Continuous and differential improvement in worldwide access to hematopoietic cell transplantation: activity has doubled in a decade with a notable increase in unrelated and non-identical related donors.

Promoting access to and excellence in hematopoietic cell transplantation (HCT) by collecting and disseminating data on global HCT activities is one of the principal activities of the Worldwide Network for Blood and Marrow Transplantation, a non-governmental organization in working relations with the World Health Organization. HCT activities are recorded annually by member societies, national registries and individual centers including indication, donor type (allogeneic/autologous), donor match and stem cell source (bone marrow/peripheral blood stem cells/cord blood). In 2018, 1,768 HCT teams in 89 countries (6 World Health Organization regions) reported 93,105 (48,680 autologous and 44,425 allogeneic) HCT. Major indications were plasma cell disorders and lymphoma for autologous, and acute leukemias and MDS/MPN for allogeneic HCT. HCT numbers increased from 48,709 in 2007. Notable increases were seen for autoimmune diseases in autologous and hemoglobinopathies in allogeneic HCT. The number of allogeneic HCT more than doubled with significant changes in donor match. While HCT from HLA-identical siblings has seen only limited growth, HCT from non-identical related donors showed significant increase worldwide. Strongest correlation between economic growth indicator of gross national income/capita and HCT activity/10 million population was observed for autologous HCT (correlation coefficient [r]=0.79). HCT from unrelated donors showed strong correlation (r=0.68), but only moderate correlation was detected from related donors (r=0.48 for HLA-identical sibling; r=0.45 for other). The use of HCT doubled in about a decade worldwide at different speed and with significant changes regarding donor match as a sign of improved access to HCT worldwide. Although narrowing, significant gaps remain between developing and non-developing countries.

Pilot Study of Donor-Engrafted Clonal Hematopoiesis Evolution and Clinical Outcomes in Allogeneic Hematopoietic Cell Transplantation Recipients Using a National Registry.

Improved treatment options, such as reduced-intensity conditioning (RIC), enable older patients to receive potentially curative allogeneic hematopoietic cell transplantation (HCT). This progress has led to increased use of older HLA-matched sibling donors. An unintended potential risk associated with older donors is transplantation of donor cells with clonal hematopoiesis (CH) into patients. We aimed to determine the prevalence of CH in older HLA-matched sibling donors pretransplantation and to assess the clinical impact of donor-engrafted CH on HCT outcomes. This was an observational study using donor peripheral blood samples from the Center for International Blood and Marrow Transplant Research repository, linked with corresponding recipient outcomes. To explore engraftment efficiency and evolution of CH mutations following HCT, recipient follow-up samples available through the Bone Marrow Transplant Clinical Trials Network (Protocol 1202) were included. Older donors and patients (both ≥55 years) receiving first RIC HCT for myeloid malignancies were eligible. DNA from archived donor blood samples was used for targeted deep sequencing to identify CH. The associations between donor CH status and recipient outcomes, including acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), overall survival, relapse, nonrelapse mortality, disease-free survival, composite GVHD-free and relapse-free survival, and cGVHD-free and relapse-free survival, were analyzed. A total of 299 donors were successfully sequenced to detect CH. At a variant allele frequency (VAF) ≥2%, there were 44 CH mutations in 13.7% (41 of 299) of HLA-matched sibling donors. CH mostly involved DNMT3A (n = 27; 61.4%) and TET2 (n= 9; 20.5%). Post-HCT samples from 13 recipients were also sequenced, of whom 7 had CH+ donors. All of the donor CH mutations (n = 7/7; 100%) were detected in recipients at day 56 or day 90 post-HCT. Overall, mutation VAFs remained relatively constant up to day 90 post-HCT (median change, .005; range, -.008 to .024). Doubling time analysis of recipient day 56 and day 90 data showed that donor-engrafted CH mutations initially expand then decrease to a stable VAF; germline mutations had longer doubling times than CH mutations. The cumulative incidence of grade II-IV aGVHD at day 100 was higher in HCT recipients with CH+ donors (37.5% versus 25.1%); however, the risk for aGVHD by donor CH status did not reach statistical significance (hazard ratio, 1.35; 95% confidence interval, .61 to 3.01; P = .47). There were no statistically significant differences in the cumulative incidence of cGVHD or any secondary outcomes by donor CH status. In subset analysis, the incidence of cGVHD was lower in recipients of grafts from DNMT3A CH+ donors versus donors without DNMT3A CH (34.4% versus 57%; P = .035). Donor cell leukemia was not reported in any donor-recipient pairs. CH in older HLA-matched sibling donors is relatively common and successfully engrafts and persists in recipients. In a homogenous population (myeloid malignancies, older donors and recipients, RICr, non-cyclophosphamide-containing GVHD prophylaxis), we did not detect a difference in cGVHD risk or other secondary outcomes by donor CH status. Subgroup analyses suggest potential differential effects by clinical characteristics and CH mutations. Larger prospective studies are needed to robustly determine which subsets of patients and CH mutations elicit meaningful impacts on clinical outcomes.