Increased MRD Persistence, Lower Rates of Remission and Survival Seen With Philadelphia-Like ALL

The phase 2 GIMEMA LAL1913 trial identified poor outcomes and increased minimal residual disease persistence among patients with Philadelphia-like acute lymphoblastic leukemia.

Patients with Philadelphia-like (PH-like) acute lymphoblastic leukemia (ALL) were found to have an association with lower rates of complete remission (CR), event-free survival (EFS), and disease-free survival (DFS), as well as increased minimal residual disease (MRD) persistence in a pediatric- and minimal residual disease (MRD)–oriented adult ALL protocol, according to data from the phase 2 GIMEMA LAL1913 trial (NCT02067143).

An EFS analysis at 24 months identified that patients with Ph-like ALL had an inferior survival rate (33.5%) compared with patients with non-Ph-like ALL (66.2%; P = .005). Similarly, the DFS was 45.5% and 72.3% for patients with Ph-like ALL and non-Ph-like ALL, respectively (P = .062). While not significant, a similar inferiority was observed in overall survival (OS) for patients with Ph-like ALL (48.5%) compared with patients with non-Ph-like ALL (72.9%; P = .16).

“The Ph-like profile is an independent risk factor for CR failure and MRD-persistence, thus further underlying the need that Ph-like cases—a primary unmet clinical need in ALL—are rapidly recognized at diagnosis in order to refine the risk stratification of Ph-negative ALL and optimize patients’ management,” according to the study’s investigators.

Eighty-eight patients with B-lineage ALL who were negative for molecular aberrations including BCR/ABL1, KT2MA and TCF3/PBX1, and BNEG were enrolled in the trial. Through the use of a BCR/ABL1-like predictor, 28 Ph-like cases and 60 non-Ph-like cases were identified, with median scores of 0.85 (range, -0.18 to 6.37) and -1.24 (range, -1.7 to -0.33), respectively. Of note, the incidence of PH-like ALL cases was higher among patients aged 36 years old or older (36.2%) than patients between the ages of 18 to 35 years (26.8%).

A Kaplan-Meier product limit was used to estimate EFS, DFS, and OS for this group of patients. EFS was defined as the time between diagnosis and failure to achieve CR. DFS was defined as the time between CR evaluation and relapse or death, while OS was defined as the time between diagnosis and death.

Focusing on time point 1 (TP1), Ph-like status was linked with treatment response, with investigators reporting that patients with PH-like ALL (74.1%) had an inferior CR rate at TP1 when compared with non–Ph-like cases (91.5%; P = .044), which translated to a lower CR achievement probability (odds ratio, 0.265; 95% CI, 0.071-0.921; P = .038).

Ultimately, MRD persistence was higher among patients with Ph-like ALL at all time points compared with non-Ph-like cases. When examining MRD status at each of the 3 time points, data indicated that 77.8% of Ph-like cases and 41.3% of non-Ph-like cases at TP1 were MRD-positive (P = .012). Moreover, 52.9% of Ph-like cases and 20% of non–Ph-like cases at time point 2 (TP2) were MRD-positive (P = .025). Additionally, 41.7% of Ph-like cases and 13.5% of non-Ph-like cases at time point 3 (TP3) were MRD-positive (P = .05).

“Taken together, the results of this study carried out on adult B-NEG ALL cases enrolled in the front-line GIMEMA LAL1913 clinical protocol confirm that the BCR/ABL1-like predictor is a valid tool to rapidly recognize Ph-like cases that account for about 30% of adult B-NEG ALL,” the study’s investigators noted. “In addition, we could show that also in a pediatric-oriented and MRD-driven clinical trial Ph-like patients have a lower probability of achieving a CR, are more likely to remain MRD-positive and have a significantly shorter EFS.”

“The possibility of an early recognition of [patients with] Ph-like ALL offers the unprecedented opportunity to refine the prognostic categories of Ph-negative ALL, and to better understand the reasons for the poor outcome,” they added.

These data reinforce the crucial need to optimize therapeutic strategies and refine risk-stratification in early stages of disease for patients with Ph-like ALL the authors of the study concluded.

Reference

  1. Chiaretti S, Messina M, Della Starza I, et al. Philadelphia-like acute lymphoblastic leukemia is associated with minimal residual disease persistence and poor outcome. First report of the minimal residual disease-oriented GIMEMA LAL1913. Haematologica. 2021;106(6):1559-1568. doi:10.3324/haematol.2020.247973