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 potentially 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 salvage therapy, and new putative mechanisms of resistance. This knowledge may help guide physicians' expectations, inform discussion with patients, and design clinical trials in patients after venetoclax failure.
This was a retrospective study to determine the outcomes 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 (clinicaltrials. 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 hematologic recovery (CRi), or morphologic leukemia-free state (MLFS) according to the European LeukemiaNet 2017 criteria. 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 outcomes, 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 cytogenetic 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 disease after VEN+HMA. The patients in the IC cohort were diagnosed between 2000 and 2018, and received treatment with IC containing at least 1 g/m2/day of cytarabine (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 follow- 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 treated 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 front-line IC, VEN+HMA showed a significantly better CR/CRi rate of 87% compared to 59% with IC (odds ratio [OR] 3.29, 95%CI: 1.79-6.01; P=0.0001), lower rate of primary refractory disease of 8% versus 24% with IC (OR 0.32, 95%CI: 0.14-0.74; P<0.01), and a lower rate of relapse of 42% versus 58% with IC (OR 0.52, 95%CI: 0.30-0.90; P=0.02). Additionally, VEN+HMA conferred superior OS of 15.1 months compared to 8.1 months with IC (HR 0.57, 95%CI: 0.44-0.75; P<0.001) (Figure 1C). However, and of interest, patients who failed frontline VEN+HMA had shorter survival of 2.3 months compared to 3.6 months in patients failing front-line IC (HR 1.76, 95%CI: 1.10-2.77; P<0.005) (Figure 1D).
Median OS after relapse were comparable for patients who achieved CR versus those who achieved CRi with VEN+HMA (Online Supplementary Figure S2). Patients with primary refractory disease versus relapse had comparable OS of 1.7 versus 2.3 months, respectively (Online Supplementary Figure S3). Median OS for de novo AML at relapse/failure was 2.5 months, for sAML was 2.8 months, and for therapy-related (t-AML) was 1.1 months (Online Supplementary Figure S4). Out of the 24 patients who received salvage therapy (see Online Supplementary Table S2 for regimens), five patients (21%) responded with CR (n=1), CRi (n=2), and MLFS (n=2). One patient underwent allogeneic stem-cell transplantation in second complete remission (CR2). Eight patients received IC, and 2 of 8 patients achieved CR and CRi with CLIA and CLIA with gemtuzumab ozogamicin, respectively. Both patients harbored NRAS mutations. Nine patients received non-intensive chemotherapy-based regimens, and 3 of 9 patients responded, including two patients with FLT3mut, with CRi in one patient with azacitidine and quizartinib, and MLFS in two patients with azacitidine, nivolumab, ipilimumab, and low-dose cytarabine with quizartinib, respectively. These five responding patients (Figure 2 and Online Supplementary Table S2) continue in remission with median DOR not reached (NR) (range 0.7-20.1) and OS NR (range, 2-21.2).
The most frequently occurring mutations in this R/R population, at initial diagnosis, included TP53, DNMT3A, N/KRAS, TET2, and ASXL1 (Figure 2). Twenty patients had 81-gene next-generation sequencing (NGS) panel results at diagnosis and at the time of R/R disease. The most frequent mutations gained at the time of R/R disease were mutations in signaling pathways (30%, NF1, FLT3-ITD, NRAS, JAK1), RNA splicing (30%, U2AF1, U2AF2, SRSF2, ZRSR2), transcription factors (30%, IKZF1, SETBP1, RUNX1, STAT5A), tumor suppressors (15% TP53, WT1), and epigenetic modifiers (10%, BCOR, CREBBP).
Among five patients with FLT3-ITD, two patients responded to salvage regimens containing a FLT3 inhibitor (Figure 2 and Online Supplementary Table S3). Out of ten patients with K/NRAS mutations receiving salvage therapy, three patients (30%) responded to IC (n=2) and HMA-based regimens (n=1). Of the five patients with TP53mut receiving salvage therapy, one patient achieved MLFS with azacitidine, nivolumab and ipilimumab. This patient was also the only one among seven patients with complex karyotype who responded to salvage therapy.
These findings summarize the characteristics and poor outcomes of patients who develop R/R disease after front-line VEN+HMA therapy. These patients presented with high-risk biology including t-AML, sAML, complex karyotype, FLT3-ITDmut, TP53mut, and N/KRASmut at diagnosis and also evolved with treatment. Patients who were expected to have durable outcomes but relapsed, e.g., NPM1mut and IDH1/2mut patients, had adverse-risk cytogenetics or co-occurring mutations in TP53, N/KRAS, FLT3, and/or KIT. The particularly high incidence of aggressive biology in these R/R patients was the likely driving factor behind the poor outcomes seen after VEN+HMA failure. Patients with AML after failure of front-line HMA and no salvage therapy have a median OS of 2 months which was comparable to our report of 1.3 months.9 However, for patients who receive salvage therapy, front-line VEN+HMA failure appears to confer a worse prognosis with median OS of 2.9 months compared to 9.5 months for patients after failure of front-line HMA.9 We believe that incorporating FLT3 inhibitors in the front-line setting as triplets with VEN+HMA may further improve outcomes in older FLT3-mutant patients.10,11 However, a sequential approach may be worth investigation in patients who achieve excellent response to induction therapy and are closely monitored by molecular methods.
Genomic analysis demonstrated a heterogeneous group of underlying genetic mechanisms of resistance to VEN+HMA. These findings add to the accumulating knowledge of venetoclax-resistance mechanisms including N/KRASmut, PTPN11mut, dependence on other antiapoptotic proteins, e.g., BCL-XL, MCL1; TP53mut and alterations in mitochondrial homeostasis.12-15 These insights may provide new directions for biological understanding and drug development in populations that fail venetoclax and provide a rationale to test novel therapeutics such as spliceosome inhibitors, MCL1, MDM2, BET inhibitors, PRIMA1 analogs, and others in VEN-resistant models as potential ways to prevent or abrogate such resistance.16-18
This was a retrospective study with all the inherent limitations of such a design. Forty-two percent of patients could not or did not receive salvage therapy. The patients who were treated received a heterogeneous group of regimens. Based on the limited number of patients who received salvage therapy, it was unclear if any specific regimen was superior after front-line VEN+HMA failure, and hence these patients should ideally be treated on clinical trials. Patients progressing after IC may have had better functional status compared to patients progressing after VEN+HMA, and this could have contributed to the difference in OS after progression. However, age is one important determinant of ‘fitness’ and we matched all patients for age to minimize this imbalance in functional status due to age alone. Notably, some patients with FLT3-ITD responded well to salvage regimens with second-generation FLT3 inhibitors and N/KRASmut patients appeared to respond to IC. Additional work on dissecting the underlying biology in pre-clinical models and testing novel combinations in this setting is ongoing.19
In summary, VEN+HMA offers superior responses and survival in older patients with ND AML; however, patients who have R/R disease after front-line VEN+HMA display high-risk disease biology and particularly poor survival. In this era of venetoclax-based regimens increasingly being utilized as front-line AML therapy, this knowledge of outcomes after failure of VEN+HMA provides useful information to discuss with patients and highlights the urgent need for novel therapies to abrogate venetoclax resistance.
Disclosures: AM has received research funding from Celgene Corporation; JEC has received research funding from Ambit BioSciences, ARIAD, Arog, Astellas Pharma, AstraZeneca, Bristol- Myers Squibb, Celator, Celgene, Novartis, Pfizer, Sanofi, Sun Pharma, and Teva; and has had a consultancy role with Ambit BioSciences, ARIAD, Astellas Pharma, BiolineRx, Bristol-Myers Squibb, Novartis, and Pfizer. NP has had a consultancy role or received honoraria from Celgene, Stemline, Incyte, Novartis, MustangBio, Roche Diagnostics, and LFB; research funding/clinical trial support from Stemline, Novartis, Abbvie, Samus, Cellectis, Plexxikon, Daiichi-Sankyo, and Affymetrix; grants or funding from Affymetrix, and SagerStrong Foundation. NGD has had a consultancy role with and received research funding from Sunesis Pharmaceuticals Inc., Karyopharm, Pfizer Inc., and Bristol-Myers Squibb Company; consultancy fees from Novartis Pharmaceuticals Corporation, Otsuka America Pharmaceutical Inc., and Jazz; research funding from Immunogen, Daiichi-Sankyo, and Kiromic; honoraria and research funding from Incyte Corporation. FR has received research funding from Amgen, Bristol-Myers Squibb, Merck, Seattle Genetics, and Sunesis Pharmaceuticals; honoraria from Amgen, Pfizer, Seattle Genetics, and Sunesis Pharmaceuticals; has had a consulting or advisory role for Amgen, Seattle Genetics, and Sunesis Pharmaceuticals. GB has received research funding from AbbVie, Incyte, Janssen, GSK, Cyclacel and Oncoceutics Inc.; and has had a consultancy role with NKarta and PTC Therapeutics; has had a consultancy role with and research funding from BioLine Rx. NJS has had a consultancy role with and research funding from Takeda Oncology; has had a consultancy role with AstraZeneca; has received honoraria from Amgen. YA has received research funding from Jazz Pharmaceuticals; honoraria from Abbott. KT has had a consultancy role with Symbio Pharmaceuticals. NJ has had a consultancy role, has received honoraria, and is a member of an entity's Board of Directors or sits on advisory committees, and has received research funding from AbbVie, Pharmacyclics, Genentech, Pfizer, ADC Therapeutics, AstraZeneca, Servier, Verastem, Precision Biosciences, and Adaptive Biotechnologies; has had a consultancy role, has received honoraria, and is a member of an entity's Board of Directors or sits on advisory committees, Janssen Pharmaceuticals Inc.; has received research funding from BMS, Incyte, and Cellectis. KS has received honoraria from Otsuka; has had a consultancy role with Pfizer. MA has had a consultancy role, and declares patents and royalties, and to have received research funding from Daiichi Sankyo, Inc.; has had a consultancy role with Jazz Pharmaceuticals, Celgene, Amgen. AstraZeneca, and 6 Dimensions Capital; he has equity ownership in Reata, Aptose, Eutropics, Oncoceutics, and Oncolyze and ia a member of an entity's Board of Directors or sits on advisory committees for Senti Bio; has received research funding from Breast Cancer Research Foundation, CPRIT, and NIH/NCI; is a member of an entity's Board of Directors or sits on advisory committees for the Center for Drug Research & Development, Cancer UK, NCI-CTEP, German Research Council, Leukemia Lymphoma Society, NCI-RDCRN (Rare Disease Clin Network), CLL Foundation, and BiolineRx; PB has had a consultancy role, has received research funding and sits on the speakers’ bureau for Incyte Corporation; has had a consultancy role and has received research funding from Celgene Corporation and Blueprint Medicines Corporation; has received research funding from Kartos Therapeutics, Constellation Pharmaceuticals, Pfizer, Astellas Pharmaceuticals, NS Pharma Research, Promedior, and CTI BioPharma; EJJ has had a consultancy role with and has received research funding from Takeda, BMS, Adaptive, Amgen, AbbVie, Pfizer, and Cyclacel Ltd. JSW has received honoraria from ArcherDx and Rigel Pharmaceuticals, and research funding from Jansen Pharmaceuticals and Notable Laboratories. CDD has received honoraria and research funding from AbbVie, Agios, Novartis, Celgene, and Daiichi-Sankyo, and research funding from Calithera Biosciences, honoraria from Jazz Pharmaceuticals, honoraria from and is a member of a scientific advisory board for Notable Laboratories. HMK has received research funding from ARIAD, Astex, BMS, Cyclacel, Daiichi-Sankyo, Jazz, and Novartis, honoraria and research funding from Pfizer and Immunogen, and honoraria from Actinium and Takeda. MYK has received research funding from Calithera, Eli Lilly, Cellectis, Ascentage, AstraZeneca and Agios, has had a consultancy role with and received honoraria from Forty-Seven, Amgen, and Kisoji; has had a consultancy role with and has received honoraria and research funding from Stemline Therapeutics, Abbvie, and F. Hoffman La-Roche, honoraria and research funding from Genentech, research funding from Ablynx; has equity ownership and patents and royalties from Reata Pharmaceuticals. CRR, GGM, KN, MO, TMK, MY, SK, GMB, AF, GCI, LM, PAT, SAW, SK, SAP, JN and WQ have no conflicts of interest to disclose.
Contributions: AM, CDD, MYK, CDD, MYK, GGM, HMK, JEC, GGM administrative support; CRR, JEC, NP, NGD, FR, GGM, GB, KN, MO, NJS, YA, CBB, TMK, KT, MY, NJ, SK, GMB, KS, A, PB, AF, GCI, EJJ, LM, PAT, SW, SJ, MG, REM, JAG, CAB, AW, SLA, ST, RT, KV, SAP, JN, WQ, JSW, HMK, MYK, CDD provision of study materials or patients; CRR, JEC, NP, NGD, FR, GGM, GB, KN, MO, NJS, YA, CBB, TMK, KT, MY, NJ, SK, GMB, KS, A, PB, AF, GCI, EJJ, LM, PAT, SW, SJ, MG, REM, JAG, CAB, AW, SLA, ST, RT, KV, SAP, JN, WQ, JSW, HMK, MYK, CDD collection and assembly of data; AM, CDD, MYK, CRR, JN, WQ, QZ, AC, HM, SAW, SNK, ZC, MG data analysis and interpretation; AM, CDD, MYK manuscript writing; all authors critical revision for important intellectual content and reviewed and approved the final version of the manuscript.
We thank the patients, their families, and their caregivers, co-investigators, collaborators, and members of the study team involved in the trial.
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