Hematological Complications of Donor Origin Following Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Khattab Ahmed , Patruni Sunita , Berteotti Gina , Jayakrishnan Thejus , Fazal Salman , Lister John 
Published: November 2020

Allogeneic hematopoietic stem cell transplant (HSCT) offers curative therapy for some malignant hematological disease and marrow failure states. Post-transplant donor cell pathology, which might become more prevalent in long term survivors of allogeneic HSCT, warrants further study. We report five recipients of allogeneic HSCT from our institution who developed donor cell abnormalities, discuss potential mechanisms underlying these disorders and propose potential avenues for future study.
Case 1 involves a 43-year-old female who developed leukopenia and adenopathy and was subsequently found to have diffuse large B-cell lymphoma. She received a matched unrelated donor (MUD) SCT from a 23-year-old male and subsequently developed a reactive lymphocytosis. In case 2, a 44-year-old male with myelodysplastic syndrome (MDS) received an allogenic peripheral blood (PB) SCT from his 50-year-old sister and later developed donor-cell derived acute myeloid leukemia (AML) with chimerism studies demonstrating 100% donor cells in CD3, CD33/66 and CD56. Case 3 involved a 72-year-old female with AML who received a PBSCT from her 65-year-old brother and subsequently developed MDS with peripheral blood chimerism studies demonstrating 100% donor cells in all three compartments. Case 4 involved a 40-year-old female with AML who achieved molecular remission following chemotherapy and underwent a double umbilical cord transplant, subsequently developing donor-cell derived AML with chimerism studies negative for host cells. Finally, case 5 highlighted a 54-year-old male with AML who underwent a MUDSCT from a 44-year-old male and passed away from progressive leukemia. Peripheral blood demonstrated only donor cells with near identity of phenotypic and molecular studies. It remains possible that no malignant cells exited the marrow. Nonetheless, this case in particular highlights the difficulty in precisely diagnosing donor cell leukemia (DCL).
DCL correlates with increasing donor age, suggesting that age-related mutation in hematopoietic stem cells might be the cause. Notably, the average donor age in our case studies was 53 years old. Hematopoiesis is maintained by both hematopoietic stem and progenitor cells and during the normal aging process becomes clonally restricted. Clonal hematopoiesis of indeterminate potential (CHIP) describes the presence of a clonal blood cell population associated with a driver mutation at a VAF ≥ 2%, in the absence of severe cytopenia or a WHO defined disorder. These mutations are found in 5% of individuals greater than 50 years of age, with the most common gene mutations being found inDNMT3A, ASXL1,andTET2. The rate of development of overt neoplasia in patients with CHIP is 0.5% to 1% per year and these patients are 4 to 15 times more likely to develop a hematologic malignancy.
CHIP mutations might confer a survival advantage allowing these clones to expand under the influence of a selection pressure such as chemotherapy or immunosuppression. These surviving clones might be the origin of DCL. DCL is estimated to account for approximately 1-5% of all post-transplant leukemia. When transplanted, expansion of these clones as required for repopulation of the hematopoietic stem cell niche might accelerate the acquisition of secondary mutations providing surviving mutated clones a survival advantage leading to malignancy.
An open question remains particularly as it concerns older donors &gt;55 years, as to whether they should be screened by next generation sequencing (NGS) for the presence of mutations known to be associated with CHIP or frank hematologic malignancy. If the incidence of DCL increases, consideration should be given to subjecting older donors to these screening methods. When multiple donors of different age are available preference can be assigned to younger donors to avoid possibly transmitting CHIP.

Disclosures
Fazal: BMS:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jansen:Speakers Bureau;Novartis:Consultancy, Speakers Bureau;Celgene:Speakers Bureau;Gilead/Kite:Consultancy, Speakers Bureau;Glaxosmith Kline:Consultancy, Speakers Bureau;Agios:Consultancy, Speakers Bureau;Takeda:Consultancy, Speakers Bureau;Incyte Corporation:Consultancy, Honoraria, Speakers Bureau;Karyopham:Speakers Bureau;Amgen:Consultancy, Speakers Bureau;Stemline:Consultancy, Speakers Bureau;Jazz Pharma:Consultancy, Speakers Bureau.