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Ex vivo CD 34+ selection prior to allogeneic hematopoietic stem Cell transplantation (allo-HCT) reduces GVHD without increasing relapse, but usually requires myeloablative conditioning. We aimed to identify toxicity patterns in older patients & the association with overall survival (OS) & non-relapse mortality (NRM). We conducted a retrospective analysis of 200 pts who underwent CD34+ selection allo-HCT using the ClinicMACS® system between 2006-2012. All grade 3-5 toxicities by CTCAE v4.0 were collected. Eighty patients ≥ 60yrs with a median age of 64 (range 60-73) were compared to 120 pts

The late adverse events in long-term survivors after myeloablative-conditioned allogeneic hematopoietic cell transplantation (HCT) with ex vivo CD34+ cell selection are not well characterized. Using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0, we assessed all grade ≥3 toxicities from the start of conditioning to the date of death, relapse, or last contact in 131 patients who survived >1 year post-HCT, identifying 285 individual toxicities among 17 organ-based toxicity groups. Pretransplantation absolute lymphocyte count >.5 K/µL and serum albumin >4.0 g/dL were associated with a reduced risk of toxicities, death, and nonrelapse mortality (NRM), whereas serum ferritin >1000 ng/mL was associated with an increased risk of toxicities and NRM after 1 year. An HCT Comorbidity Index (HCT-CI) score ≥3 was associated with an increased risk of all-cause death and NRM, but was not associated with a specific increased toxicity risk after 1 year. Patients who incurred more than the median number of toxicities (n = 7) among all patients within the first year subsequently had an increased risk of hematologic, infectious, and metabolic toxicities, as well as an increased risk of NRM and inferior 4-year overall survival (OS) (67% versus 86%; P = .003) after the 1-year landmark. The development of grade II-IV acute graft-versus-host disease (GVHD) within the first year was associated with incurring >7 toxicities within the first year (P = .016), and also with an increased risk of all-cause death and NRM after 1 year. In multivariate models, cardiovascular, hematologic, hepatic, infectious, metabolic, neurologic, and pulmonary toxicities incurred after 1 year were independently associated with increased risk of death and NRM when adjusting for both HCT-CI and grade II-IV acute GVHD within the first year. One-year survivors of ex vivo CD34+ selection had a favorable 4-year OS of 77%, although the development of grade ≥3 toxicities after the first year was associated with poorer outcomes, emphasizing the fundamental importance of improving survivorship efforts that may improve long-term toxicity burden and outcome.

We sought to develop a myeloablative chemotherapeutic regimen to secure consistent engraftment of T-cell depleted (TCD) hematopoietic stem cell transplantations (HSCT) without the need for total body irradiation, thereby reducing toxicity while maintaining low rates of graft-versus-host disease (GVHD) and without increasing relapse. We investigated the myeloablative combination of busulfan (Bu) and melphalan (Mel), with the immunosuppressive agents fludarabine (Flu) and rabbit antithymocyte globulin (r-ATG) as cytoreduction before a TCD HSCT. No post-transplantation immunosuppression was administered. Between April 2001 and May 2008, 102 patients (median age, 55 years) with a diagnosis of primary or secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) underwent cytoreduction with Bu/Mel/Flu, followed by TCD grafts. TCD was accomplished by CD34+-selection followed by E-rosette depletion for peripheral blood stem cell grafts and, for bone marrow grafts, by soybean agglutination followed by E-rosette depletion. Donors included matched and mismatched, related and unrelated donors. Risk stratification was by American Society for Blood and Marrow Transplantation risk categorization for patients with primary disease. For patients with secondary/treatment-related MDS/AML, those in complete remission (CR) 1 or with refractory anemia were classified as intermediate risk, and all other patients were considered high risk. Neutrophil engraftment occurred at a median of 11 days in 100 of 101 evaluable patients. The cumulative incidences of grades II to IV acute and chronic GVHD at 1 year were 8.8% and 5.9%, respectively. Overall- and disease-free survival (DFS) rates at 5 years were 50.0% and 46.1%, respectively, and the cumulative incidences of relapse and treatment-related mortality were 23.5% and 28.4%, respectively. Stratification by risk group demonstrated superior DFS for low-risk patients (61.5% at 5 years) compared with intermediate- or high-risk (34.2% and 40.0%, respectively, P = .021). For patients with AML, those in CR1 had superior 5-year DFS compared with those in ≥CR2 (60% and 30.6%, respectively, P = .01), without a significant difference in incidence of relapse (17.1% and 30.6%, respectively, P = .209). There were no differences in DFS for other patient, donor, or disease characteristics. In summary, cytoreduction with Bu/Mel/Flu and r-ATG secured consistent engraftment of TCD transplantations. The incidences of acute/chronic GVHD and disease relapse were low, with favorable outcomes in this patient population with high-risk myeloid malignancies.

BACKGROUND: Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who relapse after allogeneic hematopoietic cell transplantation (alloHCT) generally have poor overall survival (OS). Interventions that result in improved OS after relapse are not well established. The efficacy of second cellular therapy and specific indications are debated. OBJECTIVES: To study factors associated with post-relapse survival and efficacy of a second course of cellular therapy. STUDY DESIGN: We retrospectively analyzed consecutive AML and MDS patients who received a first alloHCT between 2010 and 2017 at our center but subsequently relapsed. One-hundred-and-four patients with AML and 44 with MDS were included (total n=148). Bone marrow (BM) and peripheral blood stem cell (PBSC) grafts were either unmodified or T-cell depleted (TCD) by CD34+ selection ex-vivo. Forty-five patients (30.4%) received second cellular therapy after relapse, either a second alloHCT (n=28, 18.9%) or donor leukocyte infusion (n=17, 11.5%). RESULTS: The median age at transplant was 60 years (range: 24–78). The median time to relapse (TTR) after transplant was 6.5 months (range: 1–60.9) and the ensuing median OS was 6 months (95% CI: 4.8–8.9). In univariable analysis, longer TTR, relapse type (MRD vs. morphologic), relapse occurring in the most recent years, and receipt of cellular therapy after relapse were associated with better outcomes, whereas adverse cytogenetics and/or abnormality of TP53, as well as NPM1 mutation in patients with AML, were associated with adverse outcomes. Relapse type, year of relapse, and a variable resulting from the combination of TTR and receipt of second cellular therapy remained significantly associated with post-relapse survival in multivariable analysis. In a separate multivariable model, only adjusted for TTR, relapse type, and receipt of second cellular therapy, an adverse effect of NPM1 mutation on survival was confirmed. We could not show an effect of post-transplant maintenance on survival after relapse. In both univariable and multivariable analysis, we found a positive association for second cellular therapy with survival after relapse in patients who relapsed early (< 6 months) after alloHCT and a similar trend in patients who relapsed late (> 12 months) after transplant. Two-year OS after second cellular therapy was 44.9% (95% CI: 28.5–61.4), and it was significantly better in patients with less than 5% BM blasts before cell infusion. We could not show a different effect on survival after second cellular therapy for DLI vs. second alloHCT in univariable analysis. CONCLUSIONS: Survival after relapse is improving over time, but this remains a challenging event, especially for patients relapsing early after transplant. We showed that second cellular therapy could offer a benefit even in these cases. Still, more research is needed to clarify which are the most appropriate treatment choices after relapse. These are probably driven by underlying genetic and immunologic conditions, which should be the focus of future studies.

Mixed phenotype acute leukemia (MPAL) represents a poorly characterized group of acute leukemias that lack an accepted therapeutic approach and are typically associated with poor outcomes. We present our experience of genomic profiling, pretransplantation therapy, and transplantation outcomes for 36 well-characterized pediatric and adult patients with MPAL, defined according to the 2016 World Health Organization leukemia update. A predominance of acute lymphoid leukemia (ALL)-associated mutations and cytogenetic abnormalities was noted. Remission rates after induction appeared comparable among adults (20 of 23) and children (11 of 13) and among those who received ALL (10 of 11) or acute myeloid leukemia-type (21 of 25) induction. Adults underwent transplantation in first remission while children underwent transplantation in the setting of relapse or MLL rearrangement. The median follow-up among the 25 patients who underwent transplantation was 39.6 months and median overall survival was not reached. Relapse after transplantation was associated with MLL rearrangement (P = .022), reduced-intensity conditioning (P .001), and higher WBC at diagnosis (P = .034). These data highlight differing therapeutic approaches between adult and pediatric MPAL and demonstrate favorable survival of adult MPAL patients consolidated with allogeneic hematopoietic cell transplantation.

T cell–depleted (TCD) allogeneic hematopoietic stem cell transplantation (HSCT) is curative treatment for hematologic malignancies in adults, shown to reduce graft-versus-host disease (GVHD) without increased relapse. We retrospectively reviewed a single-center, 11-year experience of 214 patients aged ≥ 55 years to determine tolerability and efficacy in the older adult. Most patients (70%) had myeloid diseases, and most acute leukemias were in remission. Median age was 61 years, with related and unrelated donors ≥8/10 HLA matched. Hematopoietic cell transplantation–specific comorbidity index scores were intermediate and high for 84%. Conditioning regimens were all myeloablative. Grafts were peripheral blood stem cells (97%) containing CD3 dose ≤103-4/kg body weight, without pharmacologic GVHD prophylaxis. With median follow-up of 70 months among survivors, Kaplan-Meier estimates of overall and relapse-free survival were 44% and 41%, respectively (4 years). Cumulative incidence of nonrelapse mortality at day +100 was only 10%. Incidence of GVHD for acute (grades II to IV) was 9% at day +100 and for chronic was 7% at 2 and 4 years (8 extensive, 1 overlap). Median Karnofsky performance status for patients > 2 years post-transplant was 90%. As 1 of the largest reports for patients ≥2 aged ≥55 years receiving TCD HSCTs, it demonstrates curative therapy with minimal GVHD, similar to that observed in a younger population.

The availability of cord blood (CB) and haploidentical (haplo) donors in all patient populations is not established. We have investigated the addition of haplo-CD34+ cells to CB grafts (haplo-CBT) to speed myeloid engraftment. Thus, we have prospectively assessed CB and haplo donor availability in adult patients without 8/8 HLA-allele matched unrelated donors (URDs). Analysis of 89 patients eligible for haplo-CBT revealed 4 distinct patient groups. First, 6 patients (7% of total, 33% non-European) underwent CBT only as they had no suitable family members to type. In group 2, 49 patients (45% non-European) received haplo-CBT using the first haplo donor chosen. Group 3 (n = 21, 76% non-European) underwent CBT with/without haplo. In this group, the first haplo donor chosen failed clearance in 20 patients and transplantation was too urgent to permit donor evaluation in 1. Fifty-three haplo donors were evaluated (2 to 6 per patient) for 21 group 3 patients, and 43 of 53 (81%) haplos failed clearance for predominantly medical and/or psychosocial reasons. Group 4, (n = 13, 85% non-European with a high median weight of 96 kilograms) had no CB grafts with/without no haplo donors. Overall, African patients had the worst donor availability with only 65% having a suitable CB graft and only 44% having a suitable haplo donor. Additionally, in non-European patients, a greater number of haplos required evaluation/patient to secure a suitable haplo graft. Although these data should be confirmed in a larger study, it suggests that there are barriers to the availability of both CB and haplo grafts in adult patients without 8/8 URDs, especially in those with African ancestry, and has multiple practical implications for patient management.

BACKGROUND To evaluate the impact of depression before autologous and allogeneic hematopoietic cell transplantation (HCT) on clinical outcomes posttransplantation. METHODS We analyzed data from the Center for International Blood and Marrow Transplant Research to compare outcomes after autologous (n = 3786) or allogeneic (n = 7433) HCT for adult patients with hematologic malignancies with an existing diagnosis of pre-HCT depression requiring treatment versus those without pre-HCT depression. Using Cox regression models, we compared overall survival (OS) between patients with or without depression. We compared the number of days alive and out of the hospital in the first 100 days post-HCT using Poisson models. We also compared the incidence of grade 2-4 acute and chronic graft-versus-host disease (GVHD) in allogeneic HCT. RESULTS The study included 1116 (15%) patients with pre-transplant depression and 6317 (85%) without depression who underwent allogeneic HCT between 2008 and 2012. Pre-transplant depression was associated with lower OS (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.04-1.23; P = 0.004) and a higher incidence of grade 2-4 acute GVHD (HR, 1.25; 95% CI, 1.14-1.37; P

To evaluate the association between the hematopoietic cell transplantation-comorbidity index (HCT-CI) and the recently developed age-adjusted HCT-CI (HCT-CI/age) and transplant outcomes in the setting of CD34-selected allogeneic HCT, we analyzed a homogeneous population of patients undergoing allogeneic HCT with CD34-selected grafts for acute myeloid leukemia and myelodysplastic syndrome (n = 346). Median HCT-CI and HCT-CI/age scores were 2 (percentile 25 to 75, 1 to 4) and 3 (percentile 25 to 75, 1 to 5), respectively. Higher HCT-CI and HCT-CI/age scores were associated with higher nonrelapse mortality (NRM) and lower overall survival (OS). The HCT-CI distinguished 2 risk groups (0 to 2 versus ≥3), whereas, with the HCT-CI/age, there was a progressive increase in NRM and decrease in OS with increasing scores in all 4 groups (0 versus 1 to 2 versus 3 to 4 versus ≥5). Higher scores in both models were associated with lower chronic graft-versus-host disease relapse-free survival but not with higher relapse. Both models showed a promising predictive accuracy for NRM (c− = .616 for HCT-CI and c− = .647 for HCT-CI/age). In conclusion, the HCT-CI and HCT-CI/age predict transplant outcomes in CD34-selected allo-HCT, including NRM, OS, and chronic graft-versus-host disease relapse-free survival and may be used to select appropriate patients for this approach.

Calcineurin inhibitor-sparing T cell depleted (TCD) hematopoietic stem cell transplants HSCTs are presumed less nephrotoxic than conventional HSCTs. We evaluated incidence and risk factors for kidney failure and chronic kidney disease (CKD) in 231 TCD and 212 conventional HSCT recipients. Kidney failure required a median glomerular filtration rate (GFR) 60 mL/min/1.73 m2 only exposure to nephrotoxic medications was associated with CKD (p=0.033). In the myeloablative conditioning subgroup only total body irradiation was associated with CKD (p=0.013). Of all patients, five (1.13%) required dialysis. These results confirm an impact of TCD on kidney failure but not CKD for which other risk factors such as radiation or nephrotoxic drug exposure may play a role.

Background: Venetoclax (ven) combined with azacitidine (aza/ven), decitabine (dec/ven), and low-dose cytarabine (LDAC/ven) is approved as frontline therapy for older or otherwise unfit AML patients (pts) and also frequently used for pts with relapsed/refractory (RR)-AML. However, clinical outcomes of AML pts who receive an allogeneic stem cell transplant (alloSCT) after ven combination (ven combo) therapy are unclear. Methods: All AML pts who received treatment with aza/ven, dec/ven or LDAC/ven as either initial induction or for RR disease at Memorial Sloan Kettering Cancer Center from 08/2016 to 02/2020 and underwent a subsequent allo-SCT were included. The response to ven therapy prior to alloSCT was determined using the 2017 European LeukemiaNet response criteria. The overall response rate was defined as the combination of the complete response (CR) + complete response with incomplete count recovery (CRi) + morphologic leukemia free state (MLFS) rate. Measurable residual disease (MRD) was assessed by multiparameter flow cytometric analysis of bone marrow aspirate samples. Any level of residual disease was considered MRD+. Overall survival (OS) after alloSCT was calculated from the day of graft infusion until death or time of last follow-up. Results: A total of 130 pts were treated with ven combo therapy with 18 pts (13.8% of all pts) receiving a subsequent alloSCT. Median age was 65 years (A). While 3 pts received a ven combo as the first treatment for AML, 15 pts had RR-AML. Aza/ven was most commonly used (72%) and the majority of pts (83%) received 1-2 cycles of ven therapy prior to alloSCT. For 7, 6, 4 and 1 pts the donor was a matched related, a matched unrelated, a mismatched unrelated, or haploidentical; only one pt had received a prior alloSCT for AML (B). Unmodified peripheral blood stem cells (66%) and reduced intensity conditioning regimens (77%) were most commonly used. In pts who proceeded to an alloSCT, 12/18 pts achieved a response after ven combination therapy: 4/18 MRD-CR/CRi, 4/18 MRD+CR/CRi, 4/18 MLFS; 6/18 pts had persistent disease (C and D). It is important to note that these response rates were specific to patients who received an alloSCT after ven combination therapy. While pts with DNMT3A, NPM1, IDH1/2 and FLT3 mutations had a high response rate to ven therapy prior to alloSCT, none of the pts with TP53 or NRAS mutations achieved a response prior to alloSCT (E). Only DNMT3A mutations were statistically significantly associated with a high response rate prior to alloSCT (ORR 100%, CR/CRi 63%, p=0.01). AlloSCT was able to convert pts with MRD+ or persistent disease into an MRD- state in 50% of cases (F). With a median follow up of 10 months, the median OS was not reached; 56% of pts relapsed after alloSCT. Median time to relapse for all pts was 18 months (95% CI 4 months-not reached [NR]). Disease status prior to alloSCT was a powerful predictor of post-transplant outcomes. Pts who achieved CR, CRi, or MLFS with ven therapy prior to alloSCT had significantly prolonged OS (median OS not reached) compared with pts who had persistent disease prior to alloSCT (median OS 7 months, 95% CI 2.14 months-NR; p=0.029; G). The poor OS for pts with persistent disease prior to alloSCT was mainly driven by a high incidence of relapse for these pts compared to pts who achieved a response to ven combos (H). The median time to relapse after alloSCT was 17.9 months (95% CI 6.1 months-NR) for pts who achieved CR, CRi, or MLFS prior to alloSCT, and only 3.3 months (95% CI 1.9 months-NR, p=0.052) for pts with persistent disease prior to alloSCT. While 67% of pts experienced grade I-II acute graft versus host disease (aGVHD), only 1 pt was found to have grade III aGVHD and no pt experienced grade IV aGVHD. Median time to aGVHD after alloSCT was 1.4 months (95% CI 0.89 months-NR). Conclusion: Venetoclax combination therapy can bridge some AML pts to subsequent alloSCT. Most pts who underwent alloSCT received reduced-intensity conditioning given their advanced age and comorbidities. Pts who achieved CR, CRi, or MLFS with ven-based therapy prior to alloSCT had more favorable outcomes after alloSCT. With more widespread use of venetoclax, we anticipate that alloSCT following good responses to venetoclax combination therapy will become more common in pts with AML. Longer-term studies are needed to determine durability of post-alloSCT responses following pre-alloSCT venetoclax combination therapy. Figure Disclosures Ponce: Kadmon: Membership on an entity's Board of Directors or advisory committees; Generon: Membership on an entity's Board of Directors or advisory committees; Ceramedix: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Young:Amgen: Other: Common stock; Merck: Other: Common stock; Pfizer: Other: Common stock. Gyurkocza:Actinium: Research Funding. Chan:AbbVie: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Xiao:Stemline Therapeutics: Research Funding. Glass:Gerson Lehman Group: Consultancy. King:Abbvie: Other: advisory board. Cai:Imago Biosciences, Inc.: Consultancy, Current equity holder in private company; DAVA Oncology: Honoraria. Stein:Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy; Syndax: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Biotheryx: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Giralt:GSK: 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; Actinuum: Other: Advisory board, Research Funding; Amgen: Other: Advisory Board, Research Funding; OMEROS: Research Funding; Jensenn: Membership on an entity's Board of Directors or advisory committees, Research Funding; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Research Funding; JAZZ Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; MILTENYI: Research Funding; PFIZER: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; SPECTRUM Pharma: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees. Perales:Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Cidara Therapeutics: Other; Takeda: 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; Nektar Therapeutics: 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; MolMed: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tallman:Novartis: Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Orsenix: Research Funding; ADC Therapeutics: Research Funding; UpToDate: Patents & Royalties; Abbvie: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Research Funding; Rafael: Research Funding; Amgen: Research Funding; Bioline rx: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Goldberg:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Aprea: Research Funding; AROG: Research Funding; Celularity: Research Funding; Pfizer: Research Funding; Dava Oncology: Honoraria.

Background: Rabbit anti-thymocyte globulin (rATG) is used in allogeneic hematopoietic cell transplantation (alloHCT) to prevent graft versus host-disease (GVHD) and graft rejection. In the T-cell replete setting, post-HCT rATG exposure is variable with high exposures resulting in delayed CD4+immune reconstitution (CD4+IR) and higher mortality. The goal of this study was to estimate the rATG exposure in pediatric and adult recipients of ex vivo T-cell depleted CD34+ selected alloHCT and correlate it with outcomes to determine the optimal exposure. Methods: We performed a retrospective analysis of patients who underwent their first myeloablative-conditioned ex vivo CD34+ selected alloHCT between 2008 and 2018. Post-HCT rATG exposure was estimated as area under the curve (AUC) (mg*d/L) using a validated population pharmacokinetic (PK) model (Admiraal et al.,Lancet Hematology 2017). Outcomes of interest were CD4+IR, defined as CD4+>50/uL at two consecutive measures within 100 days of HCT, non-relapse mortality (NRM), overall survival (OS), GVHD, and relapse. We evaluated the association between post-HCT rATG exposures and CD4+IR using a smoothed effect to define the optimal post-HCT rATG exposure. We subsequently analyzed outcomes in 3 post-HCT rATG exposure groups, =55 mg*d/L. Cox proportional hazard models and multi-state competing risk models were used for analyses. Results: Of 554 patients included, 239 (43%) were female, median age at HCT was 49 (range 0.2 to 73) years and 425 (76.7%) received matched donor transplant, while 129 (23.3%) patients received mismatched donor HCT. In this cohort of patients, 515 (93%) underwent alloHCT for hematologic malignancies - leukemia: 356 (64.3%), myelodysplastic syndrome: 122 (22%), and other hematological malignancies: 37 (6.7%) while 39 (7%) underwent alloHCT for non-malignant indications. Total Body Irradiation based conditioning regimen was administered in 177 (32%) patients. Among all 554 patients, 540 (97%) attained engraftment. Median post-HCT rATG exposure was 47mg*d/L (range 0 - 101 mg*d/L). A decreasing post-HCT AUC (optimum On further assessing rATG exposure post allo-HCT by three cut -off levels (=55 mg*d/L), time to CD4+IR varied depending on the ATG exposure (Figure 1e). In multivariable cox models, post-HCT rATG exposure >=55 mg*d/L was associated with an increased risk of NRM as compared to the lower exposure of =55 mg*d/L was associated with a higher risk of acute GVHD (HR: 2.28, CI: 1.01, 5.16, Figure 1h). In patients with hematologic malignancies, post-HCT rATG exposure was not associated with relapse (HR: 0.73, CI: 0.31,1.7). In the entire cohort of 554 patients, 9 (1.6%) patients had graft rejection: 1 primary rejection in the post-HCT ATG exposure =55mg*d/L group. Among all patients, 204 (37%) died secondary to reasons such as relapse of disease: 73 (36%), infection: 51 (25%), GVHD: 40 (20%), toxicity/organ failure: 29 (14%) and other causes: 11 (5%). Conclusions: In a large cohort of patients who underwent ex vivo CD34+ selected alloHCT, higher post-HCT rATG exposure led to higher NRM, a paradoxical increase in GVHD, and lower OS driven by poorer CD4+ IR. The increased rates of GVHD with higher post-HCT exposure may be related to increased infections in these cohorts, though this needs to be explored further. Individualizing rATG dosing by PK targeting to a low post-HCT rATG exposure may improve outcomes. We intend to validate these results in a forthcoming prospective clinical trial. Figure 1 Disclosures Scordo: McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board. Curran:Celgene: Research Funding; Novartis: Consultancy, Research Funding; Mesoblast: Consultancy. Kernan:Amgen: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; Johnson and Johnson: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company. O'Reilly:Atara Biotherapeutics: Consultancy, Patents & Royalties: EBV-specific T-cell bank, Research Funding. Prockop:Mesoblast, Inc,: Consultancy, Honoraria, Research Funding; Atara: Research Funding; Jasper: Research Funding. Scaradavou:Excellthera: Membership on an entity's Board of Directors or advisory committees. Shah:Amgen Inc.: Research Funding; Janssen: Research Funding. Giralt:OMEROS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Research Funding; KITE: Consultancy; MILTENYI: Consultancy, Research Funding; ACTINUUM: Consultancy, Research Funding; TAKEDA: Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding. Perales:Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Novartis: 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; Merck: Consultancy, Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; MolMed: Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Takeda: 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. Boelens:Bluebird Bio: Consultancy; Advanced Clinical: Consultancy; Race Oncology: Consultancy; Bluerock: Consultancy; Omeros: Consultancy; Avrobio: Consultancy; Takeda: Consultancy.

Introduction/Methods The trajectory of functional decline and the prevalence of geriatric syndromes have not been examined among long-term survivors of older allo-HCT recipients. We previously described significant burden and adverse impact of post-transplant geriatric syndromes, delirium and fall, among older allogeneic recipients. We report here theprevalence and impact of geriatric syndromes in 2-year, progression-free survivors among this cohort of patients using our institutional database. Baseline characteristics, transplant outcomes, geriatric assessment domains, and geriatric syndromes were obtained and analyzed as previously described. Results We identified 199 2-year, progression-free survivors of patients allografted at age ≥60 years from 2001 to 2016, including 111 out of 241 patients on the CD34+ selection platform (46%), and 88 out of 231 T-cell replete patients (38%). The median age at allo-HCT was 65.4 years (range 60 – 78.7); 73% had myeloid malignancies; 69% had high/very high risk HCT-CI/age; 14% had a mismatched donor; and 56% had a CD34+ selected graft. With a median follow-up of 5.7 years for survivors, the 3-yr OS and RFS from the 2-year landmark was 86% (95% CI, 80 – 91) and 83% (95% CI, 78 – 89). Thirty-three patients died, including 8 from relapse/disease progression, and 25 from non-relapse mortality (6 each from secondary neoplasm, organ failure, and infections). The 3-year cumulative incidence of new functional impairment (FI), defined as new admission to skilled nursing facility, fall, or assisted walking device from the 2-year landmark, was 20% (95% CI, 15 – 27). In addition, the 3-year cumulative incidence of new psychiatric illness and cognitive decline was 6% (95% CI, 3 – 11) and 5% (95% CI, 3 – 10), respectively (Figure 1). We examined factors associated with new FI and found that, among others, patients who were transplanted with a CD34+ selected graft had lower incidence of new FI in univariate (hazard ratio [HR]=0.49, 95% CI 0.28 – 0.86, P=0.014) and multivariate analysis with borderline significance (HR=0.53, 95% CI 0.27 – 1.02, P=0.056). In 2-year landmark analyses, both high/very high HCT-CI/age index and mismatched donor were significantly associated with inferior OS and RFS (Table 1). Conclusion While limited by the single institution, retrospective design, heterogenous transplant approach, and likely under-reporting, our findings nevertheless illustrate the high prevalence of FI among older allo-HCT survivors, which maybe attenuated by the CD34+ selection platform. In addition, the impact of graft-versus-host disease on the development of geriatric syndromes merits closer examination. While requiring prospective confirmation, long-term functional impairment should be considered as an important secondary outcome when comparing curative strategies to other less intense approaches in older patients with hematologic malignancies.

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.

Introduction Patients (pts) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have historically shown very poor post-relapse overall survival (prOS). Objective To study the factors and treatment strategies associated with the best prOS. Methods We conducted a retrospective analysis of all pts at our institution who received a first allo-HCT between 2010 and 2017 for AML or MDS but relapsed post-transplant. Bone marrow (BM) and peripheral blood stem cells (PBSC) grafts were included, either T-cell depleted (TCD) by ex-vivo CD34+ selection (Miltenyi CliniMACS) or unmodified. Univariate (UVA) Cox proportional hazards regression was used to examine the association between prOS and patient-, disease-, and transplant-related variables. Receipt of second cell therapy (sCT) after relapse was a time-dependent covariate. Results Key characteristics of the study population are listed in Table 1. Median time to relapse (TTR) was 6 months (range: 1-61) and median prOS was also 6 months (95%CI: 4.8-8.8) in the whole population. AML pts showed shorter median prOS compared with MDS pts (5.3 [95%CI: 3.9-8] vs. 9.4 [95%CI: 5.7-24] months, p=0.026). No statistically significant associations were observed between prOS and conditioning intensity (reduced vs. ablative) or graft manipulation (TCD vs. unmodified). There was a significant association between TTR and prOS (Fig. 1). Forty-five pts received sCT after relapse, either a second allo-HCT (28) or donor lymphocyte infusions (17). The hazard of death after relapse for these patients was lower (HR 0.53, 95%CI: 0.32-0.87, p=0.01) and 2-year survival after sCT was 44.9% (95%CI: 31.1-64.8, Fig. 2). We used a 4-level categorization of TTR ( Conclusion Although limited by the retrospective nature and potential selection bias, we show in a large, contemporary cohort that pts who relapse after ≥ 12 months from a first allo-HCT and receive sCT have the best prOS.

Background Ph-like ALL is a recently recognized high risk B-ALL subgroup, defined by a gene expression profile similar to Ph (+) ALL that activates tyrosine kinase or cytokine receptor signaling. Several studies have described inferior outcomes with conventional chemotherapy and although small series suggest that it is responsive to targeted therapies, stem cell transplant (SCT) remains the only potentially curative option. However, the SCT outcomes of Ph-like ALL are not well defined and it remains unknown whether SCT is able to overcome the adverse prognosis associated with it. Methods We retrospectively identified 77 adult patients with Ph (-) B-ALL that received a SCT at Memorial Sloan Kettering, 2008-2018, and reviewed their cytogenetic and molecular reports at diagnosis. Testing for Ph-like ALL is employed in an algorithmically driven approach at our institution including cytogenetics, chromosomal microarray and next generation sequencing (NGS). Ph-like ALL was defined by the presence of abnormalities including ABL-class fusions that phenocopy BCR-ABL (ABL1, ABL2, CSF1R and PDGFRB) or alterations of CRFL2, JAK2 and EPOR that activate JAK/STAT signaling. We then analyzed the SCT outcomes of Ph-like patients and compared them to Ph (-) patients. Results A Ph-like signature was identified in 13 of 77 (16.9%) patients by NGS (n=7), cytogenetics (n=1), both NGS/cytogenetics (n=2) or microarray (n=3). Median age of all 13 patients was 42.7 (range 23.9-67.7) years and 6 (46.2%) patients were adolescents/young adults ( At a median follow up of 17.3 (range 0.5-109.3) months, overall survival (OS) was comparable between the Ph-like and Ph (-) groups with one-year OS rates of 74% and 70% (p=0.534) respectively (Fig 2A). Causes of death in Ph-like patients were relapse (n=2) and infectious complications (n=1). One-year cumulative incidence of relapse was 32.7% in Ph-like vs 17.3% in Ph (-) patients, however it did not reach statistical significance (p=0.94, Fig 3). Among the 4 Ph-like patients who relapsed, 1 had refractory disease prior to SCT, 2 were in second remission and 1 in first remission. One-year disease free survival was also comparable between the 2 groups (67% for Ph-like vs 65% for Ph (-), p=0.719) (Fig 2B). Finally, acute GVHD rates by day 100 were 69.2% in Ph-like (n=9) vs 53.1% (n=34) in Ph (-) patients (p=0.3). Conclusions Our findings suggest that SCT overcomes the adverse prognosis associated with the Ph-like signature and should be incorporated in the treatment of patients with this disease entity.

Retrospective studies indicate that the use of unrelated hematopoietic stem cell donors with Killer Ig-like Receptor (KIR) genotypes resulting in low inhibitory interactions with recipient HLA are associated with lower relapse and higher survival in patients with myeloid neoplasia undergoing allogeneic hematopoietic cell transplantation (allo HCT). To validate these findings in a prospective fashion and to determine if advantageous KIR donors can readily be identified for patients with myeloid neoplasia, we prospectively KIR genotyped and provided KIR/HLA-based ranking for unrelated donors (URD) evaluated for patients with a diagnosis of acute myeloid leukemia or myelodysplastic syndrome undergoing workup at our center for allo HCT. Donors were prioritized first to minimize inhibitory KIR3DL1 - HLA-Bw4 interactions, followed by prioritization of donors with non-tolerized activating KIR2DS1, and finally prioritizing donors homozygous for the centromeric B haplotype. We evaluated 2,079 donors for 527 patients (median 4 donors per patient), among whom 263 ultimately underwent allo HCT. In a multivariate analysis adjusting for age, HCT-CI, and conditioning intensity, we found that the use of a KIR3DL1-low-inhibition donor was associated with an improved hazard for survival (HR = 0.58 (95% confidence interval (CI): 0.35 – 0.96), P = 0.035) and event-free survival (HR = 0.61 (95% CI: 0.39 – 0.93), P = 0.023) due to a decreased hazard for relapse (HR = 0.52, 95% CI: 0.30 – 0.90, P = 0.021) without increased non-relapse mortality when compared to KIR3DL1-non-interacting or -high-inhibition donors. Donor KIR2DS1/HLA-C1 status and centromeric haplotype B content were not predictive of relapse or survival in this cohort. Among 339 HLA-Bw4+ patients evaluated for transplant, 242 (71.4%) had an available KIR3DL1-low-inhibition donor and 205 (60.5%) had a mixture of KIR3DL1-low-inhibition with either -high-inhibition or -non-interacting donors facilitating a choice using donor KIR3DL1 genotyping. Evaluating greater numbers of donors associated with an increased probability of identifying an advantageous donor based on inhibitory KIR3DL1 interactions (P

(Val)ganciclovir (vGCV) or foscarnet (FCN) as preemptive therapy (PET) for cytomegalovirus (CMV) after allogeneic hematopoietic cell transplantation (HCT) is associated with myelosuppression and nephrotoxicity, respectively. We analyzed a cohort of CMV-seropositive (R(+)) HCT recipients managed preemptively at a single center. The objectives of our study were to (1) quantify the frequencies of neutropenia and acute kidney injury (AKI) through day +100 (D100) post-HCT and at PET discontinuation and (2) assess the impact of PET on neutropenia and AKI in multivariate models. This was a retrospective cohort study of adult CMV R(+) recipients who underwent allo-HCT at Memorial Sloan Kettering Cancer Center from March 18, 2013, through December 31, 2017, and were managed with PET. Patients were grouped by receipt of PET (PET and no PET). Neutropenia and AKI were defined by Common Terminology Criteria for Adverse Events version 4. Frequencies of toxicities by D100 were compared between relevant groups. The impact of PET on toxicities was examined in univariate and multivariate Poisson/negative binomial regression models. Of 368 CMV R(+) HCT recipients, 208 (56.5%) received PET. Neutropenia by D100 occurred in 41.8% and 28.6% patients in PET and no PET, respectively (P = .0009). PET increased the risk of neutropenia (adjusted relative risk = 1.81; 95% confidence interval [CI], 1.48 to 2.21; P < .0001) in multivariate analyses. AKI by D100 occurred in 12.0% and 7.8% patients in PET and no PET, respectively (P = .19). PET increased the risk of AKI by 2.75-fold (95% CI, 1.71 to 4.42; P < .0001). When PET recipients were grouped by first antiviral, neutropenia by D100 occurred in 34.8% and 48.9% of vGCV and FCN recipients, respectively, (P = .08), and AKI occurred in 13.0% and 34.0% of vGCV and FCN recipients, respectively (P = .001). At discontinuation of vGCV or FCN, neutropenia was present in 11.2% versus 2.1% patients, respectively (P = .08), and AKI was present in 1.9% of versus 12.8% patients respectively (P = .005). Preemptive therapy for CMV increased the risk of neutropenia and AKI in the first 100 days post-HCT by 1.8-fold and 2.8-fold, respectively. Our results underscore the need for safer antivirals for CMV management in HCT recipients.

Large series of patients with acute myelogenous leukemia (AML) after ex vivo T cell-depleted (TCD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) have not been reported previously. We retrospectively analyzed the outcomes of 266 patients (median age, 54 years) with AML who received CD34-selected TCD allo-HSCTs while in first (75%) or second (25%) complete remission (CR1/CR2) at a single institution. The conditioning regimens were all myeloablative, and no additional graft-versus-host disease (GVHD) prophylaxis was given. The cumulative incidences of grade II-IV and grade III-IV acute GVHD at 180 days were 14% (95% confidence interval [CI], 10% to 18%) and 3% (95% CI, 1% to 5%), respectively. The cumulative incidence of chronic GVHD at 3 years was 3% (95% CI, 1% to 6%). The 3-year cumulative incidence of nonrelapse mortality was 21% (95% CI, 16% to 26%) and that of relapse was 21% (95% CI, 17% to 27%). Overall survival (OS) and disease-free survival (DFS) at 1, 3, and 5 years were 75%, 61%, and 56% and 68%, 57%, and 53%, respectively. There were no significant differences in OS, DFS, and relapse rates for patients who underwent transplantation in CR1 and those who did so in CR2. However, patients with high-risk cytogenetics at diagnosis had significantly poorer outcomes. The OS and DFS rates compare favorably with those for unmodified allo-HSCT, but with considerably lower rates of GVHD.

The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34+ level before apheresis compared with younger RDs (age > 60, 59 × 106/L; age 41 to 60, 81 × 106/L; age 18 to 40, 121 × 106/L; P < .001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% ≥ 2 collections, P < .001) and higher collection volumes (52% versus 32% > 24 L, P < .001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia

While histopathologic differences have been reported between acute graft-versus-host disease (aGVHD) and non-aGVHD rash in CD34(+)-selected peripheral blood stem cell transplantation (PBSCT) recipients, skin biopsies alone are usually insufficient to determine rash etiology. As such, distinguishing inflammatory non-aGVHD rashes, such as drug eruptions, from cutaneous aGVHD after CD34(+)-selected PBSCT remains challenging and relies on clinical presentation. This study aimed to identify etiologies of skin rash in the first year after CD34(+)-selected PBSCT and to assess whether laboratory serologic markers, transplant characteristics, and rash morphology and symptomatology aid in differentiation of cutaneous aGVHD versus non-aGVHD rash. We conducted a retrospective study of 243 adult patients who received a CD34(+)-selected PBSCT at Memorial Sloan Kettering Cancer Center between 2008 and 2011. Among this cohort of transplant recipients, only 43 patients (17.7%) developed cutaneous aGVHD. In total, 152 patients (63%) were identified with rash within one year after PBSCT. The proportion of patients who experienced peripheral eosinophilia was not different between those with an aGVHD versus non-aGVHD rash (p ≥0.9), nor when stratified by CD34(+) selection method (Isolex p=0.7; CliniMACS p ≥0.9). The proportion of patients with pruritus was also not different between those with an aGVHD versus non-aGVHD rash (p=0.20), nor when stratified by CD34(+) selection modality (Isolex p=0.2; CliniMACS p=0.5). The most common cause of non-aGVHD rash among those with a clear etiology was drug (39% of Isolex; 26% of CliniMACS). Single drug culprits were identified in 51% of drug rashes. The most commonly reported offending agents included antibiotics, keratinocyte growth factor (KGF), chemotherapy, and recombinant glycosylated human interleukin-7 (IL-7).

Adults undergoing hematopoietic stem cell transplant (HSCT) are at risk for vitamin D deficiency. After HSCT, exposure to sunlight is restricted, and patients may experience poor nutrition and malabsorption from HSCT-related side effects. Vitamin D affects bone health and immunologic processes. The aim of this project is to establish a process for monitoring and treating vitamin D deficiency and to evaluate if therapeutic vitamin D levels are attainable posttransplant using an HSCT vitamin D replacement algorithm. A multidisciplinary group led by advanced practice providers established a workflow for monitoring and supplementing vitamin D and created an HSCT vitamin D replacement guideline. The medical records of 144 adult HSCT patients were reviewed, and the records of another 72 patients were reviewed a year later. Historical baseline data before the intervention found that 81% of patients were vitamin D deficient and 30% received supplementation. Postintervention and at 1-year follow-up, 76% and 65% of patients were vitamin D deficient before transplant and 97.1% and 100%, respectively, received supplementation for vitamin D deficiency. Post-HSCT compliance with monitoring demonstrated that approximately 91% of patients had a vitamin D level checked within 6 months of transplant. After implementation of the algorithm, there was a statistically significant difference (p < .001) between deficient vitamin D levels pretransplant (72.9%) and posttransplant (26.4%). Results demonstrate sustained compliance over a 2-year period with monitoring and supplementation of vitamin D pre- and peritransplant. Aggressive vitamin D repletion posttransplant decreased the incidence of vitamin D deficiency in HSCT patients. Further study is needed to investigate the long-term effects of vitamin D repletion on posttransplant complications.

Cytomegalovirus (CMV) is serious viral infection in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. November 2017, the novel CMV DNA terminase complex inhibitor letermovir was approved for prophylaxis of CMV infection in CMV-seropositive allo-HCT recipients. Here we sought to determine the effectiveness of letermovir in preventing CMV infection in CMV-seropositive patients undergoing haploidentical or mismatched adult unrelated donor allo-HCT using post-transplantation cyclophosphamide-based graft-versus host-disease prophylaxis. Sixty-four patients underwent transplantation between 2014 and 2019, of whom 32 received letermovir and 32 did not receive letermovir. The day 180 cumulative incidence of CMV infection requiring therapy was 45.3% (95% confidence interval [CI], 32.7% to 57.1%) in the entire cohort, 68.8% (95% CI, 48.9% to 82.2%) in the patients who did not receive letermovir, and 21.9% (95% CI, 9.5% to 37.6%; P.001) in patients who received letermovir. Adjusting for regimen intensity, disease histology, and age, the hazard ratio for CMV infection was .19 (95% CI, .08 to .47; P.001) in patients who received primary prophylaxis with letermovir. The 1-year cumulative incidence of treatment- related mortality was similar between patients with and without letermovir treatment (16.9% versus 18.9%), as was overall survival (64.0% versus 49.0%). Persistent CMV infection requiring28 days of therapy was more common in patients who did not receive letermovir (31.2% versus 6.2%; P = .02). In summary, letermovir was effective in preventing CMV infection in this high-risk population of HLA-mismatched allo-HCT recipients.

The effectiveness of preemptive treatment (PET) for cytomegalovirus (CMV) in recipients of ex vivo T cell–depleted (TCD) hematopoietic cell transplantation (HCT) by CD34+ selection is not well defined. We analyzed 213 adults who received TCD-HCT at our institution from June 2010 through May 2014. Patients were monitored by a CMV quantitative PCR assay if recipient (R) or donor (D) were CMV seropositive. CMV viremia occurred early (median, 27 days after HCT) in 91 of 213 (42.7%) patients for a 180-day cumulative incidence of 84.5%, 61.8%, and 0 for R+/D+, R+/D−, and R−/D+ patients, respectively. CMV disease occurred in 5% of patients. In Cox regression analysis, R+/D+ status was associated with increased risk for CMV viremia compared with R+/D− (hazard ratio [HR], 1.79, 95% confidence interval [CI], 1.16 to 2.76, P = .01), whereas matched unrelated donor allograft was associated with decreased risk (HR, .62; 95% CI, .39 to .97, P = .04). Of 91 patients with CMV viremia, 52 (57%) had persistent viremia (>28 days duration). Time lag from detection of CMV viremia to PET was associated with incremental risk for persistent viremia (HR, 1.09; 95% CI, 1.01 to 1.18; P = .03). Overall, 166 of 213 (77.9%) patients were alive 1 year after HCT, with no difference between patients with and without CMV viremia or among the different CMV serostatus pairs (P = not significant). CMV viremia occurred in 70% of R + TCD-HCT. Delay in PET initiation was associated with persistent viremia. With PET, CMV R/D serostatus did not adversely impact survival in TCD-HCT on 1-year survival in the present cohort.

We conducted a phase 2 study to determine the efficacy of HLA-haploidentical related donor natural killer (NK) cells after cyclophosphamide-based lymphodepletion in patients with relapsed or progressive acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) following allogeneic hematopoietic cell transplantation (HCT). Eight patients (2 with MDS and 6 with AML) were treated with cyclophosphamide 50 mg/kg on day -3 and day -2 before infusion of NK cells isolated from a haploidentical related donor. One patient also received fludarabine 25 mg/m2/day for 4 days. Six doses of 1 million units of interleukin-2 (IL-2) were administered on alternating days beginning on day -1. The median number of NK cells infused was 10.6 × 10(6)/kg (range, 4.3 to 22.4 × 10(6)/kg), and the median number of CD3 cells infused was 2.1 × 10(3)/kg (range, 1.9 to 40 × 10(3)/kg). NK infusions were well tolerated, with a median time to neutrophil recovery of 19 days (range, 7 days to not achieved) and no incidence of graft-versus-host disease after NK infusion. One patient with AML and 1 patient with MDS achieved a complete response, but relapsed at 1.7 and 1.8 months, respectively. One patient with MDS experienced resolution of dysplastic features but persistence of clonal karyotype abnormalities; this patient was stable at 65 months after NK cell therapy. The median duration of survival was 12.9 months (range, 0.8 to 65.3 months). Chimerism analysis of CD3(-)/CD56(+) peripheral blood cells did not detect any circulating haploidentical NK cells after infusion. NK phenotyping was performed in 7 patients during and after IL-2 infusion. We found a slight trend toward greater expression of KIR2DL2/2DL3/2DS2 (5% versus 28%; P = .03) at 14 days in patients who survived longer than 6 months from NK cell infusion (n = 4) compared with those who died within 6 months of NK cell therapy (n = 3). In summary, our data support the safety of haploidentical NK cell infusion after allogeneic HCT.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for patients with myelodysplastic syndrome (MDS). Donor T cells are critical for the graft-versus-tumor effect but carry the risk of graft-versus-host disease (GVHD). CD34 selection with immunomagnetic beads has been an effective method of depleting alloreactive donor T cells from the peripheral blood graft and has been shown to result in significant reduction in acute and chronic GVHD. We analyzed the outcomes of 102 adults (median age, 57.6 years) with advanced MDS who received a CD34-selected allo-HSCT between January 1997 and April 2012 at Memorial Sloan Kettering Cancer Center. The cumulative incidences of grades II to IV acute GVHD were 9.8% at day 100 (95% confidence interval [CI], 5.0% to 16.5%) and 15.7% at day 180 (95% CI, 9.4% to 23.4%). The cumulative incidence of chronic GVHD at 1 year was 3.9% (95% CI, 1.3% to 9.0%). The cumulative incidences of relapse were 11.8% at 1 year (95% CI, 6.4% to 18.9%) and 15.7% at 2 years (95% CI, 9.4% to 23.4%). Forty-eight patients were alive with a median follow-up of 71.7 months. Rates of overall survival (OS) were 56.9% at 2 years (95% CI, 48% to 67.3%) and 49.3% at 5 years (95% CI, 40.4% to 60.2%). Rates of relapse-free survival (RFS) were 52.0% at 2 years (95% CI, 41.9% to 61.1%) and 47.6% at 5 years (95% CI, 37.5% to 56.9%). The cumulative incidences of nonrelapse mortality were 7.8% at day 100 (95% CI, 3.7% to 14.1%), 22.5% at 1 year (95% CI, 15.0% to 31.1%), and 33.4% at 5 years (95% CI, 24.2% to 42.6%) post-transplant. The incidence of chronic GVHD/RFS overlapped with RFS. These findings demonstrate that ex vivo T cell–depleted allo-HSCT by CD34 selection offers long-term OS and RFS with low incidences of acute and chronic GVHD and without an increased risk of relapse.

Background We recently showed that empiric weight-based ATG dosing in heavier patients (pts) prior to ex vivo CD34-selected allogeneic hematopoietic cell transplantation (allo-HCT) is associated with high non-relapse mortality (NRM) and poor survival. A more precise method is to assess the relationship between ATG pharmacokinetic (PK) exposure and outcomes. Therefore, we estimated ATG exposure using a population PK model and hypothesized that peri-HCT ATG overexposure would similarly result in unfavorable outcomes secondary to poorer immune reconstitution (IR). Methods We studied 415 consecutive adult pts who underwent first myeloablative ex vivo CD34-selected allo-HCT with ATG (Thymoglobulin) between 2006 and 2017. We estimated pre-/post-HCT and total ATG area under the curve (AUC, in mg*d/L) for all pts using an established PK model (Admiraal et al., Lancet Hematol 2017). We evaluated the association between ATG exposure and outcomes using a nonparametric estimate of median relapse-free survival (RFS) by ATG exposure to define an optimal ATG AUC cut point (highest RFS) that was used to estimate RFS and NRM. We also evaluated how CD4+ T cell IR related to NRM in a subgroup of 232 pts with sufficient data. IR was defined according to prior studies as absolute CD4+ ≥ 50 at ≥ 2 time points before day +100 and 1 subsequent time point within 60 days. Results Among all pts, median age was 55 (range, 19-73), 228 (55%) were male, 204 (49%) had AML, 105 (25%) MDS, 50 (12%) ALL, and 56 (14%) other hematologic diseases. HCT-CI was 0 in 85 (20%), 1-2 in 146 (35%), and ≥ 3 in 184 (45%) of pts. Allografts were HLA matched related in 150 (36%), matched unrelated in 202 (49), and mismatched in 63 (15%). CMV serostatus was positive in 251 (60%). Conditioning regimens were chemotherapy based in 279 (67%) and TBI based in 136 (33%). All but 2 pts, who were inevaluable given early deaths, engrafted. All pts received 1-3 doses of ATG 2.5 mg/kg between days -4 and -1: 361 (87%) received 2 doses, 47 (11%) 3 doses, and 7 (2%) 1 dose. Among all pts, median estimated ATG AUC values were: pre-HCT 19 (range, 9-36), post-HCT 48 (range, 17-101), and total 66 (29-125). Median follow-up among survivors was 3.9 years (range, 0.7-12). A post-HCT ATG AUC of >60 was associated with poorer median predicted RFS (Figure 1). Pts with an estimated post-HCT ATG AUC of >60 and Conclusions Population PK modeling confirms that post-HCT ATG overexposure in certain pts undergoing ex vivo CD34-selected allo-HCT leads to inferior RFS and markedly higher NRM possibly due to poor IR. Identifying the optimal ATG exposure and individualizing ATG dosing may improve early CD4+ IR and ultimately improve survival in these pts.

Introduction Recipients of ex-vivo T-cell depleted (TCD) (CD34+ selected) hematopoietic cell transplant (HCT) are at increased risk for infections by double-stranded DNA viruses. TCD HCT recipients at Memorial Sloan Kettering Cancer Center were routinely screened for HHV-6 by plasma PCR between 2012 and 2016. The objectives of our study were to 1) report the incidence of persistent HHV-6 viremia and disease 2) identify risk factors of persistent HHV-6 viremia; 3) examine the association between persistent HHV-6 viremia and overall survival (OS) at 1-year post-HCT. Methods Recipients with TCD HCT between 2012 and 2016 routinely screened for HHV-6 by plasma PCR were reviewed retrospectively. CD34+ selection was performed by the CliniMACS CD34 Reagent system (Miltenyi Biotec, Germany). HHV-6 viremia was defined as ≥1 HHV-6 viral load (VL) >limit of quantification. Persistent HHV-6 viremia was defined as ≥2 consecutive measurements of VL ≥500 copies/mL through day+100 post-HCT, death, relapse, and second transplant whichever occurred first. Cox proportional model was used to examine the risk factors of persistent HHV-6 viremia. One-year OS was estimated by Kaplan-Meier method. Results Of 312 patients, 59% were male and median age was 55 years (range, 22-73). 67% had acute leukemia and myelodysplastic syndrome and 18% had mismatched donors. 55% developed HHV-6 viremia. Eighty-three (27%) had persistent HHV-6 viremia with a median duration of 67 days (interquartile range [IQR], 56-75) (Figure 1). Mismatched donor (P=0.04) and recipient CMV seronegativity (R-) (P=0.04) were associated with persistent HHV-6 viremia. Of 83 patients with persistent HHV6 viremia, 23 (28%) had max VL ≥10,000 copies/mL and 7 (8%) developed HHV-6 disease (encephalitis 1, pneumonitis 4, and organizing pneumonia 2). Maximum VL with HHV-6 disease was a median VL 71,700 copies/mL (IQR, 8,211-123,500). Persistent HHV-6 viremia was associated with lower absolute lymphocyte counts (ALCs) up to 1-year post-HCT (figure 2) and lower 1-year OS (P=0.02) (figure 3). Conclusion 27% of TCD HCT recipients developed persistent HHV-6 viremia. Mismatched donor and CMV R- were associated with persistent HHV-6 viremia. Among patients with persistent HHV-6 viremia, 8% developed HHV-6 disease. Persistent HHV-6 viremia was associated with lower ALCs and OS at 1-year post-HCT.

Background Co-morbidities are essential for risk-stratification before allogeneic hematopoietic stem cell transplantation (HCT). We hypothesized that only certain components of the co-morbidity index (HCT-CI) are predictive of outcomes, and that their impact is conditioning-regimen dependent. Methods This retrospective single-center analysis included 580 adult patients who underwent HCT with ex-vivo CD34+ selection following myeloablative conditioning between 2008 and 2018. Results Chemotherapy and total body irradiation (TBI)-based conditioning were given to 75% and 25% of patients, respectively. Common co-morbidities in the population included mild/severe hepatic dysfunction (25%), moderate and severe pulmonary disease (32% and 11%, respectively), prior malignancy (14%), and psychiatric disorders (13%). The median HCT-CI was 2 (IQR 1-3). Among co-morbidities meeting statistical criteria for analysis (prevalence >5% and association with at least 5 outcome events), only severe and moderate pulmonary dysfunction (Figure 1) were associated with decreased overall survival (OS) and increased non-relapse mortality (NRM; HR 1.37, p .023; HR 1.94 p Conclusions Our findings suggest that, in CD34+ selected HCT, only certain co-morbidities included in the HCT-CI are likely to contribute to the prognostic assessment of transplantation candidates. Reevaluation of the additive role of co-morbidities in this setting is warranted. In addition, the hazard of co-morbidities may be regimen-dependent, introducing another consideration when selecting the conditioning modality.

Introduction To assess the therapeutic potential of non-TBI conditioning and T-cell depleted (TCD) allo HCT for high risk malignancies, we conducted a prospective trial comparing: A. our standard 1375 cGy HFTBI + Thiotepa, 5mg/kg/dx2 + cyclophosphamide, 60mg/kg/dx2 vs B. Busulfex, 0.8mg/kg/6hx12(PK adjusted) + Melphalan 70mg/kg/dx2 + Fludarabine 25mg/m2/dx5 vs C. Clofarabine 20mg/m2/dx5 + Melphalan 70mg/m2/dx2 + Thiotepa 5mg/kg/dx2 as preparation for T-cell depleted CD34+ PBSC allografts isolated by the CliniMACS system. All pts received Thymoglobulin pre-transplant to prevent infection. No GVHD prophylaxis was given post transplant. Pts were stratified to arms A, B or C based on disease stage and clinical factors enhancing TBI risks (e.g. age >60m prior therapy or comorbidities), with Arm B the non-TBI arm used for myeloid malignancies and Arm C for lymphoid malignancies. Results From 5/13/10 to 12/31/16, 283 consenting patients were transplanted (106 in Arm A, 144 in B, 33 in C). All pts engrafted by day 10-11; 3 pts in Arm B and 1 in C had late graft failure with sustained T-cell chimerism. The 3 in Arm B reconstituted after TCD PBSC boost alone (N=2) or after CTX/ATG (N=1) conditioning. Cumulative Incidence (C.I.) of Acute Grade 3-4 GVHD was higher in Arm A (12%) than in B (4.2%) or C (3.0%) (p = 0.03), as was C. GVHD (Arm A 8.5%; B (1.5% p = 0.02); C (3%)). CI of relapse at 3 yrs was similar in all arms (A=28%; B=21%; C15%) (p = 0.22). Although pts in Arm B were older (med. 58.5 yrs) than in A (32 yrs) or C(32 yrs), NRM at 3 yrs for Arm B (16%) and A (14.8) were similar. However, NRM in Arm C (32.7%) was higher (p = 0.09). Because the median age of patients in Arm B (58.5 yrs) differed significantly from Arms A (31.9 yrs) and C (32.3 yrs); we evaluated DFS for each arm in 20 year cohorts of increasing age (Fig 1 A,B,C). Because of low cohort size, pts in Arm C aged 20-40) and 54% (Age 40-60). In Arm B, 5 year DFS for pts ≤ 20 was 69.3% and 85.7% for those >20-40, 48.6% for those >40-60 and 46.8% for those 60+ respectively (p = 0.02). In Arm C, 5 year DFS for pts ≤40 was 65% and for those >40, 30.7% (p = 0.01). Conclusion These results demonstrate that these chemotherapy-based regimens secure engraftment and hematopoietic reconstitution and similarly low rates of GVHD and relapse. They also suggest an advantage for patients ≤40 treated on Arm B. In >40-60yo patients, DFS for Arm B is equivalent to Arm A and also yields favorable results in older pts (>60-73 yrs). However, while patients ≤40 yrs of age fared well on Arm C, older patients were less likely to achieve extended OS and DFS than those on Arms A or B, likely as a consequence of increased TRM.

Background Anti-thymocyte globulin-free dCBT is associated with high rates of acute GVHD (aGVHD) especially involving the GI tract. Investigation of augmented aGVHD prophylaxis is indicated. Methods We are investigating the addition of a single dose of tocilizumab 8 mg/kg (day -1) to CSA/ MMF (starting day -3) aGVHD prophylaxis in adult patients (pts) with hematologic malignancies undergoing dCBT with intermediate intensity Cy 50/ Flu 150/ Thio 10/ TBI 400 conditioning (NCT03434730). Outcomes of the first 26 patients (with survivor follow-up of at least 100 days) were analyzed & compared to 54 dCBT historic controls transplanted with identical conditioning & only CSA/ MMF. All patients received letermovir if CMV seropositive. Results 26 pts [median age 47 years (range 26-60), median weight 82 kg (range 59-125), 11 AML, 8 ALL, 2 MPAL, 3 MDS/ CML, 2 NHL, median age-adjusted HCT-CI 2.5 (range 0-6)] received dCB grafts with a median CD34+ cell dose of 1.5 × 105/kg/unit (range 0.23-5.94) & median unit-recipient 8-allele HLA-match of 5/8 (range 3-6). One patient had graft failure in the setting of low graft viability/ disseminated adenovirus & a second pt had early transplant-related mortality (TRM) with incomplete count recovery. The remaining 24 patients engrafted at a median of 24 days (range 18-40) for a cumulative incidence of 92% (95%CI:67-98). 88% (95%CI:59-97) of pts engrafted platelets at a median of 43 days (range 32-78). Of evaluable pts, 68% & 83% had 100% single-unit donor chimerism in the blood at days 30 & 100, respectively; single-unit dominance was observed in the remaining cases. Six of 26 pts (23%) developed pre-engraftment syndrome (PES) at a median of 12.5 days, & only 3 of these (12%) required systemic corticosteroids. Additionally, 16 pts (62%) had no neutropenic fever prior to engraftment. The day 100 cumulative incidence of grade II-III & grade III aGVHD was 62% (95%CI:39-78) & 4% (95%CI: Conclusions Tocilizumab-based dCBT appears safe with reduced PES & grade III-IV aGVHD. While many pts developed upper GI aGVHD, the marked reduction in lower GI aGVHD supports preferential reduction of T-cell homing to the lower gut. Investigation of this approach including aGVHD treatment responses, immune recovery & correlative biomarker/ microbiota studies are ongoing.

Background Isolated mixed T-cell chimerism in otherwise fully engrafted recipients of TCDHCT has been associated, in some series, with risk of graft rejection or relapses and an indication for DLI. Thereto, we have analyzed the impact of donor chimerism on outcomes in a prospective clinical trial of conditioning regimens used with CD34+ selected TCDHCT. Methods The trial (NCT0119066) compares A) HFTBI, Thiotepa and cyclophosphamide with B) Busulfex, melphalan and fludarabine or C) Clofarabine, melphalan and thiotepa as conditioning for CD34+ TCDHCT used to treat high risk hematologic malignancies. As part of the trial, we sequentially assessed lineage-specific donor chimerism in the marrow and the myeloid cells and T-cells in blood by analysis of donor and host-specific STRs in cell fractions isolated by immunotype. In the landmark analysis, quartiles of donor chimerism were compared for T-cell levels, and clinical outcomes. Results 283 consecutive patients, transplanted between 5/13/2010 and 12/31/2016 (106 in Arm A, 144 in Arm B, 33 in Arm C). All engrafted by day 10-11. While 3 pts in Arm B and 1 in C had late graft failure, all others from 3 mos on had full donor chimerism in marrow and myeloid blood cells. However, at 3 mos median donor CD3+ T-cell chimerism (MDTC), was mixed in each arm but significantly lower in Arm B (10%) vs A (50%) and C (63%) (p To assess the impact of this sustained mixed chimerism, we did a landmark analysis at 3 months, comparing subsequent T-cell recovery and clinical outcomes for pts in the first (lowest) and fourth (highest) quartile of T-cell chimerism in Arms A and B. As shown in Table 1, CD3+ and CD8+ T-cells in both arms were significantly higher in Q1, as were CD3+CD4+ cells in Arm B. Non-relapse mortality (NRM) at 2 yrs was also significantly lower for Q1 pts in both arms but relapse risks were not. In Arm B, but not A, 2yr OS and DFS were also significantly better in Q1 vs Q4. Conclusions Conditioning with Bu/Mel/Flu (Arm B) secured durable engraftment and hematopoietic reconstitution but a high proportion of pts have isolated and persistent mixed T-cell chimerism. However, surviving host T-cells can expand, persist and contribute significantly to earlier T-cell recovery and long-term reduction of NRM without increasing risk of graft rejection, relapse or need for DLI.

BACKGROUND: Allogeneic hematopoietic cell transplant (HCT) recipients are at risk for herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Routine prophylaxis with acyclovir is recommended during periods of immunosuppression. Brincidofovir (BCV, CMX001), a lipid conjugate of cidofovir, is active in vitro activity against HSV/VZV, but has not been formally studied for HSV/VZV prophylaxis. We report our clinical experience of BCV for HSV/VZV prophylaxis in HCT recipients. METHODS: This was a retrospective review of 30 hematopoietic cell transplant (HCT) recipients between 8/2010 and 8/2015 who received BCV doses not to exceed 200mg/week for adults/adolescents and 4mg/kg/week for pediatric (

TP53 alterations portend extremely poor prognosis in patients with mantle cell lymphoma treated with standard treatment modalities. We reviewed outcomes of 42 patients with available TP53 status who had received a reduced-intensity or non-myeloablative allogeneic haematopoietic cell transplant at our institution. We demonstrated a 2-year overall survival and progression-free survival of 78% [95% confidence interval (CI) 60-88] and 61% (95% CI 43-75), respectively. The 2-year cumulative incidences of relapse and non-relapse mortality were 19% and 20%, respectively. Importantly, there is no significant difference among patients with and without TP53 alterations, suggesting for the first time a beneficial treatment modality for these high-risk patients.

Non-graft-versus-host disease (GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT) but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplantation physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment and ocular toxicities associated with medications. We summarize the incidence, risk factors, screening, prevention, and treatment of individual complications and generate evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical signs and symptoms and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplantation physicians and ophthalmologists should be knowledgeable about non-GVHD ocular complications and provide comprehensive collaborative team care.

Despite numerous reports of significant distress and burden for hematopoietic stem cell transplantation (HSCT) patients and caregivers (CGs), HSCT-specific coping interventions remain rare. The few in use lack specificity and are often not easily accessible or cost-effective. Whereas the development of new interventions is resource-intensive, theory-informed adaptation of existing evidence-based interventions is promising. To date, no HSCT-specific intervention has relied on a formal adaptation approach. Using the Center for Disease Control and Prevention’s Map of Adaptation, this two-phase qualitative descriptive study seeks to understand the perceptions of HSCT patients, CGs, individually, and in dyads, and clinicians about Coping Together (CT) for the preliminary adaptation (Phase 1), and then explores perceptions of the modified intervention in additional mixed sample (Phase 2). Six to ten participants including outpatients, CGs and dyads and five to seven HSCT clinician participants will be recruited for Phase 1. For Phase 2, 14 to 16 participants including outpatients, CGs and dyads will be recruited. Individual and dyadic semi-structured interviews will take place between 100 and 130 days post-HSCT. Verbatim transcripts will be analyzed using content analysis. It is paramount to have HSCT-specific supportive interventions that address patients’ and CGs’ multidimensional and complex needs. The timely involvement of key stakeholders throughout the adaptation process is likely to optimize the relevance and uptake of such tailored intervention. This study is registered on October 6, 2016 in ClinicalTrials.gov at (identifier number NCT02928185 ).

Older patients with acute myelogenous leukemia (AML) are at increased risk for mortality and morbidity. While allogeneic stem cell transplantation may provide cure in some patients, many still relapse after transplant and are then left with limited therapeutic options and poor survival. Moreover, the quality of the end-of-life care for these patients has not been previously reported. We describe here the end-of-life experience of a cohort of 72 older patients with AML who relapsed after first allogeneic stem cell transplant at our dedicated cancer center. Despite a median overall survival of only 4 months, we find a high level of primary palliative care delivered by transplant/leukemia physicians through goals of care discussions and/or advanced care planning and provide evidence for high-quality end-of-life care outcomes, often with concurrent disease-directed therapy. Our results compare favorably with end-of-life care outcomes reported for older AML patients, including those who did not undergo transplant. Given the poor prognosis and unique underlying vulnerabilities in this high-risk patient population, incorporating timely advanced care planning and palliative care delivery while exploring available salvage options may further improve end-of-life care outcomes.

Total body irradiation (TBI) has been included in standard conditioning for acute lymphoblastic leukemia (ALL) before hematopoietic cell transplantation (HCT). Non-TBI regimens have incorporated busulfan (Bu) to decrease toxicity. This retrospective study analyzed TBI and Bu on outcomes of ALL patients 18–60 years old, in first or second complete remission (CR), undergoing HLA-compatible sibling, related, or unrelated donor HCT, who reported to the Center for International Blood and Marrow Transplant Research from 2005 to 2014. TBI plus etoposide (25%) or cyclophosphamide (75%) was used in 819 patients, and intravenous Bu plus fludarabine (41%), clofarabine (30%), cyclophosphamide (15%), or melphalan (13%) was used in 299 patients. Bu-containing regimens were analyzed together, since no significant differences for patient outcomes were noted between them. Bu patients were older, with better performance status; took longer to achieve first CR and receive HCT; were treated more recently; and were more likely to receive peripheral blood grafts, antithymocyte globulin, or tyrosine kinase inhibitors. With median follow-up of 3.6 years for Bu and 5.3 years for TBI, adjusted 3-year outcomes showed treatment-related mortality Bu 19% versus TBI 25% (P = .04); relapse Bu 37% versus TBI 28% (P = .007); disease-free survival (DFS) Bu 45% versus TBI 48% (P = .35); and overall survival (OS) Bu 57% versus TBI 53% (P = .35). In multivariate analysis, Bu patients had higher risk of relapse (relative risk, 1.46; 95% confidence interval, 1.15 to 1.85; P = .002) compared with TBI patients. Despite the higher relapse, Bu-containing conditioning led to similar OS and DFS following HCT for ALL.

Reduced-intensity conditioning (RIC) and T cell depletion (TCD) through CD34+ cell selection without the use of post-transplantation immunosuppression are 2 strategies used to reduce nonrelapse mortality (NRM) in older patients after allogeneic hematopoietic cell transplantation (allo-HCT). To compare the efficacy of the RIC and TCD approaches, we evaluated the outcomes of patients age >50 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who underwent allo-HCT from an HLA-matched donor with one of these strategies. Baseline characteristics were comparable in the patients receiving TCD (n = 204) and those receiving RIC (n = 151), except for a higher proportion of unrelated donors (68% versus 40%; P 50 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who underwent allo-HCT from an HLA-matched donor with one of these strategies. Baseline characteristics were comparable in the patients receiving TCD (n = 204) and those receiving RIC (n = 151), except for a higher proportion of unrelated donors (68% versus 40%; P 50 years with AML and MDS.

Background Graft-versus-host disease (GVHD) is one of the leading causes of non-relapse mortality and morbidity after allogeneic hematopoietic stem cell transplantation (allo-HCT). Methods We evaluated the outcomes of two well-established strategies used for GVHD prevention: in vivo T cell depletion using antithymocyte globulin (ATG) and ex vivo T cell depletion using a CD34-selected (CD34+) graft. A total of 525 adult patients (363 ATG, 162 CD34+) with intermediate or high-risk cytogenetics acute myeloid leukemia (AML) in first complete remission (CR1) were included. Patients underwent myeloablative allo-HCT using matched related or unrelated donors. Results Two-year overall survival estimate was 69.9% (95% CI, 58.5–69.4) in the ATG group and 67.6% (95% CI, 60.3–74.9) in the CD34+ group (p = 0.31). The cumulative incidence of grade II–IV acute GVHD and chronic GVHD was higher in the ATG cohort [HR 2.0 (95% CI 1.1–3.7), p = 0.02; HR 15.1 (95% CI 5.3–42.2), p

Background: The development of reduced intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RD) of PBSC. The effects of age on donation efficacy, toxicity, and long-term recovery in RD are poorly understood. Methods: We analyzed hematologic variables, pain, donation-related symptoms and recovery in 1211 related PBSC donors aged 18-79 enrolled in the Related Donor Safety Study (RDSafe). Results: RD >60 had a lower median CD34 level pre-apheresis compared to younger RD (age >60, 59x106/L; age 41-60, 81x106/L; age 18-40, 121x106/L; p 24L, p 60 with post-collection thrombocytopenia

Background Limited data is available on long-term effects of autologous hematopoietic cell transplantation (AHCT) in older patients (pts). Methods This single-center, retrospective study examines late cardiopulmonary effects, and overall outcomes of AHCT in 41 pts age ≥ 70, with non-Hodgkin lymphoma (NHL), between 2000-2016. Pre- and post-HCT pulmonary function tests (PFT) and echocardiograms (echo) were compared. Overall survival (OS) and progression-free survival (PFS) were analyzed according to age, gender, histology, stage, number of lines of treatment, diffusing capacity of lungs for carbon monoxide (DLCO), left ventricular ejection fraction (LVEF), and comorbidity index (HCT-CI). Results 41 pts [median age 72 (range 70-75)] received AHCT for follicular or diffuse large B-cell lymphoma (n=18 44%), mantle cell lymphoma (n=15 37%) and T-cell or other NHL subtypes (n=8 20%). Eight (20%), 6 (15%) and 27 (66%) pts had a low (0), intermediate (1-2) and high (≥3) HCT-CI, respectively. All pts except 1, had received anthracycline as part of initial therapy. BEAM was the most common conditioning regimen (n=38 93%). Pre-HCT LVEF was normal in all pts except 1 (45%). Median (range) pre- and post-HCT LVEF was 63% (45-74%) and 64% (39-71%), respectively. Of the 23 pts who had post-HCT echo (median time between pre- and post-HCT echo was 423 days), a mild decrease in LVEF was noted in 3. Only 1 pt had a significant decline of 19%. Pre- and post-HCT pulmonary artery pressure was normal in all. The median (range) of pre-transplant DLCO, FEV1 and FVC were 70% (48-125%), 97% (83-141%), and 98% (57-123%), respectively. Of the 10 pts who had post-HCT PFT (median time between pre- and post-HCT PFT was 405 days), DLCO decline of >10% was the most common abnormality and developed in 4. In 5 pts DLCO improvement of >10% was observed. A >15% improvement in FEV1 and FVC was observed in 5 and 4 pts respectively. The median improvements in FVC, FEV1 and DLCO were 4%, 6% and 10%, respectively. With a median follow-up of 58 months (range 5-123) for survivors, PFS and OS at 3 years were 84% (95% CI, 67-92%) and 94% (95% CI, 80-99%), respectively. In a univariate analysis, age, gender, histology, stage, number of lines of treatment, DLCO, LVEF, and HCT-CI did not affect OS or PFS. Relapse occurred in 11 pts (27%), 8 of whom died. Median time to relapse was 38 months (range 27-100). Secondary malignancies developed in 4 pts (10%) and led to death in 3. Conclusion In our cohort of elderly pts who underwent AHCT, late declines in cardiopulmonary function were minimal, and none resulted in mortality. The most common cause of death was lymphoma recurrence. Secondary malignancy was the only cause of non-relapse mortality. While prospective studies with larger number of pts are needed to evaluate long-term effects of AHCT on different organ functions in elderly, strategies to mitigate risk of relapse remain the most important area to improve outcomes.

Background The less stringent CB HLA-match requirement extends allograft access. The extent to which HLA-mismatch can adversely affect CBT outcomes & the maximum permitted HLA-mismatch, however, are not established. Methods We analyzed TRM, relapse & PFS after cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy TBI dCBT in adults with hematologic malignancies. Eligible patients (pts) were 1st allograft recipients ≤ 65 years transplanted 1/2014 - 12/2017. TNC & CD34+ dose were typically given priority over HLA-match in unit selection. Results 102 pts [51 (50%) non-European, median 50 years (range 21-65), median 80 kg (range 36-137), 71 acute leukemias & 17 CML/ MPD/ MDS (all ≤ 10% blasts pre-CBT), 14 NHLs] received double unit grafts. The majority of units [181 (89%)] were 4/6 matched. At high resolution the unit-recipient 8-allele HLA-match was a median of 5/8 (range 3-7). The median infused viable CD34+ dose was 1.3 × 105/kg/unit (range 0.2-8.6). 48 (47%) pts also received haplo-identical CD34+ cells as a myeloid bridge. 97% (95%CI 90-99) engrafted with CB. All pts had a dominant unit (1 early death excluded). Day 180 grade II-IV & III-IV aGVHD were 89% (95%CI 81-94) & 23% (95%CI 15-31), respectively. 1-yr cGVHD was 4% (95%CI 1-9). Day 180 TRM was 9% (95%CI 4-15) & 14% (95%CI 8-22) at 2 yrs. 11% (95%CI 6-19) of pts relapsed by 2 yrs. With a median survivor follow-up of 2 yrs 3 months (range 6 - 51), 2-yr OS is 82% (95%CI 75-90) & PFS is 74% (95%CI 66-84). Causes of death were transplant-related in 16 pts [6 aGVHD, 4 infection (2 viral, 1 bacterial, 1 fungal), 4 organ failure, 1 graft failure, 1 unknown] & relapse in 4 pts. By 2-yrs, engrafting unit-recipient HLA-allele match had no association with TRM or PFS ( Figure ). Analysis of the association between recipient/ graft variables & TRM/ relapse/ PFS are shown ( Table ). Pts In multivariate analysis, aaHCT-CI was associated with worse PFS [HR 2.82 (1.28-6.25) if score 4-9 vs 0-3, p = 0.01]; neither rDRI [HR 1.21 (0.54-2.69) if high-very high vs low-intermediate, p = 0.64] nor engrafting unit-recipient HLA-match [HR 2.06 (0.89-4.74) if 5-7/8 vs 3-4/8 matched (p = 0.09] were significant. Conclusions dCBT with mismatched units facilitates allograft access extension & has a high PFS. While further investigation of the CD34+ dose – HLA-mismatch interaction is required, this supports unit selection prioritizing quality & dose in adults to optimize engraftment. Finally, this data supports CBT in younger pts, those with low 0-3 aaHCT-CI, or high rDRI given the high 2-yr PFS in such pts.

Introduction In patients with poor risk AML or MDS in first complete remission (CR1), alloSCT can be potentially curative. Comparison of the non-hematologic toxicities between total body irradiation (TBI)-based conditioning versus chemotherapy alone prior to CD34-selected alloSCT requires further validation. Objective The primary objective of this analysis is to review the incidence of grade 3 or 4 non-hematologic toxicities at day 100 and 365. Methods Patients with AML or MDS in CR1 who underwent their first CD34-selected alloSCT were identified from our institutional database. Transplant outcomes and toxicity rates were assessed using cox proportional hazards regression. Toxicities were graded according to the NCI Common Technology Criteria for Adverse Effects v4.03. Baseline characteristics were assessed using the Wilcoxon rank-sum test, Fisher's exact test, and the chi-squared test. The cumulative incidence method was used to control for competing risks. Results 221 patients underwent CD34-selected alloSCT from Jan 2010-Dec 2016. 48 (22%) received HFTBI/Thio/Cy and 173 (78%) Bu/Mel/Flu. A statistically significant difference was noted in age, disease state, and Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) score as summarized in Table 1. The cumulative incidence of non-hematologic toxicities most frequently reported at 12mo were infections (87.8%, 95% CI: 82.6-91.5), oral/GI (72.4%, 95% CI: 66-77.8) and metabolic (69.2%, 95% CI: 62.7-74.9). Incidence of gr 3/4 cardiovascular (43.4% vs. 18.8%, P = 0.002) at 12mo were significantly higher in the Bu/Mel/Flu arm. Incidence of gr 3/4 oral/GI toxicities (93.8% vs. 66.5%, P Conclusion Amongst adults with AML or MDS undergoing CD34-selected alloSCT, chemotherapy-based and TBI-based conditioning regimens appear to be associated with similar toxicity profiles. Most differences observed in the incidence of toxicities between the 2 groups can be attributed to the known side effects of the individual conditioning agents, however, we cannot determine impact of age on the toxicities due to the significant difference in age distribution between the 2 groups.

Background While dCBT is associated with high rates of sustained donor engraftment, delayed neutrophil recovery is frequent. Methods We investigated the addition of CD34+ selected haplo-identical PBSC to double unit CB grafts (haplo-dCBT) in patients (pts) undergoing ablative dCBT with the aim to provide a myeloid bridge prior to CB engraftment. ATG was not used due to its adverse effects on immune recovery & potential to increase relapse risk. Results 78 adult pts [median 48.5 years (range 21-68), median 82 kgs (range 48-138), 3 with prior allografts, 54 (69%) acute leukemias or 10 (13%) MDS/ MPN (all 4/8 haplo-recipient HLA-match & ≥ 3/8 winning unit-haplo HLA-match were associated with higher likelihood of bridging (Table 2). Haplo CD34+ dose & winning unit-haplo HLA-match remained significant in multivariate analysis. While there was no difference in the day 100 TRM in the 34 optimal bridge pts vs others [9% (95%CI 2-21) vs 15% (95%CI 6-27), p = 0.388], optimal bridge pts had earlier hospital discharge [28.5 (range 20-60) vs 36 days (range 28-98)]. Conclusions ATG-free haplo-dCBT can speed neutrophil recovery but this benefit is highly variable, and a successful myeloid bridge is not guaranteed due to early haplo rejection. For these reasons our data does not support pursuit of haplo-dCBT. It is likely that similar limitations will also apply to ATG-free single CB unit-haplo transplants. Our findings also have significance for strategies that combine unmanipulated CB with third-party or ex vivo expanded T-cell depleted products given higher CD34+ cell dose & better HLA-match to the unmanipulated CB unit could improve successful bridging.

Introduction Acute graft-versus-host disease (aGVHD) remains a substantial cause of morbidity and mortality after unmodified and ex-vivo CD34+ selected/T-cell depleted (TCD) allogeneic hematopoietic stem cell transplantation (alloHSCT). We identified a cluster of patients who developed severe cutaneous aGVHD and expressed MHC class I HLA-A*0101. Objective To investigate if HLA-A*0101 expression correlates with an increased risk of severe cutaneous aGVHD after alloHSCT. Methods We evaluated 831 patients who received unmodified or TCD allograft at a single institution between 03/2010 and 02/2017. Patients who received cord blood transplants or Results HLA-A*0101 was expressed in 206 (25%) patients (98 TCD, 108 unmodified). These patients had similar demographics to those lacking HLA-A*0101 (Table). At day 180, patients expressing HLA-A*0101 had higher incidence of grade III-IV cutaneous aGVHD compared with patients lacking HLA-A*0101 expression in both the TCD (8% vs. 3%, p=0.027) and unmodified (11% vs. 4%, p=0.01) cohorts (Fig 1). In a multivariate cause-specific Cox model, the presence of HLA-A*0101 in the TCD alloHSCT cohort correlated with increased risk of grade III-IV cutaneous aGVHD [HR=2.79 (95% CI: 1.07-7.28), p=0.036] after adjusting for related status of donor. In the unmodified alloHSCT cohort, presence of HLA-A*0101 allele correlated with increased risk of grade III-IV cutaneous aGVHD [HR=2.68 (95% CI: 1.24-5.79), p = 0.012)] after adjusting for myeloablative v non-myeloablative conditioning and donor relationship status. There were no statistically significant differences in OS or TRM between HLA-A*0101 expressing vs non-expressing patients in the cohorts. Conclusions In this group, donor/recipient expression of HLA-A*0101 correlated with an increased incidence and severity of cutaneous aGVHD after TCD and unmodified alloHSCT. If confirmed in a larger cohort, these findings have potential practical implications in the development of prophylaxis or early therapeutic strategies targeting the skin in this high-risk population.

Background CMV seropositive CBT recipients have a high risk of CMV infection. Early pre-emptive therapy is required to avoid CMV disease but is associated with significant toxicities. Methods This analysis compares the day +100 incidence & severity of clinically significant CMV infection (viremia leading to pre-emptive treatment or disease) in CMV seropositive CBT adult patients (pts) who received letermovir prophylaxis transplanted 12/2017-6/2018 vs historic controls transplanted 3/2013-12/2017. Control pts received ganciclovir prophylaxis days -7 to -2 then standard dose acyclovir. Letermovir pts received standard dose acyclovir & started letermovir IV or PO on day +7 & continued beyond day +100. All pts received uniform intermediate intensity Cy 50 mg/kg / Flu 150 mg/m2/ Thio 5-10 mg/kg / TBI 400 cGy conditioning with CSA/ MMF. Pts were monitored by qPCR twice weekly from approximately day +14-60 & then 1-2 x/weekly days +60-100. Results 62 [median age 51 years (range 23-66), 46 leukemia, 7 MDS/ MPD, 9 NHL/ HL] historic control pts received double unit grafts with a median unit-recipient HLA-allele match of 5/8 (range 2-7). By day +100, 51 pts developed clinically significant CMV infection for a day +100 cumulative incidence of 82% (95%CI: 70-90). The median viremia onset was 34 days (range 5-74) & 5 pts developed CMV disease by day +100 (3 pulmonary, 2 GI). Initial therapy was with foscarnet in 28 pts & ganciclovir/ valganciclovir in 23. Clinically significant therapy toxicities (renal &/or myelosuppression) were observed in 38/51 (75%) pts (Table 1). By day +100, CMV caused or contributed to 3 pulmonary deaths. 10 pts [median age 48 years (range 24-59), 9 leukemia, 1 MDS/ MPD, median 5/8 (range 3-6) unit-recipient HLA-match] received letermovir prophylaxis (8 IV, 2 PO) (Table 2). All pts engrafted. The day +100 cumulative incidence of clinically significant CMV infection was 0% (p Conclusions This analysis suggests letermovir prophylaxis is highly effective at mitigating CMV disease, CMV-related mortality, & the need for toxic CMV therapies. Moreover, it has been well tolerated in CBT recipients. While further detailed investigation in a larger population is required, this data is very promising & the extent of the benefit suggests that letermovir could be a cost-effective new standard of care in adult CBT. The duration of needed prophylaxis beyond day +100 in CBT recipients also requires investigation.

Background TCD is being investigated as a CNI-free strategy for GVHD prophylaxis (BMT CTN 1301) & dCBT has previously been associated with PFS comparable to 8/8 MUD TCD transplants with low rates of relapse. However, how outcomes of MRD TCD, MUD TCD, & dCB transplants compare when adjusted for aaHCT-CI & rDRI is not established. Methods We compared dCBT (Cy/ Flu/ Thio/ TBI 400 & CSA/ MMF) with MRD or MUD (Bu/Mel/Flu, Cy/Thio/TBI1375 or Flu/Thio/TBI1375) CD34+ selected transplants. Eligible patients (pts) were 1st allograft recipients 21 - 60 years transplanted 1/2012 - 8/2017 for myeloid malignancies [AML/ MDS/ MPD ( Results Of 206 pts (Table 1), 76 received dCB, 52 MRD, 78 MUD transplants. Pts had similar age, gender, weight, recipient CMV+ status, & aaHCT-CI/ diagnosis distribution. Each group differed according to donor age. rDRI also differed by graft source with fewer dCBT pts having low risk disease. Significantly more MRD/ MUD transplants received high dose TBI & there were marked differences in graft dose & donor-recipient HLA-match. While the incidence of engraftment at day 45 was lower in dCBT (96%) than MRD & MUD pts (both 100%, p 3 was associated with higher TRM whereas graft source was not significant. High/ V. High rDRI was associated with higher relapse. Also, MRD pts had a higher relapse risk than dCBT pts. Both > 3 aaHCT-CI & High/ V. High rDRI had worse PFS whereas donor type was not significant. In a subset analysis of the 132 (64%) pts with an aaHCT-CI of 0-3, the 3-yr PFS was 76% (65-90) in dCBT, 61% (46-80) in MRD, & 79% (68-91) in MUD pts (Figure 1B). Conclusions This data supports dCBT in pts without promptly available MRD or MUD donors. dCBT pts had a low incidence of relapse supporting a potent GVL effect. Relapse after dCBT was significantly lower than after MRD transplants, & this finding was despite more than half of MRD pts receiving high dose conditioning. New strategies to further lower TRM in dCBT recipients may translate to dCBT being a preferred therapy over TCD MRD in the future especially in pts with low aaHCT-CI.