Incidence, Risk Factors and Clinical Outcome Of Leukemia Relapses Due To Loss Of The Mismatched HLA Haplotype After Partially-Incompatible Hematopoietic Stem Cell Transplantation

Introduction Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) represents the best curative option for many patients with high-risk myeloid malignancies, mainly due to its potent immuno-mediated antileukemic effect. Still, post-transplantation relapse remains an unsolved issue. We and others described genomic loss of the mismatched HLA haplotype as a mechanism by which leukemic cells evade donor T cell-mediated immune pressure and cause clinical relapse after partially HLA-incompatible HSCT ( Vago et al, N Engl J Med, 2009 ), but the actual incidence and risk factors of this phenomenon are to date largely unknown. Methods We analyzed retrospectively 224 consecutive partially HLA-mismatched HSCTs performed in our Institute in the last ten years (Unrelated Donor, UD: 60; Mismatched Related Donor, MMRD: 164) in patients affected by myeloid malignancies (Acute Myeloid Leukemia, AML: 173; Myelodisplastic Syndrome, MDS: 27, Myeloproliferative Neoplasms: 17; others: 7). All patients received myeloablative conditioning and infusion of donor T cells, either as part of the graft or as an add-back. Patients’ follow-up included bone marrow genomic HLA typing to identify HLA loss relapses. In selected cases of HLA loss relapse cryopreserved serial serum samples harvested after HSCT were analyzed for the eventual presence of anti HLA Class I or Class II antibodies. Results We documented 77 cases of relapse: 66 after MMRD and 11 after UD HSCT. Out of 77 relapses 21 (27%) were due to genomic loss of the mismatched HLA in leukemic cells. HLA loss occurred in 19 patients with AML, one with MDS and one with myelofibrosis. All the 21 cases of HLA loss occurred after MMRD HSCT (32%), so the analysis for putative risk factors were limited to this subgroup of transplants (n=164), comparing the frequencies of putative risk factors between patients with HLA loss and “classical” relapses (n=21 and 45, respectively). HLA loss relapses occurred significantly later than their classical counterparts (median time to relapse 307 vs 86 days, p Conclusions Genomic loss of the mismatched HLA haplotype is an extremely frequent mechanism of leukemia immune evasion and relapse after MMRD HSCT. It appears to be prompted by selective immune pressure mediated by donor-derived T cells, and accordingly occurs more frequently upon T cell-repleted transplants and in the presence of acute and chronic GvHD, clinical hallmarks of T cell alloreactivity. Conversely the role of NK and B cells in HLA loss needs further investigation, but appears to date less pronounced. Given the poor outcome of re-transplantation, mainly due to toxicity, novel diagnostic and therapeutic approaches are needed to anticipate the detection and improve the treatment of these frequent variants of leukemia relapse. Disclosures: Bordignon: MolMed SpA: Employment. Bonini: MolMed SpA: Consultancy.