Abstract
FLT3, IDH1 and IDH2 inhibitors as well as venetoclax in combination with hypomethylating agents or low-dose cytarabine have expanded treatment options for patients with acute myeloid leukemia (AML). However, little data exist on the efficacy of venetoclax-based therapies in AML patients previously treated with FLT3 or IDH1/2 inhibitors. In this multicenter, retrospective cohort study, we included 44 patients who received venetoclax-based therapy after FLT3, IDH1 or IDH2 inhibitors. The overall response rate (ORR; composite of complete remission [CR]/CR with incomplete count recovery, partial remission, and morphologic leukemia free state) was 56.8% (18.2% CR) and a median overall survival of 9.2 months. While 6 out of 7 patients with IDH1 mutations who had previously been treated with ivosidenib responded to venetoclax-based therapy, FLT3-ITD mutations were associated with a lower response rate. Our data suggest that venetoclax can be an effective salvage therapy in patients previously treated with IDH1/2 or FLT3 inhibitors.
Keywords: Acute myeloid leukemia, AML, targeted agents, venetoclax, outcomes
Introduction
Advances in the detection and understanding of the pathophysiology of recurrent genetic mutations in patients with acute myeloid leukemia (AML) have enabled the approval of several novel therapeutic options for the treatment of AML. These includeFLT3 (midostaurin, gilteritinib), IDH1 (ivosidenib), and IDH2 (enasidenib) inhibitors for the subset of patients with FLT3, IDH1, or IDH2-mutant AML.(1-6) Although the BCL-2 inhibitor venetoclax with hypomethylating agents (HMA) or low-dose cytarabine (LDAC) has been approved in the frontline setting, these combinations are also frequently used in patients with relapsed or refractory AML (R/R AML).(7-9) However, little data exist on the efficacy of venetoclax-based salvage therapies in the specific subset of AML patients previously treated with FLT3 and IDH1/2 targeted agents. Venetoclax-based combination therapy has demonstrated high response rates in patients with IDH1/2-mutant AML when used in the frontline setting.(10) However, it is unclear whether IDH1/2-mutant AML remains sensitive to venetoclax after prior exposure to and/or failure of IDH inhibitors. This raises important and clinically relevant questions related to the optimal sequence of targeted agents and venetoclax-based therapies. In addition, little is known regarding clinical, genetic, and molecular predictors of response and resistance to venetoclax-based therapy after prior treatment with targeted therapy. Here, we report results of a retrospective, multicenter study of the efficacy of venetoclax-based combinations for patients with R/R AML who had previously been treated with IDH1, IDH2, or FLT3 inhibitors.
Methods
Data source and eligibility
Data were retrospectively collected at Memorial Sloan Kettering Cancer Center, City of Hope, and Yale Cancer Center. All adult patients with AML who received venetoclax with either hypomethylating agents or low-dose cytarabine directly after treatment with FLT3, IDH1 or IDH2 inhibitors from January 2016 to December 2021 were included. FLT3, IDH1, or IDH2 inhibitors could have been administered either alone or as part of investigational or standard-of-care combination therapies. Patients were excluded if venetoclax and FLT3, IDH1, or IDH2 inhibitors were not administered in direct sequence or if therapies of interest were given as post-transplant maintenance therapy. The study was approved by the Institutional Review Boards at the participating sites.
Patient and treatment characteristics
Clinical, cytogenetic and genetic data were collected before the start of venetoclax treatment. Venetoclax combinations were administered per routine clinical practice with dose adjustments at the discretion of the treating physician.(11) All lines of therapy before and after venetoclax including receipt of allogeneic hematopoietic cell transplant (allo-HCT) were recorded. Next-generation sequencing was performed prior to the initiation of venetoclax-based salvage therapies per routine institutional practice at the participating sites.
Response assessment and survival
Response to therapy was assessed based on 2017 European LeukemiaNet (ELN) response criteria for AML.(12) The overall response rate (ORR) was defined as a composite of complete remission (CR), CR with incomplete count recovery (CRi), partial remission (PR) and morphologic leukemia free state (MLFS). In a sensitivity analysis we defined the ORR as a composite of CR and CRi. Responses are reported as best response at any point during treatment with venetoclax. Multiparametric flow cytometric analysis of bone marrow aspirate samples was used to determine presence of minimal residual disease (MRD) per routine institutional practice at the participating sites. Any level of residual disease was considered MRD-positive. Overall survival (OS) was calculated from the time of initiation of venetoclax. Relapse-free survival (RFS) was defined as the time from achieving an objective response to disease relapse or death, whichever occurred first.
Statistical analysis
Categorical patient characteristics are reported as frequencies. Univariate analysis was conducted to evaluate associations between overall response and demographic, disease and molecular characteristics, and were tested by Fisher’s exact test. Univariate Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for associations between mortality and demographic, disease, and molecular characteristics. P-values for the significance of these associations were calculated by log-rank test. OS and RFS were evaluated by the Kaplan-Meier method. Subgroup analyses were performed for patients who had previously been treated with FLT3 vs IDH1/2 inhibitors, patients who had refractory disease vs those with relapsed disease after an initial response to targeted agents, and by allelic ratio (<0.5 vs ≥0.5) for patients with FLT3-ITD mutations. Patients who discontinued treatment due to adverse events prior to response assessment (n=3 patients) were excluded from the subgroup analysis comparing patients with relapsed vs refractory disease. Statistical significance was defined using a two-sided significance level at 0.05. All statistical analyses were performed using R version 3.6.1.
Results
Patient characteristics
Forty-four patients who received venetoclax-based regimens following treatment with FLT3, IDH1 or IDH2 inhibitors were identified. Venetoclax was given in combination with azacitidine, decitabine, ASTX727, and low-dose cytarabine in 16 (36%), 22 (50%), 1 (2%), and 5 (11%) patients, respectively. Table 1 provides an overview of the baseline characteristics for the combined patient cohort as well as by prior treatment with FLT3 or IDH1/2 inhibitor. This patient cohort was extensively pre-treated with 36 (82%), 17 (39%), and 13 (30%) patients having received intensive chemotherapy, HMA, or allo-HCT, respectively. Nine patients (20.5%) who were treated with venetoclax, had previously received targeted agents as part of a frontline combination therapy. All of these patients had been treated with FLT3 inhibitors. Accordingly, compared to patients previously treated with IDH1/2 inhibitors, patients with FLT3 inhibitors were more likely to have received intensive chemotherapy (93% vs 65%; p=0.04) and to have received targeted therapies in combination with intensive chemotherapy (44% vs 0%; p=0.001). In terms of baseline molecular characteristics other than the FLT3 or IDH1/2 mutations, patients previously treated with FLT3 inhibitors were less likely to have a co-mutation in ASXL1 (4% vs 36%). All other baseline patient, treatment, and molecular characteristics were comparable between both groups. Table 2 provides an overview of the baseline characteristics by response to prior targeted therapies (i.e., relapsed vs refractory disease). The median duration of response to prior targeted therapies among patients with relapsed disease was 7.1 months (R: 0.8 – 51.6 months).
Table 1:
Patient characteristics
| Total (N=44) | FLT3 (N=27) | IDH1/2 (N=17) | P-value^ | |
|---|---|---|---|---|
| Patient age (years) | ||||
| Median (R) | 63 (29-90) | 63 (29-90) | 63 (29-90) | |
| <70 years | 32 (73%) | 22 (81%) | 10 (59%) | |
| ≥70 years | 12 (27%) | 5 (19%) | 7 (41%) | 1.00 |
| Male sex (n; %) | 21 (48%) | 10 (37%) | 11 (65%) | 0.12 |
| AML subtype | ||||
| De novo AML | 27 (61%) | 20 (75%) | 7 (41%) | |
| AML-MRC | 12 (27%) | 5 (18%) | 7 (41%) | |
| Therapy-related AML | 0 (0%) | 0 | 0 | |
| Other (e.g., blast-phase MPN, prior CMML) | 5 (11%) | 2 (7%) | 3 (18%) | 0.06 |
| ELN risk | ||||
| Favorable | 8 (18%) | 5 (19%) | 3 (18%) | |
| Intermediate | 16 (36%) | 10 (37%) | 6 (35%) | |
| Adverse | 20 (45%) | 12 (44%) | 8 (47%) | 1.00 |
| Disease status before targeted therapy | ||||
| Newly diagnosed AML | 10 (23%) | 8 (30%) | 2 (12%) | |
| R/R AML | 34 (77%) | 19 (70%) | 15 (88%) | 0.27 |
| Targeted agent | ||||
| Ivosidenib | 5 (11%) | 0 | 5 (29%) | |
| Enasidenib | 12 (27%) | 0 | 12 (71%) | |
| Gilteritinib | 14 (30%) | 14 (52%) | 0 | |
| Midostaurin | 8 (20%) | 8 (30%) | 0 | |
| Sorafenib | 2 (5%) | 2 (7%) | 0 | |
| Quizartinib | 1 (2%) | 1 (4%) | 0 | |
| Crenolanib | 2 (5%) | 2 (7%) | 0 | N/A |
| Targeted agent combination therapy | ||||
| Targeted agent monotherapy | 28 (64%) | 13 (48%) | 15 (88%) | |
| Targeted agent + intensive chemotherapy | 12 (27%) | 12 (44%) | 0 | |
| Targeted agent + non-intensive therapy | 4 (9%) | 2 (7%) | 2 (12%) | 0.001 |
| Prior treatment before venetoclax * | ||||
| Intensive chemotherapy | 36 (82%) | 25 (93%) | 11 (65%) | 0.04 |
| HMA | 17 (39%) | 7 (26%) | 10 (59%) | 0.06 |
| Targeted agent monotherapy | 30 (68%) | 14 (52%) | 16 (94%) | 0.004 |
| Allo-HCT | 13 (30%) | 8 (30%) | 5 (29%) | 1 |
| None | 0 | 0 | 0 | 1 |
| Venetoclax based therapy | ||||
| Azacitidine + venetoclax | 16 (36%) | 11 (41%) | 5 (29%) | |
| Decitabine + venetoclax | 22 (50%) | 13 (48%) | 9 (53%) | |
| ASTX727 + venetoclax | 1 (2%) | 1 (4%) | 0 | |
| Low dose Ara-C + venetoclax | 5 (11%) | 2 (7%) | 3 (18%) | 0.66 |
| Allo-HCT following venetoclax based therapy | 9 (20%) | 8 (30%) | 1 (6%) | 0.12 |
| Molecular abnormalities at time of venetoclax therapy initiation | ||||
| FLT3-ITD | 19 (46%) | 16 (59%) | 3 (21%) | 0.046 |
| FLT3-TKD | 6 (15%) | 5 (19%) | 1 (7%) | 0.40 |
| IDH1 | 7 (18%) | 2 (8%) | 5 (33%) | 0.08 |
| IDH2 | 13 (33%) | 4 (17%) | 9 (60%) | 0.013 |
| DNMT3A | 12 (34%) | 8 (33%) | 4 (36%) | 1.00 |
| NPM1 | 12 (33%) | 10 (42%) | 2 (17%) | 0.26 |
| TP53 | 2 (6%) | 1 (4%) | 1 (9%) | 0.54 |
| RUNX1 | 5 (14%) | 3 (12%) | 2 (18%) | 0.64 |
| ASXL1 | 5 (14%) | 1 (4%) | 4 (36%) | 0.026 |
| RAS pathway (NRAS, KRAS, PTPN11, NF1) | 4 (12%) | 3 (12%) | 1 (9%) | 1.00 |
| Splicing mutations (SF3B1, SRSF2, U2AF1) | 5 (14%) | 2 (8%) | 3 (27%) | 0.31 |
| Patient age (years) | ||||
| Median (R) | 63 (29-90) | 63 (29-90) | 63 (29-90) | |
| <70 years | 32 (73%) | 22 (81%) | 10 (59%) | |
| ≥70 years | 12 (27%) | 5 (19%) | 7 (41%) | 1.00 |
Patients could have received multiple lines of prior therapy. All prior lines of therapy listed.
P-values refers to the comparison of patients previously treated with FLT3 and IDH1/2 inhibitors
Table 2:
Baseline patient and disease characteristics for refractory and relapsed patients
| Refractory cohort (n=25) | Relapsed cohort (n=16) | |
|---|---|---|
| Patient age (years) | ||
| Median (R) | 65 (29-82) | 61 (31-90) |
| <70 years | 17 (68%) | 13 (81%) |
| ≥70 years | 8 (32%) | 3 (19%) |
| Male sex (n; %) | 13 (52%) | 5 (31%) |
| AML subtype | ||
| De novo AML | 13 (52%) | 12 (75%) |
| AML-MRC | 8 (32%) | 4 (25%) |
| Therapy-related AML | 0 | 0 |
| Other (e.g., blast-phase MPN, prior CMML) | 4 (16%) | 0 |
| ELN risk | ||
| Favorable | 2 (8%) | 6 (38%) |
| Intermediate | 7 (28%) | 7 (44%) |
| Adverse | 16 (64%) | 3 (19%) |
| Disease status before targeted therapy | ||
| Newly diagnosed AML | 5 (20%) | 5 (31%) |
| R/R AML | 20 (80%) | 11 (69%) |
| Targeted agent | ||
| Ivosidenib | 3 (12%) | 2 (12%) |
| Enasidenib | 8 (32%) | 3 (18%) |
| Gilteritinib | 7 (28%) | 5 (24%) |
| Midostaurin | 5 (20%) | 5 (24%) |
| Sorafenib | 2 (8%) | 0 |
| Crenolanib | 0 | 1 (6%) |
| Targeted agent combination therapy | ||
| Targeted agent monotherapy | 16 (64%) | 9 (56%) |
| Targeted agent + intensive chemotherapy | 6 (24%) | 6 (38%) |
| Targeted agent + non-intensive therapy | 3 (12%) | 1 (6%) |
| Prior treatment before venetoclax * | ||
| Intensive chemotherapy | 20 (80%) | 13 (81%) |
| HMA | 11 (44%) | 4 (25%) |
| Targeted agent monotherapy | 17 (68%) | 10 (63%) |
| Allo-HCT | 9 (36%) | 4 (25%) |
| Venetoclax based therapy | ||
| azacitidine + venetoclax | 9 (36%) | 5 (31%) |
| decitabine + venetoclax | 11 (44%) | 9 (56%) |
| ASTX727 + venetoclax | 3 (12%) | 1 (6%) |
| low dose Ara-C + venetoclax | 0 | 1 (6%) |
| Allo-HCT following venetoclax based therapy | 5 (20%) | 2 (12%) |
| Molecular abnormalities at time of venetoclax therapy initiation | ||
| FLT3-ITD | 12 (52%) | 6 (40%) |
| FLT3-TKD | 1 (5%) | 3 (20%) |
| IDH1 | 4 (17%) | 3 (21%) |
| IDH2 | 8 (35%) | 1 (21%) |
| DNMT3A | 4 (20%) | 7 (54%) |
| NPM1 | 4 (20%) | 8 (57%) |
| TP53 | 1 (5%) | 1 (8%) |
| RUNX1 | 3 (15%) | 1 (8%) |
| ASXL1 | 4 (20%) | 1 (8%) |
| RAS pathway (NRAS, KRAS, PTPN11, NF1) | 3 (15%) | 1 (8%) |
| Splicing mutations (SF3B1, SRSF2, U2AF1) | 1 (5%) | 1 (8%) |
Patients could have received more than one therapeutic modality prior to venetoclax
Response and survival to venetoclax therapy after prior treatment with targeted agents
The ORR to venetoclax-based therapy was 56.8% (n=25 patients) with 18.2% and 25.0% achieving a CR (11% MRD-negative by flow cytometry) and CRi, respectively. The five patients with MRD-negative CR had previously received gilteritinib (n=1), ivosidenib (n=2) and enasidenib (n=2). The median duration of response for the combined cohort was 8.1 months (95% CI: 3.2 months – not reached). Nine patients (8 previously treated with FLT3 inhibitors and 1 with ivosidenib) were able to undergo allo-HCT after venetoclax-based salvage therapy.
An oncoprint visualizing patient-level responses by molecular profile is shown in Figure 2. Notably, six out of seven patients (86%) with IDH1-mutant AML achieved an objective response to venetoclax-based salvage therapy. While patients with FLT3-ITD-mutant AML had a trend towards a lower likelihood of response to venetoclax-based salvage therapy compared to patients without FLT3-ITD-mutant AML (ORR: 42% vs. 73%; p=0.06), IDH2 mutation status did not impact response rate (ORR: 62% vs 58%; p=1.00). None of the other baseline demographic, disease, or prior treatment characteristics predicted a higher likelihood of response to venetoclax-based salvage therapy. Supplemental Table 1 shows univariate predictors of response to venetoclax following targeted agents. When comparing patients who had relapsed disease after initial response to targeted agents (n= 16 patients) compared to patients with refractory disease (n=25 patients), there was no statistically significant difference in ORR (relapsed patients: 73% vs 54%; p=0.32). Univariate predictors of response of response to venetoclax following targeted agents for patients with relapsed disease and those with refractory disease are shown in Supplemental Table 2. The only baseline patient or molecular disease characteristic associated with a higher response rate was age ≥70 years in the refractory disease patient cohort (ORR age ≥70 years: 88% vs 38% for age <70 years; p=0.03).
Figure 2: Oncoprint of molecular predictors of response.
Figure 2 shows molecular patterns of response to venetoclax-based combinations on an individual patient basis. Molecular testing was performed at the time of venetoclax initiation. Molecular testing was performed either as panel testing at the participating sites or targeted testing for genes of interest.
As prior studies have demonstrated inferior long-term outcomes among patients attaining MLFS compared to CR/CRi after treatment with venetoclax-based regimens, (9, 13) we also analyzed univariate predictors of response to venetoclax among the 19 patients who achieved a CR/CRi compared to patients without CR/CRi (Supplemental Table 3). Only the presence of a FLT3-ITD mutation was associated with a lower CR/CRi rate (FLT3-ITD: 28% vs no FLT3-ITD mutation: 70%; p=0.02). No other baseline patient, disease, or molecular characteristics were associated with a higher response rate to venetoclax-based salvage therapy.
At a median follow up of 31.7 months, the median OS for patients treated with venetoclax-based salvage therapy following targeted agents was 9.2 months (95% CI: 7.2 – 17.4 months). Responding patients had an improved OS compared to non-responding patients (HR for death: 0.39; 95% CI: 0.18 – 0.87; p=0.02). At a median duration of follow up of 28.3 months, the nine patients who underwent an allo-HCT after treatment with venetoclax-based salvage therapy had a median OS of 17.8 months (95% CI: 14.6 months – not reached) from the time of allo-HCT. Among baseline demographic, clinical, and molecular characteristics (Supplemental Table 4), only FLT3-ITD mutations were associated with a shorter median OS (HR for death: 3.26; 95% CI: 1.56-6.81; p=0.001). Median OS from the time of venetoclax initiation was comparable (HR for death for patients with relapsed disease vs refractory disease: 0.68 [95% CI: 0.31 – 1.47]; p=0.32) with 8.2 months (95% CI: 3.4 months – not reached) and 9.2 months (95% CI: 3.8 – 17.5 months) for patients with relapsed and those with refractory disease, respectively. Among patients with relapsed disease, the presence of a FLT3-ITD mutation was associated with inferior OS (HR for death: 8.66 [95% CI: 1.65 – 45.37], p=0.003). Conversely, NPM1 mutations were associated with inferior OS among patients with refractory disease (HR for death: 4.77 [95% CI: 1.36 – 16.67], p=0.008). Additionally, among patients with relapsed disease, patients with favorable disease risk by ELN 2017 criteria(12) had better OS compared to patients with adverse risk (HR for death: 0.04 [95% CI: 0.01 – 0.45]; p=0.009). This association was not found among patients with refractory disease (Supplemental Table 5).
Response and survival to venetoclax therapy after prior treatment with FLT3 inhibitors
Venetoclax-treated patients who had previously received a FLT3 inhibitor had an ORR of 51.8% (11.1% CR [n=3 patients]; Figure 1A)with a median duration of response of 3.7 months (95% CI: 3.1 months – not reached)
Figure 1: Response assessment and OS outcomes.
Figure 1 shows the response rates (%) among patients who received venetoclax-based therapy after disease progression on FLT3 inhibitors (A) and IDH1/2 inhibitors (B), respectively. OS for patients previously treated with FLT3 inhibitors (panel C) or IDH1/2 inhibitors (panel D). CR – complete remission; CRi – complete remission with incomplete hematologic recovery; MLFS – morphologic leukemia-free state; OS – overall survival; PD – persistent disease.
When dichotomizing the 18 patients with FLT3-ITD-mutant AML by allelic ratio into high (defined as allelic ratio ≥0.5) and low (allelic ratio <0.5), we found no statistically significant difference in ORR and median OS among patients with FLT3-ITD-mutant AML based on the FLT3-ITD allelic ratio (FLT3-ITD allelic ratio ≥0.5: ORR: 38% vs 50% for FLT3-ITD allelic ratio <0.5, p=0.66; median OS: 5.1 months [95% CI: 2.3 months – not reached] vs 7.8 months [95% CI: 3.4 months – not reached]; p=0.70).
At a median follow up of 32.3 months, the median OS from the time of venetoclax initiation for patients previously treated with FLT3 inhibitor and was 8.2 months (95% CI: 3.8 – 15.7 months; Figure 1C).
Response and survival to venetoclax therapy after prior treatment with IDH1/2 inhibitors
Venetoclax-treated patients who had previously received an IDH1/2 inhibitor had an ORR 64.7% (29.4% CR [n=6 patients]; Figure 1B). The median duration of response was 8.1 months (95% CI: 4.4 months – not reached) among patients who had previously received IDH1/2 inhibitor. At a median follow up of 31.7 months, the median OS from the time of venetoclax initiation for patients previously treated with IDH1/2 inhibitors was 12.8 months (95% CI: 7.2 months – not reached; Figure 1D).
Discussion:
While azacitidine + venetoclax has only been approved for patients ≥75 years of age or those ineligible for intensive therapy with newly diagnosed AML, venetoclax-based combinations are also frequently used in patients with R/R-AML.(7, 8, 14) However, their efficacy in patients previously treated with targeted agents is unclear. Our real-world, multicenter experience is the first to report on the outcomes of venetoclax-based therapy in patients previously treated with targeted therapy. We found that venetoclax-based regimens retained clinically meaningful efficacy following targeted therapy with an ORR of 56.8% and a median OS of 9.2 months. While these results are inferior to the results seen with azacitidine + venetoclax in newly diagnosed patients in the VIALE-A trial,(15) they appear comparable to the ORR and OS reported in studies of unselected patients treated with venetoclax combination therapy in the R/R setting.(7-9) As the emergence of FLT3 mutations has been described as a mechanism of resistance to azacitidine + venetoclax, this could explain the lower response rates to venetoclax seen in patients previously treated with FLT3 inhibitors.(16) In contrast, both IDH1 and IDH2 mutations have been shown to confer sensitivity to venetoclax.(16) In our study, we found that 85.7% of patients with IDH1 mutations had a response to venetoclax after treatment with ivosidenib supporting the use of venetoclax-based combinations in this setting. Patients with IDH2-mutant AML treated with venetoclax-based combinations after prior exposure to enasidenib continued to have an ORR of 62%, which is encouraging but numerically inferior to the 86% response rate seen in previously untreated patients treated with azacitidine + venetoclax.(10)
Apart from FLT3-ITD mutations, no other patient, clinical, or molecular characteristics predicted outcomes to venetoclax-based therapy and additional studies are needed to better characterize the mechanisms of resistance to venetoclax-based therapy after prior treatment with FLT3 or IDH1/2 inhibitors. Importantly, patients who had relapsed disease after an initial response to targeted agents and those with refractory disease had comparable ORR and median OS supporting the use of venetoclax-based salvage therapy in either setting.
We believe that our data will be of interest to practicing hematologists/oncologists and patients alike as it is setting an important benchmark for expectations for response and survival achieved with venetoclax therapy after prior targeted therapy is administered. Our data will also be important to inform future clinical trials testing venetoclax either in combination or in sequence with targeted therapy.
Several clinical trials are currently testing venetoclax in combination with targeted therapy in both the frontline and R/R setting. For example, in a phase I/II trial the combination of azacitidine, venetoclax and gilteritinib, yielded an ORR (defined as a composite of CR, CRi, and MLFS) of 100% (n=11 patients; CR 73%) and 67% (CR 7%) in patients with newly diagnosed and R/R AML, respectively.(17) Additionally, the recent phase III AGILE trial randomized newly diagnosed patients with IDH1-mutant AML who were ineligible for intensive chemotherapy because of age (≥75 years) or comorbidities to ivosidenib + azacitidine or placebo + azacitidine.(18) While limitations in terms of use of ivosidenib as 2nd line therapy and the choice of azacitidine monotherapy as control arm have been pointed out, the trial showed superiority for ivosidenib + azacitidine compared to azacitidine alone in terms of event-free survival and OS.(18) A main finding of our study was that patients who had previously been treated with ivosidenib had a response rate of 86% to venetoclax-based combination therapy. Our data showing that venetoclax-based combinations retain clinical efficacy after prior treatment with targeted agents could support a strategy of treatment with a targeted agent first followed by venetoclax-based salvage therapy. However, additional larger trials are needed to evaluate whether such a sequence of targeted agent first followed by venetoclax-based salvage therapy is indeed efficacious in patients who also had prior HMA exposure or whether upfront triplet therapies constitute the best approach. Furthermore, the additive myelosuppressive effects with triplet combinations need to be considered and may warrant dose adjustments.(17)
While this was a multicenter study with robust clinical and molecular data available for analysis, limitations inherent to the retrospective nature of this analysis apply. Due to the small sample size in some of the analyses, our statistical power to detect prognostic biomarkers of response and resistance to venetoclax-based therapy was limited. Finally, differences in prior and subsequent treatment patterns are likely affecting survival outcomes and duration of response and limit the comparison across sequencing strategies.
In summary, in this multicenter, retrospective cohort of AML patients having received prior treatment with FLT3, IDH1 or IDH2 inhibitors, we found that more than half of patients remained sensitive to venetoclax based therapy with an encouraging ORR of 56.8% and a median OS of 9.2 months. Patients with IDH1-mutant AML, in particular, had a high response rate to venetoclax-based salvage therapy, while presence of FLT3-ITD mutations was associated with a lower response rate.
Supplementary Material
Acknowledgements:
M.S. received funding from the MSKCC Clinical Scholars T32 Program under award number 2T32 CA009512-31. This work was funded by a Conquer Cancer Foundation Young Investigator Award (award number GC241610). A.D.G. received funding from an American Society of Hematology (ASH) Fellow Scholar Award in Clinical Research and a Conquer Cancer Foundation Young Investigator Award. Any opinions, findings, and conclusions expressed in this material are those of the author(s) and do not necessarily reflect those of the American Society of Clinical Oncology® or Conquer Cancer®. Research reported in this publication was supported by the NCI of the National Institutes of Health under Award Number P30 CA016359 and P01 CA23766, and Cancer Center Support Grant/Core Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748) The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Statement:
There was no dedicated funding associated with this manuscript
Footnotes
Conflict of interest disclosure: R.M.S. participated in advisory boards, and/or had a consultancy with and received honoraria from Bristol Myers Squibb and Gilead Sciences, Inc; divested equity interest in Curis Oncology. A.D.G. received research funding from Celularity, ADC Therapeutics, Aprea, AROG, Pfizer, Prelude, and Trillium; received research funding from and served as a consultant for Aptose and Daiichi Sankyo; served as a consultant and member of advisory committees for Astellas, Celgene, and Genentech; received research funding from, served as a consultant for, and was a member of advisory committees for AbbVie; and received honoraria from Dava Oncology. A.M.Z. received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene/Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. A.M.Z. participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, and Tyme. A.M.Z. served on clinical trial committees for Novartis, Abbvie, Geron and Celgene/BMS. A.M.Z. received travel support for meetings from Pfizer, Novartis, and Cardiff Oncology. E.M.S. received research funding from Bayer; was a consultant for Amgen, AbbVie, Seattle Genetics, and Biotheryx; served as a consultant and received research funding from Syndax; was a member of the Board of Directors or advisory committee for PTC Therapeutics and Syros; served as a consultant and was member of the Board of Directors or advisory committee for Astellas Pharmaceutical, Agios Pharmaceuticals, and Genentech; served as a consultant, received research funding, and was a member of the Board of Directors or advisory committee for Daiichi-Sankyo, Celgene Pharmaceuticals, and Novartis; and is a current equity holder in privately held Auron Therapeutics. G.M. received research funding from Merck, served on the scientific board for BMS, and Abbvie, and participated as a speaker for Abbvie. A.S. served on the speakers bureau for Amgen. D.J.D. had a consultancy with Abbvie Amgen, Autolus, Blueprint, Forty-Seven, Glycomimetrics, Inctye, Jazz, Kite, Novartis, Pfizer, Servier, and Takeda. D.J.D. received grant/research funding Abbvie, Novartis, Blueprint, Glycomimetrics. R.M.S. received personal fees from Abbvie, Actinium, Agios, Astellas, Biolinerx, Celgene, Daiichi-Sankyo, Elevate, Gemoab, Janssen, Jazz, Macrogenics, Novartis, OncoNova, Syndax, Syntrix, Syros, Takeda, Trovagene, BerGenBio, Foghorn Therapeutics, GlaxoSmith Kline, Aprea, Innate, Amgen, BMS, Boston Pharmaceuticals, Kura Oncology, and Epizyme. R.M.S. received grant funding from Abbvie, Agios, Arog, and Novartis. IA serves on advisory boards for Amgen, Kite pharmaceuticals, AbbVie, JAZZ and Agios Pharmaceuticals, and is a consultant for Pfizer, Autolus Therapeutics and Amgen, and received research support by MacroGenics and Abbvie. B.J.B. served on the advisory board for Oncovalent. MS is a member of the advisory board for Novartis and is consulting for Curis Oncology, Haymarket Media and Boston Consulting.
Data availability statement:
Original data can be requested from the corresponding author
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Data Availability Statement
Original data can be requested from the corresponding author