Haploidentical transplantation versus unrelated donor hematopoietic stem cell transplantation

The gold standard donor for hematopoietic stem cell transplantation (HSCT) is a matched sibling donor (MSD), but for most, the only available option is HSCT from a human leukocyte antigen (HLA) matched unrelated donor (MUD), and increasingly from a related haploidentical donor. Haploidentical donors are defined as being at least 50% HLA-identical to the recipient and are usually first-degree relatives. The introduction of post-transplant cyclophosphamide (PTCy) to prevent graft-versus-host disease (GvHD) has greatly improved the outcome of haploidentical HSCT.¹

Leonardo Javier Arcuri from the Insitituto Nacional de Câncer, Centro de Transplante de Medula Óssea, Rio de Janeiro, Brazil, and colleagues performed a systematic review² to compare overall survival (OS), non-relapse mortality (NRM), GvHD (acute [aGvHD] and chronic [cGvHD]) and relapse rates in patients with hematological malignancies treated with either haploidentical HSCT with PTCy or standard unrelated donor (URD) HSCT. In their Biology of Blood and Marrow Transplantation publication (August 2019) they detail their searches of the PubMed and Cochrane databases for studies comparing haploidentical HSCT with PTCy against URD HSCT indexed between 1^st January 2008 and 1^st January 2019. The group screened 113 abstracts, before reviewing 46 full texts for eligibility. There were 20 observational studies remaining after eligibility checks, which totalled 1,783 haploidentical HSCT recipients and 6,077 URD HSCT recipients. One study was not included in the meta-analysis due to a lack of extractable data on standard deviations. Study characteristics and a summary of results are detailed in Tables 1 and 2 respectively.

Results

OS: The study found no difference in overall survival between the two different donor HSCT treatments (hazard ratio (HR) 0.98 (95% CI, 0.88–1.08) and risk difference (RD) for death of 4 percentage points (pp) (95% CI, -8 to +1 pp).

Relapse: There was also no difference for relapse risk which was 2 pp higher (95% CI, -2 to +6 pp) in the haploidentical donor HSCT group and the hazard ratio was 1.06 (95% CI, 0.95–1.19). This was also true when only patients with active or high-risk disease were analyzed.

NRM: In studies in which all haploidentical donor HSCTs used a PTCy approach, NRM was lower for haploidentical donor transplantation by 6 pp (95% CI, -10 to -3) and had a HR of 0.85 (95% CI, 0.72–1.00).

GvHD: In terms of aGvHD, both grade II-IV and grade III-IV were lower in the haploidentical HSCT groups (grade II-IV: RD, -12 pp [95% CI, -17 to -7 pp]; HR, 0.52 [95% CI, 0.47–0.82] and grade III-IV: RD, -9 pp [95% CI, -13 to -5 pp]; HR, 0.66 [95% CI, 0.48–0.92]).

The RD of cGvHD was 12 pp lower in the haploidentical donor HSCT group (95% CI, -20 to -4 pp). However, the team reported a high heterogeneity (Ι² = 86%) and found that this was associated with the use of peripheral blood stem cells (PBSCs) and the proportional difference between the two donor groups (31% of participants in the haploidentical donor HSCT group received PBSCs vs 85% in the URD HSCT group). Meta-regression analysis found an association of PBSC transplantation with cGvHD in the haploidentical donor HSCT groups (cGvHD was 3.7 pp lower in the haploidentical donor HSCT group for each 10-pp PBSC proportion difference [p < 0.001; R² = 70%]).

Discussion

The meta-analysis found that there is no difference in OS between the two donor types. The team also reported no evidence of higher relapse rates in the haploidentical donor HSCT group, and this finding was upheld even when analying only high-risk disease studies.

However, the incidence rates of all forms of GvHD and NRM are lower with haploidentical donor HSCT compared to URD HSCT. The team point out that this could be partially explained by the use of PTCy-based GvHD prophylaxis for haploidentical donor HSCT as well as the lower use of PBSCs in this group.

The finding that haploidentical donor HSCT is comparable with URD HSCT in terms of OS and relapse rate, while showing lower rates of NRM and GvHD, encouraged the authors to recommend performing haploidentical donor HSCT with PTCy in patients who are being treated in experienced centers, and cannot wait 2–3 months for identification of an URD. This would allow speeding up of the donor identification process, especially for patients with hematologic malignancy with a high risk of relapse.

Arcuri and colleagues highlight some limitations of their study, such as incomplete data extraction from included studies, all of the studies included were retrospective, outcomes of studies were sometimes reported as cumulative incidence with no confidence intervals, and HRs either reported with inadequate reference categories or not reported at all. They also note that they were unable to find any randomized controlled trials comparing these donor transplantations.

Table 1: Study Characteristics

Table 2: Summary of pooled results