Haploidentical Stem Cell Transplantation: The Always Present but Overlooked Donor

Abstract

Haploidentical stem cell transplantation is a treatment option for the approximately 70% of patients who do not have an HLA-identical sibling donor. The availability of a haploidentical donor in most families is a potential advantage, both for avoiding the need to find an alternative unrelated donor, and for the potentially more potent graft-versus-tumor effect that can be induced. The early complications of severe graftversus-host disease (GVHD) following T-cell replete stem cell transplantation (SCT), and graft failure and recurrent malignancy (after T-cell depleted SCT) have limited the applications of this approach. Newer strategies employing T-cell depletion of the graft, using either very high-dose peripheral blood stem cells and/ or more intensive conditioning therapy have overcome some of the problems of conventional transplantation. Nonmyeloablative SCT approaches have overcome some of the morbidity and mortality associated with the early complications of SCT and have been associated with favorable engraftment and GVHD profiles. Induction of mixed lymphohematopoietic chimerism as a platform for adoptive cellular immunotherapy (via delayed donor lymphocyte infusions) may have important application in avoiding early GVHD, while ultimately capturing a very potent graft-versus-tumor effect. Current strategies are focusing on improvement of immune reconstitution and prevention of recurrence of the underlying malignancy.Haploidentical related donor stem cell transplantation (SCT) has been evaluated over the past two to three decades as an alternative transplant option for the approximately 70% of patients who do not have an HLA-identical related donor 1-8 ( Table 1). The advantages of haploidentical SCT are that nearly all patients have an immediately available donor and that a stronger graft-versus-tumor effect can be realized with partial HLA disparity. The disadvantages of haploidentical SCT are the immunological consequences of crossing the major histocompatibility barrier, namely graft-versus-host disease (GVHD), graft rejection, and delayed or incomplete immune reconstitution. With very intensive conditioning therapy, graft rejection has been largely overcome. Severe acute or chronic GVHD, however, have been formidable obstacles to the success of T-cell replete transplants following myeloablative conditioning. 1-3 Historical PerspectiveThe early post-transplant complications of myeloablative T-cell replete haploidentical bone marrow transplantation were well described by Powles and colleagues.1 Of 35 patients with advanced acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL) who received a one-to three-antigen mismatched bone marrow transplantation (BMT), 12 patients died from an early syndrome characterized by pulmonary edema, seizures, intravascular hemolysis, and acute renal failure. Ten of the 35 patients had engraftment failure, requiring regrafting from the same donor, though 11 patients were alive at the time of reporting. There was no difference in survival between HLA-1 to 2 antigen...

The impact of T-cell depletion techniques on the outcome after haploidentical hematopoietic SCT

“…Over the years, a wealth of studies has led to a variety of different transplantation techniques with regard to patient selection, TCD, conditioning regimens, stem cell numbers as well as many other factors, and its complexity has been highlighted by a number of recent reviews. [2][3][4][5][6]10,13,15,16 In reality, however, transplant centers generally choose one transplant technique according to the feasibility in their institution and continue with this technique with slight modifications. Nevertheless, although direct comparisons of different TCD are sparse, studies in haploidentical HSCT generally consider them as comparable.…”

“…Three patients had grade III acute GVHD (4%), whereas none had grade IV acute GVHD. The median time to onset of acute grade II-IV GVHD was 19 days (range, 9-79) and cumulative incidence of grade II-IV GVHD at day 100 was 15% (95% CI, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] (Figure 1). Patients with in vivo TCD had a higher incidence of grade II-IV GVHD compared with in vitro TCD (cumulative incidence at day 100: 31 vs 9%, P ¼ 0.045).…”

Outcome of alloanergized haploidentical bone marrow transplantation after ex vivo costimulatory blockade: results of 2 phase 1 studies

“…Although the majority of such patients will lack fully HLA-matched related donors, and many will also lack available HLA-matched unrelated donors, almost all will have available HLA-mismatched related donors. 1 However, HLA-mismatched HSCT is associated with increased graft failure, graft-versus-host disease (GVHD), and a higher risk of treatment failure. 2 GVHD is mediated predominantly by alloreactive donor T cells, which expand in vivo posttransplantation.…”

Infusion of HLA-mismatched peripheral blood stem cells improves the outcome of chemotherapy for acute myeloid leukemia in elderly patients

“…[10][11][12] RIC-haploidentical transplantation may provide available donors, but it is limited by significant morbidity and mortality (eg, GVHD and infections). [13][14][15] To date, a number of studies have shown that donor lymphocyte infusion (DLI) can mediate stronger graft-versus-leukemia (GVL) effects but is associated with severe GVHD and delayed neutrophil recovery on the basis of alloSCT. 12,16 Furthermore, it has been reported that G-CSF-mobilized donor peripheral blood stem cell (G-PBSC) infusion can also mediate GVL effects and hasten hematologic recovery without amplifying GVHD.…”