Reduced-intensity Conditioning allo-HCT Research Articles

Favorable Survival Outcomes in AML Patients Undergoing Allogeneic Hematopoietic Cell Transplant with Fludarabine/Melphalan-Conditioning with Tacrolimus/Sirolimus-Based Gvhd Prophylaxis

Introduction: Fludarabine/melphalan (F/M) conditioning is associated with superior disease-free survival (DFS) compared to busulfan-based reduced-intensity conditioning (RIC) regimens in patients with AML/MDS undergoing allogeneic hematopoietic cell transplantation (alloHCT). A recent CIBMTR analysis in AML patients reported 5-year OS, cumulative incidence of Relapse (CIR) and NRM of 29%, 36% and 36% respectively after F/M conditioning when Tac/MTX was used for graft-vs-host disease (GVHD) prophylaxis (Blood Adv 2020). At City of Hope (COH), tacrolimus and sirolimus (T/S)-based GVHD prophylaxis has been used in patients undergoing HLA-matched sibling and unrelated donor alloHCT, based on the results of a phase 2 study by Rodriguez et al (Blood 2010). Here, we retrospectively reviewed clinical outcomes of 409 consecutive AML patients who underwent RIC alloHCT at COH from 2008-2019 with F/M conditioning and T/S-based GVHD prophylaxis. The primary objective was to assess long term survival outcomes and associated risk factors adjusted for secular trends in patient demographics undergoing alloHCT over time. Methods: Descriptive statistics were used to summarize patient demographics, and disease characteristics. Kaplan-Meier curves and log-rank test were used to evaluate OS and LFS. Cumulative incidence curves and Gray test were used to examine differences in relapse and NRM. The assumptions of proportionality for Cox regression and Fine-Gray models were checked by corresponding tests and plots of the scaled Schoenfeld residuals. To study changes in patient demographics, we divided patients into early era of 2008-2012 (n=140; 34%) and late era of 2013-2019 (n=269; 66%). Results: Patient and HCT characteristics are shown in Table 1. Briefly, the median age was 63 years (range: 19-78) and 70% of patients underwent alloHCT in CR-1. Cytogenetics (ELN 2017) were classified as adverse risk in 25% (n=104) and intermediate risk in 65% (n=265) patients. By disease risk index (DRI), patients were categorized as low (32%; n=131), intermediate (47%; n=193), or high/very high risk (20%; n=84). KPS of 80-100 was recorded in 93% of patients and HCT comorbidity index score of ≥3 was seen in 41%. AML-from prior hematologic disorder (secondary AML) or therapy related was documented in 32% (n=133) and data on somatic mutations and measurable residual disease (MRD) were available only in the recent era. Compared to the early era, HCT recipients of the recent era were significantly older(64 vs 60 years; p=0.0001), had higher HCT-CI (median score of 3 vs 1; p<0.0001), and more patients with KPS < 80 (9% vs 2 %; p=0.0024). With the median follow-up duration of 4 years (range: 0.3-12.5) for the whole cohort, the 5-year OS and DFS were 53% (95% CI: 0.48-0.58) and 51% (95% CI: 0.46-0.56), respectively. The cumulative incidence of relapse (CIR) at 5 years was 23% (95% CI: 0.19-0.28). The non-relapse mortality (NRM) at day+100 and 5 years were 5% (95% CI: 0.03-0.08) and 25% (95% CI:0.20-0.29), respectively. Day +100 grade 2-4 acute GVHD was 37% (95% CI: 0.32-0.42) and 2-year chronic GVHD was 70% (95% CI: 0.65-0.74). Overall survival (OS) and disease-free survival (DFS) were not significantly different in the two eras (Figure 1). Despite high incidence of cGVHD, only 21% (n=86) required prednisone at one year with median dose of 10 mg/day (range: 2-60mg/day). In key subgroups of interest, the 5-year OS were: 70% for FLT3-ITD mutation (n=50), 70% for NPM1 mutation (n=47), 83% for IDH 1/2 mutation (n=30), 65% for patients older than ≥70 (n=55), and 55% (95%CI :43-63) for secondary AML (n=102). MRD by multi-color flow cytometry was available in 58 patients in CR of whom 18 were MRD-positive; this was associated with worse 5-year OS (26%: 95% CI: 5.5-53%). Multivariate analyses (MVA) identified DRI high/very high-risk as the only independent variable associated with worse OS (HR=1.62, [95%CI: 1.16-2.27]) and DFS (HR=1.76, [95%CI: 1.28-2.41]), primarily due to increased NRM (HR 1.86, 95%CI [1.21-2.87]), while its impact on relapse was insignificant. Conclusion: Fludarabine-melphalan with T/S associated with favorable long-term OS with good disease control without excessive NRM, even in high-risk patient subgroups and changing demographics of older adults with higher comorbidity. However, cGVHD rates remain high and novel strategies are being explored to realize the OS benefits of the FM backbone while attenuating chronic GVHD and NRM.

Phase I Trial of Allogeneic Donor Gamma Delta T Cell Infusion Post-Hematopoietic Cell Transplantation, an Interim Safety Report

Background Patients with 2017 European LeukemiaNet (ELN) adverse risk acute myeloid leukemia (AML) are at 40% risk of relapse leading to poor survival after allogeneic hematopoietic cell transplantation (allo-HCT) (Hansen TCT 2021, Jimenez BMT 2021). Ex vivo donor-derived gamma delta T cells (GDT) expanded with artificial antigen presented calls (aAPC) are a novel therapy with potent MHC-independent antineoplastic cytotoxicity. An ongoing phase 1/1b study is evaluating the safety and potential efficacy of ex vivo expanded donor GDT after reduced-intensity conditioning (RIC) allo-HCT in patients with ELN adverse risk AML ( NCT05015426). We report on manufacturing, safety, and correlative biology of expanded donor GDT after allo-HCT in the first 5 treated patients (Table 1). Methods The primary endpoint is the maximum-tolerated dose (MTD) of allogeneic donor GDT as a single infusion at day 60 after RIC allo-HCT. Next generation sequencing was used for measurable residual disease (MRD) assessment pre-HCT and post-GDT infusion. Donor GDT collected from the same donor of the allo-HCT were enriched from non-mobilized leukapheresis product by stimulation with zoledronic acid and IL-2 for 7 days followed by alpha beta T cell depletion using the Miltenyi CliniMACS. Enriched GDT (>90% TCRVδ2) were then co-cultured with irradiated aAPCs in Wilson Wolf G-Rex 100MCS over 10 days (Boucher J. Immunother 2023). This single center, investigator-initiated phase 1 trial is testing 3 distinct dose cohorts of infused GDT (5 x 10 6 cells/kg, 2.5 x 10 7 cells/kg, and 1 x 10 8 cells/kg) with acceptable range of 25% margin. A Bayesian optimal interval design is used to guide dose escalation/de-escalation decisions. Results First 3 patients enrolled in dose level 1 (DL1) cohort received GDT dose of 6.25 x 10 6 cells/kg, while last 2 patients enrolled in DL2 cohort received 3.13 x 10 7 cells/kg dose. Dose-limiting toxicities (DLT) were evaluated for 42 days following GDT infusion and no DLT were observed. None of the treated patients experienced cytokine release syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) or graft-versus-host disease (GVHD) during DLT period. Among patients treated on DL1, patient #01 had ASXL1 AML with MRD pos (VAF 43.9%) prior to RIC haploidentical (Haplo) HCT. He is in ongoing complete remission (CR) 9 months post-HCT and has had no GVHD. Patient #02 had MRD pos (VAF 61.7%) AML with TP53 mutation/complex karyotype prior to RIC matched sibling donor allo-HCT. He is in CR and has mild chronic GVHD at 7 months post-HCT. Patient #03 with pre-HCT MRD negRUNX1 AML is in ongoing CR 7 months post-RIC Haplo HCT with no GVHD. At day 28 and day 120 post-GDT, all 3 patients were MRD neg in bone marrow and had 100% bone marrow and peripheral blood leukocyte and granulocyte chimerism. In DL2 cohort, patient #04 with RUNX1 AML and patient #05 with t(9;22) AML both were MRD neg prior to RIC Haplo HCT and remain in CR with no GVHD at 5 and 4 months post-HCT, respectively. At day 28 post-GDT, both patients were MRD neg and had 100% chimerism. Patient #05 had a fall during DLT period in a setting of orthostatic hypotension requiring hospitalization for 24 hours for hydration. This was the only grade 3 adverse event observed in this trial. Serum cytokines analyzed included IL2, IL6, IL15, IFNγ, TNFα, Angiopoietin 1&2, and GM-CSF (Figure 1). We compared results prior and up to 90 days post-GDT infusion and found no significant differences, which can explain no CRS or ICANS events yet observed on this trial. Immunophenotype (TCRVδ2, TCRVδ1, PD1, CTLA4, TIGIT and CD28) of GDT was analyzed in samples of donor apheresis, pre- and post-enrichment, infused GDT product and at days 28 and 90 post-infusion. GDT (TCRVδ2) persisted at day 28 and day 90 post-infusion and expressed low levels of cell surface inhibitory receptors. Conclusion This preliminary interim report demonstrates favorable safety and tolerability of donor GDT therapy with no CRS, ICANS or GVHD in first 5 patients treated in this trial. All these patients with adverse risk AML are in ongoing MRD neg CR following RIC allo-HCT, including 2 pre-HCT MRD pos cases with TP53 AML and AXSL1 AML. Early results of this trial are promising, which provides validation for continued testing of adoptive transfer of ex vivo expanded donor GDT. Updated results of this trial will be presented at the annual conference.

Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil As the New Standard for Graft-Versus-Host Disease (GVHD) Prophylaxis in Reduced Intensity Conditioning: Results from Phase III BMT CTN 1703

Introduction: Controlling both GVHD and disease relapse is essential for allogeneic hematopoietic cell transplantation (alloHCT) success. For three decades, the standard GVHD prophylaxis strategy has been a calcineurin inhibitor such as tacrolimus (Tac) plus methotrexate (MTX). Although several approaches have been tried in recent years to improve upon Tac/MTX, intensifying immunosuppression frequently comes with an increased risk of serious infections or relapse and usually no effect on chronic GVHD even if acute GVHD is reduced. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) previously completed a phase II study comparing three novel GVHD prophylaxis regimens to contemporaneous controls receiving Tac/MTX (BMT CTN 1203) in order to determine the most promising novel GVHD prophylaxis approach with reduced intensity conditioning (RIC). The most promising GVHD prophylaxis regimen in BMT CTN 1203 was a 3-drug combination of post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil (PTCy/Tac/MMF). Here, we report the results of the randomized phase III study comparing outcomes of alloHCT in those randomized to receive PTCy/Tac/MMF versus standard Tac/MTX. Patients and Methods: Eligible adults (age 18+) with hematologic malignancies undergoing RIC alloHCT with an 6/6 matched related (N=128), 8/8 matched unrelated (N=288), or 7/8 single mismatch (N=15) peripheral blood stem cell donor, satisfactory organ function, and adequate performance status were randomized 1:1 to receive PTCy/Tac/MMF (N=214) or Tac/MTX (N=217), stratified by transplant center and Disease Risk Index (DRI). The primary endpoint of the study was GVHD/relapse or progression-free survival (GRFS), a time-to-event outcome defined as grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, disease relapse or progression, or death by any cause. The primary hypothesis was that PTCy/Tac/MMF has a ≥15% higher GRFS at 1 year than Tac/MTX in the intent-to-treat population. Secondary endpoints included the incidence/severity of acute and chronic GVHD, engraftment/chimerism, relapse/progression, infections, and survival. Results: The 2 study arms were well balanced by patient sex, age, Karnofsky performance status, disease risk, comorbidities, donor match, conditioning regimen, and post-transplant maintenance therapy (Figure panel A). In the multivariate Cox regression model of the primary endpoint, the PTCy treatment group had a significantly lower hazard of GRFS than Tac/MTX (hazard ratio 0.641, 95% confidence interval [CI] 0.492 to 0.835, p=0.001). The adjusted 1-year GRFS rate was 52.7% (95% CI: 45.8%, 59.2%) for the PTCy arm and 34.9% (95% CI: 28.6%, 41.3%) for the control arm, Figure panel B). The lower proportion of GRFS events in the PTCy arm was due to a reduction in both acute and chronic GVHD. The Day 100 grade III-IV acute GVHD was 6.3% vs 14.7% (p=0.001), and chronic GVHD rate at 1 year was 21.9% vs 35.1% (p=0.005) for PTCy vs Tac/MTX, respectively. There was no difference in the relapse/progression rate at 1 year (20.8% vs 20.2%, p=0.9), or OS rate at 1 year post transplant (76.8% vs 72.6% , p=0.3), in PTCy vs Tac/MTX. The cumulative incidence of engraftment was lower for PTCy for neutrophils ≥ 500/mm3 by day +28 (90.3% vs 93.4%, p=0.03), platelets ≥ 50,000/mm3 by day +100 (79.5% vs 83.7%, p<0.001), and lymphocytes ≥ 1000/mm3 by 1 year (47.1% vs 63.2%, p<0.001). Grade 3 infection rates were similar between the arms (12.2% for PTCy vs 13.3%, p=0.8) but grade 2 infections were greater for PTCy (33.7% vs 23.5%, p=0.002). There was no difference in CMV reactivation between the treatment arms (7.3% for PTCy vs 7.1%, p=0.8). There was no significant difference in proportion of chimerism at day +100 (>95% donor in 68.6% for PTCy vs 67.8%, p=0.2) or secondary graft failure between the arms (2.9% for PTCy vs 0.9%, p=0.2). Conclusions: BMT CTN 1703 met its primary endpoint, demonstrating a higher 1-year GRFS with PTCy/Tac/MMF compared to Tac/MTX owing to significant improvements in GVHD risk without increased risk of relapse or death. PTCy/Tac/MMF, which has become standard of care for mismatched transplants, should also become the standard of care for GVHD prophylaxis from closely-matched donors receiving reduced intensity conditioning. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Multicenter Phase II, Double-Blind, Placebo-Controlled Trial of Maintenance Ixazomib After Allogeneic Transplantation for High-Risk Multiple Myeloma: Results of the Blood and Marrow Transplant Clinical Trials Network 1302 Trial

The role of allogeneic hematopoietic cell transplantation (allo-HCT) followed by maintenance therapy in high-risk multiple myeloma (MM) remains controversial. We evaluated the efficacy of ixazomib maintenance therapy after reduced-intensity conditioning allo-HCT from HLA-matched donors in patients with high-risk MM. The primary study endpoint was progression-free survival (PFS) postrandomization, treated as a time to event. Secondary endpoints were grade II-IV and grade II-IV acute graft-versus-host-disease (GVHD), chronic GVHD, best response, disease progression, nonrelapse mortality (NRM), overall survival (OS), toxicity, infection, and health-related quality of life. In this phase 2, double-blinded, prospective multicenter trial, we randomized patients with high-risk MM (ie, those with poor-risk cytogenetics, plasma cell leukemia, or relapsing within 24 months after autologous HCT) to ixazomib (3 mg on days 1, 8, and 15) or placebo after allo-HCT. The conditioning regimen included fludarabine/melphalan/bortezomib with tacrolimus plus methotrexate for GVHD. Fifty-seven patients were enrolled, of whom 52 (91.2%) underwent allo-HCT and 43 (82.7%) were randomized to ixazomib versus placebo. At 21 months postrandomization, the ixazomib and placebo groups had similar PFS (55.3% versus 59.1%; P=1.00) and OS (94.7% versus 86.4%; P=.17). The cumulative incidences of grade III-IV acute GVHD at 100 days (9.5% versus 0%) and chronic GVHD at 12 months (68.6% versus 63.6%) also were similar in the 2 groups. The secondary analysis showed that at 24 months post-allo-HCT, PFS and OS were 52% and 82%, respectively, with a corresponding NRM of 11.7%. These results demonstrate the safety and durable disease control with allo-HCT in high-risk MM patients. We could not adequately assess the efficacy of ixazomib maintenance because the trial terminated early owing to enrollment delays, but there was no indication of any impact on outcomes.

Real-World Experience of Cryopreserved Allogeneic Hematopoietic Grafts during the COVID-19 Pandemic: A Single-Center Report

In response to the widespread COVID-19 pandemic, cryopreservation of allogeneic donor apheresis products was implemented to mitigate the challenges of donor availability and product transport. Although logistically beneficial, the impact of cryopreservation on clinical outcomes and graft composition remains unclear. In this study, we compared outcomes and graft composition with cryopreserved versus fresh allografts in the setting of allogeneic hematopoietic cell transplantation (allo-HCT). We retrospectively analyzed the clinical outcomes of 30 consecutive patients who received cryopreserved allografts between March and August 2020 and 60 consecutive patients who received fresh allografts before the COVID-19 pandemic. Primary endpoints were hematopoietic engraftment and graft failure (GF), and secondary outcomes were overall survival (OS), relapse-free survival (RFS) and nonrelapse mortality (NRM). In addition, extended immunophenotype analysis was performed on cryopreserved and prospectively collected fresh apheresis samples. Compared with recipients of fresh allografts, both neutrophil and platelet recovery were delayed in recipients of cryopreserved reduced-intensity conditioning (RIC) allo-HCT, with a median time to engraftment of 24 days versus 18 days (P = .01) for neutrophils and 27 days versus 18 days (P = .069) for platelets. We observed primary GF in 4 of 30 patients in the cryopreserved cohort (13.3%) versus only 1 of 60 patients (1.7 %) in the fresh cohort (P = .03). Cryopreserved RIC allo-HCT was associated with significantly lower median total, myeloid, and T cell donor chimerism at 1 month. OS and RFS were inferior for cryopreserved graft recipients (hazard ratio [HR], 2.16; 95% confidence interval [CI], 1.00 to 4.67) and HR, 1.90; 95% CI, 0.95 to 3.79, respectively. Using an extended immunophenotype analysis, we compared 14 samples from the cryopreserved cohort to 6 prospectively collected fresh apheresis donor samples. These analyses showed both a decrease in total cell viability and a significantly reduced absolute number of natural killer cells (CD3−CD56+) in the cryopreserved apheresis samples. In this single-institution study, we found delayed engraftment and a trend toward clinical inferiority of cryopreserved allografts compared with fresh allografts. Further evaluation of the use of cryopreserved allografts and their impact on clinical and laboratory outcomes is warranted.

A high transfusion burden following an ambulatory-allogeneic hematopoietic cell transplantation using reduced-intensity conditioning is associated with adverse outcomes

ObjectivesAmbulatory allogeneic hematopoietic cell transplantation (allo-HCT) after reduced-intensity conditioning (RIC) is a cost-effective option for hematology patients. Data on the impact of transfusion burden in this setting are scarce; we analyzed this retrospectively. MethodsA study of 177 HLA-identical and haploidentical allo-HCT recipients on an outpatient basis was conducted between 2013 and 2019. Packed red blood cell (PRBC) and platelet transfusions were documented from days 0–100 after HCT. ResultsA total of 121 patients (68.4%) required transfusion while 56 (31.6%) did not. In the multivariate analysis, a lower disease-free (DFS) and overall survival (OS) were documented for patients that received ≥9 total blood products (p = 0.018) (p = 0.014), those who required hospitalization (p = 0.001) (p < 0.001), had acute graft-versus-host disease (p = 0.016) (p = 0.004), and a high/very high Disease-Risk-Index (p = 0.002; p = 0.004), respectively. Transfusion of ≥5 PRBC units was associated with a lower OS (p = 0.027). The cumulative incidence of transplant-related mortality at two years for an HLA-identical transplant was 9.5% and for haploidentical, it was 27.1% (p = 0.027); this last group had significantly more transfusion demands than HLA-identical recipients (p = 0.029). ConclusionIncreased blood product utilization is an independent predictor of decreased survival in ambulatory RIC allo-HCT recipients. Further evidence leading to individualized guidelines to transfuse in this complex scenario is needed.

Allogeneic hematopoietic cell transplantation for multiple myeloma: A retrospective analysis of the Polish Myeloma Group

PurposeIn this multicenter retrospective analysis of the Polish Myeloma Group we assessed the real-life application of allogeneic transplantations (alloHCT) in multiple myeloma (MM) outside clinical trials in Poland. MethodsAnonymized clinical data of patients who underwent alloHCT were retrospectively collected from eight transplant centers and analyzed to identify factors affecting the outcome. ResultsSixty patients (34 males, 26 females) at median age of 45 (22–59) years who received alloHCT between 1993 and 2016 were included. In this group, 16 (27%) patients underwent myeloablative conditioning and 44 (73%) reduced-intensity conditioning alloHCT. Acute graft versus host disease (GvHD) occurred in 27 (45%) patients, while chronic GvHD was diagnosed in 13 (22%) patients. With the median observation time after alloHCT of 10 months, the relapse rate was 38%. Median progression-free survival (PFS) reached 9 months (0–183) while median overall survival (OS) was 23 months (0–183). Main causes of death included disease progression in 16 (43%), infections in 10 (27%), and GvHD in 7 patients (19%). Presence of chronic GvHD was the only factor associated with prolonged PFS (28 vs. 6 months; p = 0.05), however its impact on OS was not statistically significant (73 vs. 8 months; p = 0.09). ConclusionsIn this relatively small and heterogeneous study we observed that alloHCT was associated with high risk of severe complications, but resulted in long-term survival in a proportion of patients. Decisions on optimal indications and timing of the alloHCT in MM need to be taken in the broader context of reported outcomes including data from large studies.

Less Is More: Superior Graft-versus-Host Disease-Free/Relapse-Free Survival with Reduced-Intensity Conditioning and Dual T Cell Depletion in Acute Myelogenous Leukemia.

In this study, we compared the outcomes of patients with acute myelogenous leukemia (AML) in complete remission treated with myeloablative conditioning (MAC) and those treated with reduced-intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HCT). In addition, we explored the efficacy of dual T cell depletion using anti-thymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) for the prevention of graft-versus-host disease (GVHD) in patients undergoing RIC allo-HCT. Our study cohort comprised 356 adults with AML in complete remission who underwent allo-HCT between 2013 and 2018. One hundred eleven patients (31.2%) received a MAC regimen, and 245 (68.8%) received an RIC regimen. One hundred seventy-one of the patients who received an RIC regimen (68.4%) received ATG, PTCy, and cyclosporine (ATG-PTCY-CsA) for GVHD prophylaxis in accordance with our institutional protocol. Data were collected retrospectively and updated in July 2019. With a median follow-up of 14.5 months (range, 0 to 76 months), 161 patients (45.2%) died, and 66 (18.5%) relapsed. Two-year overall survival (OS), relapse-free survival (RFS), and GVHD-free/RFS (GRFS) were 55%, 52.6%, and 35%, respectively. The intensity of the conditioning regimen, with or without ATG-PTCY-CsA, did not have a significant impact on OS and RFS. However, RIC in combination with ATG-PTCY-CsA was associated with a significantly lower cumulative incidence of acute GVHD and chronic GVHD. The use of RIC with ATG-PTCy-CsA was a significant predictor for higher GRFS secondary to the reduction of clinically relevant GVHD (P= .0001). In patients with AML, RIC allografts and dual T cell modulation with ATG and PTCy led to superior GRFS. The use of this GVHD prophylaxis strategy, along with mitigation of conditioning toxicity using RIC, may result in better long-term quality of life for allo-HCT recipients.

Higher Total Body Irradiation Dose Intensity in Fludarabine/TBI-Based Reduced-Intensity Conditioning Regimen Is Associated with Inferior Survival in Non-Hodgkin Lymphoma Patients Undergoing Allogeneic Transplantation.

Disease relapse is the most common cause of therapy failure in patients with non-Hodgkin lymphoma (NHL) undergoing reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT). It is not known whether or not increasing total body irradiation (TBI) dose from 2 to 4 Gy in a RIC platform can provide improved disease control without increasing nonrelapse mortality (NRM). Using the Center for International Blood & Marrow Transplant Research (CIBMTR) database, we evaluated the outcomes of patients with NHL receiving RIC allo-HCT with either fludarabine (Flu)/2-Gy TBI versus Flu/4-Gy TBI. In the CIBMTR registry, 413 adult patients with NHL underwent a first allo-HCT using either a matched related or unrelated donor between 2008 and 2017, using a RIC regimen with either Flu/2-Gy TBI (n=349) or Flu/4-Gy TBI (n=64). The primary endpoint was overall survival (OS). Secondary endpoints included acute (a) and chronic (c) graft-versus-host disease (GVHD), NRM, relapse/progression, and progression-free survival (PFS). At baseline, the Flu/2-Gy TBI cohort had significantly fewer patients with Karnofsky performance status ≥90 and significantly more patients had a higher HCT-comorbidity index. On multivariate analysis, the 2 conditioning cohorts were not significantly different in terms of risk of grade 3 to 4 aGVHD or cGVHD. Compared to Flu/2-Gy TBI, the Flu/4-Gy TBI conditioning was associated with a significantly higher risk of NRM (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.11 to 2.89; P=.02) and inferior OS (HR, 1.51; 95% CI, 1.03 to 2.23, P=.03). No significant differences were seen in the risk of relapse/progression (HR, 0.78; 95% CI, 0.47 to 1.29, P=.33) or PFS (HR, 1.09; 95% CI, 0.78 to 1.54, P=.61) between the 2 regimens. Comparing Flu/2-Gy TBI versus Flu/4-Gy TBI cohorts, the 5-year adjusted outcomes were NRM (28% versus 47%; P=.005), relapse/progression (35% versus 29%; P=.28), PFS (37% versus 24%; P=.03), and OS (51% versus 31%; P=.001), respectively. Relapse was the most common cause of death in both cohorts. In patients with NHL undergoing Flu/TB I-based conditioning, augmenting TBI dose from 2 to 4 Gy is associated with higher NRM and inferior OS, without any significant benefit in terms of disease control. The optimal dose is 2-Gy in the RIC Flu/TBI platform for lymphomas.

Don't Let the HCT-CI Fool You: Similar Outcomes with Myeloablative CD34+ Selected Allo-HCT Compared to Unmodified RIC Allo-HCT in Patients with AML or MDS and High Comorbidity Scores.

Introduction The BMT CTN 0901 phase 3 trial showed improved relapse-free survival (RFS) in patients with AML or MDS with myeloablative-conditioning (MAC) vs. Reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT). However, overall survival (OS) increase was not statistically significant because of higher non-relapse mortality (NRM) compared to RIC allo-HCT. HCT-CI ≥ 3 also predicts for poor OS related to high NRM in patients undergoing MAC CD34+ selected allo-HCT. Objectives We aimed to evaluate impact on OS, NRM and RFS of MAC CD34+ selected vs. RIC allo-HCT in patients with high comorbidity burden. Methods We retrospectively compared the outcomes of 221 patients with AML or MDS with HCT-CI ≥ 3 who underwent MAC CD34+ selected (n=157) vs. RIC allo-HCT (n=64) at our institution from 2009 to 2017. The indication for MAC CD34+ vs. RIC allo-HCT was based on multidisciplinary consensus and primary physician's choice. Results Patients in the RIC group were older, had a higher proportion of high disease risk index (DRI), and higher use of matched unrelated donors compared to the MAC CD34+ group. HCTCI grades were balanced between the two cohorts, but the RIC group had a higher though non-significant proportion of patients with HCTCI > 5 (Figure 1). When comparing the MAC CD34+ vs. unmodified RIC cohorts, respectively, no difference was seen in OS [43% (95% CI 32-59) vs. 53% (95% CI 46-52), p=0.37], NRM [31% (95% CI 19-44) vs. 30% (95% CI 23-38), p=0.74], and relapse-free survival (RFS) [34% (95% CI 23-49) vs. 48% (95% CI 41-57) p=0.1], even when adjusting for age, DRI, and donor differences (Figure 2). However, incidence of acute and chronic graft versus host disease (GVHD) was lower for MAC CD34+ allo-HCT. When evaluating outcomes by HCT-CI subgroups (3, 4-5 and >5), MAC CD34+ allo-HCT resulted in higher 3-year estimated RFS [54% (95% CI 44-68) vs. 28% (95% CI 14-58), p=0.03] in patients with HCT-CI = 3, though this did not translate into an OS advantage [44% (95% CI 27-73) vs 59% (95% CI 48-72), p=0.26], possibly related to higher though non-significant NRM [16% (95% CI 4-35) vs. 28% (95% CI 18-39), p=0.26] (figure 3). When adjusting for differences in age, DRI, and donor, the difference in RFS was no longer statistically significant (p=0.13). Conclusions Though limited by their retrospective nature, our data suggest that CD34+ selected allografts after myeloablative conditioning can be feasible in selected patients with comorbidity scores over 3 with low rates of acute and chronic GVHD. However, further prospective studies are needed to reduce NRM and optimize this treatment platform in older patients with comorbidities.

Higher Total Body Irradiation (TBI) Dose-Intensity in Fludarabine (Flu)/TBI-Based Reduced-Intensity Conditioning (RIC) Regimen Is Associated with Inferior Survival in Non-Hodgkin Lymphoma (NHL) Patients Undergoing Allogeneic Hematopoietic Cell Transplantation (alloHCT).

<h3>Introduction</h3> Disease relapse is the most common cause of therapy failure in NHL patients undergoing RIC alloHCT. Whether increasing TBI dose from 2Gy to 4Gy in RIC-platform can provide improved disease control without increasing non-relapse mortality (NRM) is not known. Using the CIBMTR database we evaluated the outcomes of NHL patients receiving RIC alloHCT with either Flu/2Gy TBI vs. Flu/4Gy TBI. <h3>Methods</h3> In the CIBMTR registry, 413 adult NHL patients underwent a first alloHCT using either a matched related or unrelated donor between 2008-2017, utilizing a RIC regimen with either Flu/2Gy TBI (n=349) or Flu/4Gy TBI (n=64). Graft-versus-host disease (GVHD) prophylaxis was calcineurin inhibitor-based. The primary endpoint was overall survival (OS). Secondary endpoints included acute (a) and chronic (c) GVHD, NRM, relapse/progression and progression-free survival (PFS). Probabilities of OS and PFS were calculated using the Kaplan-Meier estimator. Multivariable regression analysis was performed for GVHD, relapse/progression, NRM, PFS, and OS. Covariates with a p<0.05 were considered significant. <h3>Results</h3> Baseline characteristics are shown in Figure 1. The Flu/2Gy TBI cohort had significantly fewer patients with KPS ≥90 and significantly more patients with HCT-CI ≥3. On multivariate analysis (Figure 2), the two conditioning cohorts were not significantly different in terms of risk of grade 3-4 aGVHD or cGVHD. Compared to Flu/2Gy TBI, the Flu/4Gy TBI conditioning was associated with a significantly higher risk of NRM (HR 1.79, 95%CI=1.11-2.89, p=0.02), and inferior OS (HR 1.51, 95%CI=1.03-2.23, p=0.03). No significant differences were seen in the risk of relapse/progression (HR 0.78, 95%CI=0.47-1.29, p=0.33) or PFS (HR 1.09, 95%CI=0.78-1.54, p=0.61) between the two regimens. Comparing Flu/2Gy TBI vs. Flu/4Gy TBI cohorts the 5-year adjusted outcomes were; NRM (28% vs. 47%; p=0.005), relapse/progression (35% vs. 29%; p=0.28), PFS (37% vs. 24%; p=0.03) and OS (51% vs. 31%; p=0.001), respectively (Figure 3). Rate of graft failure at day100 in similar order was 0.6% vs. 1.6% (p = 0.54), respectively. Relapse was the most common cause of death in both cohorts. <h3>Conclusions</h3> In NHL patients undergoing Flu/TBI-based conditioning, augmenting TBI dose from 2Gy to 4Gy is associated with higher NRM and inferior OS, without any significant benefit in terms of disease control. 2Gy is optimal dose in the RIC Flu/TBI platform for lymphomas.

Higher CD34 Cell Dose Is Associated with Improved 5-Year Survival after Peripheral Blood Allogeneic Hematopoietic Cell Transplantation in Adults with Hematologic Malignancies

<h3>Introduction</h3> Higher CD34+ cell dose is associated with improved short-term outcomes (e.g., engraftment) but may also be associated with an increased risk of complications after allogeneic hematopoietic stem cell transplantation (alloHCT), including graft-versus-host disease (GVHD). We examined the impact of CD34+ cell dose by actual and ideal body weight (ABW, IBW) on overall survival (OS) and graft-versus-host disease-free, relapse free survival (GRFS) in patients undergoing alloHCT with peripheral blood stem cell (PBSC) graft source. <h3>Methods</h3> We identified 377 adults with hematologic malignancies who received myeloablative or reduced-intensity conditioning alloHCT with matched sibling donor PBSC at the University of Minnesota from 2002-2015. <h3>Results</h3> Patients had a median age of 52 years (range 18-74), were predominantly male (n=237, 63%) and had primarily leukemia (68%) or lymphoma (25%) with an intermediate disease risk index (n=258, 68%). Median CD34+ dose was 6.1 × 10⁶/kg by ABW (quartiles in Table 1) and 7.72 × 10⁶/kg by IBW [QT1 <5.93, QT2 5.93,7.72, QT3 7.72, 10.12, QT4 >10.12]. Patients in higher quartiles were younger at transplant (p <0.02) with younger donors (p <0.01). QT4 donors required fewer collections (median 1, range 1-5, p<0.01). Highest quartile cell dose by ABW was associated with increased OS at both 1 year [HR 0.48 (0.29-0.80), p=0.02] and 5 years [HR 0.56 (0.38-0.83), p=0.01] (Figure 1) and platelet engraftment [HR 1.58 (1.19-2.09), p<0.01] in multivariate analysis. The top 3 quartiles by ABW showed significantly increased ANC engraftment and a trend toward increased GRFS at both 1 and 5 years. There was no association between cell dose and acute or chronic GVHD. Cell dose by IBW was not associated with survival, relapse, engraftment or treatment-related mortality. <h3>Conclusion</h3> The highest quartile of CD34+ cell dose by ABW is associated with superior OS at 5 years and improved engraftment without increased risk of morbidity. These data support further development of novel stem cell mobilization techniques in donors at higher risk for low collection yield. Further studies should evaluate if cell dose has similar prognostic impact in 5-year survival in alternative donor transplant.

Comparison of Conditioning Regimens for Allogeneic Hematopoietic Cell Transplantation in Non-Hodgkin Lymphoma

<h3>Background</h3> Allogeneic hematopoietic cell transplantation (allo-HCT) allows for the possibility of cure in patients (pts) with Non-Hodgkin Lymphoma (NHL) as it provides an immunologic graft-versus-lymphoma effect. Non-relapse mortality (NRM) was prohibitive in myeloablative regimens, but technical advances with the advent of reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) regimens have decreased these rates. RIC regimens are generally associated with more toxicity and higher NRM than NMA regimens. Though studies showed both approaches are safe and effective, there is lack of direct comparison between these different intensities in NHL. <h3>Methods</h3> This retrospective study identified pts aged ≥ 18 years who underwent allo-HCT for relapsed/refractory NHL between 3/2008-6/2017 at our center. Outcomes were compared between pts who received NMA and RIC conditioning, with intensity defined per CIBMTR. Progression-free survival (PFS) was the primary outcome. Secondary outcomes included overall survival (OS) and non-relapse mortality (NRM). Additional outcomes included rates of acute GVHD at Day 100, chronic GVHD, and CMV reactivation at Day 100. Regimen intensity and other variables significant by univariate analysis were included in the multivariate analysis <h3>Results</h3> For the 144 pts identified, median age was 56 years (range, 19-79). More pts received NMA regimens (n=80, 56%) and most did not undergo prior autologous HCT (n=103, 72%). NMA regimens were given more frequently to pts with indolent B-cell lymphoma and were more likely to receive ATG and/or rituximab (p = 0.008, p < 0.001, and p < 0.001, respectively). At a median overall follow-up of 57.8 months (range 49 - 75.1) neither median PFS or OS were reached. In univariate analysis, NMA conditioning was associated with a longer PFS than RIC [HR 1.9 (1.11-3.24), p = 0.019). No difference was found in OS [HR 1.56 (0.85-2.85), p = 0.15). There was an increase in all grades of aGVHD [HR 3.68 (2.16, 6.28), p < 0.001)] with RIC regimens, but only 12 events of grade III/IV aGVHD overall. In multivariate analyses (with histology and ATG as covariates) NMA with rituximab had improved PFS compared to RIC without rituximab [HR 0.43 (95% CI 0.22, 0.81; p=0.009)]. However, PFS was similar comparing NMA and RIC groups [HR 0.72 (95% CI 0.37, 1.41; p=0.3)]. Similarly, aGVHD (any grade) risk was lower in NMA pts receiving rituximab compared to RIC pts who did not [HR 0.15 (0.07-0.32), p < 0.001). No significant differences were noted in NRM or CMV reactivation between groups. <h3>Conclusion</h3> Our study suggests that there are comparable and favorable outcomes between RIC and NMA regimens in allo-HCT for NHL with careful patient and regimen selection. Further studies are needed to better define criteria in choosing between NMA and RIC allo-HCT regimens for pts with NHL.

HLA-mismatched donor and high ferritin level showed poor clinical outcomes after allogeneic hematopoietic cell transplantation in patients with advanced myelofibrosis.

Background:Preconditioning intensity, donor choice and graft-versus-host disease (GVHD) prophylaxis of allogeneic hematopoietic cell transplantation (allo-HCT) for advanced myelofibrosis (MF) have not been fully elucidated.Methods:Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling donors first, followed by matched or mismatched unrelated donors and familial mismatched donors. Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation ⩽400cGy.Results:All showed engraftments, but four showed either leukemic relapse or delayed graft failure. Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III–IV acute GVHD (eight grade III and four grade IV) was higher in human leukocyte antigen (HLA)-mismatched donor HCT compared with HLA-matched HCT (70% versus 20%). Chronic GVHD was observed in 16 patients, and a cumulative incidence of severe chronic GVHD was 33% in HLA-mismatched donor HCT and 7.7% in HLA-matched HCT. Significant hepatic GVHD was observed in nine patients (five acute, four chronic) and six of them died. Multivariate analysis revealed inferior OS in HLA-mismatched donor HCT (hazard ratio (HR) = 6.40, 95% confidence interval (CI) 1.6–25.7, p = 0.009) and in patients with high ferritin level at the time of pre-conditioning period (HR = 7.22, 95% CI 1.9–27.5, p = 0.004), which were related to higher incidence of hepatic GVHD with high NRM rate.Conclusion:RIC allo-HCT can be a valid choice providing graft-versus-fibrosis effect for advanced MF patients. However, HLA-mismatched donor and high pre-HCT ferritin level related to fatal hepatic GVHD should be regarded as poor-risk parameters.

Poor Outcomes of HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation and High Ferritin Levels after a Reduced-Intensity Conditioning Regimen in Patients with Advanced Myelofibrosis

Allogeneic hematopoietic cell transplantation (allo-HCT) preconditioning intensity, donor choice, and graft-versus-host disease (GVHD) prophylaxis for advanced myelofibrosis (MF) have not been fully elucidated. Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling (n=16) followed by matched (n=10) or mismatched (n=5) unrelated and familial mismatched donors (n=4). Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation≤ 400cGy. All showed engraftments, but four (11.4%) showed either leukemic relapse (n=3) or delayed graft failure (n=1). Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III-IV acute GVHD was higher with HLA-mismatch (70% vs. 20%, p=0.008). Significant hepatic GVHD was observed in nine patients (5 acute, 4 chronic), and six of them died. Multivariate analysis revealed inferior OS with HLA-mismatch (HR=6.40, 95%CI 1.6-25.7, p=0.009) and in patients with high ferritin level at post-HCT D+21 (HR=7.22, 95%CI 1.9-27.5, p=0.004), which were related to hepatic GVHD and high NRM. RIC allo-HCT can be a valid choice for advanced MF. However, HLA-mismatch and high post-HCT ferritin levels related to significant hepatic GVHD should be regarded as poor-risk parameters. Disclosures Kim: Handok: Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL &amp; H: Research Funding; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

Outcomes of Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation Performed in the Inpatient versus Outpatient Setting

Allogeneic hematopoietic cell transplantation (allo-HCT) with reduced-intensity conditioning (RIC) is commonly performed as an inpatient procedure. The feasibility and outcomes of RIC allo-HCT in the outpatient setting is not known. We performed a single-center retrospective cohort study of patients aged ≥ 18years with hematologic malignancies who underwent RIC allo-HCT either in the inpatient or outpatient setting. Donor types included HLA-matched sibling and well-matched unrelated donors. The objectives were to compare the survival, complications, charges, and incidences of relapse, nonrelapse mortality (NRM), and acute and chronic graft-versus-host disease (GVHD) between the 2 groups. Between 2014 and 2017, 151 eligible patients were included, with 116 undergoing RIC allo-HCT in the inpatient setting and 35 patients undergoing RIC allo-HCT in the outpatient setting. Baseline characteristics were comparable between the 2 groups except for a higher proportion of patients with myeloma in the outpatient cohort (inpatient 15.5% versus outpatient 37.1%). The cumulative incidence of grades II to IV acute GVHD (inpatient 25.2% versus outpatient 25.7%), grades III to IV acute GVHD (inpatient 10.4% versus outpatient 8.5%), chronic GVHD (inpatient 38.3% versus outpatient 51.6%), NRM at 1 year (inpatient 10.8% versus outpatient 3.2%), and relapse (inpatient 24.8% versus outpatient 33.2%) did not significantly differ between the 2 cohorts. One-year progression-free survival (inpatient 64.4% versus outpatient 63.6%, P = .39) and overall survival (inpatient 73.8% versus outpatient 82.8%, P = .93) were also not significantly different between the 2 groups. The proportion of patients who developed neutropenic fever (inpatient 25.8% versus outpatient 8.5%, P = .03) and mucositis (inpatient 50.8% versus outpatient 8.5%, P < .001) and who required total parenteral nutrition (inpatient 20.6% versus outpatient 5.7%, P = .04) were more frequent in the inpatient cohort. About 51.5% of the outpatient cohort never required hospital admission in the first 100days. Outpatient HCT resulted in significantly lower charges than inpatient HCT in the first 100days (median charges: inpatient $339,621 versus outpatient $247,334; P < .001). On multivariate analysis the site of the HCT (outpatient versus inpatient) was not a significant predictor of either overall or progression-free survival. Outpatient RIC allo-HCT is feasible and safe with daily outpatient evaluation and aggressive supportive care resulting in outcomes comparable with those who received the transplant in the inpatient setting.

Safety and Efficacy of Yttrium-90-Labeled Anti-CD45 Antibody (90Y-DOTA-BC8) Followed By a Standard Reduced-Intensity Hematopoietic Stem Cell Transplant (HCT) Regimen for Patients with Refractory/Relapsed Leukemia or High-Risk Myelodysplastic Syndrome (MDS)

▪Although HCT offers the best potential for cure for patients with high risk leukemia and MDS, the procedure may not be an option for all patients due to the toxicity of the conditioning regimen. Reduced-intensity conditioning (RIC) allo-HCT regimens are associated with lower non-relapse mortality (NRM), but patients receiving these regimens have a higher risk of relapse. Radioimmunotherapy (RIT) can potentially deliver high doses of targeted radiation while minimizing toxicity to normal tissue. When combined with RIC allo-HCT, RIT may improve responses without increasing toxicity associated with myeloablative conditioning.We evaluated the safety and efficacy of yttrium 90 (90Y)-anti-CD45 antibody (MAb; BC8) followed by a standard RIC regimen with fludarabine (Flu) and 2 Gy total body irradiation (TBI) as a means of developing an improved HCT strategy for high-risk acute leukemia or MDS patients. We used CD45 as a target due to its ubiquitous expression on hematopoietic stem cells including the leukemic blasts. We used the high-energy (2.2 MeVmax) beta-emitter 90Y, which has a relatively short half-life (2.7 days) to eliminate targeted malignant cells.This phase I dose-escalation trial (NCT01300572) was designed to estimate the safety, feasibility and maximum tolerated dose (MTD) of 90Y-BC8-DOTA MAb when combined with Flu and 2 Gy TBI followed by HLA‐matched, related or unrelated allo-HCT for patients with high-risk leukemia or MDS. The MTD was defined as the radiation absorbed dose delivered by 90Y-BC8-DOTA MAb associated with a true dose-limiting toxicity (DLT) rate of 25%, where a DLT is defined as Bearman grade III/IV regimen-related toxicity. Doses of 90Y were escalated in increments of 2 Gy depending on the occurrence of DLT. Inclusion required patients to have advanced leukemia or high-risk MDS (defined as primary refractory or relapsed AML/ALL, secondary AML, MDS expressed as RAEB or CMML). To determine the dose of 90Y-BC8-DOTA, patients first underwent a biodistribution step using a trace-labeled infusion of 111Indium (111In)-BC8-DOTA followed by gamma-camera imaging. On pre-HCT day -12, patients received 90Y-BC8-DOTA at a prescribed radiation dose calculated from the trace-labeled 111In-BC8-DOTA biodistribution, followed by Flu (30 mg/m2/day) on days -4 to -2. TBI (2 Gy) was administered on day 0, prior to G-CSF mobilized donor PBSC infusion. GVHD prophylaxis consisted of mycophenolate mofetil and cyclosporine.Fifteen patients, median age of 62 (range 37-76), were treated (10 with advanced AML, 5 with high-risk MDS). At time of HCT, 9 patients had refractory active disease while 6 were in remission with minimal residual disease (Table 1). The patients received 22.8 to 151.2 mCi of 90Y, delivering an average of 10.5 Gy to marrow, 70 Gy to spleen, and 17 Gy to liver. Although a maximum dose of 28 Gy was delivered to the liver, no DLT was observed. Therefore, the MTD could not be estimated.Treatment led to complete remission in 13 patients (87%), 2 patients had persistent disease after HCT. All patients engrafted with a median donor-derived CD3 and CD33 chimerism both 100% by day 28 after HCT. Ten patients (67%) developed grade II-IV acute GVHD (grade II: n=7; III: n=2; IV: n=1). Five patients (33%) developed chronic GVHD. Six patients relapsed, 5 of whom subsequently died due to progression of disease. The median time to relapse among these 6 patients was 59 days (range, 6- 351 days). One patient died from stage IV steroid-refractory GVHD. One patient died in remission from acute renal failure at 7 months after HCT. Eight patients (53%) are surviving with a median follow-up of 1.8 (range, 0.9-5.9) years. Estimated overall survival at one and two years were 66% and 46%, respectively, with progression-free survival estimated to be 46% at each of these time points. The 1-year estimate of relapse was 41% (Fig. 1).The inclusion of 90Y-BC8-DOTA into a RIC allo-HCT regimen is feasible, tolerable and no DLTs were observed. The efficacy of this approach is promising considering the high-risk leukemia/MDS patients with active disease enrolled. Current studies are evaluating the use of an alpha emitter, astatine-211, which is short-lived (t ½ = 7.2 hours) and provides high-energy radiation, conjugated to anti-CD45 MAb BC8 as part of an HCT conditioning regimen for patients with advanced AML, ALL, or high-risk MDS, in place of 90Y with the goal of continuing to improve outcomes using RIT for allo-HCT (NCT03128034). [Display omitted] DisclosuresOrozco:Actinium Pharmaceuticals: Research Funding. Green:Juno Therapeutics: Patents & Royalties, Research Funding. Gopal:Incyte: Consultancy; Pfizer: Research Funding; Gilead: Consultancy, Research Funding; Teva: Research Funding; Aptevo: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Takeda: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy, Research Funding; Brim: Consultancy; Asana: Consultancy. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy.

Reduced-Intensity Conditioning Versus Myeloablative Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients with Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis of Randomized Trials

Background:Allogenic hematopoietic cell transplantation (alloHCT) is a curative option for patients with high-risk myelodysplastic syndrome (MDS). The benefit of higher conditioning intensity in MDS is controversial. While myeloablative conditioning (MAC) regimens can mitigate the risk of relapse, they are associated with higher non-relapse mortality (NRM). In contrast, the reduced intensity conditioning (RIC) regimens are associated with higher risk of relapse. And owing to the lower NRM, they are feasible in patients with advanced age or comorbidities.Methods:We report here a systematic review and meta-analysis of randomized controlled trials (RCTs) that directly compared the safety and efficacy of MAC vs RIC regimens in MDS. The efficacy was evaluated in terms of overall survival (OS), relapse-free survival (RFS) and relapse incidence (RI). The safety was evaluated in terms of non-related mortality (NRM) and incidence of acute (a) and chronic (c) graft-versus-host disease (GVHD). A systematic search of databases using PubMed, Embase, Web of science, Cochrane database and Clinicaltrials.gov was performed on May 6th, 2018 with no restrictions of language or time period. RCTs comparing MAC with RIC regimens that include MDS patients were considered eligible for inclusion. After duplicates removal, a total of 683 articles were scrutinized for relevance by screening the abstracts and/or full length articles. Based on the eligibility criteria, only two randomized studies (BMT CTN 0901 Trial Scott, B. et al. 2017 & EBMT RICMAC Trial Kroger, N. et al. 2017) qualified for inclusion and quantitative synthesis. The quality assessment was done using the Cochrane tool regarding the bias in study selection, performance, detection, attrition and reporting of the clinical trials.Results:Out of total 392 MDS and acute myeloid leukemia (AML) patients enrolled in these two trial, 169 patients had MDS (N=115 in Kroger et al and N=54 cases in Scott et al). Eighty one patients received MAC and 88 patients received RIC followed by either a related or unrelated alloHCT. The median age range at the time of transplant was 50-54 years and these patients were followed for a period of 18-24 months. There were no statistically significant differences in the baseline patient characteristics between two regimen groups in the both trials. The use of RIC regimen was associated with a statistically non-significant trend towards improved OS (OR 1.52: 95% CI: 0.93-2.5, p-value= 0.097), along with a significantly reduced risk of NRM (OR 0.39: 95% CI: 0.16-0.94, p-value= 0.04). The RIC alloHCT was not associated with a higher risk of disease relapse (OR: 4.24, 95% CI: 0.34-52.22, p-value= 0.26) or inferior RFS (OR: 0.64, 95% CI: 0.196-2.06, p-value= 0.45). There was no difference between the two conditioning intensities in terms of risk of developing aGVHD (OR: 0.51, 95% CI: 0.11-2.27, p-value= 0.37) or cGVHD (OR: 0.50, 95% CI: 0.18-1.40, p-value= 0.19). The meta-analysis results are shown in figure-1. The Infectious complications were comparable for both groups in Scott, et al. But Kroger et al reported significantly lower overall infections rate at day 100 (4.3 vs. 6.9, p=0.002) and at total follow up (1.4 vs. 2.0, p= 0.002) for RIC.Conclusion:In adult patients with MDS undergoing alloHCT, RIC regimens were associated with a significantly lower risk of NRM, without increased risk of relapse, mortality or GVHD. It is unknown if any specific poor risk groups regarding clinical indicators (e.g. IPSS score) or genomic predictors (e.g. p53 mutations or RAS pathway mutations) may benefit from higher conditioning intensity and warrants further investigation. DisclosuresHamadani:Sanofi Genzyme: Research Funding, Speakers Bureau; ADC Therapeutics: Research Funding; Ostuka: Research Funding; Janssen: Consultancy; Merck: Research Funding; MedImmune: Consultancy, Research Funding; Cellerant: Consultancy; Celgene Corporation: Consultancy; Takeda: Research Funding.

Disease Risk Index Is Independently Associated with Long-Term Outcomes of Allogeneic Transplantation Post Reduced-Intensity Conditioning in Lymphoid Malignancies

Introduction: Allogeneic hematopoietic cell transplantation (alloHCT) with reduced-intensity conditioning (RIC) has been used in heavily pretreated lymphoma patients with the promise of decreased treatment-related mortality. Despite overall improvements in outcomes of patients with lymphoid malignancies, several new agents are emerging as potential therapies. However, investigation is ongoing. Therefore, we aimed to describe our long-term experience in Hodgkin (HL), non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL).Methods: In this retrospective study, we enrolled consecutive patients who underwent allo-HCT for lymphoid malignancies in our institution between 2001-2018. We performed a retrospective review of data in our prospectively acquired database.Results: In total, 50 patients (male=35, female=15, median age 36 years, range 15-64) underwent allo-HCT for HL (n=24), NHL (n=21, including mantle cell n=12, follicular n=3, aggressive B-NHL n=4, T-NHL n=2) and CLL (n=5). The majority of patients were diagnosed at stage IV (48%), 34% had bone marrow involvement and 66% had previously undergone autologous HCT. Most patients were heavily pretreated (median treatment lines=4, range 1-11), 21 of them had received more than 4 treatment lines and at the time of transplantation only 14 had complete response of the disease, while 9 had partial response and 27 were refractory. According to Disease-Risk Index (DRI), patients were stratified at low (n=11, 23.4%), intermediate (n=12, 25.5%), high (n=20, 42.6%) or very high (n=4, 8.5%) category.Among patients with Hodgkin lymphoma, Brentuximab vedotin was administered in 7, and 4 of them were effectively bridged to AHCT.All patients received RIC, mainly Fludarabine (150mg/m2)-Cyclophosphamide (2g/ m2) in CLL and NHL and Thiotepa (10mg/kg)-Fludarabine (120 mg/m2)-Cyclophosphamide (60mg/kg) in HL from matched sibling (n=27), matched unrelated (n=15) or mismatched unrelated (n=8) donor. GVHD prophylaxis consisted of cyclosporine or tacrolimus and mycophenolate mofetil or short- term methotrexate and additional low dose antithymocyte globulin (5mg/kg) in unrelated donors. Peripheral blood was the main stem cell source (only two patients received bone marrow graft) and median number of CD34+ cells infused was 6.37 x106 /kg (1.33-14.5). Two patients succumbed to advanced underlying disease before engraftment, in all other engraftment was successful. Median time until neutrophil engraftment was 10 days (7-23) and until platelet engraftment 12 days (7-28). Eighteen patients (36.7%) developed acute GVHD (grade I,n=1,grade II, n=12,grade III-IV, n=5), steroid sensitive in 10 (62.5%). Cumulative incidence (CI) of chronic extensive GVHD at first year was 78.2%, and 13 patients required more than one additional line of immunosuppression (range 1-5 lines). Ten patients presented CMV reactivation successfully treated with antiviral medication and 1 patient died from HSV7 encephalitis. With a median follow of 3 years (1-16 years), 10-year OS was 40.4%, 10-year non-relapse mortality CI 23.4% and 10-year DFS 32%. There was no difference in survival according to original disease (5yr, NHL=61.1%, HL=47.1%, CLL=30%%, p=0.67). Multivariate analysis revealed high and very high DRI as the single predicting factor for OS (HR 9.69, CI 1.55-60.55, p=0.015), when assessing impact of disease, DRI, number of prior treatment lines, cGVHD and bone marrow infiltration at diagnosis.Conclusions: Our data suggest that RIC allo-HCT provides encouraging survival rates, potentially offers the chance of cure, with acceptable 10-year TRM in selected high risk patients with lymphoid malignancies, despite high risk of chronic GVHD. Disease risk index that is mainly associated with disease stage at transplant independently affects survival. Therefore, efforts need to continue to improve clinical application of novel agents targeting specific pathways with the aim of lowering disease stage pre-transplant. These therapeutic strategies merit further investigation in prospective studies in order to select potential therapeutic targets and best regimens for individual patients. DisclosuresGavriilaki:European Hematology Association: Research Funding.

A Phase II Study of Dasatinib and Dexamethasone As Primary Therapy Followed By Transplantation for Adults with Newly Diagnosed Ph/BCR-ABL1-Positive Acute Lymphoblastic Leukemia (Ph+ ALL): Final Results of Alliance/CALGB Study 10701

Dasatinib with corticosteroid yields high complete remission (CR) rates in Ph+ ALL with minimal induction death. Optimal post-remission therapy is not known. We report a prospective study evaluating dasatinib/dexamethasone induction then consolidation with reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT), autologous HCT (autoHCT), or chemotherapy alone (chemo), followed by dasatinib-based maintenance. Methods: We conducted a phase II, 3-arm, non-randomized trial (NCT01256398, Support: U10CA180821, U10CA180882, U10CA180861, U24CA196171) at 17 US centers with primary objectives to determine 3-year overall survival (OS) and disease-free survival (DFS) of adults ≥18 years (yrs) old with untreated Ph+ ALL treated with dasatinib/dexamethasone induction, CNS prophylaxis with systemic and intrathecal methotrexate, consolidation with alloHCT, autoHCT, or chemo, then dasatinib maintenance. Induction (Course I) used dasatinib 140 mg orally daily and dexamethasone 10 mg/m2/day orally or IV days 1-7. If ≤20% lymphoblasts in marrow at Day 15, Course II continued dasatinib with 7 days of dexamethasone. If >20% lymphoblasts, patients (pts) also received vincristine and daunorubicin. Pts not in CR/CRi received a second induction (Course III) with dasatinib, cyclophosphamide, vincristine, daunorubicin, and dexamethasone. CNS prophylaxis (Course IV) used dasatinib, IV vincristine and IV, oral, and intrathecal methotrexate. Course V consisted of HCT or chemo. Pts 18-70 yrs old underwent RIC alloHCT if they had a HLA-matched donor; otherwise they underwent autoHCT. AlloHCT conditioning used fludarabine 30 mg/m2/day IV day -7 through -3, alemtuzumab 20 mg/day IV day -7 through -3, and melphalan 140 mg/m2 IV once on day -2. GVHD prophylaxis with tacrolimus began day -2. Pts undergoing autoHCT received etoposide 10 mg/kg/day (age >65, 5 mg/kg/day) CIV for 4 days and cytarabine 2 g/m2 (age >65, 1 g/m2) IV every 12 hours for 8 doses then G-CSF for mobilization. AutoHCT conditioning was melphalan 100 mg/m2/day IV on days -2 and -1. Pts >70 yrs old or unable to undergo HCT received etoposide/cytarabine alone. Dasatinib maintenance (Course VI) began day 30 of Course V and continued for 12 months and until 2 consecutive negative BCR-ABL1 RT-PCR assays 3 months apart or relapse. BCR-ABL1 isoform and ABL1 kinase domain (KD) mutation determination were done locally. Results: From 12/15/2010 to 11/14/2014, 64 eligible pts enrolled. Median age was 60 yrs (22-87); median WBC 23.2 x 103/μl (0.3-454). The dominant BCR-ABL1 isoform was p190 in 59%, p210 in 17%, and not reported in 23%. The CR rate was 97% with no induction deaths. Fifty-five pts completed CNS prophylaxis (Course IV). Twenty pts underwent protocol-specified alloHCT, 7 autoHCT, and 9 chemo. Nine pts underwent off-study alloHCT and 5 skipped Course V. Dasatinib maintenance was tolerable with 72%, 80%, and 80% receiving >50% of planned maintenance doses in alloHCT, autoHCT, and chemo arms, respectively. With a median follow up of 48 months (37-78) for survivors, 3-yr OS and DFS were 55% (median OS 45 months) and 43% (median DFS 30 months), respectively. For pts undergoing consolidation with protocol-specified alloHCT, autoHCT, or chemo, 3-yr OS was 75%, 71%, and 55% respectively with median OS not reached (NR) for all groups. DFS at 3-yrs was 55%, 43%, and 46% respectively. Median DFS for alloHCT was 42 months vs 15 months for autoHCT and 34 months for chemo (Log-Rank P=0.4). Outcomes were similar with inclusion of off-study alloHCT and chemo patients skipping Course V. Relative to p190 BCR-ABL1 isoform, p210 was associated with shorter median OS (NR vs 16 months, P=0.04) and median DFS (35 months vs 10 months, P Conclusions: Dasatinib and dexamethasone followed by alloHCT, autoHCT, or chemo yield similar 3-yr survival comparable to approaches using intensive induction chemotherapy. Pts with the p210 BCR-ABL1 isoform had dismal outcomes and may benefit from alternate approaches. T315I mutation was the major cause of relapse and should be addressed in future studies. Disclosures Wieduwilt:Amgen: Research Funding; Reata Pharmaceuticals: Equity Ownership; Daiichi Sankyo: Membership on an entity9s Board of Directors or advisory committees; Leadiant: Research Funding; Shire: Research Funding; Merck: Research Funding. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Powell:Rafael Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees. Kolitz:Magellan Health: Consultancy, Honoraria. Liedtke:Caelum: Membership on an entity9s Board of Directors or advisory committees; Takeda: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity9s Board of Directors or advisory committees, Research Funding; celgene: Research Funding; Genentech/Roche: Research Funding; Pfizer: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; BlueBirdBio: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Devine:Kiadis Pharma: Consultancy. Larson:BristolMyers Squibb: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.