Data from the largest series of pediatric patients with Fanconi anemia (FA) to date suggest that hematopoietic cell transplantation (HCT) should be offered at a young age in patients with aplastic anemia (AA) or bone marrow failure (BMF). The new study confirms excellent survival after matched family or unrelated donor HCT and improved survival after haploidentical (HID) HCT using either ex vivo T-cell depletion or post-transplant cyclophosphamide. Su Han Lum, MD, honorary consultant and senior clinical research fellow at Newcastle University in the United Kingdom, and colleagues published their findings from the largest-to-date multicenter study of HCT in pediatric FA in Blood.
Although HCT is a curative therapy for the rare inherited disorder of DNA repair, Fanconi-associated hematologic abnormalities, and BMF, it does not modify the risk of cancer. Advances in HCT for FA have included the use of minimal-intensity conditioning, and this has greatly contributed to transplant survival in patients with FA. HID donor HCT has thus emerged as a promising alternative donor strategy in all indications of HCT for patients without a matched donor. Nevertheless, while fludarabine-cyclophosphamide-based minimal-intensity conditioning improves overall survival (OS) in patients with FA receiving HCT, graft-versus-host disease (GVHD) remains a problem and is associated with an increased risk of post-transplant malignancy. In the case of patients with FA who develop acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) before HCT, questions remain as to whether these patients need pretransplant chemotherapy, and if they do benefit from pretransplant chemotherapy, which regimen is associated with the best outcomes.
In the current retrospective study of 813 pediatric patients, the investigators found that a matched family donor (MFD) transplant without serotherapy was associated with a higher incidence of acute GVHD and chronic GVHD. Patients 10 years or older experienced worse event-free survival (EFS) and GVHD-free, relapse-free survival than those younger than 10 years. In addition, AML/MDS compared to BMF/AA, donor types other than MFD were associated with GVHD-free, relapse-free survival. The cumulative indices (CIN) of primary and secondary graft failure in the entire population were 2% and 3%, respectively. CIN of grade 2-4 acute GVHD, grade 3-4 acute GVHD, and chronic GVHD were 23%, 12%, and 8%, respectively. The five-year CIN of secondary malignancy was 2%. OS and EFS after MFD (OS=88%; EFS=85%) and matched unrelated donor (OS=85%; EFS=80%) were comparable. The authors concluded that their results contributed to the re-evaluation of the potential role of alternative donors and the timing of HCT in children with FA.
“If you delay the transplant, that has consequences,” said coauthor Sujith Samarasinghe, MBBS, PhD, of the Great Ormond Street Hospital for Children in the United Kingdom. He said the pediatric series results confirm that patients who receive HCT at a young age have good outcomes. “It is not surprising, but it is nice to actually confirm that and show it,” he said.
Dr. Samarasinghe explained that patients with FA are often referred to hematologists because of congenital abnormalities. More recently, hematologists have received referrals of teenagers and adults with early-onset cancers. He encouraged clinicians not to wait until the patient has clonal abnormalities. Instead, he believes that BMF should be considered a reason to move to transplant. He pointed out that patients with FA are “exquisitely sensitive to the effects of GVHD.” Thus, he emphasized the importance of using serotherapy even in the MFD setting.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Lum SH, Eikema D, Piepenbroek B, et al. Outcome of hematopoietic stem cell transplantation in 813 pediatric patients with Fanconi anemia [published online ahead of print, 2024 July 5]. Blood. doi: 10.1182/blood.2023022751.
