Sibling Donor Hematopoietic Cell Transplantation Research Articles

Umbilical Cord Blood Transplantation for Fanconi Anemia With a Special Focus on Late Complications: a Study on Behalf of Eurocord and SAAWP-EBMT

Hematopoietic cell transplantation (HCT) remains the sole available curative treatment for Fanconi anemia (FA), with particularly favorable outcomes reported after matched sibling donor (MSD) HCT. This study aimed to describe outcomes, with a special focus on late complications, of FA patients who underwent umbilical cord blood transplantation (UCBT). In this retrospective analysis of allogeneic UCBT for FA performed between 1988 and 2021 in European Society for Blood and Marrow Transplantation (EBMT)-affiliated centers, a total of 205 FA patients underwent UCBT (55 related and 150 unrelated) across 77 transplant centers. Indications for UCBT were bone marrow failure in 190 patients and acute leukemia/myelodysplasia in 15 patients. The median age at transplantation was 9 years (range, 1.2 to 43 years), with only 20 patients aged >18 years. Among the donor-recipient pairs, 56% (n = 116) had a 0 to 1/6 HLA mismatch. Limited-field radiotherapy was administered to 28% (n = 58) and 78% (n = 160) received a fludarabine (Flu)-based conditioning regimen. Serotherapy consisted of antithymocyte globulin (n = 159; 78%) or alemtuzumab (n = 12; 6%). The median follow-up was 10 years for related UCBT and 7 years for unrelated UCBT. Excellent outcomes were observed in the setting of related UCBT, including a 60-day cumulative incidence (CuI) of neutrophil recovery of 98.1% (95% confidence interval [CI], 93.9% to 100%), a 100-day CuI of grade II-IV acute graft-versus-host disease (GVHD) of 17.3% (95% CI, 9.5% to 31.6%), and a 5-year CuI of chronic GVHD (cGVHD) of 22.7% (95% CI, 13.3% to 38.7%; 13% extensive). Five-year overall survival (OS) was 88%. In multivariate analysis, none of the factors included in the model predicted a better OS. In unrelated UCBT, the 60-day CuI of neutrophil recovery was 78.7% (95% CI, 71.9% to 86.3%), the 100-day CuI of grade II-IV aGVHD was 31.4% (95% CI, 24.6% to 40.2%), and the 5-year CuI of cGVHD was 24.3% (95% CI, 17.8% to 32.2%; 12% extensive). Five-year OS was 44%. In multivariate analysis, negative recipient cytomegalovirus serology, Flu-based conditioning, age <9 years at UCBT, and 0 to 1/6 HLA mismatch were associated with improved OS. A total of 106 patients, including 5 with acute leukemia/myelodysplasia, survived for >2 years after UCBT. Nine of these patients developed subsequent neoplasms (SNs), including 1 donor-derived acute myelogenous leukemia and 8 solid tumors, at a median of 9.7 years (range, 2.3 to 21.8 years) post-UCBT (1 related and 8 unrelated UCBT). In a subset of 49 patients with available data, late nonmalignant complications affecting various organ systems were observed at a median of 8.7 years (range, 2.7 to 28.8 years) post-UCBT. UCB is a valid source of stem cells for transplantation in patients with FA, with the best results observed after related UCBT. After unrelated UCBT, improved survival was observed in patients who underwent transplantation at a younger age, with Flu-based conditioning, and with better HLA parity. The incidence of organ-specific complications and SNs was relatively low. The incidence of SNs, mostly squamous cell carcinoma, increases with time. Rigorous follow-up and lifelong screening are crucial in survivors of UCBT for FA.

Myocardial Fibrosis Improves in Young Patients with Sickle Cell Disease after Hematopoietic Cell Transplantation

Introduction: Cardiovascular complications are a leading cause of early mortality in patients with sickle cell disease (SCD). Chronic anemia, iron overload and repeated microvascular ischemic insults with reperfusion injury often result in progressive myocardial injury and maladaptive remodeling in SCD patients. Patients with SCD develop diffuse myocardial fibrosis, which can be detected by quantifying the myocardial extracellular volume (ECV) using cardiovascular magnetic resonance (CMR) imaging. Our group and others have previously shown that diffuse myocardial fibrosis is highly prevalent in both children and young adults with SCD, including those who have normal ventricular size and function by echocardiography. Additionally, we have shown that the disease modifying therapies (DMT) such as hydroxyurea or chronic transfusions do not appear to be protective against development of diffuse myocardial fibrosis. In a retrospective study, we found no difference in the myocardial ECV in patients who began DMT early (less than 6 years of age) versus later in life (at least 6 years or after) (Morin CE and Sharma A et al. Blood 2023.). Hematopoietic cell transplantation (HCT) can cure SCD, but myocardial effects of the therapy are unknown. Our goal was to evaluate cardiovascular parameters of function and injury, especially the progression of diffuse myocardial fibrosis, by comparing serial CMR studies performed before and after HCT in patients with SCD. Methods: We performed prospective CMR evaluation of children and young adults with SCD who received a matched sibling donor (MSD) or haploidentical donor (HAPLO) HCT following a reduced toxicity conditioning on a clinical trial (NCT04362293). CMR was performed pre-HCT, and at 1 month, and 12 months post-HCT. CMR-derived ventricular and atrial volumes were calculated. ECV was measured from T1 maps with a modified Look-Locker inversion recovery (MOLLI) sequence in short-axis. T2 and T2* maps were obtained. Regions of interest in the mid-ventricular septum were identified for analysis. We report descriptive statistics for CMR measures along with paired t-tests comparing patient ECV levels at 1-month and 12-months post-HCT to their respective baseline ECV. Results: Our study cohort consisted of 14 patients with SCD who underwent HCT and had serial CMR evaluations available. Thirteen patients had HbSS genotype and one had HbSC genotype. All patients were receiving DMT, either with hydroxyurea or chronic transfusions prior to HCT. Participants were majority male (57%) with median age of 15.2 years (range 6.8-21.3) at the pre-HCT CMR. Six received an MSD HCT and 8 received a HAPLO HCT. Ten patients each had follow up CMR evaluations performed at 1 month, and 12 months post-HCT. At 1 and 12 months post-HCT ejection fraction was preserved while biventricular volume and cardiac index decreased (Table 1). Compared to pre-HCT, ECV decreased from median 29% [range 27-38] to 28% (range 21-35, P= 0.061) at 1 month and 27% (range 24-31, P= 0.043) at 12 months post-HCT. There was no difference in the cardiac chamber sizes or the ECV measurements of those who received a MSD versus HAPLO HCT. Conclusions: We observed an improvement in cardiac chamber sizes with preservation of cardiac function as early as one month after HCT in patients with SCD. We further noted a reduction in ECV indicating a decrease in diffuse myocardial fibrosis in these young patients with SCD. To our knowledge, this is the first study to show that diffuse myocardial fibrosis can improve in patients with SCD after HCT. In addition to further corroborating the organ function protective effects of HCT in patients with SCD, these data further demonstrate the use of CMR as an essential non-invasive tool to assess the effects of therapeutic interventions on SCD-cardiac injury.

Clinical Characteristics, Management, and Allogeneic Hematopoietic Cell Transplantation of Patients with Toll-like Receptor 8 Gain-of-Function Mutations

Toll-like receptor 8 gain-of-function (TLR8 GOF) is a recently described inborn error of immunity due to germline or somatic mutations in the TLR8 gene and characterized by severe neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases, bone marrow failure. Treatment of TLR8 GOF has been challenging to date, and guidance for optimal therapy is lacking. We describe the clinical characteristics and management of 10 patients with TLR8 GOF variants, including the first female patient and further clinical outcome on the 6 patients initially reported with this disease with a focus on the role of allogeneic hematopoietic cell transplantation (HCT). All but one patient were male ranging from 0.5 months to 28 years at age of symptom onset. Eight patients had somatic mutations with variant allele frequencies of 7-26%; two patients had germline mutations. The 9 male patients all had severe neutropenia and varying degrees of anemia and/or thrombocytopenia. Oral ulcers, recurrent infections, hepatosplenomegaly, and hypogammaglobulinemia were common. Immune phenotype was variable, ranging from severe lymphopenia to marked T cell lymphoproliferation. Several patients had an inverted CD4:CD8 T cell ratio and skewing of T cell subsets to the terminal effector memory phenotype. Increased double-negative T cells were also observed. All patients had low class switched memory B cells. Bone marrows were hypo- to hypercellular with marked myeloid hypoplasia, and in most cases, with increased T cells, large granular lymphocytes, and/or lymphoid aggregates. Neutropenia was initially responsive to granulocyte colony stimulating factor (GCSF) +/- steroids in several patients but ultimately become refractory to therapy. Immunomodulatory agents and chemotherapy were unsuccessful. Six patients underwent allogeneic HCT; two patients died at 8 and 18 years without definitive therapy; and one patient was lost to follow-up. The female patient had germline disease and presented with pure red blood cell aplasia at 2 weeks of life and is scheduled to undergo HCT. Transplant data were available for 5 of 6 patients who underwent HCT. Age at transplant was 3 to 21 years. One patient who received a graft from a 7/8 HLA-matched unrelated donor developed severe veno-occlusive disease and secondary graft failure. The patient underwent a second transplant and ultimately died. Another patient received a matched sibling donor HCT while critically ill from Candida lusitaniae and mucormycosis infection with associated multisystem organ failure. The patient engrafted with 100% donor chimerism but died on day +15 post-HCT. The remaining 3 patients are alive and well 8 months to 2 years post-HCT. Two patients received grafts from HLA-matched donors (1 sibling and 1 unrelated) with reduced intensity conditioning and cyclophosphamide, mycophenolate mofetil and vorinostat for graft-versus-host disease (GVHD) prophylaxis. The third patient underwent a haploidentical HCT with myeloablative conditioning and post-transplant cyclophosphamide. Post-HCT complications included acute skin and/or gastrointestinal GVHD that was responsive to therapy in all patients, and severe lung GVHD in one patient. There were no major infectious complications. All three patients had full donor chimerism in myeloid and T cells with complete resolution of disease phenotype at last follow-up. The patient for whom detailed transplant data is not available received a haploidentical HCT. He developed mixed myeloid chimerism for which he received multiple donor lymphocyte infusions and was alive at last contact &amp;gt;3 years post-HCT. TLR8 GOF should be considered in male and female patients with severe, unexplained neutropenia refractory to GCSF, and particular care should be taken when investigating for mutations given the disease-causing variant allele frequencies as low as 7%. Neutropenia and immune dysregulation were refractory to all therapies in our cohort, and TLR8 GOF was fatal in two patients who did not receive definitive therapy. Allogeneic HCT is curative and should be considered without delay for medically suitable patients.

Post-transplantation cyclophosphamide is associated with increased bacterial infections.

Post-transplant cyclophosphamide (PTCy) is increasingly used to reduce graft-versus-host disease after hematopoietic cell transplantation (HCT); however, it might be associated with more infections. All patients who were ≥2 years old, receiving haploidentical or matched sibling donor (Sib) HCT for acute leukemias or myelodysplastic syndrome, and either calcineurin inhibitor (CNI)- or PTCy-based GVHD prophylaxis [Haploidentical HCT with PTCy (HaploCy), 757; Sibling with PTCy (SibCy), 403; Sibling with CNI-based (SibCNI), 1605] were included. Most bacterial infections occurred within the first 100 days; 953 patients (34.5%) had at least 1 infection and 352 patients (13%) had ≥2 infections. Patients receiving PTCy had a greater incidence of bacterial infections by day 180 [HaploCy 46%; SibCy 48%; SibCNI 35%; p < 0.001]. Compared with the SibCNI without infection cohort, 1.99-fold, 3.33-fold, 2.78-fold, and 2.53-fold increased TRM was seen for the HaploCy cohort without infection and HaploCy, SibCy, and SibCNI cohorts with infection, respectively. Bacterial infections increased mortality [HaploCy (HR1.84, 99% CI: 1.45-2.33, p < 0.0001), SibCy cohort (HR,1.68, 99% CI: 1.30-2.19, p < 0.0001), and SibCNI cohort (HR,1.76, 99% CI: 1.43-2.16, p < 0.0001). PTCy was associated with increased bacterial infections regardless of donor, and bacterial infections were associated with increased mortality irrespective of GVHD prophylaxis. Patients receiving PTCy should be monitored carefully for bacterial infections following PTCy.

Day 4 collection of granulocyte colony-stimulating factor-mobilized HLA-matched sibling donor peripheral blood allografts demonstrates no long-term increase in chronic graft-versus-host disease or relapse rates

Background aimsIn a previous pilot study of HLA-matched sibling donor hematopoietic cell transplantation (HCT), the authors determined the feasibility of day 4 versus day 5 granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (PBSC) collection compared with a historical cohort. Given identified differences in the PBSC product (day 4 cohort with significantly lower infused total nucleated, mononuclear and CD3 cells compared with other collection cohorts), the authors performed a follow-up study to determine long-term post-HCT outcomes, including detailed characterization of chronic graft-versus-host disease (GVHD). MethodsThis was a prospective observational study, and the authors collected data on chronic GVHD, staging, sites of involvement and treatments. Performance status, incidence of relapse, overall survival and duration of immunosuppressive therapy (IST) were also evaluated. Data were examined retrospectively. To account for differences in length of follow-up among cohorts, the authors also determined performance status and chronic GVHD staging, sites and treatment at 2 years post-HCT. ResultsAt 2 years post-HCT, the overall survival rate was 71.7% in the day 4 cohort compared with 61.5%, 52% and 56% in the day 5, 2-day and historical cohorts, respectively (P = 0.283). The cumulative incidence of chronic GVHD was 65.2% in the day 4 cohort versus 46.4% in the day 5 cohort, 51.1% in the 2-day cohort and 65% in the historical cohort (P = 0.26). There was no significant difference in the maximum overall stage of chronic GVHD (P = 0.513), median number of sites involved (P = 0.401) or cumulative incidence of discontinuation of IST (P = 0.32). Death from chronic GVHD was less common in the day 4 and day 5 cohorts compared with the 2-day and historical cohorts, though this did not reach statistical significance. ConclusionsThe authors’ preliminary results demonstrated that collection of allogeneic matched sibling donor PBSCs on day 4 of G-CSF was feasible, reduced donor exposure to growth factor and was associated with an initial cost savings. Importantly, the authors now demonstrate that transplantation of day 4 mobilized PBSCs is not associated with any adverse outcomes post-HCT, including late effects such as chronic GVHD. Further investigation of donor G-CSF collection algorithms is merited in other HCT settings, including unrelated and mismatched related donors.

Similar Risk of Relapse and Survival with Post-Transplant Cyclophosphamide Compared to Standard Gvhd Prophylaxis after Allogeneic Hematopoietic Cell Transplantation for AML and MDS

Similar Risk of Relapse and Survival with Post-Transplant Cyclophosphamide Compared to Standard GVHD Prophylaxis after Allogeneic Hematopoietic Cell Transplantation for AML and MDS Background: Post-transplant cyclophosphamide (PTCy) is frequently used after allogeneic hematopoietic cell transplant (HCT) as it results in lower rates of graft versus host disease (GVHD). In addition to its predominant use in haploidentical and HLA mismatched donor HCT, PTCy showed potential to become the standard of care GVHD prophylaxis in a setting of HLA matched related and unrelated donor HCT as well (Bolaños-Meade, Lancet 2019). However, recent registry study reported higher risk of relapse after PTCy-based vs.calcineurin inhibitor (CNI) and methotrexate (MTX) GVHD prophylaxis in patients with acute myeloid leukemia (AML) receiving matched sibling donor HCT (Nagler, Transplant Cell Ther 2022). Thus, additional studies are needed to determine whether the benefit of GVHD prevention with PTCy comes at the cost of compromising the graft versus leukemia effect yielding higher relapse of AML and myelodysplastic syndromes (MDS) after HCT. In this retrospective study, we compared the HCT outcomes of PTCy-based vs. CNI-based GVHD prophylaxis in patients with AML and MDS. Methods: We included patients with AML and MDS who received an allogeneic HCT in first or second complete remission at our institution from 1/1/2014 to 12/31/2019. Patients received either a PTCy-based or a CNI-based GVHD prophylaxis regimen. CNI-based regimen consisted of either CNI/sirolimus +/- other (CNI/Siro group) or CNI/MTX +/- other (CNI/MTX group). The graft source in all the patients was peripheral blood (n=582) or bone marrow (n=23). Results: Total of 605 patients were identified: 442 with AML and 163 with MDS (Table 1.). GVHD prophylaxis with PTCy was used in 137 (23%), CNI/Siro in 402 (66%) and CNI/MTX in 66 (11%) patients. The PTCy group had higher proportion of patients who were Caucasian, received haploidentical donor HCT, reduced intensity (RIC) or non-myeloablative (NMA) conditioning or a bone marrow graft. Otherwise, baseline characteristics were similar between the GVHD prophylaxis groups. With a median follow up of 47 months, 149 (25%) patients relapsed, and 265 (44%) patients died. The probability of relapse at 2 years after HCT was similar between the GVHD prophylaxis groups: 23% in PTCy, 26% in CNI/Siro and 23% in CNI/MTX (p=0.94) (Figure 1). Similarly, there were no significant differences in 2-year overall survival (OS) between the groups: 58% in PTCy, 62% in CNI/Siro and 69% in CNI/MTX (p=0.33). We also observed no differences in non-relapsed mortality (NRM) between the groups. Median time to post-HCT relapse was 175 days in PTCy group, 180 days in CNI/Siro group and 131 days in CNI/MTX group. Management for post-HCT relapse included chemotherapy alone (n=58), chemotherapy +/- targeted therapy (n=53), chemotherapy + donor lymphocyte infusion (n=6), second HCT (n=3) and supportive care (n=29). GVHD prophylaxis groups did not differ by type of treatment used for relapse. Post-relapse OS at 2 years was 6% in PTCy, 20% in CNI/Siro and 31% in CNI/MTX groups (p=0.34). In multivariable analysis, the type of GVHD prophylaxis regimen did not significantly influence the post-HCT relapse, NRM, OS or post-relapse survival. Relapse was affected by DRI (p<0.001) and by type of conditioning regimen (p=0.002). NRM was influenced by HCT-CI (p=0.007) and by type of conditioning regimen (p=0.006). OS was inferior with high/very high risk DRI (p<0.001) and HCT-CI ≥ 3 (p<0.001). Survival after post-HCT relapse was better in patients relapsing >12 months after receiving HCT (p=0.003) and in those receiving treatment other than supportive care (p<0.001). Conclusion: In patients with AML and MDS receiving allogeneic HCT, we found similar risk of relapse and survival with PTCy-based and standard GVHD prophylaxis regimens. Survival after post-HCT relapse was also similar between the GVHD prophylaxis groups. The findings of this study support the use of PTCy-based regimen as GVHD prophylaxis after allogeneic HCT in patients with AML and MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Neuropsychological, behavioral, and quality‐of‐life outcomes in children and adolescents with sickle cell disease treated with nonmyeloablative matched sibling donor hematopoietic cell transplantation: A case series

Despite advances in the treatment of sickle cell disease (SCD), cerebrovascular and cognitive insults can have lifelong consequences. Hematopoietic cell transplantation (HCT) is an established curative therapy, and recent studies have demonstrated efficacy with reduced toxicity nonmyeloablative (NMA) regimens, but little is known about neuropsychological outcomes. The objective of this study was to describe neuropsychological, behavioral, and quality-of-life outcomes with medical correlates in children with SCD who received an NMA matched sibling donor (MSD) HCT. Retrospective cohort analysis of nine recipients with hemoglobin SS SCD who underwent MSD HCT using the National Institutes of Health (NIH) NMA protocol. Mean full-scale intellectual functioning (FSIQ) was average pre-HCT (FSIQ= 92.1, SD 9.0; n = 8) and 2years post-HCT (mean FSIQ= 96.6; SD 11.1; N = 9). Neuropsychological functioning was largely average across all cognitive domains, and no pre/post-HCT differences were found to be statistically significant given the small sample size. However, effect sizes revealed moderate improvements in processing speed (Cohen's d = .72) and verbal memory (Cohen's d = .60) post-HCT, and declines in measures of attention (Cohen's d = -.54) and fine motor speed and dexterity (Cohen's d = -.94). Parents endorsed better quality of life (Cohen's d = .91), less impact of SCD on their family, and less worry about their child's future (Cohen's d = 1.44). Neuropsychological functioning in a sample of children and adolescents treated uniformly with NMA MSD HCT remained stable or improved in most cognitive domains, and improvements in quality of life and family functioning were observed.

Haploidentical versus Matched Unrelated versus Matched Sibling Donor Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide

With the use of post-transplantation cyclophosphamide (PTCy), the outcomes of mismatched related donor hematopoietic cell transplantation (HCT) are now approaching those of matched donor HCT. Here we compared haploidentical donor HCT versus HLA-matched unrelated donor (MUD) HCT and HLA-identical sibling donor (MSD) HCT in a cohort in which all patients received PTCy for graft-versus-host disease (GVHD) prophylaxis. We included 661 patients (275 haploidentical, 246 MUD, and 140 MSD HCT). The most common diagnoses were acute myelogenous leukemia and myelodysplastic syndrome. In multivariate analysis, the haploidentical group was found to have significantly higher nonrelapse mortality (NRM) (hazard ratio [HR], 3.2; 95% confidence interval [CI], 2 to 4.9; P < .001) and inferior progression-free survival (HR, 1.8; 95% CI, 1.4 to 2.4; P < .001) and overall survival (OS; HR, 2.2; 95% CI, 1.6 to 3; P < .001) compared with the MUD group. Relapse was the most common cause of death in all groups. Among causes of NRM, the haploidentical group had more infection-related deaths and fewer GVHD-related deaths than the other groups. The haploidentical group also had a higher risk of viral and fungal infections, grade ≥3 hemorrhagic cystitis, and cardiovascular toxicities and slower reconstitution of CD4, CD8, and regulatory T cells but faster reconstitution of natural killer cells. In an exploratory analysis, older patients with older donors (>50 years for both) appeared to have particularly high NRM and lower OS in the haploidentical group compared with the other groups. Our data suggest that even with the use of PTCy, the outcomes of haploidentical HCT are inferior to those of HLA-matched donor HCT.

Predictors and outcomes of flares in chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) requires prolonged immunosuppressive therapy (IST), often requiring slow tapering with patients experiencing cGVHD flares and treatment failure. In 145 adult recipients developing cGVHD after matched sibling or umbilical cord blood donor HCT from 2010 to 2018, 2-year cumulative incidence of flares after cGVHD diagnosis was estimated at 60% (95% CI, 51-70%), with median time-to-first flare of 188 days (range, 16-751). Of 88 patients experiencing a flare, 32 (36%) had multiple flares (range, 2-4). First flare treatment consisted of an increase in prednisone dose in 77 patients (88%), plus topical therapy in 8 (9%) or another systemic IST in 43 patients (49%). Higher flare risk was associated with quiescent type of cGVHD at onset (HR 1.8; 95% CI: 1.1-2.7; p = 0.04). Patients without a flare required a shorter duration of IST and were more likely to achieve a durable discontinuation of systemic IST (86% vs. 31% for ≥6 consecutive months). Flares were associated with protective effect on relapse (HR 0.2, 95% CI: 0.1-0.3), however not with worsened 2-year NRM or OS. Flares of cGVHD identify a group needing better approaches to limit the duration of IST and thus the morbidity of cGVHD.

Outcome of allogeneic transplantation for mature T-cell lymphomas: impact of donor source and disease characteristics

AbstractMature T-cell lymphomas constitute the most common indication for allogeneic hematopoietic cell transplantation (allo-HCT) of all lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) between 2008 and 2018. Hematopoietic cell transplantation (HCT) platforms compared were posttransplant cyclophosphamide-based haploidentical (haplo-)HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in vivo T-cell depletion (MUD TCD+), and matched unrelated donor HCT without in vivo T-cell depletion (MUD TCD−). Coprimary end points were overall survival (OS) and progression-free survival (PFS); secondary end points included nonrelapse mortality (NRM), and relapse/progression incidence (RI). A total of 1942 patients were eligible (237 haplo-HCT; 911 MSD; 468 MUD TCD+; 326 MUD TCD−). Cohorts were comparable for baseline characteristics with the exception of higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. Using univariate and multivariate comparisons, OS, PFS, RI, and NRM were not significantly different among the haplo-HCT, MSD, MUD TCD+, and MUD TCD− cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%, respectively, and 50%, 50%, 48%, and 52%, respectively. Significant predictors of inferior OS and PFS on multivariate analysis were active disease status at HCT and decreased PS. AITL was associated with significantly reduced relapse risk and better PFS compared with PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma (TCL). Outcomes of haplo-HCT were comparable to those of matched donor allo-HCT.

Similar Event-Free Survival but Higher Incidence of Mixed T Cell Chimerism after Hematopoietic Cell Transplantation for Sickle Cell Disease Using Rabbit Versus Horse ATG: a Study from the Sickle Transplant Alliance for Research (STAR)

▪Background: Myeloablative HLA-matched sibling donor hematopoietic cell transplantation (HCT) is highly curative for children and young adults with sickle cell disease (SCD). The most common regimen used worldwide has been Busulfan, Cyclophosphamide and anti-thymocyte globulin (ATG). The optimal type of ATG for this approach remains unclear.Objective: To compare HCT outcomes of horse ATG (hATG) versus rabbit ATG (rATG) in patients with SCD undergoing HCT.Methods: Multicenter retrospective data from patients with SCD undergoing HCT were abstracted from the Sickle Transplant Alliance for Research (STAR) database. Patients undergoing myeloablative and reduced intensity conditioning HCT with matched related donors where the conditioning regimen included ATG were included in the analysis. Baseline characteristics were compared between the groups using chi-square and Wilcoxon Rank-Sum tests. Kaplan-Meier curves were used to assess time-to-event outcomes, such as overall and event free survival (EFS), and compared with log-rank tests. Death, disease recurrence (acute sickle cell symptoms/HbS >50%) and graft failure (whole blood or myeloid chimerism < 5%) were considered events for EFS. Full donor chimerism was defined as ≥95% donor. P-values less than 0.05 were considered statistically significant.Results: 103 patients (hATG = 78, rATG = 25) from 7 U.S. centers and one Canadian site were available in the database for analysis. Median age at HCT (8.1 years vs 7.6 years, p = 0.866) and gender distribution (55.1% vs 56.0% male, p = 0.939) was similar between the cohorts. Sickle cell genotype was 97.4% vs. 84% HbSS, 1.3% vs. 12.0% HbSBetazero, 1.3% vs. 0% HbSC, and 0% vs.4% other. Pre-transplant disease acute symptoms were similar between the groups. Myeloablative conditioning was used in 92.3% and 96.0% in the hATG group versus the rATG group (p=1) and the most common conditioning regimen was Busulfan and Cyclophosphamide +/- Fludarabine in both groups (93.2%). Donor age and source of graft were similar between the two groups. Median follow-up for hATG and rATG groups were 3.0 and 3.6 years respectively. The year of transplant for the two groups ranged from 1993 to 2015 (hATG) and 2003 to 2014 (rATG). Three-year OS for the entire group was 92.6% (95% CI: 87.4-98.0), with 90.1% (95% CI: 83.4-97.4) in the hATG group and 100% (95% CI: 100-100) in the rATG group (p = 0.122) (Figure 1). Three-year EFS was 90% vs. 96% (p=0.415) in hATG vs. rATG group with 2-year graft failure incidence of 0% vs. 4% (p =0.085) respectively. Limiting the analysis to transplants performed after 2000 did not materially alter the analyses for OS and EFS. Causes of death were GVHD related (n=5) and infection/sepsis (n=3) in the hATG group versus no deaths in rATG group. Six month incidence of acute grade III-IV GVHD and 3 year incidence of chronic GVHD for hATG vs. rATG groups was 3.9% vs. 0% (p=0.319) and 16.8% vs. 15.5% (p=0.549) respectively. Prevalence of full donor myeloid chimerism was similar between the two groups at Day +30, Day +100 and >6months. Prevalence of full donor whole blood chimerism was significantly lower at day+100 and 1 year (p < 0.05) in the rATG group. Full donor T cell chimerism was similar at Day 30 and Day 100, but significantly less prevalent at >6 months in the rATG group (p = 0.001) (Table 1).Discussion/Conclusion: In our cohort mortality was low overall and the hATG and rATG groups had similar OS, EFS, and similar incidence of acute grade III-IV and chronic GVHD. However the prevalence of full donor T cell chimerism at greater than 6 months after HCT was significantly lower in the rATG group.Table 1. Incidence of full donor chimerism (≥ 95%) by lymphocyte depleting antibody, %Fig 1. Overall and Event Free survival of hATG vs. rATG based conditioning regimens in HCT for SCDFig 2. Incidence of acute grade III-IV and chronic GVHD in hATG vs. rATG based conditioning regimens in HCT for SCD [Display omitted] DisclosuresGuilcher:Jazz pharmaceuticals: Consultancy; Canada Market Research: Consultancy; Patient Access Solutions: Consultancy.

High incidence of thromboembolism in patients with chronic GVHD: association with severity of GVHD and donor-recipient ABO blood group

Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) is associated with systemic inflammation and endothelial dysfunction, increasing risk for thromboembolic events (TEE). In 145 adult recipients who developed cGVHD after a matched sibling or umbilical cord blood donor HCT from 2010 to 2018, 32(22%) developed at least 1 TEE event, and 14(10%) developed 2 TEE events. The 5-year cumulative incidence of TEE was 22% (95% CI, 15–29%) with a median time from cGVHD to TEE of 234 days (range, 12–2050). Median time to the development of LE DVT or PE was 107 (range, 12–1925) compared to 450 days (range, 158–1300) for UE DVT. Cumulative incidence of TEE was 9% (95% CI, 0–20%), 17% (95% CI, 9–25%), and 38% (95% CI, 22–55%) in those with mild, moderate, and severe GVHD, respectively. Higher risk for TEE was associated with cGVHD severity (hazard ratio [HR] 4.9, [95% CI, 1.1–22.0]; p = 0.03), non-O-donor to recipient ABO match compared to O-donor to O-recipient match (HR 2.7, [95% CI, 1.0–7.5]; p = 0.053), and personal history of coronary artery disease (HR 2.4, [95% CI, 1.1–5.3]; p = 0.03). TEE was not associated with 2-year non-relapse mortality or 5-year overall survival.

Use of Potentially Inappropriate Medications in Older Allogeneic Hematopoietic Cell Transplantation Recipients

The use of potentially inappropriate medications (PIMs) using Beers criteria and its impact on older allogeneic hematopoietic cell transplantation (HCT) recipients is not known. Here the use of any PIMs and their therapeutic classes in reduced-intensity conditioning allogeneic HCT recipients were compared between older (≥65 years; n=114)and younger (40 to 64 years; n=240) patients during their initial HCT admission, defined as the number of days that a patient received 1 or more PIMs between day -14 and day +28. Poisson regression was used to determine rate ratios (RRs) in the 2 groups. In the ≥65 years group, we evaluated the impact of PIMs on Common Terminology Criteria for Adverse Events (CTCAE) grade 3-4 toxicities within 100 days and on overall mortality within 1 year post-HCT. The rate of any PIM use was similar in the older and younger groups (RR, .98; 95% confidence interval [CI], .90 to 1.06; P=.65). In terms of PIM classes, the older group had a 48% higher rate of gastrointestinal (GI) medication use (RR, 1.48; 95% CI, 1.32 to 1.65; P < .01) and a 25% higher rate of genitourinary (GU) medication use (RR, 1.25; 95% CI, 1.02 to 1.53; P=.03). Compared with males, females had a 19% higher rate of central nervous system (CNS) medication use (RR, 1.19; 95% CI, 1.03 to 1.37; P=.02) and a 30% higher rate of benzodiazepine use (RR, 1.30; 95% CI. 1.09 to 1.54; P < .01). A high-risk HCT-CI was associated with a higher rate of use of any PIMs (RR, 1.13; 95% CI, 1.01 to 1.26; P=.02), CNS medications (RR, 1.26; 95% CI, 1.04 to 1.53; P=.02) and GU medications (RR, 1.46; 95% CI, 1.09 to 1.94; P=.01). Compared with matched sibling donor HCT recipients, umbilical cord blood transplantation recipients had higher rates of GI medication use (RR, 1.32; 95% CI, 1.14 to 1.53; P < .01) and anticholinergic medication use (RR, 1.30; 95% CI, 1.06 to 1.61; P=.01). In the ≥65 years group, increasing duration of narcotic use was associated with a 1.3-fold (95% CI, 1.0 to 1.7; P=.05) higher risk of overall mortality and a 1.6-fold (95% CI, 1.02 to 2.69) greater odds of CTCAE grade 3-4 toxicities (P=.04). Our data show that older recipients (≥65 years) were as likely as their younger counterparts to receive PIMs. Among older recipients, the use of PIMs, particularly narcotics, was associated with higher mortality and higher incidence of grade 3-4 toxicities.Identifying and reducing the use of PIMs in older HCT recipients may help decrease the burden of adverse events and associated health care costs.

Blastic plasmacytoid dendritic cell neoplasm in a young female: Rare and challenging

AbstractBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematopoietic malignancy with an aggressive behavior, seen commonly in the elderly age group and usually involves the skin. Evaluation, diagnosis, and treatment pose unique challenges with poor outcomes. We report a case of an 18-year-old female who presented with lymphadenopathy and bicytopenia. The diagnosis of BPDCN was an initial challenge. She thereafter received intensive chemotherapy followed by an allogenic partially mismatched sibling donor hematopoietic cell transplantation, only to relapse in a few months. Beginning from the diagnosis, the management of this rare disorder and its relapse until her last followup provided several learning opportunities.

The Effect of Granulocyte Colony-Stimulating Factor Use on Hospital Length of Stay after Allogeneic Hematopoietic Cell Transplantation: A Retrospective Multicenter Cohort Study.

Granulocyte colony-stimulating factor (G-CSF) is administered after allogeneic hematopoietic cell transplantation (HCT) to aid neutrophil recovery. We compared the effect of empiric G-CSF administration on the duration of index inpatient hospitalization stay after HCT for patients aged ≥18 years with a hematologic malignancy. G-CSF was considered empiric if administered between day -3 and day +6 in relation to graft infusion. We studied 3562 HCTs (1487 HLA-matched sibling donor HCTs and 2075 HLA-matched unrelated donor HCTs) between 2007 and 2016. Three hundred and thirteen (21%) recipients of HLA-matched sibling donor HCT and 417 (20%) recipients of HLA-matched unrelated donor HCT received empiric G-CSF therapy. The effect of G-CSF therapy on the index hospitalization stay was examined in generalized linear models (GLMs) with adjustment for other patient, disease, and transplantation characteristics and acute graft-versus-host disease and infection post-transplantation. The duration of index hospitalization by treatment group did not differ for HLA-matched sibling donor HCT but was shorter with G-CSF for HLA-matched unrelated donor HCT (15 days versus 19 days; P < .001). Our GLMs confirmed shorter hospitalization with the use of G-CSF therapy for HLA-matched unrelated donor HCT (P=.01). G-CSF therapy was not associated with early survival for either donor type, and there was no benefit or disadvantage of giving G-CSF to promote neutrophil recovery.

Pediatric acute graft-versus-host disease prophylaxis and treatment: surveyed real-life approach reveals dissimilarities compared to published recommendations.

SummaryPediatric allogeneic hematopoietic cell transplantation (HCT) practices differ from those of adults, particularly the heterogeneity of transplantable nonmalignant diseases and the lower incidence of graft‐versus‐host disease (GVHD). Several guidelines regarding the management of acute (a) GVHD in adult HCT have been published. We aimed to capture the real‐life approaches for pediatric aGVHD prophylaxis/treatment, and data from 75/193 (response rate 39%) EBMT centers (26 countries) were included, representing half (48%) of the pediatric EBMT‐HCT activity. Results with ≥75% approval from respondents (74/75) for GVHD prophylaxis after myeloablative HCT for malignancies partially contradict published guidelines: Single‐agent cyclosporine A (CsA) was used for matched sibling donor HCT in 47%; blood CsA levels were reported lower; the relapse risk in malignant diseases influenced GVHD prophylaxis with early withdrawal of CsA; distinct longer duration of CsA was employed in nonmalignant diseases. Most centers used additional anti‐thymocyte globulin for matched unrelated and mismatched donor HCT, but not for matched siblings. Regarding prophylaxis in nonmyeloablative conditioning (mainly for nonmalignant diseases), responses showed broad heterogeneity. High conformity was found for first‐line treatment; however, results regarding steroid‐refractory aGVHD indicate an earlier diagnosis in children. Our findings highlight the need for standardized pediatric approaches toward aGVHD prophylaxis/treatment differentiated for malignant and nonmalignant underlying diseases.

A Phase II Trial to Compare Allogeneic Transplant Vs. Standard of Care for Severe Sickle Cell Disease: Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 1503

Background: Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for sickle cell disease (SCD). A pilot trial confirmed the suitability of a myeloablative conditioning regimen (busulfan/fludarabine/r-ATG) for HLA-matched sibling and unrelated donor HCT for severe SCD. This led to the current phase II trial funded by the NHLBI. The primary aim is to determine the efficacy of treatment options (HCT vs. standard of care) for adolescents and young adults with severe SCD (NCT02766465). Study design and Treatment: This is a "biologic assignment" trial in which subjects with an HLA-matched sibling or HLA-matched unrelated donor are assigned to a donor arm (expected to receive HCT). Those without a suitable donor are assigned to a no-donor arm and expected to receive current therapies for SCD at the discretion of their provider. Although randomization is the gold standard for comparing treatments, such an approach for a rare disease is not feasible for the following reasons: 1) timely completion of the trial (~30% expected to identify a matched sibling and ~20%, a matched unrelated donor) and 2) accrual is challenging when the two arms of a randomized trial have markedly disparate treatments (i.e., one arm is an intervention with about 10-20% upfront mortality vs. the other arm also expected to have mortality risks but accepted as a consequence of disease). While we expect some to decline HCT (donor arm) or proceed to a mismatched related or unrelated donor HCT (no-donor arm), through education /counselling prior to consent, we anticipate &lt;5% cross-over. Major Inclusion Criteria: Age 15 - 40 years with SCD (stroke or neurologic deficit, recurrent vaso-occlusive crisis, acute chest syndrome, high impact chronic pain or tricuspid regurgitant jet velocity ≥2.7m/second. Subjects who already have a suitable donor are excluded. Statistical Methods: Subjects are screened for eligibility and enrolled without knowing their biological assignment. HLA typing of the subject and donor search can be undertaken only after enrollment. Treatment arm assignment, (donor or no-donor arm) has to occur within 6 months of enrollment. We hypothesize that subjects on the donor arm will exert an early impact on survival and that survival will plateau by 1-year. Those on the no-donor arm are expected to follow the natural history of their disease with risk of premature mortality. A non-inferiority framework was chosen to test the non-inferiority of the donor arm compared to the no donor arm. The non-inferiority margin of 0.20 was chosen to establish that the difference in the proportion of subjects surviving at 2 years between the donor arm is no more than 0.20 worse than the no donor arm. If we reject the non-inferiority null hypothesis with a one-sided test, we will declare that the non-inferiority margin is met and that the difference in the probability of 2-year survival between the donor and no-donor arm is no more than 20%. Endpoints: The primary endpoint is the estimate of overall survival at 2-years after enrollment. Regardless of treatment received subjects will remain in their assigned treatment arm for analysis of survival (intent-to-treat principle). Secondary endpoints include comparison of occurrence of sickle related events in both treatment groups over 2 years (pulmonary hypertension, cerebrovascular, renal, avascular necrosis, leg ulcer), and functional assessment (6-minute walk distance test, 28-day e-pain diary [mean pain intensity] and HRQoL. Exact logistic regression will be used to estimate an odds ratio of such events, assuming that at least one such event occurs on study in each of the treatment arms, controlling for other patient-related characteristics and individual history of the event of interest. The trial is on-going and has met ~55% of projected accrual. Obstacles to accrual include: physician bias, subjects were not aware of a curative option for their disease, payment for HCT on a clinical trial in some US states despite meeting the Center for Medicare/Medicaid Services (CMS) requirement for coverage with evidence determination (CED), prior HLA typing and knowledge regarding donor availability, competing treatment options and the fact that substantial numbers of potentially eligible subjects are followed in the community and lack access to academic sites. Overcoming obstacles took ~2 years. The trial is now at "steady state accrual" and expected to complete accrual in ~18-24 months. Disclosures Neuberg: Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership. Stevenson:Celgene: Research Funding. Waller:Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents &amp; Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents &amp; Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Walters:Editas Medicine: Consultancy; TruCode: Consultancy; AllCells, Inc: Consultancy.

Reduced Toxicity Conditioning for Non-Malignant Hematopoietic Cell Transplants

Background. Reduced-intensity conditioning (RIC) regimens are commonly used for hematopoietic cell transplantation (HCT) in non-malignant disorders to minimize potential drug-related toxicity from myeloablative conditioning (MAC). However, melphalan-based RIC regimens are associated with poor engraftment and need for second HCT or donor lymphocyte infusions (DLIs). This study expands on our previous experience with targeted busulfan, fludarabine, and intravenous (IV) alemtuzumab as a low-toxicity but myeloablative regimen to achieve sustained donor engraftment. Methods. We conducted a retrospective analysis of patients ≤25 years of age with non-malignant disorders who received targeted busulfan, fludarabine and IV alemtuzumab as conditioning for their first HCT between 2004 and 2018. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitors in all patients, plus methotrexate (n=59), methylprednisolone (n=2), or mycophenolate (n=1). The primary end point was 3-year overall survival (OS). Secondary end points included treatment-related mortality (TRM), event-free survival (EFS) defined as alive without second HCT or disease progression, and incidence of acute and chronic GVHD (aGVHD and cGVHD). Other end points included incidence of graft failure (GF) defined as &lt;5% donor chimerism in whole blood, sinusoidal obstruction syndrome (SOS) and CMV viremia. Analysis was stratified by era of HCT (2004-2011 vs. 2012-2018). Results. We identified 62 patients with a median age of 5.5 years and male:female of 46:16. Diagnoses included primary immune deficiencies (60%), hemoglobinopathies (22%), bone marrow failure disorders (8%) and inherited metabolic disorders (10%). The median busulfan cumulative area-under-the-curve (cAUC) was 70 mg*h/L (range, 57-108 mg*h/L). Donors were matched sibling (MSD) in 27%, 8/8 allele-matched unrelated (MUD) in 50% and Class I allele-mismatched (MM) in 23%. All but 2 of the Class I allele-MM donors were unrelated. The source was bone marrow (BM) in 74% and peripheral blood stem cells (PBSC) in 26%. The cumulative incidence (CI) of GF was 8% (95% CI, 1-16%). In engrafted patients, the median donor chimerism in whole blood, CD3, CD14/15, and CD19 at 1-year was 96%, 90%, 99%, and 99%, respectively. Only 1 patient required DLIs for poor chimerism. T-cell reconstitution (CD4 &gt;200 x 109/L and PHA response &gt;50% control) was achieved at a median of 182 days (range, 76-585 days). Two patients died following disease progression despite 100% donor chimerism. The CI of TRM was 10% (95% CI, 2-17%). Causes of TRM included infectious complications (n=2), hemorrhage (n=1), respiratory failure (n=3 with 2 following subsequent transplants after graft rejection). TRM incidence was significantly higher in patients with Class I MM compared to those with MSD or 8/8 allele-MUD (29% vs 6% vs 3%; p=0.024; Figure 1A). SOS occurred in 5% of patients and all resolved with supportive therapy (n=1) or defibrotide (n=2). Post-transplant CMV viremia occurred in 26% of all patients and in 71% of CMV seropositive patients. None developed CMV disease and all infections resolved with anti-viral therapy. OS and EFS at 3-years were 87% (95% CI, 78-95%) and 80% (95% CI, 70-90%), respectively. HCTs performed in the more recent era showed an OS of 97% compared to 79% in HCTs performed earlier (p=0.057; Figure 1B). OS was 97% in patients with 8/8 allele-MUD compared to 79% in those with MSD and 71% in those with Class I allele-MM (p=0.051). The 6-month CI of grade II-IV aGVHD was 7% (95% CI, 3-13%), while the 3-year CI of cGVHD was 5% (95% CI, 0-11%). GVHD incidence was higher in patients receiving PBSC compared to BM (25% vs 0%; p&lt;0.001) and in patients ≥5 years of age compared to those &lt;5 years of age (13% vs 0%; p=0.043). Patients with inherited metabolic disorders showed significantly worse OS (44%, p=0.016), EFS (33%, p=0.001) and aGVHD (33%, p=0.008) than those in other disease groups. Univariate analysis did not show any significant differences in survival or GVHD incidence by race or sex. Conclusions. Use of targeted busulfan, fludarabine and IV alemtuzumab as myeloablative conditioning in pediatric patients with primary immunodeficiencies, hemoglobinopathies, and bone marrow failure syndromes undergoing matched sibling or well-matched unrelated donor HCT provides a well-tolerated option to achieve sustained engraftment with low incidence of GVHD and toxicities such as SOS. Figure 1 Disclosures Shimano: Pfizer: Research Funding; Daiichi Sankyo: Research Funding; Novartis: Research Funding. Huang:Novartis: Research Funding. Cowan:Homology Medicine: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Leadiant: Consultancy; California Institute Of Regenerative Medicine: Research Funding; NIH NIAD: Research Funding; Rocket Pharma: Consultancy; UpToDate: Honoraria; bluebird bio: Consultancy. Dvorak:Alexion Inc: Consultancy; Jazz Pharmaceuticals: Consultancy.

Nonmyeloablative Matched Sibling Donor Hematopoietic Cell Transplantation in Children and Adolescents with Sickle Cell Disease.

Sickle cell disease is a potentially debilitating hemoglobinopathy associated with early mortality. The only established curative therapy is hematopoietic cell transplantation (HCT) with a matched sibling donor. The National Institutes of Health nonmyeloablative regimen of alemtuzumab/300 cGy total body irradiation and prolonged sirolimus exposure for graft-versus-host disease (GVHD) prophylaxis was administered to 16 children and adolescents. Infused products were unmanipulated granulocyte colony stimulating factor mobilized peripheral blood stem cells. All patients achieved mixed donor-recipient engraftment with no cases of secondary graft failure to date. Two patients have donor myeloid chimerism in the range of 30% to 40%. No sickling crises post-HCT have been observed. Event-free and overall survival rates are 100% with median follow-up of 19.5 months. No cases of GVHD have been observed. Sirolimus weaning was possible in all but one eligible patient to date. Ongoing follow-up and a larger prospective clinical trial are required to determine the long-term safety and efficacy of this regimen in children.

New-Onset Post-Transplant Diabetes Mellitus after Allogeneic Hematopoietic Cell Transplant Is Initiated by Insulin Resistance, Not Immunosuppressive Medications.

New-onset post-transplant diabetes mellitus (PTDM) occurs frequently after allogeneic hematopoietic cell transplant (HCT). Although calcineurin inhibitors and corticosteroids are assumed to be the cause for hyperglycemia, patients developing PTDM have elevated fasting C-peptide levels before HCT and before immunosuppressive medications. To determine if PTDM results from established insulin resistance present before transplant, we performed oral glucose tolerance tests (OGTTs) and measured whole body, peripheral, and hepatic insulin sensitivity with euglycemic hyperinsulinemic clamps before and 90 days after HLA-identical sibling donor HCT in 20 patients without pretransplant diabetes. HCT recipients were prospectively followed for the development of new-onset PTDM defined as a weekly fasting blood glucose ≥ 126 mg/dL or random blood glucose ≥ 200 mg/dL. During the first 100 days all patients received calcineurin inhibitors, and 11 individuals (55%) were prospectively diagnosed with new-onset PTDM. PTDM diagnosis preceded corticosteroid treatment. During the pretransplant OGTT, elevated fasting (87 mg/dL versus 101 mg/dL; P = .005) but not 2-hour postprandial glucose levels predicted PTDM diagnosis (P = .648). In response to insulin infusion during the euglycemic hyperinsulinemic clamp, patients developing PTDM had lower whole body glucose utilization (P = .047) and decreased peripheral/skeletal muscle uptake (P = .031) before and after transplant, respectively, when compared with non-PTDM patients. Hepatic insulin sensitivity did not differ. Survival was decreased in PTDM patients (2-year estimate, 55% versus 100%; P = .039). Insulin resistance before HCT is a risk factor for PTDM independent of immunosuppression. Fasting pretransplant glucose levels identified PTDM susceptibility, and peripheral insulin resistance could be targeted for prevention and treatment of PTDM after HCT.