Prognostic significance of measurable residual disease in patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation in second or later complete remission

To the Editor: Current guidelines from the American Society for Transplantation and Cellular Therapy recommend allogeneic hematopoietic stem cell transplantation (AlloSCT) in first complete remission (CR1) for adult patients with Philadelphia chromosome-negative ALL with high-risk features. For a growing number of patients with acute lymphoblastic leukemia (ALL), alloSCT is deferred at CR1, with hope that adequate response to salvage treatment and subsequent transplantation would be possible in second complete remission (CR2), if necessary. However, in reality, achieving and maintaining a second complete remission with subsequent alloSCT consolidation is challenging. Still, for patients who do achieve a second CR after relapse, alloSCT offers a chance at cure. Measurable residual disease (MRD) status has proven to be a strong predictor of outcomes at different stages of treatment. MRD positivity prior to transplant at CR1 has been shown to correlate with post-transplant relapse rates and overall survival (OS). The prognostic significance of MRD status prior to alloSCT for patients ALL later than CR1 has not been elucidated. Herein, we present outcomes for patients with ALL who underwent alloSCT in CR2 or beyond, according to pre-transplant MRD status, as measured by 6-color flow cytometry with a sensitivity of 0.01%. The primary outcome was the cumulative incidence of leukemia relapse. Secondary outcomes included OS, progression-free survival (PFS), and non-relapse mortality (NRM). OS and PFS were estimated using the Kaplan–Meier method. The cumulative incidence method, accounting for completing risks, was used to estimate the incidence of relapse and NRM. Cox proportional hazards regression analysis was used to evaluate predictors of OS and PFS and Fine and Gray regression for predictors of relapse and NRM. A total of 162 consecutive pediatric and adult patients with ALL in CR2 or beyond underwent first alloSCT at MD Anderson Cancer Center from February 2004 through December 2021, 123 (76%) with B-ALL and the remainder with T-ALL. The majority (80%) of patients were in CR2 at the time of transplant, the remainder in third CR or beyond (CR3+). One hundred and five (65%) patients were male, and the median age at transplant was 31 (range, 4–69) years. Graft source was either a matched unrelated donor (MUD) (43%), a matched sibling donor (MSD) (24%), haploidentical (18%), or cord blood (CBT) (15%). Most patients (73%) received MAC regimens. Pre-transplant MRD status was determined for 150 (93%) of patients, and was positive in 43 (26%). There was no statistical difference in characteristics according to MRD status except for higher proportion of CR3+ patients (33% vs. 16%, p = .02) and comorbidity index >2 (70% vs. 40%, p = .001) in MRD positive versus negative patients. Patient and transplant characteristics by MRD status are presented in Table S1. With a median follow-up in surviving patients of 51 (range, 2–200) months, the 3-year PFS and OS for the entire cohort were 36% (95% CI 28%–43%) and 40% (32%–48%), respectively. Patients with pretransplant MRD negative status had superior 3-year PFS [44% (34%– 53%) versus 18% (8%–31%)] and OS [50% (39%–59%) versus 23% (11%–36%)] compared to those with pre-transplant MRD positivity. There were 53 deaths in the MRD negative patients and 35 deaths in the MRD positive patients. Leukemia progression was the leading cause of death in both groups (55% vs. 71%, respectively). A complete list of causes of death is presented in Table S2. In univariate analysis (Table S3) evaluating transplantation outcomes at 3 years, MRD positivity prior to transplant (HR 2, 95% CI 1.2–3.5; p = .01), not using total body irradiation (TBI) in the conditioning regimen (HR 2, 95% CI 1.1–5.0; p = .03) and more than 2 prior lines of therapy (HR 2.2, 95% CI 1.2–3.9; p = .01) were associated with increased rate of disease relapse. Conditioning intensity (MAC vs. RIC) was not associated with relapse (p = .7) or NRM (p = .3). Transplant in CR3 or beyond was the only significant predictor associated with increased risk of NRM (HR 2, 95% CI 1.2–4.7; p = .01) (Figure 1D). MRD positivity prior to transplant (HR 1.8, 95% CI 1.2– 2.9; p = .01), transplant at CR3 or above (HR 1.9, 95% CI 1.2–3.1; p = .004), and HCT-CI >2 (HR 1.9, 95% CI 1.3–3.0; p = .003), were associated with worse OS. In multivariate analysis (Table S4) evaluating transplantation outcomes at 3 years, pre-transplant MRD positivity was associated with a higher rate of disease relapse (HR 1.9, 95% CI 1.1–3.6; p = .02) (Figure 1A). MRD positivity was also associated with less favorable overall (HR 2.1, 95% CI 1.3–3.6; p = .004) and PFS (HR 2.5, 95% CI 1.5–4.1; p = .001) (Figure 1B,C). MRD positivity had no significant impact on NRM (HR 0.8, 95% CI 0.4–1.8; p = .6) (Figure 1D). For patients receiving alloSCT at CR2 with pre-transplant MRD positivity, relapse rates, PFS, and OS were comparable to patients receiving alloSCT at CR3+ (Figure S1). Received: 4 November 2022 Accepted: 18 November 2022