Publication Full Title: Donor cell-derived haematological neoplasms after allogeneic haematopoietic cell transplantation: recommendations from the EBMT Practice Harmonisation and Guidelines Committee
Publication Link: https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(26)00046-3/abstract
Comment by: Carmelo Gurnari, Associate Professor of Hematology, University of Rome Tor Vergata, Italy
Summary
This review from the EBMT Practice Harmonisation and Guidelines Committee addresses donor cell-derived haematological neoplasms (DDHN)—rare malignancies arising from transplanted donor cells rather than the recipient's original disease. DDHN most commonly manifests as myeloid disorders (AML, MDS) with a cumulative incidence of approximately 0.13% at 10 years post-transplant. Prognosis is poor, with median survival around 11–36 months.
The pathogenesis involves several routes of which the most common is the transfer of donor cells with germline predisposition mutations (particularly DDX41). Rarely, clonal haematopoiesis in donors or inadvertent transfer of leukaemic clones may also happen (the latter virtually impossible with current donor screenings). Diagnosis requires demonstrating full donor chimerism and confirming a novel malignancy unrelated to the original disease.
Key recommendations include prevention of DDHN via screening of patients and potential donors with family history of haematological disease for germline predisposition traits, though routine clonal haematopoiesis screening is not recommended until further evidence is gathered. Treatment follows standard protocols for the specific malignancy phenotype with extended resequencing to possibly identify not only germline alterations responsible for the DDHN but also therapeutic vulnerabilities. Second allogeneic transplant from a different donor offers the only potentially curative option. Finally, the committee emphasises careful donor management, including pre-donation counselling about potential genetic findings and post-DDHN notification protocols, given that some donors later develop similar malignancies themselves.
Comment
This consensus document addresses a genuinely vexing problem at the intersection of transplant medicine, cancer genetics, and medical ethics. While DDHN remains rare, its implications extend far beyond the affected patients.
The emphasis on germline predisposition—particularly DDX41 mutations, as common as 1 carrier in ~400 normal individuals—reflects how dramatically our understanding has shifted. A decade ago, DDHN was largely a diagnostic curiosity; now it represents a window into hereditary cancer syndromes that may have been invisible at the time of transplant. The finding that approximately 12% of donors whose recipients develop DDHN subsequently develop haematological malignancies themselves transforms this from a recipient problem into a family health matter.
The committee's decision not to recommend routine donor clonal haematopoiesis screening deserves attention. This pragmatic stance acknowledges that while CHIP is common in older donors, progression to DDHN remains exceptionally rare, and the clinical actionability of such findings is limited. The cost, logistical burden, and ethical complexity of informing healthy donors about clonal abnormalities that may never cause disease would likely outweigh benefits at a population level. Therefore, until further evidence is gathered, CHIP screening in not universally recommended.
The ethical framework for donor notification warrants further development. The document acknowledges this gap but offers limited guidance. When a recipient develops DDHN with a shared germline mutation, what are the obligations to related donors who may carry the same variant? How should unrelated donor registries handle information about clonal haematopoiesis detected retrospectively? The authors plea for a global consensus within scientific societies in line with national and supranational legal frameworks.
Finally, the poor outcomes despite treatment underscore the need for prevention with identification of families at risk before the first transplant, prospective registries and translational research. Until we better understand why some donor clones transform and others do not, prevention and early intervention will remain EBMT goals.