Haploidentical donor is preferred over matched sibling donor for pre-transplantation MRD positive ALL: a phase 3 genetically randomized study

Currently, haploidentical donors have been an alternative source for allo-stem cell transplantation (SCT) for patients that require transplantation but have no related or unrelated donors with matching human leukocyte antigen (HLA) [1‐5]. With the increasingly used haploidentical SCT (HIDT), HLA-identical sibling donors remain the first choice, though a number of studies have shown that treating patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) using haploidentical donors (HIDs) could achieve comparable outcomes to those who undergoing HLA-matched sibling donor transplantation (MSDT) [3, 6, 7]. On the other hand, using haploidentical transplants, the graft-versus-leukemia (GVL) effect may be stronger, as mismatches for HLA antigens on leukemic cells would provide allo-immune targets [4, 5, 8‐13]. A recent large European Society for Blood and Marrow Transplantation (EBMT) study indicated that HIDT has a lower incidence of relapse than MSDT for low-risk (HR = 0.83, P = 0.011) and intermediate-risk (HR = 0.85, P = 0.033) hematological malignancies [5]. The better relapse rate with HIDT compared to MSDT has also been observed in patients with lymphomas [8, 9]. Our previous studies showed that HIDT is superior to MSDT in terms of a lower relapse rate for patients with high-risk leukemia [11]. Furthermore, for older patients with acute leukemia, offspring donors not only result in lower non-relapse mortality (NRM), but also tended to be associated with a lower risk of relapse than MSDT [12]. Although these reports have effectively proven the potential superiority of HIDT to MSDT in the context of relapse risk in treating patients with some specified subgroups of hematological malignancies [4, 5, 8‐12], they cannot inform decision-making in choosing one donor type over another for a specific patient due to the retrospective nature of the studies or highly diverse populations and various transplant regimens [4, 5, 8‐13].

Apart from heterogeneous disease type, the variations in comparative outcomes between HIDT and MSDT could also be related to differences in disease status at the time of allo-SCT (i.e., less advanced disease or minimal residual disease [MRD]) [2, 4, 6, 13‐17]. Therefore, studies have been performed in more homogenous groups [10]. Our group recently reported that, for AML patients with pre-transplantation MDR positivity (pre-HSCT MRDpos), HIDT could achieve a significantly lower cumulative incidence of relapse (CIR) and better survival than those who underwent MSDT [10]. Although this study included a prospective cohort with an homogenous population, there are some limitations with this prospective subgroup [10]. First, the sample size for pre-HSCT MRDpos (n = 76) was not large enough to reach reliable statistic power. Second, although the percentages of preemptive donor lymphocyte infusion (DLI) for post-HSCT MRD were described, there was neither a direct comparison of the incidence of post-transplantation MRD positivity (post-HSCT MRDpos) between donor sources nor a comparison of the proportion of interventions for post-HSCT MRDpos [10]. Considering these limitations [10], prospective comparative studies with enough power and more solid evidence of HIDT being better at eradiating leukemia cells are needed to challenge the traditional donor hierarchy of matching sibling donors (MSDs) being the first choice [14, 15].

For patients with ALL, a more recent EBMT study revealed that HIDT can obscure the negative effects of pre-HSCT MRDpos before transplantation in a subgroup analysis (CIR, 29% vs. 26% and leukemia-free survival, LFS, 50% vs. 50% for pre-HSCT MRDpos and pre-HSCT MRDneg, respectively) [16]. Though all of these findings [5, 8‐11, 13] suggested a benefit associated with HIDT in certain contexts, the choice of an optimal candidate in terms of a stronger GVL effect warrants further investigation. Therefore, we designed a prospective genetically randomized study to evaluate donor options by comparing the endpoints related to disease control between ALL patients with pre-HSCT MRDpos who underwent HIDT and those who received MSDT. In this study with an homogenous population and unified transplant regimen, we provide convincing evidence that HIDT is favorable over MSDT in certain groups of patients, possibly by exerting a stronger GVL effect. Our results demonstrate that HIDT is associated with a lower incidence of post-HSCT MRDpos, lower CIR, and superior survival compared to MSDT. Our findings could have a major impact on donor selection regardless of available MSDs [14, 15].

The criteria for selecting the most appropriate transplant donor remain a topic of ongoing debate [4, 5, 8, 9, 11, 12, 14, 15]. This prospective, genetically randomized study provided the most robust evidence thus far that HIDT is superior to MSDT, potentially due to stronger GVL effects in certain patients. As opposed to most retrospective comparative studies between HIDT and MSDT, or a few prospective cohorts with limited statistical power [5, 8‐11, 13]. The strengths of this analysis include a relatively large number of homogenous patients using consistent supportive care algorithms, conditioning regimens, and stem cell sources. Such genetically randomized studies are one means of providing guidance regarding a change in the traditional donor hierarchy of MSD being first choice in certain circumstances [14, 15].

In theory, choosing a donor with greater HLA disparity from the recipient could mitigate the relapse risk induced by a greater allo-immune GVL effect [5, 16, 28]. However, apart from donor type, many factors can influence GVL [2, 22, 23, 25], including disease type and remission status before HSCT, patient age, conditioning regimen, GVHD prophylaxis, number of T cells infused, presence of GVHD, use of immunotherapy and targeted drugs, and other factors. Because of the profound effect of MRD on transplant outcomes [21, 27, 29], this situation was chosen for close examination in the scenario of evaluating donor selection. The current study demonstrated that, for ALL patients with pre-HSCT MRDpos, HIDT can achieve lower CIR and better survival than MSDT. Moreover, we observed that, compared to patients undergoing MSDT, patients who underwent HID had a lower incidence of post-HSCT MRDpos and a lower proportion required preemptive therapy. All patients in the two study groups were treated with similar conditioning regimens without in vitro T-cell depletion. The one disparity in the GVHD prophylaxis schedule was that all HIDT recipients received ATG, which was not used for MSDT recipients [3, 19]. The requirement for additional immunosuppression in the HIDT protocol is an integral aspect of the current standards of GVHD prophylaxis [6, 19]. Furthermore, the use of ATG to facilitate engraftment and prevent GVHD without influencing relapse may not weaken the GVL effect [30]. Also, low-dose corticosteroid prophylaxis given to high GVHD risk HIDT patients did not influence relapse (data not shown), which confirmed our previous results [19]. Another unbalanced feature between the two groups is patient age. Due to the one child policy in China, half of our HIDs were parents [2, 3, 6]; thus, an age difference existed between the two study groups (Table 1). Though younger patients are prone to biologically less aggressive leukemia [31], our study populations were all transplanted in CR with pre-HSCT MRDpos, and age was not a significant factor affecting CIR in the multivariate analysis. Therefore, the lower incidence of post-HSCT MRDpos and lower CIR in the HIDT group cannot be explained exclusively by any of the confounding factors discussed. Our data, together with other studies on AML or Hodgkin’s lymphoma [8, 9], offer the most compelling evidence that choosing a HID over MSD has a favorable anti-leukemia effect [32]. However, the biological and immunological mechanism of donor choice based on GVL needs to be explored further. Apart from donor source, disease type and status also affected CIR, with T-ALL being worse than B-ALL and more than CR1 being inferior to CR1 as expected.

As disease control can be improved with greater use of immunomodulatory or targeted approaches [22, 23], we described preemptive interventions for MRD post-transplantation. Among patients with post-HSCT MRDpos, both the proportion and methods of preemptive interventions were similar between the two groups, with IFN most frequently used, followed by DLI [22, 23]. HIDT tended to have a lower relapse rate than MSDT after preemptive intervention for MRD post-transplantation (31% vs. 56%, P = 0.12) or in subgroup analysis after IFN (31% vs. 64%, P = 0.08). These data confirmed the predictive role of MRD on prognosis [21, 29] and the effectiveness of preemptive therapies in both transplant modalities, but they also provide further evidence that HIDT offers an advantage over MSDT in terms of a better response to preemptive interventions for MRD post-transplantation [22, 23].

Weighing the likelihood of relapse versus GVHD and non-relapse mortality could guide donor selection [2, 4, 14, 15]. The similar rate of acute GVHD between the two groups was somewhat contradictory to our previous comparative studies with higher grades II–IV acute GVHD in HIDT than MSDT [3, 6]. Our risk stratification-directed, low-dose corticosteroid prophylaxis for GVHD in HIDT and lower proportion of female donors (29% vs. 41%) in the HIDT group may contribute to the comparable GVHD incidence between the two cohorts [2, 19]. Instead, disease status and time from diagnosis to HSCT affected acute or chronic GVHD. The equivalent NRM was in accordance with our previous reports of acute leukemia patients transplanted in CR [3, 10]. Thus, the HLA-antigen mismatch with HIDs contributes to greater allo-immunity against the tumor without affecting the allo-immunity against the host, partly due to advancements in GVHD prevention and infection control [2, 6, 19]. Thus, the tension between relapse and NRM translated to superior survival after HIDT [4]. Apart from donor source, T-ALL, more than CR1, acute GVHD had detrimental effect on survival while platelet engraftment and chronic GVHD had protective effect on survival. In addition, patients with pre-HSCT MRDneg had a higher LFS than those with pre-HSCT MRDpos in MSDT settings (P = 0.004), but LFS was comparable in HIDT settings for patients with pre-HSCT MRDneg versus pre-HSCT MRDpos (Figure S1), which indicated that, in accordance with our previous results of AML patients [10], HIDT could obscure the negative effect of pre-HSCT MRDpos in ALL patients while MSDT could not.

Regarding health-related quality of life (HRQoL), our previous retrospective study showed that the HRQoL of patients receiving HIDT is comparable to that of patients receiving MSDT [33], and chronic GVHD severity strongly correlates with negative impacts on patients’ HRQoL [34]. Although the current study does not include HRQoL analysis, cGVHD incidence and severity was comparable between the 2 groups and GRFS was higher in HIDT cohort. Further prospective studies investigating HRQoL are needed to evaluate if HID should replace MSD in some situation.

In conclusion, this prospective genetically randomized study is powered to detect that HIDT beats MSDT in regard to favorable anti-leukemia activity for ALL patients with pre-HSCT MRDpos. The current study paves the way to determine that HIDs should be the preferred choice regardless of available MSDs in a subgroup population. Our findings warrant further investigation and could inform decision-making and the development of donor-selection algorithms [2, 4, 14, 15, 18, 35]. More multi-center, prospective trials and mechanism studies are necessary to evaluate donor selection in regard to the anti-leukemia effect.