Measurable Residual Disease and Fusion Partner Independently Predict Survival and Relapse Risk in Childhood KMT2A-Rearranged Acute Myeloid Leukemia: A Study by the International Berlin-Frankfurt-Münster Study Group

Abstract

Purpose: A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood KMT2A-rearranged (KMT2A-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease.

Methods: A total of 1,130 children with KMT2A-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non-high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (<0.1%) or positive (≥0.1%). End points were 5-year event-free survival (EFS), cumulative incidence of relapse (CIR), and overall survival (OS).

Results: The high-risk group had inferior EFS (30.3% high risk v 54.0% non-high risk; P < .0001), CIR (59.7% v 35.2%; P < .0001), and OS (49.2% v 70.5%; P < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity v n = 43; 16.3% MRD positivity; P < .0001) and OS (n = 413; 66.0% v n = 43; 27.9%; P < .0001), and showed a trend toward lower CIR (n = 392; 46.1% v n = 26; 65.4%; P = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non-high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; P = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS.

Conclusion: EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood KMT2A-r AML. Treatment approaches other than allo-SCT in CR1 are needed to improve prognosis.

FIG 1.

Flow diagram of the cohort of children with KMT2A-rearranged AML recruited by the collaborative study groups/countries between January 1, 2005, and December 31, 2016. Patients with unidentified fusion partners or those occurring in less than 10 patients were assigned to the KMT2A-other group. Fusion partners in the KMT2A-other group could not be risk group-assigned because of their unknown prognostic impact and were excluded. AIEOP, Associazione Italiana Ematologia Oncologia Pediatrica (Italy); allo-SCT, allogeneic stem-cell transplantation; BFM, Berlin-Frankfurt-Münster (Germany and Austria); BSPHO, Belgian Society of Pediatric Hematology Oncology (Belgium); CCLG, Children's Cancer and Leukaemia Group (United Kingdom); COG, Children's Oncology Group (United States); CPH, Czech Pediatric Hematology (Czech Republic); CR1, first complete remission; DCOG, Dutch Childhood Oncology Group (the Netherlands); EOI1, end of induction 1; EOI2, end of induction 2; HKPHOSG, Hong Kong Pediatric Hematology and Oncology Study Group (Hong Kong); I-BFM, International Berlin-Frankfurt-Münster; INS, Israel National Study (Israel); JPLSG, Japanese Pediatric Leukemia/Lymphoma Study Group (Japan); LAME, Leucémie Aiguë Myéloblastique Enfant (France); LFU, last follow-up; MRD, measurable residual disease; No., number of patients; NOPHO, Nordic Society for Pediatric Hematology and Oncology (Scandinavia); SEHOP, Spanish Society of Pediatric Hematology and Oncology (Spain); St Jude, St Jude Children's Research Hospital (United States).

FIG 2.

(A) EFS, (B) CIR, and (C) OS curves of patients with EOI2 MRD negativity and MRD positivity. (D) EFS, (E) CIR, and (F) OS curves of patients with EOI2 MRD negativity and MRD positivity stratified by KMT2A fusion partner-based risk group. The group of patients with EOI2 MRD negativity included patients who were EOI1 MRD-negative and EOI2 MRD-negative (– –), as well as patients who were EOI1 MRD-positive and EOI2 MRD-negative (+ –). The group of patients with EOI2 MRD positivity included patients who were EOI1 MRD-positive and EOI2 MRD-positive (+ +), as well as patients who were EOI1 MRD-negative and EOI2 MRD-positive (– +). CIR, cumulative incidence of relapse; EFS, event-free survival; EOI1, end of induction 1; EOI2, end of induction 2; MRD, measurable residual disease; OS, overall survival.

FIG 3.

(A) CIR and (B) OS curves to visually compare (with a 90-day landmark) patients who did and did not receive allo-SCT in CR1. (C) CIR and (D) OS curves to visually compare (with a 90-day landmark) patients who did and did not receive allo-SCT in CR1 stratified by KMT2A fusion partner-based risk group. P values are not shown as these figures are only used for visual comparison. allo-SCT, allogeneic stem-cell transplantation; CIR, cumulative incidence of relapse; CR1, first complete remission; OS, overall survival.