Unmanipulated haploidentical transplantation for adult patients with hematological malignancies.

The number of patients transplanted using Haplo-HSCT is increasing consistently in Europe and United States.

Haplo-HSCT with the use of PTCy for GVHD prophylaxis, allows low incidence of grade III to IV acute GVHD, chronic GVHD, and comparable survival with HLA-matched unrelated and cord blood transplantation.

Introduction

Allogeneic hematopoietic stem cell transplantation (HSCT) represents a curative treatment for different hematological disease. HSCT from a human leukocyte antigen (HLA)-matched sibling donor (MSD) is the standard of care for treating those patients, however only 25% to 30% of the patients in need have a MSD available. Even with the use of large unrelated donor registries, 25% of Caucasian patients are unable to find an HLA matched unrelated donor (MUD), and this percentage increases to 50% to 85% for individuals of other ethnicities.

Historically, the use of mismatched related donor was limited by the high level of HLA disparities, rendering this strategy such an alternative, using a “megadose of CD34+ selected graft” after ex-vivo T-cells depletion, to avoid severe graft versus host disease (GVHD). However, this approach was associated with high risk of graft failure, relapse and delayed immune recostitution.

More recently, the use of novel strategies without ex-vivo T-cell depletion made the use of unmanipulated haploidentical transplants (haplo-HSCT) feasible, allowing a continuous increase in its use in different countries.

Current state of the art

Haplo HSCT are attractive because do not require any graft manipulation, and allow important reduction of costs, making the procedure affordable for the majority of transplant centers. In addition, family donors are easily available and highly motivated, the procedure may be organized fast, avoiding delay. There are several platforms of haplo-HSCT available, and among them, two main approaches were developed in the last decades with different platform of GVHD-prophylaxis, based either on anti-thymocyte globulin (ATG) or on post-transplant cyclophosphamide (PT-Cy). Details on the recent studies available are showed in Table .

ATG allows extensive in vivo T-cell depletion and induces tolerance with expansion of regulatory T-cells. ATG effectively reduce GVHD incidence after both MSD and MUD HSCT. The Beijing group firstly reported the efficacy of the “GIAC protocol” in haplo-HSCT, using intensified immunosuppression through ATG, cyclosporine (CSA), mycophenolate-mofetil (MMF), short-course methotrexate, and monoclonal antibodies. On the other hand, Luznik et al introduced the use of high dose PT-Cy for GVHD prophylaxis in the combination with reduced-intensity conditioning regimen (RIC) and bone marrow (BM) as stem-cell source. In the absence of prospective trials comparing the different platforms of haplo-HSCT, most of the data come from single centers or registries reports.

The PT-Cy is more frequently associated with calcineurin inhibitors and MMF, however some authors reported the efficacy of the PT-Cy in combination with rapamycin to enhance regulatory T-cells, showing low rates of acute GVHD and NRM, and favorable immune reconstitution profile.

Despite the low incidence of acute and chronic GVHD and the low NRM also for older patients reported with RIC PT-Cy, disease recurrence is rather high, partially due to the high risk disease in most of the transplanted patients.

The broad HLA disparities in the haplo setting was a limitation to the use of peripheral blood stem cell (PBSC). With the intent to overcome the relapse rate some centers explored PBSC in the unmanipulated haplo-HSCT. Recently, 2 independent studies by CIBMTR and EBMT compared transplant outcomes of BM and PBSC recipients. Bashey et al reported 681 haplo-HSCT with different hematological malignancies receiving either PBSC or BM as stem cell source with PT-Cy. Results were comparable with, however, higher risk of acute and chronic GVHD in PBSC recipients. The ALWP-EBMT registry, analyzed 451 patients with AML and ALL. Overall survival and LFS as well chronic-GVHD and relapse risk were not different using BM versus PBSC, while acute GVHD grade 2–4 was significantly higher in PBSC recipients. Together, these two retrospective confirmed the increased risk of grade 2–4 aGVHD with comparable survival outcomes using PBSC or BM with PT-Cy.

The optimal conditioning intensity regimen is another debated topic. The ALWP recently reported equivalent outcomes after MAC or RIC on 912 AML patients older than 45 years. RIC may offer the possibility of lowering early toxicity and enhance post-transplantation maintenance therapy to prevent relapse, therefore in the absence of prospective trials, the appropriate regimen should be chosen according to disease risk features, patients’ comorbidities, and transplant center experience.

Another important risk factor for haplo-HSCT outcomes is the presence of donor-specific anti-HLA antibodies (DSA). DSA are an important barrier against successful engraftment of donor cells, and can affect transplant survival. Before haplo-HSCT, recipient screening for detection of DSA and desensitization strategies, in case of absence of different donor, are recommended.

Several prospective trials comparing haplo-HSCT with other donors are currently ongoing (NCT01597778, NCT03250546, NCT03275636, NCT01751997). So far, the retrospective studies available by single centers experience and registries, reported that the toxic profile and survival outcomes of haplo-HSCT are similar to HSCT from MUD or UCBT.,

Comparison between haplo-HSCT and MSD resulted in the advantage of MSD-HSCT, mainly for decreased GVHD and NRM. To date, HSCT from MSD remain the standard of care for patient with an available fully matched related donor.

Future prospective

The use of unmanipulated haplo grafts may provide access to HSCT virtually to all patients in need also in elderly population. Although, relapse remains one of the major cause of transplant failure, in the haplo-HSCT the antigenic disparities between donor and recipient can strengthen the immunological response against the original disease. Furthermore, the rapid availability of donors, makes haplo-HSCT an ideal platform to develop further strategies of immunomodulation after HSCT, or with donor lymphocyte infusion (DLI) in patients with minimal residual disease (MRD) or relapse. Some authors reported the use of DLI without severe toxicity of fatal GVHD in the haplo-HSCT setting, for relapse treatment or as pre-emptive strategies, as reported in other donor setting. Ideally, DLI after haplo-HSCT should be performed in the setting of clinical trials.

In conclusion, haplo-HSCT is an effective strategy for patients lacking a MSD-HSCT. The use of haplo-HSCT with PT-Cy is rapidly increasing due to the easy graft procurement, and the low cost of graft acquisition and manipulation. Indeed, the donor accessibility could allow reduction of time to proceed to HSCT and help in decreasing the risk of disease recurrence, in patients with impending relapse, also with strategies of post-transplant immunotherapy.

Table 1

Results of haploidentical HSCT with PTCy in hematological malignancies