Review on Haploidentical Hematopoietic Cell Transplantation in Patients with Hematologic Malignancies

Abstract

Allogenic hematopoietic cell transplantation (HSCT) is typically the preferred curative therapy for adult patients with acute myeloid leukemia, but its use has been reduced as a consequence of limited donor availability in the form of either matched-related donors (MRD) or matched-unrelated donors (MUD). Alternative options such as unrelated umbilical cord blood (UCB) transplantation and haploidentical HSCT have been increasingly studied in the past few decades to overcome these obstacles. A human leukocyte antigen- (HLA-) haploidentical donor is a recipient's relative who shares an exact haplotype with the recipient but is mismatched for HLA genes on the unshared haplotype. These dissimilarities pose several challenges to the outcomes of the patient receiving such a type of HSCT, including higher rates of bidirectional alloreactivity and graft failure. In the past 5 years, however, several nonrandomized studies have shown promising results in terms of graft success and decreased rates of alloreactivity, in part due to newer grafting techniques and graft-versus-host disease (GVHD) prophylaxis. We present here a summary and review of the latest results of these studies as well as a brief discussion on the advantages and challenges of haploidentical HSCT.

Immune tolerance induction by nonmyeloablative haploidentical HSCT combining T-cell depletion and posttransplant cyclophosphamide

“…Thus, transplantation of HSCT following an NMAC regimen has been largely limited over the past 2 decades to T-cell-replete transplants, attaining engraftment by virtue of the large number of donor alloreactive T cells at the expense of the substantial risk of acute and chronic GVHD, even with extensive posttransplant GVHD prophylaxis. [3][4][5] As described above, the use of high-dose PTCY has reduced the risk of GVHD, but not enough to justify such transplants as a platform for organ transplantation or in the treatment of nonmalignant diseases 1,[6][7][8][9] or highrisk hematological malignancies in which posttransplant immune suppression can adversely impact antitumor immunity. On the other hand, attaining engraftment following TCD bone marrow (BM) transplants, especially in haploidentical patients conditioned with a nonmyeloablative regimen, still represents a major challenge.…”

Immunity to Infections After Haploidentical Hematopoietic Stem Cell Transplantation

“…Naıve T cells are produced months after transplantation because conditioning induced tissue damage prevents T cell homing to peripheral lymphoid tissues, where T cell memory is generated and maintained 17. Furthermore, the post-HSCT adaptive immune response is influenced by the strategy used to prevent GvHD 3,6,13. In unmanipulated haplo-HSCT, peripheral T-cell expansion is antagonized by the immune suppressive therapy for GVHD prophylaxis.…”

“…Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a valuable treatment option for patients with various hematological disorders who lack a suitable HLA matched donor or for whom an HSCT is urgently required 1–3. Actually, the road to full maturity of haplo-HSCT was beset by clinical problems.…”

“…Actually, the road to full maturity of haplo-HSCT was beset by clinical problems. Until the early 1990s, haplo-HSCT was associated with a high incidence of graft rejection in T-cell–depleted transplants and severe graft-vs-host disease (GVHD) in unmanipulated transplants because of the high frequency of T cells that recognized major class I or II HLA disparities between donor and recipient 3–5. To overcome these problems, two approaches were developed: a megadose of T-cell–depleted hematopoietic progenitor cells without any post-transplant immunosuppression4,6,8,9 and unmanipulated grafts with innovative pharmacological immunosuppression for GVHD prophylaxis 3,5,10–12…”

“…Whereas the use of reduced intensity conditioning (RIC), infusion of mega doses of CD34+ cells, and graft manipulations such as selective T cell depletion were helpful to achieve engraftment with lower rates of GvHD and toxicity, delayed immune reconstitution and infectious complications remain outstanding issues for haplo-HSCT and are important causes of morbidity and mortality 3,7,10,12,13. In the early post-transplant period, neutropenia is the principal risk factor for infections while, once engrafted, the capacity to mount an adaptive immune response to pathogens is a key factor for protecting from severe and recurrent infectious complications.…”