Haploidentical hematopoietic cell transplantation: Current status and future prospects
Author(s): Suparno Chakrabarti and Sarita Rani Jaiswal
Abstract
HLA-Haploidentical HCT has emerged as a front-runner for alternate donor transplantation for hematological malignancies over the past decade. The primary reason has been the employment of post-transplantation cyclophosphamide (PTCy) as GVHD prophylaxis, which by dint of both its ease of application and impressive outcomes, has made haploidentical HCT feasible across the globe. Large registry-based studies have confirmed the equivalence of this approach as compared to matched related and unrelated donor sources in acute leukemia as well lymphomas, with low incidences of both acute and chronic GVHD. However, the risk of relapse has remained unchanged across the donor sources depending on the nature of the underlying malignancy. Moreover, the suitability of this approach remains questionable in younger children and those with non-malignant disorders. Adoptive immunotherapy following haploidentical HCT has barely been used due to concerns related to GVHD. However, several recent studies have shown that early G-CSF mobilized donor lymphocyte infusions (DLI) can reduce the relapse risk in relapsed/refractory leukemia. The use of T cell costimulation blockade with CTLA4Ig in conjunction with PTCy has shown to improve reconstitution of Tregs early after haploidentical HCT in children with aplastic anemia. The same approach when used in children with leukemia was not associated with increased relapse. Interestingly, CTLA4Ig does not block natural killer (NK) cell activation and might even potentiate its cytotoxicity. Based on this principle, employment of CTLA4Ig-primed DLI in patients with advanced leukemia showed marked proliferation of mature NK cells which correlated with disease-free survival with low incidences of GVHD and non-relapse mortality. This approach has been shown to be effective in both lymphoma as well as myeloma in pilot studies. However, the success of any such approach rests on the appropriate selection of the donor vis-à-vis graft composition. It remains to be seen whether haploidentical HCT with unique approaches to NK cell mediated immunotherapy post-HCT might re-position this as a preferred option for advanced malignancies. This approach with universal donor availability might pave the way for innovative immunotherapies for solid tumors as well.