Pretransplant MRD Prognostic for Outcomes in Adults With ALL

Arnon Nagler, MD

Adults with acute lymphoblastic leukemia had worse outcomes, including lower survival, after myeloablative allogeneic transplantation if they remained positive for minimal residual disease (MRD) at the time of transplant, a large retrospective review showed.¹

Patients who attained MRD negativity prior to transplant had a 2-year overall survival (OS) of 67% compared with 61% for patients who remained MRD positive. MRD-negative status also was associated with significantly better leukemia-free survival (LFS) and a significantly lower rate of relapse, as reported at the 2019 Transplantation and Cellular Therapy Meetings.

“A multivariate analysis showed that MRD positivity was a significant, independent factor for lower survival and leukemia-free survival and for a higher relapse incidence,” said Arnon Nagler, MD, of the Chaim Sheba Medical Center in Tel-Hashomer, Israel. “No significant interaction was found between MRD status and conditioning.”

The analysis did show that patients had better outcomes, regardless of MRD status, if they underwent conditioning that included total body irradiation (TBI), he added.

MRD has emerged as a key measure of disease status that has rapidly transformed the prognostic landscape of multiple hematologic malignancies. In ALL, MRD assessment has proven useful for gauging treatment response and early identification of impending relapse.²

Previous research showed that MRD positivity prior to allogeneic hematopoietic cell transplant for ALL is associated with worse outcomes.³ Whether outcomes differ by the type of conditioning remained unclear.

Nagler and associates performed a multicenter retrospective study to examined relationships among myeloablative conditioning, MRD status, and subsequent outcome among adults with ALL undergoing allogeneic transplants. A key prespecified analysis compared outcomes among patients who had TBI-based conditioning versus those who had conditioning with chemotherapy only.

Patients included in the analysis were at least 18 years old and underwent a first allogeneic transplant between 2000 and 2017. Eligible patients had de novo ALL, known disease status at transplant of morphological first or second complete remission, and known MRD status. The patients received either unmanipulated blood progenitor cells or bone marrow, obtained from a sibling or unrelated matched donor.

The analysis comprised 1816 patients who were MRD negative at transplant and 964 who were MRD positive. The MRD-positive subgroup was slightly older (38 vs 36; P <.001) and more likely to have B-ALL Philadelphia chromosome-positive subtype (66% vs 49%; P <.001). Other baseline characteristics were similar between the 2 groups.

Univariate analysis showed that MRD-positive subgroup had significantly worse 2-year overall survival (HR, 1.19; P = .0027), significantly worse LFS (50% vs 58%; HR, 1.26; P <.001), and a significantly higher incidence of relapse (32% vs 24%; HR, 1.51; P <.001). The multivariate analysis confirmed MRD status as in independent predictor of survival, LFS, and relapse.

The prespecified analysis of outcomes by conditioning regimen consisted of 1943 patients who had TBI-based conditioning (1278 MRD negative, 680 MRD positive) and 571 who received chemotherapy-based conditioning (382 MRD negative, 205 MRD positive). In the TBI subgroup, MRD-positive status was associated with worse OS (HR, 1.26; P = .012), LFS (HR, 1.3; P = .002), and relapse incidence (HR, 1.53; P <.001). Patients who underwent chemotherapy-based conditioning had a significantly higher risk of relapse (HR, 1.58; P = .008) and numerically worse LFS (HR, 1.25; P = .093) and overall survival (HR, 1.04; P = .81).

Nagler said that patients who were MRD-positive at transplant had worse outcomes with either type of conditioning, but that TBI-based conditioning was associated with improved outcomes for both the MRD-positive and MRD-negative patient groups.

“Patients in this study did not receive blinatumomab (Blincyto) or inotuzumab ozogamicin (Besponsa),” he noted. “More patients are likely to achieve MRD with these agents. Will the prognostic value of MRD remain with these new agents? Is TBI going to be valuable with modern immunotherapy?”

References

1. Pavlu J, Labopin M, Niittyvuopio R, et al. The role of measurable residual disease (MRD) at time of allogeneic hematopoietic cell transplantation in adults with acute lymphoblastic leukemia transplanted after myeloablative conditioning. Presented at: TCT Meetings; February 20-24, 2019; Houston, TX. Abstract 7.
2. Brüggemann M, Raff T, and Kneba M, et al. Has MRD monitoring superseded other prognostic factors in adult ALL? Blood. 2012;120:4470-4481. doi: https://doi.org/10.1182/blood-2012-06-379040.
3. Spinelli O, Peruta B, Tosi M, et al. Clearance of minimal residual disease after allogeneic stem cell transplantation and the prediction of the clinical outcome of adult patients with high-risk acute lymphoblastic leukemia. Haematologica. 2007;92(5):612-618.

<<< 2019 Transplantation and Cellular Therapy Meetings