+HMA had intermediate- or high-risk genetic features. The median number of treatment cycles given was 3 (range 1-20). Median survival was 11 months and estimated 6-month and 12-month survival was 82% and 36%, respectively. Three patients remain alive with median 16.5 months follow-up (range 2.5-32). Conclusion: Venetoclax in combination with HMA is a viable salvage option in patients with relapsed AML or progressive MDS after allogeneic HCT, including those with prior exposure to HMA. Although one patient in this cohort sustained long term complete remission, overall prognosis remains dismal in this high-risk patient population and improved treatment options for relapsed/refractory AML following alloHCT remain needed. Disclosures Damon: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Martin:Amgen, Sanofi, Seattle Genetics: Research Funding; Roche and Juno: Consultancy. Olin:MedImmune: Research Funding; Ignyta: Research Funding; Clovis: Research Funding; AstraZeneca: Research Funding; Revolution Medicine: Consultancy; Daiichi Sankyo: Research Funding; Astellas: Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Mirati Therapeutics: Research Funding; Spectrum: Research Funding. Smith:Astellas Pharma: Research Funding; Abbvie: Research Funding; fujiFilm: Research Funding; Revolution Medicines: Research Funding. Logan:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pharmacyclics: Research Funding; Astellas: Research Funding; Jazz: Research Funding; Kite: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; TeneoBio: Consultancy; Kiadis: Consultancy; Kadmon: Research Funding; Abbvie: Consultancy.

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A Novel Reduced Intensity Conditioning Regimen Induces a High Incidence of Sustained Donor Neutrophil and Platelet Engraftment After Double-Unit Cord Blood Transplantation

Blood ◽

10.1182/blood.v120.21.4155.4155 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4155-4155

Author(s):

Doris M Ponce ◽

Craig S. Sauter ◽

Devlin Sean ◽

Marissa N Lubin ◽

Anne Marie R Gonzales ◽

...

Keyword(s):

High Risk ◽

Cord Blood ◽

Board Of Directors ◽

Research Funding ◽

Conditioning Regimen ◽

High Dose ◽

Cell Transplant ◽

Myeloablative Conditioning ◽

Advisory Committees ◽

Reduced Intensity

Abstract Abstract 4155 Introduction: Cord blood (CB) transplant (CBT) can be curative for patients with high-risk hematologic malignancies. However, patients of older age and/or with significant co-morbidities do not tolerate CBT with high-dose myeloablative conditioning. Non-myeloablative (NMA) conditioning can reduce transplant-related mortality (TRM) and extend transplant access to older or infirm patients, but it is limited by the risks of graft rejection in patients without extensive prior chemotherapy and relapse. While the addition of anti-thymocyte globulin (ATG) may reduce rejection, it increases the risk of viral infections, including Epstein-Barr virus lymphoproliferative disease, and may also increase relapse risk. Methods: We investigated the safety and efficacy of an ATG-free regimen of intermediate intensity prior to double-unit CBT in 30 patients with acute leukemias and myelodysplasia. Units were 4–6/6 HLA-A, B antigen, DRB1 allele matched to the patient. The conditioning regimen included cyclophosphamide 50 mg/kg (day -6), fludarabine 30 mg/m2/day × 5 (days -6 to -2), thiotepa 5 mg/kg/day × 2 (days -5 and -4), total body irradiation 200 cGy × 2 (days -2 and -1), and cyclosporine-A/mycophenolate mofetil immunosuppression. The indication for this regimen was one or more risk factors for TRM including age > 50 years, extensive prior therapy, and/or significant co-morbidities. The hematopoietic cell transplant co-morbidity index (HCT-CI) score of Sorror was retrospectively assigned. Results: The median age was 56 years (range 18–69). All but one patient had high-risk disease. Twenty-one had AML (16 CR1, 5 CR2) with all CR1 patients having high-risk features, including high-risk cytogenetics (n = 3), FLT-3 ITD mutation (n = 5), therapy-related disease or prior MDS (n = 6), and/or > 3 consecutive induction chemotherapies (n = 2). Five had ALL (4 CR1, 1 CR3); the 4 in CR1 had BCR/ABL mutations (n = 3) or prior refractory CNS disease (n = 1). Four patients had MDS with 3 having an IPSS score > 2. The median HCT-CI score was 2.5 (range 1–5). Median infused TNC doses were 2.6 (larger unit) and 1.9 (smaller unit) × 107/kg, respectively. Ninety-seven percent of patients engrafted (95%CI: 87–100) at a median of 26 days (range 13–43). The median day 21 total donor bone marrow chimerism was 100% (range 71–100). All surviving patients were 100% donor by day 100, and sustained hematopoiesis has been mediated by a single unit in all but one patient. The cumulative incidence of platelet recovery > 20 × 109/L by day 180 was 93% (95%CI: 83–100), and occurred at a median of 46 days (range 30–79). Day 180 TRM and 2-year relapse incidences were 20% and 11%, respectively. With a median 26.5 months (range 9–53) follow-up of survivors, the 2-year overall survival and disease-free survival (DFS) are both 60% (95%CI: 44–82). There was a hierarchy in 2-year DFS according to the Sorror HCT-CI score (Figure): the 11 patients (median age 55 years) with a score of 1 had a DFS of 82%. This compared with a 2-year DFS of 62% in the 9 patients (median age 51 years) with a score of 2–3, and 40% in the 11 patients (median age 58 years) with a score of 4–5 (p = 0.13). Discussion: This reduced intensity regimen combined with double-unit CBT reliably facilitates sustained donor engraftment without ATG. This regimen is associated with less toxicity than high-dose myeloablative conditioning. While other approaches are needed in patients with high comorbidity scores, this regimen is highly effective in older patients who are otherwise reasonably fit, as evidenced by the 82% 2-year DFS in patients with a median age of 55 years. Given the relatively low risk of relapse, it also represents a promising alternative to high-dose conditioning in younger patients. Disclosures: Giralt: Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees.

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Genetic Alterations at Diagnosis Predict Outcome of AML Patients Age 60 or Older Undergoing Allogeneic Transplantation in First Remission

Blood ◽

10.1182/blood-2019-125967 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 48-48 ◽

Cited By ~ 1

Author(s):

H. Moses Murdock ◽

Haesook T. Kim ◽

Bryan Hambley ◽

Pankit Vachhani ◽

Nathan Denlinger ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Genetic Risk ◽

Research Funding ◽

Gene Mutations ◽

Genetic Alterations ◽

Advisory Committees ◽

Genetic Characteristics ◽

The Impact ◽

Advisory Role

Background: Older age is associated with inferior outcomes after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML). High risk genetic characteristics are common among older patients and linked to poor outcomes in the non-transplant setting. An enhanced understanding of genetic risk may thus provide a basis for improving transplant outcomes in these patients. We evaluated the impact of leukemia genetic characteristics at diagnosis on HSCT outcomes in a multi-center cohort of AML patients age 60 or older receiving HSCT in first complete remission (CR1). Methods: We performed targeted sequencing of 112 genes on diagnostic leukemia samples from 257 patients with AML age 60 or older who received allogeneic HSCT in CR1 at 5 US transplant centers. Median age at diagnosis and HSCT were 65 (range 59-76) and 66 (range 60-76), respectively. 31% had clinically defined secondary AML, 11% had therapy-related AML, and 23% had adverse cytogenetics by 2017 ELN classification. Most (84%) were treated with anthracycline-based induction chemotherapy, while 16% received non-intensive induction. Conditioning was either reduced-intensity or non-myeloablative in 94% of patients. Median follow-up for survivors was 3.7 years; 3-year overall survival (OS) and leukemia-free survival (LFS) were 48% and 44%, respectively. Results: All patients had recurrent genetic alterations at the time of diagnosis, including 251 (98%) with gene mutations and 6 with only cytogenetic abnormalities. The most frequent gene mutations were DNMT3A (25%), NPM1 (23%), FLT3-ITD (22%), ASXL1 (21%), TET2 (21%), RUNX1 (20%), and SRSF2 (18%). Secondary-type mutations associated with antecedent MDS occurred in 42%, and 10% had TP53 mutations. As expected, secondary-type and TP53 mutations were associated with clinically-defined secondary AML (p<0.001), need for reinduction (p=0.03), and CR with incomplete count recovery (p= 0.03). Despite the older age at leukemia diagnosis, putative germline pathogenic variants were identified in 22 (8.6%) patients, including 17 (6.6%) with DDX41 mutations (13/17 with somatic mutation of the second allele), and 5 with TERT or TERC variants not found in population databases. We evaluated the impact of gene mutations on LFS using univariable and multivariable Cox models and developed a hierarchical model of 3 molecular genetic risk groups according to the hazard ratios (Fig 1A): (1) patients with TP53 mutation or JAK2 mutation or FLT3-ITD/NPM1-WT (high risk), (2) patients without high risk mutations who have DNMT3A or GATA2 or DDX41 mutations (low risk) (3) patients without high- or low-risk mutations (intermediate risk), with 3-year LFS of 8%, 65%, and 47% (p<0.001), respectively. Next, we combined molecular genetic and cytogenetic risk to derive a final genetic model comprised of 4 groups with distinct 3-year LFS (69%, 50%, 27%, and 0%) (Fig 1B). Poor LFS in the very high-risk group was due almost entirely to relapse (3-year relapse rate > 90%), but was driven by a combination of relapse and non-relapse mortality in the intermediate and high-risk groups (Fig 2). Conclusion: Genetic characteristics at diagnosis are highly associated with OS and LFS in AML patients age 60 or older who undergo allogeneic transplantation in CR1. We identify patients with low genetic risk and remarkably good outcomes who may be candidates for strategies aimed at reducing toxicity, and those with very high-risk genetics who have limited benefit from current transplant approaches. Among intermediate and high-risk patients, the impact of disease genetics on LFS is mostly due to relapse, suggesting that a model incorporating measurement of residual disease in CR1 and after transplantation could enable a more dynamic estimation of risk. Disclosures Perales: Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding. Koreth:Equillium: Consultancy; Amgen: Consultancy; Cugene: Consultancy. Ho:Jazz Pharmaceuticals: Consultancy. Soiffer:Mana therapeutic: Consultancy; Kiadis: Other: supervisory board; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Jazz: Consultancy; Cugene: Consultancy. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy. Vasu:Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Clinical trial support. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Lindsley:Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding.

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Outcomes of Total Body Irradiation- Versus Chemotherapy-Based Myeloablative Conditioning Regimen in Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide for Acute Lymphoblastic Leukemia: ALWP of the EBMT Study

Blood ◽

10.1182/blood-2019-122258 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 320-320 ◽

Cited By ~ 1

Author(s):

Bhagirathbhai Dholaria ◽

Myriam Labopin ◽

Emanuele Angelucci ◽

Johanna Tischer ◽

Mutlu Arat ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Univariate Analysis ◽

Disease Status ◽

Advisory Board ◽

Hematopoietic Cell ◽

Advisory Committees

Background The intensity of a conditioning regimen has significant impact on outcomes of allogeneic hematopoietic cell transplantation in acute leukemia. In acute lymphoblastic leukemia (ALL) patients undergoing matched donor transplant, total body irradiation (TBI)- based myeloablative conditioning (MAC) regimen was associated with improved leukemia free survival (LFS) compared to chemotherapy (CT)-based MAC (Eder S. et al. 2017). Haploidentical hematopoietic cell transplantation(haplo-HCT) with post-transplant cyclophosphamide (PTCy) has emerged as a safe alternative in absence of a matched donor. The optimal MAC in haplo-HCT setting is yet to be defined. We studied the outcomes of TBI- vs. CT-based MAC in ALL patients undergoing haplo-HCT and reported to the Acute Leukemia Working Party of the EBMT. Methods The study included 427 ALL (B-ALL-75%) patients, that underwent haplo-HCT with PTCy during the years 2010-2018, following TBI- (n=188, 44%) or CT- (n=239, 56%) based MAC. Regimen intensity was defined by EBMT criteria and cases with busulfan dose <9 mg/kg or TBI dose ≤6 Gy were excluded. All disease status were included (CR1=208, CR2+=135; advanced=84). Ninety-one (27%) patients had Philadelphia+ disease. Graft source was bone marrow in 229 (54%) patients. Fludarabine-TBI (72%) and thiotepa-busulfan-fludarabine (65%) were the most common TBI and CT-based regimens, respectively. Cyclosporin with mycophenolate was used as GVHD prophylaxis in 64% of patients. The patients, disease, and transplant related characteristics were similar in both cohorts. Median patient age was 32 yrs and the median follow ups for TBI and CT cohort were 20.7 (IQR-11.7-35.3) and 26.2 (IQR-10.2-41) months, respectively. Results In univariate analysis, day 100 incidences of acute GVHD II-IV and III-VI were 38% vs. 30% (p-0.07) and 19% vs. 13% (p-0.14) for TBI and CT cohort, respectively. Two-year overall and severe chronic GVHD incidences were 34% vs. 30% (p-0.51) and 17% vs. 12% (p-0.18) for TBI and CT cohort, respectively. Graft failure was reported in 6 (3%) and 19 (8%)(p-0.09) patients who received TBI and CT-based MAC, respectively. Death from veno-occlusive disease was reported in 4 (5%) TBI patients and 8 (7%) CT patients. There was no difference in reported deaths due to infection (28%) or interstitial pneumonitis (4%) among study cohorts. In multivariate analysis, TBI was associated with significant improvement in nonrelapse mortality (NRM) [HR=0.51, 95% CI:0.32-0.83, p<0.01] and LFS [HR=0.71, 95% CI:0.52-0.97, p-0.03] and higher incidence of aGVHD II-IV [HR=1.5, 95% CI:1.02-2.19, p-0.04]. Finally, relapse incidence (RI), acute GVHD (aGVHD) III-IV, OS and GVHD free relapse free survival (GRFS) did not differ between the groups. Two-year NRM, LFS and OS of TBI and CT cohort were 21% vs. 31% (p<0.01); 45% vs. 37% (p-0.05) and 51% vs. 47% (p-0.18), respectively (Figure 1). Other factors negatively impacting OS were disease status (CR2, HR=1.69, p-0.01 or advance, HR=2.62, p<0.01) and use of peripheral blood as graft source (HR=1.49, p-0.02). Interestingly, peripheral blood graft source also negatively impacted LFS (HR=1.44, p-0.02), aGVHD II-IV (HR=1.58, p-0.02 and GRFS (HR=1.54, p<0.01). Philadelphia+ disease was associated with reduced RI (HR=0.39, p-0.01) but had no impact on LFS (HR=0.80, p-0.29) or OS (HR=0.81, p-0.34)(Table 1). In a subgroup univariate analysis of patients <40 yrs old, TBI was associated with reduced 2-year NRM (19% vs. 28%, p-0.04) without impacting other outcome measures. In patients with pre-HCT disease status CR2 or advance disease, improvement in 2-year NRM (22% vs. 36%, p-0.02) was observed with TBI but no interaction was seen with other endpoints. Conclusions TBI based MAC resulted in significant reduction of NRM, translating into a better LFS without impacting aGVHD III-IV, chronic GVHD, RI or OS when compared to CT based MAC. Non-significant difference in OS between TBI and CT cohorts might be related to lower number of events, short follow-up and/or salvage therapies after relapse. These novel findings based on a large cohort of ALL patients, support the use of TBI based MAC and bone marrow graft in haplo-HCT with PTCy. Disclosures Dholaria: Celgene: Honoraria. Labopin:Jazz Pharmaceuticals: Honoraria. Angelucci:Novatis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC. Apperley:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Socie:Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

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Clearance of Somatic Gene Mutations in Patients with Acute Myeloid Leukemia Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) Predicts Outcome

Blood ◽

10.1182/blood-2019-130922 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4621-4621

Author(s):

Onyee Chan ◽

Chetasi Talati ◽

Hannah Asghari ◽

Nelli Bejanyan ◽

Hany Elmariah ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Residual Disease ◽

Conditioning Regimen ◽

Gene Mutations ◽

Advisory Committees ◽

Somatic Gene ◽

Line Of Therapy

Background: In recent years, genomic studies have uncovered a number of driver gene mutations in acute myeloid leukemia (AML). There is great interest in leveraging residual disease detection methods including next-generation sequencing (NGS) to predict outcomes, especially in the setting of allogeneic hematopoietic cell transplantation (HCT). One study showed measurable minimal residual disease (MRD) at the time of HCT increases the risk of relapse in patients who received a reduced-intensity conditioning (RIC) regimen (Hourigan et al. 2019). In this study, we evaluate the prognostic impact of somatic mutation clearance using NGS prior to HCT in patients with AML. Methods: We identified a total of 139 patients with AML who underwent HCT at the Moffitt Cancer Center (2013-2018). Using European LeukemiaNet (ELN) criteria, patients were included if at the time of HCT they were adverse risk in complete remission (CR)1, intermediate risk in CR1, favorable risk in CR1 if indication for transplant present, or favorable risk in CR2 with at least one time point when NGS was performed before and after HCT. We utilized clinical data captured by BMT Research and Analysis Information Network (BRAIN). Molecular testing via NGS included 54-gene TruSight Myeloid panel tested on Illumina sequencers with a lower limit of detection of 5%. Positive persistent detectable disease (PDD) was defined as presence of detectable mutations on NGS at HCT. Univariate and multivariate analyses were conducted using log-rank and Cox regression, respectively. Kaplan-Meier analysis was used to estimate overall survival (OS) and relapse free survival (RFS) from the time of diagnosis. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated by the Fine and Gray model. Results: Of the 139 patients (74 males/65 females), 59% were PDD positive at HCT and 41% PDD negative at HCT. Median age at HCT was 59 years. More patients were in ELN-defined adverse risk (46.8%) in comparison to intermediate risk (35.3%) or favorable risk (18%). In both cohorts, majority of the patients had 1 line of therapy prior to HCT. Overall, 57.6% of patients received myeloablative conditioning regimen (MAC) with the remaining receiving RIC. More patients received MAC in both PDD positive at HCT and PPD negative at HCT groups (Table 1). There were 35 patients (25.2%) who relapsed after HCT, and 17 had NGS available at diagnosis, at the time of HCT, and at relapse. The mutation frequencies and changes over time are shown in Figure 1. Univariate analysis showed inferior OS in patients who are PDD positive at HCT compared to PDD negative at HCT (HR 1.98, 95% CI 1.06-3.72, p=0.032). After adjusting for ELN risk and PDD status, the patients who received more than 1 line of therapy prior to HCT had significantly worse OS (p=0.005). Patients with negative PDD at HCT had a significantly better OS at 2-year compared to PDD positive at HCT patients, 78.7% vs. 62.4% (p=0.029) with a median follow up of 29.9 months (Figure 2A). The RFS at 2-year were 72.6% for PDD negative at HCT patients and 51.8% for PDD positive at HCT patients (p=0.090). There was no difference in NRM or CIR between these two groups (p=0.605 and p=0.136, respectively). Further subgroup analysis did not find a significant difference between PDD status and different types of conditioning regimen (Figure 2B). Conclusions: In this study, we report that clearance of somatic gene mutations in AML patients prior to HCT confers better outcomes compared to those with measurable PDD at HCT. There is a survival advantage in patients who received fewer lines of treatment prior to HCT. Larger cohort and greater depth of NGS coverage is needed to better clarify the impact of conditioning regimen in this population. Disclosures Talati: Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria. Bejanyan:Kiadis Pharma: Other: advisory board. Komrokji:JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau. Kuykendall:Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Abbvie: Honoraria; Celgene: Honoraria. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Pfizer: Consultancy; Incyte: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy; Jazz: Speakers Bureau.

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