Outcomes in patients with newly diagnosed Acute Myeloid Leukemia with KMT2A rearrangement treated with cladribine, idarubicin, cytarabine (CLIA) with or without venetoclax

Abstract

Abstract Background Rearrangements involving the KMT2A gene (KMT2Ar) are recurrent genetic abnormalities in acute myeloid leukemia (AML) associated with high rates of relapse and adverse outcomes. The recent development of menin inhibitors has led to availability of a targeted therapy for KMT2Ar AML. We sought to examine the outcomes of KMT2Ar AML treated in the frontline setting with an intensive chemotherapy (IC) combination, Cladribine, Idarubicin, Cytarabine (CLIA) with or without the BCL2 inhibitor Venetoclax (Ven). Methods We identified patients(pts) with KMT2Ar AML treated on a prospective phase II clinical trial (NCT02115295). Inclusion criteria of the trial included age ≤65, newly diagnosed AML, with adequate organ function, and ECOG performance status of ≤2. We evaluated patients treated with CLIA alone as well as those treated on the cohort of CLIA + ven. Induction was with cladribine 5 mg/m2 IV on D1-5, cytarabine 1.5 g/m2 IV on D1-5, and idarubicin 10 mg/m2 IV on D1-3; For patients in the Ven cohort, venetoclax was given at a dose of 400mg PO on D2-8 without ramp up with each cycle. Consolidation consisted of 3 days of CLIA (2 days of idarubicin). Ven was dose-modified for CYP3A4 inhibitors. All patients underwent MRD testing by multiparameter flow cytometry at the time of response assessment. Results A total of 22 pts with KMT2Ar AML were treated on study including 6 (35%) receiving CLIA and 16 (65%) receiving CLIA-Ven. Median age was 51 yrs (range, 37-60) for CLIA arm and 41 yrs (range, 21-56) for CLIA-Ven arm. 1 (16%) pt in CLIA arm and 4 (25%) pts in CLIA-ven arm had therapy related AML. The most common KMT2A translocation on study was t(9;11)(p21.3;q23.3) including 2 (33%) in CLIA arm and 6 (38%) in CLIA-ven arm. Other KMT2A translocation partners were t(11;19)(q23.3;p13.1) (n=2 in CLIA , n=5 in CLIA-ven); t(11;17)(q23;q12) (n=1 each in CLIA and CLIA-ven), t(6;11)(q27;q23.3)(n=2 in CLIA-ven) and t(11;17)(q23.3;q25) (n=1 in CLIA-ven). Additional cytogenetic abnormalities included +8 in two pts and -9, +21 and +X in one patient each. The most commonly mutated genes were NRAS (n=3 CLIA ; n=7 CLIA-ven), KRAS (n=3 CLIA-ven) and TET2 (n=2 CLIA-ven). All patients were evaluable for response. Median follow up of the entire cohort was 30.2 months (range, 0.3-127), a median of 70.7 months in the CLIA arm and 30.2 months in the CLIA-ven arm. Pts treated with CLIA received a median of 2.5 cycles (range, 1-5); the CR/CRi rate was 83% (5/6) including 4 (66%) CR and 1 CRi (16%). 2/5 (40%) responders achieved a flow cytometry MRD negative response, and 3/5 (60%) responders underwent a subsequent Allo-SCT at a median of 5.4 months (range, 2.7-7.2) from start of therapy. At the time of Allo SCT, 2 pts were flow MRD negative while 1 was flow MRD positive with detectable KMT2Ar by FISH. One patient (16%) died within 8 weeks. Two patients (40%) in this cohort had a subsequent relapse. Patients treated with CLIA-ven arm received a median of 2 (2-4) cycles; the CR/CRi rate was 100% including 15 CR (94%) and 1 (6%) CRi. All 16 (100%) pts achieved a flow cytometry MRD negative response, and 15/16 (94%) responders underwent a subsequent Allo-SCT at a median of 3.2 months (2.3-6.7) from initiating therapy. 4- and 8-week mortality was 0 (0%) and 1 (9%), respectively. One patient (9%) had a subsequent relapse. The 2-year OS and EFS of the whole cohort was 76% and 73% respectively and the median OS and EFS was not reached. The 2-year EFS was 81% and 50% for CLIA-Ven and CLIA, respectively (HR 0.28, p=0.09). The 2-year OS was 81% and 50% for CLIA-Ven and CLIA, respectively (HR 0.37, p=0.19). There were a total of 3 deaths in the CLIA arm: 1 death was treatment related mortality on day 10 of first cycle of the CLIA due to DAH and intracranial bleed and two deaths were secondary to relapsed disease. There were 3 deaths in CLIA-Ven arm: 1 death was due to severe COVID-19 related complication after 2 cycles of chemo, 1 death due to infectious complications 21 days post Allo SCT and 1 death was due to relapsed disease. Conclusion Among young and fit patients with newly diagnosed AML with KMT2Ar, IC with CLIA induced high rates of MRD negative remissions, allowing a majority of patients to proceed with a potentially curative alloSCT. The addition of venetoclax with CLIA appeared to produce a higher rate of MRD negative complete remission, low rate of relapse, and promising long term survival in a high risk subset of AML.