Phase III study confirms superior outcomes using haploidentical donors in patients with pretransplant MRD-positive ALL

The criteria for choosing the most appropriate transplant donor is still a topic of hot debate. Haploidentical donor transplantation (HIDT) has been shown to yield comparable outcomes to matched sibling donor transplantation (MSDT) in the setting of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and lymphomas, and may even be preferred over MSDT in some high-risk patients due to the better graft-versus-leukemia reaction experienced. However, most studies in this context have been retrospective in nature and may not serve as suitable evidence for treatment decisions. Therefore, selection of optimal donor options needs further investigation in prospective trials.

In this prospective, genetically randomized study (NCT02185261) recently published in Journal of Hematology & Oncology, Ying-Jun Chang and colleagues evaluated donor options in patients with ALL who were positive for measurable residual disease (MRD) pre-transplantation and underwent MSDT or HIDT.¹

Study design

The inclusion criteria for this study were patients aged 3–65 years with ALL in complete remission (CR) and pre-hematopoietic stem cell transplantation (HSCT) MRD positivity. Exclusion criteria were severe cardiac, renal, or hepatic disease, a prior transplant, and hypersensitivity to rabbit anti-thymocyte globulin (ATG) if a haploidentical donor was available.

A total of 745 patients with ALL who achieved CR after chemotherapy treatment were included (Figure 1). Initially, 20 patients were excluded because they received HLA-matched unrelated donor transplant, and 517 patients were then excluded due to achieving CR with pre-transplantation MRD negativity. Finally, 208 patients with positive pre-transplantation MRD were genetically randomized to receive HIDT (169 patients) or MSDT (39 patients).

Figure 1. CONSORT (the Consolidated Standards of Reporting Trials) diagram¹

ALL, acute lymphoblastic leukemia; CR, complete remission; HIDT, haploidentical donor transplantation; HLA, human leukocyte antigen; MRD, measurable residual disease; MSDT, HLA-matched sibling donor transplantation.

Results

Patient and donor characteristics are summarized in Table 1. Transplant outcomes between patients who underwent HIDT and those who received MSDT are detailed in Table 2. Uni- and multivariate analysis of factors associated with transplantation outcomes are summarized in Table 3. Primary causes of death among patients that underwent allogeneic stem cell transplantation are given in Table 4.

The Epstein-Barr virus reactivation at Day 100 post-transplantation in the HIDT group (15%; 95% CI, 10–21) was significantly higher than that of the MSDT group (0%; p = 0.011).

Multivariate analysis demonstrated that: (Table 3)

• Higher than median CD34 cell count infused (when comparing less vs higher than median) was the only significant element associated with both neutrophil (HR, 0.749; 95% CI, 0.567–0.988; p = 0.041) and platelet engraftment (HR, 0.671; 95% CI, 0.506–0.889; p = 0.006).
• Higher levels of pretransplant MRD increased the risk of MRD positivity after transplantation (HR, 1.281; 95% CI, 1.043–1.572; p = 0.014).
• Transplant modality (HIDT vs MSDT) was also linked with MRD positivity after transplantation (HR, 0.492; 95% CI, 0.280–0.866; p = 0.018).

Similar to factors associated with overall survival (OS; Table 3), multivariate analysis also demonstrated a significant association with leukemia-free survival for:

• Pretransplant MRD levels (HR, 1.747; 95% CI, 1.011–3.021; p = 0.046),
• Transplant modality (HIDT vs MSDT; HR, 0.425; 95% CI, 0.252–0.718; p = 0.001),
• Disease status (≥ CR2 vs CR1; HR, 1.789; 95% CI, 1.059–3.024; p = 0.030),
• Grades II–IV acute graft-versus-host disease (GvHD) (HR, 1.727; 95% CI, 1.036–2.879; p = 0.036),
• Chronic GvHD (yes vs no; HR, 0.476; 95% CI, 0.282–0.803; p = 0.005), and
• Posttransplant MRD positivity (HR, 1.707; 95% CI, 1.059–2.752; p = 0.028).

This study conducted analysis for 128 patients with very low MRD levels (sensitivity at 0.01%) in the bone marrow for pre-HSCT. Of those 128 patients, 24 received MSDT and 104 had HIDT. Given as patients who underwent MSDT versus HIDT:

• 3-year cumulative incidence of relapse: 46% (95% CI, 24–68) vs 29% (95% CI, 20–38); p = 0.159.
• Leukemia-free survival: 37% (95% CI, 17– 57) vs 55% (95% CI, 45–65); p = 0.175.
• Overall survival: 43% (95% CI, 23–63) vs 59% (95% CI, 49–69); p = 0.270.
• Non-relapse mortality rates were comparable: 17% (95% CI, 0–34) vs 15% (95% CI, 8–22); p = 0.782.

The 517 patients who were pre-HSCT MRD negative were also analyzed for either MSDT (n = 92) or HIDT (n = 425). Compared to patients receiving HIDT, patients who underwent MSDT had similar outcomes for

• 3-year cumulative incidence of relapse (16% vs 15%; p = 0.776),
• leukemia-free survival (72% vs 68%; p = 0.463),
• OS (73% vs 70%; p = 0.528),
• non-relapse mortality (12% vs 16%; p = 0.274).

Table 1. Patient and donor characteristics¹

 Table 2. Transplant outcomes between patients who underwent HIDT and those who received MSDT¹

 Table 3. Uni- and multivariate analysis of factors associated with transplantation outcomes (n = 208)¹

Table 4. Primary cause of death among patients that underwent allogeneic stem cell transplantation¹

Conclusion

Based on the outcome of this prospective phase III study, HIDT is preferred over MSDT (regardless of available matched sibling donors) for patients with pretransplant MRD-positive ALL, in view of favorable anti-leukemia activity of cells derived from haploidentical donors. Furthermore, disease status (≥ CR2), development of chronic GvHD, and use of MSDT predicted inferior leukemia-free survival, cumulative incidence of relapse, and OS in a multivariate analysis. These findings could inform decision making and the development of donor-selection algorithms.