Hematopoietic Cell Transplantation for Congenital Dyserythropoietic Anemia: A Report from the Pediatric Transplant and Cellular Therapy Consortium.

Hematopoietic cell transplantation (HCT) is the sole curative option for congenital dyserythropoietic anemia (CDA), a rare type of hemolytic anemia characterized by anemia, ineffective erythropoiesis, and secondary hemochromatosis. In this retrospective multicenter study, we report the outcomes of children with CDA who underwent HCT at participating Pediatric Transplantation and Cellular Therapy Consortium centers. Clinical information on HCT and associated outcomes was collected retrospectively using a common questionnaire. Data were analyzed using descriptive statistics and appropriate analysis. Eighteen patients with CDA who underwent allogeneic HCT between 2002 and 2020 were identified. The majority of patients (n = 13) had CDA type II, and the remainder had either CDA type I (n = 2) or CDA of unknown type (n = 3). Mutations were identified in 7 patients (39%), including SEC23B in 5, GATA1 in 1, and abnormality of chromosome 20 in 1. Thirteen patients had evidence of iron overload pre-HCT and received chelation therapy for a median duration of 10 months (range, 2 months to 17 years) pre-HCT. The median age at the time of HCT was 5.5 years (range, 0.7 to 26 years). Donors were HLA-matched (sibling, 4; unrelated, 10) and mismatched (haploidentical, 1; unrelated, 3). Graft sources were bone marrow in 15 patients, umbilical cord blood in 2 patients, or both in 1 patient. Conditioning included busulfan-based myeloablative (67%), fludarabine-based reduced-intensity (27%), or nonmyeloablative (6%) regimens. Five patients developed veno-occlusive disease, and 4 had viral reactivation. The cumulative incidence of acute graft-versus-host disease (GVHD) was 33%, and that of chronic GVHD was 22%. Four patients (22%) experienced graft failure; all engrafted following either a second HCT (n = 2) or third HCT (n = 2) but sustained considerable morbidities (3 GVHD, 1 death, 2 viral reactivation). With a median follow-up of 3.2 years (range, 0.6 to 14 years)), the 2-year overall survival, event-free survival (EFS), and GVHD-free EFS were 88% (95% confidence interval [CI], 73% to 100%), 65% (95% CI, 45% to 92%), and 60% (95% CI, 40% to 88%), respectively. Univariate analysis did not identify any patient- or transplantation-related variables impacting outcomes. Our study indicates that HCT can be curative for patients with CDA. Strategies such as aggressive chelation, use of preconditioning therapy, and early HCT in the presence of a suitable donor before comorbidities occur are needed to improve engraftment without increasing the risk for toxicity and mortality.

Ultra-High Dose Vitamin D in Pediatric Hematopoietic Stem Cell Transplantation: A Nonrandomized Controlled Trial.

Vitamin D is essential for bone health and has immunomodulatory properties. Most pediatric patients are vitamin D insufficient (<30 ng/mL) before hematopoietic stem cell transplantation (HSCT). Standard supplementation strategies fail to achieve vitamin D sufficiency in the acute post-transplantation period, and there are scarce data to support optimal vitamin D supplementation in this patient population. This study aimed to evaluate whether a single, oral, weight-based ultra-high dose of vitamin D (Stoss dosing) was more effective than standard supplementation to achieve pre-HSCT vitamin D sufficiency and reduce the incidence of HSCT-related complications (acute graft-versus-host disease, veno-occlusive disease, and/or transplant-associated thrombotic microangiopathy) that are associated with immune-mediated endothelial damage. Secondary endpoints examined the immunomodulatory properties of vitamin D. We conducted a nonrandomized controlled clinical trial of Stoss-dosed vitamin D in pediatric patients receiving HSCT. The study prospectively enrolled 33 patients, 29 of whom successfully received Stoss-dosed vitamin D and were compared to 136 patients in a historical control. Patient characteristics were compared using Fisher's exact test or t-test. The one-sided Fisher's exact test was used for cohort comparison of the primary endpoints. Logistic regression was used to examine the association between patient-specific factors and total 25-hydroxy vitamin D (25-OHD) levels and the compiled HSCT complications. In the Stoss cohort, 97% (n = 28/29) of patients achieved pre-HSCT vitamin D sufficiency compared to 67% (n = 10/15) of patients in the historical control who were on standard supplementation at the time the total 25-OHD level was assessed (P = .013). The mean total 25-OHD level in the Stoss cohort was significantly higher than patients in the historical control who received standard supplementation (72.2 ng/mL versus 35.8 ng/mL, P < .001). Nine patients in the Stoss cohort maintained vitamin D sufficiency throughout the first 100 days after HSCT, and the remaining 19 patients maintained sufficiency for a median of 63 days (range 6-105 days) from the Stoss dose. Patients receiving Stoss-dosed vitamin D developed a lower combined incidence of HSCT-related complications than the historical control (25% [n = 7/28] versus 42% [n = 57/136], P = .055). After Stoss dosing, immunophenotyping studies found a significant decrease in subsets of CD8+ T cells and mononuclear cells (P = .040 and.013, respectively), and, in a subset of cells, larger decreases in phosphoprotein expression were seen with greater increases in total 25-OHD levels. Inflammatory cytokines did not change significantly after Stoss dosing. Stoss dosing is therefore a safe and effective approach to maintain vitamin D sufficiency in the immediate post-HSCT period and may be associated with decreased HSCT-related complications. Randomized studies are warranted to further investigate the efficacy of Stoss-dosed vitamin D to improve bone health and reduce complications in pediatric patients receiving HSCT.

GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia.

We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy-requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen-mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, P < .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation-based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB (P < .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; P = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; P = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; P = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; P = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; P = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors.

Unrelated donor hematopoietic stem cell transplantation for the treatment of non-malignant genetic diseases: An alemtuzumab based regimen is associated with cure of clinical disease; earlier clearance of alemtuzumab may be associated with graft rejection.

Hematopoietic stem cell transplantation (HSCT) with matched unrelated donors (MUD), offers potentially curative therapy for patients with non-malignant genetic diseases. In this pilot study conducted from 2006 to 2014, we report the outcomes of 15 patients with non-malignant genetic diseases who received a myeloablative regimen with a reduced cyclophosphamide dose, adjunctive serotherapy and MUD HSCT [intravenous alemtuzumab (52 mg/m(2) ), busulfan (16 mg/kg), fludarabine (140mg/m(2) ), and cyclophosphamide (105 mg/kg)]. Graft-versus-host-disease (GVHD) prophylaxis consisted of tacrolimus/cyclosporine and methylprednisolone. Median (range) time to neutrophil engraftment (>500 cells/µL) and platelet engraftment (>20,000/mm(3) ) were 15 (12-28) and 25 (17-30) days, respectively. At a median follow-up of 2 (0.2-5.4) years, the overall survival (OS) was 93.3% (95% CI: 0.61-0.99) and disease-free survival (DFS) was 73.3% (95% CI: 0.44-0.89). Among this small sample, earlier alemtuzumab clearance was significantly associated with graft rejection (P = 0.047), earlier PHA response (P = 0.009) and a trend toward earlier recovery of recent thymic emigrants (RTE) (P = 0.06). This regimen was associated with durable donor engraftment and relatively low rates of regimen related toxicity (RRT); future alemtuzumab pharmacokinetic studies may improve outcomes, by allowing targeted alemtuzumab clearance to reduce graft rejection and promote more rapid immune reconstitution.