Abstract
A metronomic, low-dose schedule of decitabine and venetoclax was safe and effective in myeloid malignancies with few dose reductions or interruptions in an older diverse population. Median overall survival for patients with acute myeloid leukemia and a TP53-mutation was 16.1 and 11.3 months, respectively. This trial was registered at www.clinicaltrials.gov as #NCT05184842.
When an entirely new class of drug such as BCL2 inhibitors enters practice, optimizing benefits and reducing risks typically require exploration beyond registration trials. Goldfinger et al report on a prospective phase 2 clinical trial testing weekly dosing of venetoclax and decitabine in first-line therapy of patients with acute myeloid leukemia or high-risk myelodysplasia. The regimen is tolerable, with 90% of patients able to receive continuous therapy without dose reductions or delays. Preliminary efficacy is encouraging, but prospective randomized comparison to standard regimens is required to understand the potential place of this regimen.
TO THE EDITOR:
Venetoclax (Ven) added to the hypomethylating agent (HMA) azacitidine (Aza) or decitabine is now a standard of care for older patients with acute myeloid leukemia (AML), and early phase trials have also shown benefits in high-risk myelodysplastic syndrome (HR-MDS).1,2 However, the currently approved dosing schedule of HMA + Ven, consisting of 5 to 7 days of an HMA with 28 daily doses of Ven, causes severe myelosuppression such that the vast majority of patients require treatment delays or dose reductions, and approximately 30% require treatment discontinuation.3 As once-weekly low-dose decitabine has shown to be effective in myeloid malignancies4,5 and a single dose of Ven given concomitantly with HMA has been shown to reverse HMA resistance,6 we tested once-weekly doses of Ven and low-dose decitabine as a potentially effective, minimally toxic regimen.
In this phase 2 trial, patients received a once-weekly dose of decitabine (0.2 mg/kg subcutaneously) and 1 dose of Ven (400 mg orally) on days 1, 8, 15, and 22 of a 28-day cycle. The induction period consisted of 3 cycles (12 weeks), followed by weekly maintenance. Bone marrow was assessed every 12 weeks. Primary end point was the percentage of participants who were able to continue treatment without dose interruptions or delays during the induction phase (weeks 1-12). The study was designed according to Good Clinical Practice Guidelines and the Declaration of Helsinki.
Between April 2022 and September 2023, 31 patients (21 with AML, 6 with HR-MDS, 2 with MDS or myeloproliferative neoplasm, and 2 with chronic myelomonocytic leukemia were enrolled) (Table 1). Patients with AML were not candidates for induction chemotherapy due to age ≥75 in 16 patients (74%), and 5 were felt to be too frail and unfit. Nearly half of the patients were from diverse racial and ethnic backgrounds reflecting the demographics of an inner-city hospital in the Bronx, New York City. The median age was 73 (52-87) years. Of the 21 patients with AML, 14 (67%) had ELN-2022 adverse risk, 6 (29%) had TP53-mutated disease, 7 (33%) had complex cytogenetics, and 8 (38%) had secondary AML. All 6 patients with HR-MDS had TP53-mutated disease with 5 having complex cytogenetics (supplemental Figure 1, available on the Blood website).
Table 1.
Baseline demographic and clinical characteristics of the patients
| Characteristics | Cohort |
Total (n = 31) | ||
|---|---|---|---|---|
| AML (n = 21) | HR-MDS (n = 6) | Other∗ (n = 4) | ||
| Median age (range), y | 75 (62-83) | 61.5 (52-87) | 67.5 (62-70) | 73 (52-87) |
| Age >75 y, n (%) | 9 (43) | 1 (17) | 0 (0) | 10 (32) |
| Sex, n (%) | ||||
| Male | 10 (48) | 2 (33) | 2 (50) | 14 (45) |
| Female | 11 (52) | 4 (67) | 2 (50) | 17 (55) |
| ECOG PS, n (%) | ||||
| 0 | 7 (33) | 4 (67) | 2 (50) | 13 (42) |
| 1 | 10 (48) | 2 (33) | 2 (50) | 14 (45) |
| 2 | 4 (19) | 0 (0) | 0 (0) | 4 (13) |
| AML type, n (%) | ||||
| De novo | 15 (71) | |||
| Secondary or t-AML | 6 (29) | |||
| Bone marrow blast count, n (%) | ||||
| <30% | 13 (62) | |||
| ≥30% | 8 (38) | |||
| ELN, n (%) | ||||
| Adverse risk | 14 (66) | |||
| Intermediate risk | 6 (29) | |||
| Favorable risk | 1 (5) | |||
| R-IPSS, n (%) | ||||
| High | 1 (17) | |||
| Very high | 5 (83) | |||
| Somatic mutations, n (%) | ||||
| IDH1 or IDH2 | 6 (29) | 6 (29) | ||
| NPM1 | 1 (5) | 1 (5) | ||
| FLT3 ITD | 2 (10) | 2 (10) | ||
| N/KRAS | 4 (19) | 4 (19) | ||
| TP53 | 5 (24) | 6 (100) | 11 (36) | |
| Baseline transfusion dependence, n (%) | ||||
| Red cells and/or platelets | 11 (53) | 5 (83) | 2 (50) | 18 (58) |
| Race, n (%) | ||||
| White | 12 (57) | 4 (66) | 0 (0) | 16 (52) |
| Black | 4 (19) | 1 (17) | 1 (25) | 6 (19) |
| Hispanic | 4 (19) | 1 (17) | 2 (50) | 7 (23) |
| Asian | 1 (5) | 0 (0) | 1 (25) | 2 (6) |
ECOG PS, Eastern Cooperative Oncology Group performance status; ELN, European leukemia index; R-IPSS, revised international prognostic scoring system; t-AML, therapy-related AML.
Patients with MDS/myeloproliferative neoplasm, chronic myelomonocytic leukemia, and myelofibrosis.
At the cutoff date of 18 January 2024, the median time on study for the entire cohort was 3.9 months (range, 1.6-17.03), and the median duration of follow-up was 12.6 months (95% confidence interval [CI], 8.6-17.5). The primary end point of being able to continue treatment without dose interruptions or delays during the 12-week induction was achieved in 28 of 31 (90%) of patients, with 3 patients having missed just 1 dose during induction and none requiring any dose reductions. Five patients did not complete the 12-week induction (all 5 had AML): 2 patients had disease progression, 1 was lost to follow-up, 1 withdrew consent, and 1 patient could not resume therapy after developing bone marrow aplasia thought to be immune related. Postinduction, only 2 patients required a dose interruption (2 of 31; 7%), and no patient required dose reductions.
The median follow-up for patients with AML (≥20% blasts) was 12.2 months (95% CI, 8.1 to not reached [NR]). In the intention-to-treat (ITT) population for patients with AML (n = 21), the overall response rate (ORR) (complete response [CR] + complete response with incomplete blood count recovery [CRi] + morphologic leukemia-free state [MLFS]) was 57% (12 of 21), and the median overall survival (OS) was 16.1 months (95% CI, 11.3 to NR) (Table 2 and supplemental Figure 2). In the ITT per protocol analysis of 19 patients with AML (excluding 2 patients not evaluable), an overall leukemia response rate (CR + CRi + MLFS) of 63% (12 of 19) was achieved, with 10 patients (53%) achieving a CR, 1 having CRi, and 1 having MLFS for a CR/CRi rate of 58%. Of the responding patients, 9 of 19 (47%) achieved measurable residual disease (MRD) negativity by multiparameter flow cytometry, and the median duration of response (DOR) was 5.5 months (supplemental Figure 3).
Table 2.
Response rate and early mortality for patients with MDS and AML
| Characteristics | Cohort |
||
|---|---|---|---|
| AML ITT (n = 21), n (%) | AML ITT-PP (n = 19),∗ n (%) | HR-MDS (n = 6), n (%) | |
| Overall survival, mo | 16.1 | 9.6 | |
| ORR (CR + CRi + MLFS) ORR (CR + mCR) |
12 (57) | 12 (63) | 4 (67) |
| CR/CRi | 11 (52) | 11 (58) | |
| Best response | |||
| CR | 10 (48) | 10 (53) | 3 (50) |
| mCR | 1 (17) | ||
| CRi | 1 (5) | 1 (5) | 2 (33) |
| MLFS | 1 (5) | 1 (5) | |
| No response | 9 (43) | 7 (37) | |
| MRD− (hematologics flow) | 9 (43) | 9 (47) | 4 (67) |
| Median duration of response, mo (range)∗ | 5.5 (3.9 to NR) | 5.2 (4.8 to NR) | |
| Mortality rate at 8 wk | 0 | 0 | 0 |
ITT-PP, ITT per protocol.
DOR was evaluated from the time of response after 12 weeks of induction until progression.
The median follow-up for the MDS cohort was 8.6 months (95% CI, 6.9 months to NR), with an ORR (CR + marrow CR [mCR]) of 67% with 3 patients achieving CR and 1 achieving mCR. The median OS for the HR-MDS cohort was 9.6 months (95% CI, 8.5 to NR), and the median DOR was 5.2 months. The median OS in the 10 evaluable patients with TP53-mutated disease (6 HR-MDS and 4 AML) was 11.3 months (95% CI, 8.5 to NR). Of the 18 patients who were transfusion dependent, 11 (61%) became transfusion independent. There were no deaths during the first 8 weeks of starting therapy. Of 31 patients, 16 (52%) had a grade 3 treatment-emergent adverse event, and 1 patient experienced a grade 4 treatment-emergent adverse event. There were no therapy-related fatalities.
In this prospective study, 90% of patients were able to receive continuous therapy without dose reductions or delays. There were no treatment-related mortalities, with a 100% 60-day survival. By contrast, in the VIALE-A trial, 72% of patients required dose interruptions or delays, 25% of patients had treatment-related deaths,1,3 and a recent real-world experience using HMA + Ven in AML reported a 60-day mortality of 19%.7 In addition, this trial is, to our knowledge, the largest prospective experience in a predominant minority elderly population with myeloid malignancies and strengthens its applicability to real-world patients.
The need for a less toxic HMA + Ven backbone is important, as it is clear that HMA + Ven by itself is not a cure and further progress will require the addition of a third agent (triplet therapy). Recent trials using triplets have been hampered by toxicity from high rates of myelosuppression.8,9 Metronomic weekly low-dose decitabine + Ven may offer a safety margin for the incorporation of additional agents without incurring excess hematologic toxicities.
In terms of efficacy, although the CR/CRi rate for patients with AML was 58%, and lower than the 66% CR/CRi reported in the VIALE-A trial, the median OS in our AML cohort was 16.1 months, which is similar to 14.7 months in the VIALE-A trial. In addition, when only including VIALE-A-eligible patients, the CR/CRi rate was 61%. The potential improvement in OS in our cohort is likely related to a decrease in treatment-related morbidity and mortality with a noncytotoxic approach. As a result, 100% of relapsed patients and 6 of 9 nonresponders (67%) were able to receive additional therapy postprogression. In contrast, in the VIALE-A trial, only 14.6% received second-line therapy.3 It is also important to note that there have now been at least 6 published real-world experiences using HMA + Ven as prescribed in VIALE-A, and all have been consistent in showing inferior OS, ranging between 8.5 and 12.5 months.7,10, 11, 12, 13, 14
Long-term follow-up from VIALE-A continues to show that achieving CR and MRD− remission is a predictor for improved OS.3 In our AML cohort, the CR rate of 53% and MRD− rate of 82% in patients achieving CR/CRi (9 of 11) compares favorably with standard HMA + Ven where CR and MRD− rate in responders were 38.8% and 42%, respectively. The observed median OS of 11.3 months for patients with TP53-mutated disease also compares favorably with the 5.2 months OS seen with trials of the standard HMA + Ven regimen, and even more so with the dismal OS of 2.5 months reported in real-world settings.
The major limitations of our study are the relatively small numbers and implementation at a single academic center. This study does, however, provide evidence that metronomic dosing is effective with a much improved safety profile. The activity of the present regimen should be formally compared with VIALE-A. Importantly, our regimen can be continuously dosed, and the lack of hematopoietic toxicity allows for a strong backbone to be tested in future trials.
Conflict-of-interest disclosure: A.S. received research funding from Kymera Therapeutics; advisory board fees from Gilead Sciences, Rigel Pharmaceuticals, and Kymera Therapeutics; consultancy fees from Janssen Pharmaceuticals; and honoraria from National Association of Continuing Education and PeerView. Y. Saunthararajah holds equity and board positions in EpiDestiny and Treebough Therapies and has patents: “Compositions comprising decitabine and tetrahydrouridine and uses thereof” (US-9259469-B2; US-9265785-B2; US-9895391-B2) and “Compositions containing decitabine, 5-azacitidine and tetrahydrouridine and uses thereof” (US-11376270-B2) and “Antitumor derivatives for differentiation therapy” (US-9926316-B2). K.G. receives research funding from iOnctura SA and ADC Therapeutics. B.A.J. is a consultant/advisor for AbbVie, Bristol Myers Squibb, Daiichi Sankyo, Gilead, GlycoMimetics, Kymera, Kura, Rigel, Schrodinger, Syndax, and Treadwell; is a member of the protocol steering committee for GlycoMimetics and the data monitoring committee for Gilead; and has received travel reimbursement/support from Rigel and research funding to his institution from AbbVie, Amgen, Aptose, Arog, Biomea Fusion, Bristol Myers Squibb, Celgene, F. Hoffmann-La Roche, Forma, Forty-Seven, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Jazz, Kymera, Loxo, Pfizer, Pharmacyclics, and Treadwell. M.K. has received research funding from AbbVie, Allogene, AstraZeneca, Genentech, Gilead, ImmunoGen, MEI Pharma, Precision, Rafael, Sanofi, Stemline; advisory/consulting fees for AbbVie, AstraZeneca, Auxenion, Bakx, Boehringer, Dark Blue Therapeutics, F. Hoffman La-Roche, Genentech, Gilead, Janssen, Legend, MEI Pharma, Redona, Sanofi, Sellas, Stemline, Vincerx; stock options or royalties from Reata Pharmaceutical (IP), Patent: Novartis, Eli Lilly, Reata Pharmaceutica. A.V. received research funding from Prelude, Bristol Myers Squibb, GlaxoSmithKline, Incyte, Medpacto, Curis, and Eli Lilly; is a scientific advisor for Stelexis, Novartis, Acceleron, and Celgene; receives honoraria from Stelexis and Janssen; and holds equity in Stelexis and Throws Exception. The remaining authors declare no competing financial interests.
Acknowledgments
This study was supported in part by a gift from Izzy Englander and a grant from the Leukemia and Lymphoma Society.
Authorship
Contribution: M.G. designed and performed research and collected, analyzed, and interpreted data and wrote the manuscript; I.M. designed and performed research, analyzed and interpreted data, and reviewed and edited the manuscript; A.S., Y. Saunthararajah, K.G., R.A.S., N.S., L.C.S., B.A.J., D.L.C., M.K., and A.V. performed research, analyzed and interpreted data, and reviewed and edited the manuscript; N.K., D.L., B.R., R.G., M.C., S.K., Y. Shi, and I.B. performed research and analyzed and interpreted data; K.P. contributed analytical tools, collected, analyzed, and interpreted data, and performed statistical analysis; X.X. designed research, contributed analytical tools, analyzed and interpreted data, and performed statistical analysis; A.M., A.D., K.F., and J.A.V. performed research and collected, analyzed, and interpreted data; E.J.F. designed and performed research and reviewed and edited the manuscript.
Footnotes
A.V., E.J.F., and M.K. contributed equally to this manuscript.
For original data, please contact mgoldfin@montefiore.org.
The online version of this article contains a data supplement.
Supplementary Material
References
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