The prognostic impact of genetic alterations and MRD status in KMT2A-rearranged B-ALL

KMT2A-rearranged (KMT2A-r) B-cell precursor acute lymphoblastic leukemia (B-ALL) is considered a high-risk ALL subtype in both children and adult patients. Patients with this ALL subtype have traditionally experienced poor outcomes, with a lack of robust data on adult patients treated with modern protocols and a general uncertainty as to the optimal treatment strategy for this patient population. Recent efforts have indicated that the presence of certain genetic co-mutations and minimal residual disease (MRD) status may provide an accurate means of predicting clinical outcomes and guiding treatment decisions for patients.

Kim et al.¹ recently analyzed a large cohort of patients treated in three consecutive clinical trials, published in Blood, to identify subsets of patients with heterogenous clinical outcomes. Below, we summarize their key findings.

Study design

• The study included patients with newly diagnosed Philadelphia-negative B-ALL.
• Patients were treated in three consecutive clinical trials (NCT00222027, NCT00327678, and NCT02617004) by the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL), where they underwent modern intensive protocols.
• The presence of genetic rearrangements was determined via cytogenetic analysis, and MRD was assessed via quantitative polymerase chain reaction (qPCR).
• The study objectives were to investigate the association between genetic subtypes and clinical outcomes (CIR, DFS, and OS )

Key findings 

• Overall, 1,091 patients aged 15-59 years with newly diagnosed Philadelphia-negative B-ALL were included in the study (KMT2A-r positive: n = 141).
• KMT2A-r B-ALL was shown to be associated with typical high-risk presenting features including older age, increased white blood cell counts, and pro-B phenotype; however, this did not appear to influence the ability to achieve complete response.
• Historical risk criteria could not predict distinct clinical outcomes within KMT2A-r B-ALL.
• Genetic analysis showed KMT2A-r B-ALL to be associated with a specific pattern of genetic alterations, primarily targeting the RTK-RAS pathway, and the TP53, CDKN2A, and IKZF1 tumor-suppressor genes.
  • TP53 alterations and IKZF1 deletions were associated with a significantly worse cumulative incidence of relapse (CIR; p = 0.005 and p = 0.01, respectively), disease-free survival (p = 0.034 and p = 0.053, respectively), and overall survival (p = 0.007 and p = 0.11, respectively).
• MRD1 and MRD2 positivity among patients with KMT2A-r B-ALL were significantly associated with worse outcomes.
  • Further analysis demonstrated an advantage in response evaluation and predicting treatment outcomes for gKMT2A-based MRD over IG/TR-based MRD.
• Combining oncogenetics and gKMT2A-based MRD allowed for the highlighting of three subgroups of patients with distinct clinical outcomes (Figure 1): Onco^–/MRD^–, Onco^–/MRD⁺, and Onco⁺/MRD⁺.

 

CIR, cumulative incidence of relapse; DFS, disease-free survival; MRD, minimal residual disease; Onco, oncogenetics; OS, overall survival.
*Adapted from Kim et al.¹

 

Key learnings

Intensive pediatric-inspired ALL regimens may represent a curative option for certain subsets of patients.  The presence of TP53/IKZF1 alterations revealed a subgroup of patients with significantly poorer outcomes. Overall, the results indicate a high degree of heterogeneity in outcomes among adult patients with KMT2A-r B-ALL, providing a novel biomarker to guide treatment decisions and risk-based stratification.