Daniel Weisdorf

Strategies that eliminate or inhibit B cells can be therapeutic in steroid refractory cGVHD, and two phase II trials have demonstrated effective prevention of cGVHD using post-transplant rituximab. Obinutuzumab (Obin, Genentech) is a 2nd generation monoclonal anti-CD20 antibody with enhanced B cell depletion activity over rituximab. We performed a randomized double-blind, placebo-controlled trial of 4 doses of Obin/placebo (1000 mg iv at 3, 6, 9, 12 months) to determine if steroid-requiring cGVHD (SR-cGVHD) could be prevented 12 months after HCT (NCT# 02867384). SR-cGVHD was felt to be a more objective measurement of cGVHD severity than NIH cGVHD stage alone. We present clinical trial results and compelling biologic correlates here.Results181 subjects were enrolled (92 Obin, 89 placebo). 167 subjects followed for >1 year from HSCT (84 Obin, 83 placebo) are presented here. The primary …

Background Blood or marrow transplantation (BMT) survivors carry a high burden of morbidity, yet health care utilization by this vulnerable population remains understudied. Patterns and predictors of various domains of health care utilization in long‐term BMT survivors were evaluated. Methods Study participants were drawn from the Bone Marrow Transplant Survivor Study (BMTSS). Patients transplanted between 1974 and 2014 at one of three transplant centers who had survived ≥2 years after BMT and were aged ≥18 years at the time of the study were included. A BMTSS survey served as the source of data for health care utilization, sociodemographics, and chronic health conditions. Domains of health care utilization in the 2 years preceding study participation included routine checkups, BMT‐related visits, transplant/cancer center visits, emergency room (ER) visits, hospitalizations, and high health care …

We examined the prevalence, risk factors, and association between pre-frailty and subsequent mortality after blood or marrow transplantation (BMT). Study participants were drawn from the BMT Survivor Study (BMTSS) and included 3346 individuals who underwent BMT between 1974 and 2014 at one of three transplant centers and survived ≥2 years post-BMT. Participants completed the BMTSS survey at a median of 9 years from BMT and were followed for subsequent mortality for a median of 5 years after survey completion. Closest-age and same-sex biological siblings also completed the survey. Previously published self-reported indices (exhaustion, weakness, low energy expenditure, slowness, unintentional weight loss) classified participants as non-frail (0–1 indices) or pre-frail (2 indices). National Death Index was used to determine vital status and cause of death. Overall, 626 (18.7%) BMT survivors were …

IntroductionOur phase I graft-versus-host disease (GVHD) prevention trial of pacritinib (recommended phase II dose: 100mg po BID day 0 to +70, dose level 2) plus sirolimus and tacrolimus (PAC/SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). PAC inhibits JAK2-cytokines (IL-6, IL-12, and IL-23) and pathogenic Th1/Th17 differentiation. Herein we report on our completed phase II trial of PAC/SIR/TAC after 8/8-HLA matched alloHCT.MethodsThis single-arm phase II trial (NCT02891603) was powered to determine if PAC/SIR/TAC suppressed %pSTAT3+ CD4+ T cells at day +21 (primary endpoint: %pSTAT3+ CD4+ T cells ≤ 35%) and determine the cumulative incidence of grade II-IV acute GVHD by day +100. The impact of PAC/SIR/TAC on CD4 T cell differentiation, CD28 (pS6 and pH3ser10), and IL-2 receptor …

We determined the risk of late morbidity and mortality after autologous blood or marrow transplantation (BMT) for lymphoma performed before age 40. The cohort included autologous BMT recipients who had survived ≥2 years after transplantation (N = 583 [HL = 59.9%; NHL = 40.1%]) and a comparison cohort (N = 1070). Participants self-reported sociodemographics and chronic health conditions. A severity score (grade 3 [severe], 4 [life threatening] or 5 [fatal]) was assigned to the conditions using CTCAE v5.0. Logistic regression estimated the odds of grade 3–4 conditions in survivors vs. comparison subjects. Proportional subdistribution hazards models identified predictors of grade 3–5 conditions among BMT recipients. Median age at BMT was 30.0 years (range: 2.0–40.0) and median follow-up was 9.8 years (2.0–32.1). Survivors were at a 3-fold higher adjusted odds for grade 3–4 conditions (95% CI …

Author contributions and disclosures: SB, MM and GC designed the experiment. THHC, SB, GC, WL, JI and EM analyzed data. TR, ALG, MM, JA, TRWOGAAB, ED, MG and JN curated samples, provided pathology input and/or performed experiments. MT provided clinical genetics expertise. AS provided statistical input. SB and GC wrote the manuscript with input from all authors. SB and MM directed the study.

We investigated the impact of donor age (younger [≤35 years] vs. older [>35 years]) after accounting for other non‐HLA and HLA factors on outcomes of patients with acute myeloid leukemia undergoing HLA‐haploidentical hematopoietic cell transplantation (n = 790). The effect differed by conditioning—partly related to the differences in the recipient age in myeloablative (MAC; median 46 years) versus reduced‐intensity/non‐myeloablative conditioning (RIC/NMA; median 61 years) groups. With MAC (n = 320), donor age had no impact on acute graft‐versus‐host disease (GVHD), but older donors were associated with a significantly higher risk of chronic GVHD (hazard ratio [HR]: 1.6, 95% confidence interval [CI]: 1.10–2.30, p = .02) independent of recipient age and other factors. Donor age had no impact on either relapse or non‐relapse mortality (NRM). The impact of donor/recipient age on overall …

Abstract In acute myeloid leukemia (AML), donor natural killer cell killer immunoglobulin–like receptors (KIR) and recipient HLA interactions may contribute to the graft-versus-leukemia effect of allogeneic hematopoietic cell transplantation (HCT). Analyses of individual KIR/HLA interactions, however, have yielded conflicting findings, and their importance in the HLA-matched unrelated donor (MUD) setting remains controversial. We systematically studied outcomes of individual donor-KIR/recipient-HLA interactions for HCT outcomes and empirically evaluated prevalent KIR genotypes for clinical benefit. Adult patients with AML (n = 2025) who received HCT with MUD grafts in complete remission reported to the Center for International Blood and Marrow Transplantation were evaluated. Only the donor-2DL2+/recipient-HLA-C1+ pair was associated with reduced relapse (hazard ratio [HR], 0.79; 95 …