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.

A study assessing the feasibility of randomization of pediatric and young adult patients between matched unrelated donor bone marrow transplantation and immune-suppressive therapy for newly diagnosed severe aplastic anemia: A joint pilot trial of the North American Pediatric Aplastic Anemia Consortium and the Pediatric Transplantation and Cellular Therapy Consortium.

BACKGROUND: Recent data show survival after matched unrelated donor (MUD) bone marrow transplantation (BMT) is similar to matched sibling procedures for young patients with severe aplastic anemia (SAA). Donor delays, risk of transplant-related mortality (TRM), and concern about chronic graft versus host disease raise questions about whether MUD BMT or immune suppression therapy (IST) should be preferred initial therapy for young patients lacking matched sibling donors. PROCEDURE: We performed a pilot trial to assess the feasibility of randomizing patients under age 26 with newly diagnosed SAA to receive IST versus MUD BMT. Primary aims assessed the acceptability of randomization and timing of BMT. Secondary aims measured toxicities, response, and survival. RESULTS: Sixty-seven patients with possible SAA were screened at nine centers. Of 57 with confirmed SAA, 23 underwent randomization and received therapy with a median follow-up of 18 months. Of 12 randomized to BMT, 10 started BMT as initial therapy at a median of 36 days after randomization. One BMT recipient experienced secondary graft failure, requiring a second procedure. Six of 11 randomized to IST responded, whereas five with refractory disease underwent successful salvage BMT. One patient achieving complete response relapsed after discontinuation of immune suppression and died of infection after salvage BMT. CONCLUSIONS: This feasibility study showed that a high percentage of patients underwent randomization and received up-front MUD BMT. Our study lays the groundwork for a larger randomized trial that will define best initial therapy for young patients with SAA who have an available MUD.

Impact of autologous blood transfusion after bone marrow harvest on unrelated donor's health and outcome: a CIBMTR analysis.

Pre-harvest autologous blood collection from bone marrow (BM) donors is performed to meet potential post-operative transfusion needs. This study examines the impact of autologous blood transfusion on BM donor's health and safety. The study included first-time unrelated BM donors from the United States whose BM harvest was facilitated by the National Marrow Donor Program (NMDP) centers between 2006 and 2017. Examination of 7024 BM donors revealed that 60% received at least one unit of autologous blood. The donors who received autologous blood were older, had lower hemoglobin pre-harvest, underwent longer duration of anesthesia, and higher volume BM harvest. Only donors who underwent high-volume BM harvest, defined as a BM harvest volume >27% of donor's blood volume, benefited from autologous transfusion. After a high-volume BM harvest, autologous blood transfusion was shown to decrease grade 2 to 4 collection-associated toxicities within 48 h of BM donation (p = 0.010) and shorten the time to donor-reported "complete" recovery from donation-associated symptoms (p < 0.001). Therefore, autologous transfusion could be avoided as support of marrow donation in the majority of unrelated BM donors and should be limited to cases where the planned BM harvest volume is expected to exceed 27% of donor's blood volume.

NCI, NHLBI/PBMTC first international conference on late effects after pediatric hematopoietic cell transplantation: endocrine challenges-thyroid dysfunction, growth impairment, bone health, & reproductive risks.

The endocrine system is highly susceptible to damage by high-dose chemotherapy and/or irradiation before hematopoietic cell transplantation (HCT) during childhood. The specific endocrine organs most affected by HCT include the thyroid gland, the pituitary, and the gonads. In addition, hormones that support development and stability of the skeletal system are also affected. Insufficiency of thyroid hormone is 1 of the most common late sequelae of HCT, and occurs more often in young children. Deficiency in the pituitary's production of growth hormone is a problem of unique concern to the pediatric population. The reproductive risks of HCT depend on the patient's gender and pubertal status at the time of HCT. Pubertal or gonadal failure frequently occurs, especially in females. Infertility risks for both genders remain high, whereas methods of fertility preservation are limited in all but postpubertal males. Bone health post-HCT can be compromised by low bone mineral density as well as avascular necrosis, but the data on both problems in the pediatric HCT population are limited. In this paper, the current state of knowledge, gaps in that knowledge, and recommendations for future research are addressed in detail for each of these systems.