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Letters to the Editor
Outcomes of relapsed or refractory acute myeloid leukemia after front-line hypomethylating agent and venetoclax regimens
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Outcomes of intensive chemotherapy (IC) in older patients with AML continue to be suboptimal due to comorbidities, frailty, complex biology and resistance to chemotherapy.1-3 Front-line venetoclax (VEN) with hypomethylating agents (HMA) (VEN+HMA) have shown good tolerability with poten- tially better outcomes compared to HMA alone.4-6 Consequently, VEN+HMA regimens have emerged as a reasonable new standard of care for older patients.7 However, little is known about outcomes of patients after failure of front-line venetoclax-based regimens. We found that patients failing front-line VEN+HMA have high-risk biology, dismal overall survival (OS) despite sal- vage therapy, and new putative mechanisms of resist- ance. This knowledge may help guide physicians' expec- tations, inform discussion with patients, and design clin- ical trials in patients after venetoclax failure.
This was a retrospective study to determine the out- comes of patients after failure of front-line VEN+HMA therapy. Patients with newly diagnosed (ND) AML enrolled on two clinical trials of VEN and HMA at our institute, either with primary refractory disease or relapse (R/R) after initial response were included (Online Supplementary Figure S1). In one trial, patients with ND AML aged 65 years or older received venetoclax 400- 1,200 mg daily with decitabine 20 mg/m2 for 5 days or azacitidine 75 mg/m2 for 7 days every 4 weeks (clinicaltri- als.gov identifier: NCT02203773).4 The other trial enrolled patients with ND AML aged 60 years or older, and patients received venetoclax 400 mg daily or equivalent with decitabine 20 mg/m2 for 10 days every 4 weeks until response, followed by 5-day decitabine with venetoclax cycles (clinicaltrials.gov identifier: NCT03404193).5 None of the patients included in these analyses received any third agents such as targeted therapies. Responses included complete remission (CR), CR with incomplete hemato- logic recovery (CRi), or morphologic leukemia-free state (MLFS) according to the European LeukemiaNet 2017 cri- teria.8 Primary refractory disease was defined as lack of reduction of bone marrow (BM) blasts to 5% or less by up to cycle 4 of VEN+HMA, as originally defined in these two protocols designed in 2014 and 2017. Relapse was defined as clinically significant progressive disease with increase in BM blasts to more than 5% after achievement of CR/CRi/MLFS. OS was measured from the date of establishment of primary refractory disease or relapse after VEN+HMA therapy, until death or censored at last follow-up. The data cut-off date for this report was July 8th, 2019.
To provide context for this analysis, we compared out- comes, both from initial therapy, and from time of R/R disease, with front-line IC using a historical cohort. We found 278 patients treated with IC who matched for both age and European LeukemiaNet (ELN) 2017 cytoge- netic risk status with 88 out of 95 patients treated with VEN+HMA. There were no patients in our historical IC cohort who matched for both age and cytogenetic risk status of seven patients who received VEN+HMA, and hence the comparison was limited to those 88 patients. Two out of those seven unmatched patients had R/R dis- ease after VEN+HMA. The patients in the IC cohort were diagnosed between 2000 and 2018, and received treat- ment with IC containing at least 1 g/m2/day of cytarabine
Table 1. Baseline characteristics of patients with relapsed or refrac- tory acute myeloid leukemia (AML) after front-line venetoclax and hypomethylating agent-based regimens, n=41.
Characteristics
Age
de novo AML Secondary AML Therapy-related AML
ELN 2017 risk group at diagnosis
Intermediate
N (%), median [range]
74 [62-85]
23 (56) 2 [0-44] 15 [1-95]
22 (54) 12 (29) 7 (17)
8 (19)
33 (81)
19 (46) 18 (44) 4 (10)
19 (46) 11 (27)
3 (7)
8 (20) 5.3 [0.9-34.1] 4 [1-29]
4 (10)
ECOG PS ≥2
Peripheral blood blasts, % Bone marrow blasts, % Diagnosis
Adverse
Venetoclax and hypomethylating agent regimen
DEC10-VEN DEC5-VEN AZA-VEN
Response to VEN+HMA
CR
CRi
MLFS
Primary refractory
Duration of response, months No. of VEN+HMA cycles received Allo-SCT in CR1
ECOG PS: Eastern Co-operative Oncology Group Performance Status; ELN: European LeukemiaNet; DEC10: decitabine for 10 days; DEC5: decitabine for 5 days; AZA: azacitidine; VEN: venetoclax; HMA: hypomethylating agents; CR: complete remission; Cri: CR with incomplete hematologic recovery; CR1: first CR; MLFS: mor- phologic leukemia-free state; allo-SCT: allogeneic stem cell transplantation.
(Online Supplementary Table S1). For comparison of OS with front-line VEN+HMA versus IC, OS was measured from start of therapy until death, or censored at last fol- low-up. χ2 test was used to compare proportions between groups and Kaplan-Meier method with log-rank test was used to compare OS.
Between November 2014 and February 2019, we treat- ed 95 patients with ND AML on two front-line VEN+HMA trials, and we identified 41 patients (43%) with R/R disease after front-line VEN+HMA. Eight patients (20%) had primary refractory disease while 33 patients (80%) had relapse after initial response. The median age was 74 years (range 62-85), 12 patients (29%) had secondary AML (sAML), 33 patients (81%) had ELN adverse risk AML, 16 patients (39%) had TP53mut, 11 patients (27%) had N/KRASmut, and five patients (12%) had FLT3-ITDmut at screening. Patients had received a median of four cycles of therapy (range 1-29) (Table 1). The median follow-up duration for all patients was 21 months.
The median OS after VEN+HMA failure for all 41 patients was 2.4 months (range 0.1-21.2) (Figure 1A). Patients who received salvage therapy (n=24) had longer OS compared to patients who could not or did not receive salvage therapy (n=17, 2.9 vs. 1.3 months, hazard ratio [HR]=0.41, 95% confidence interval [CI]: 0.19-0.88; P=0.003) (Figure 1B). When compared to an age- and cytogenetic risk-matched cohort of 278 patients receiving
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haematologica | 2021; 106(3)