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Dose-Adjusted VEN-HMA Regimens Safe, Effective in Very Old Patients With AML

July 31, 2024

August 2024

Leah Lawrence

Leah Lawrence is a freelance health writer and editor based in Delaware.

A significant portion of patients in their 80s and 90s with acute myeloid leukemia (AML) can live longer if they are treated with dose-modified venetoclax (VEN) plus a hypomethylating agent (HMA), according to the results of a retrospective study published in Blood Neoplasia.

The analysis of patients aged 80 or older showed that more than half responded to receipt of a VEN-HMA regimen, and about one-quarter had prolonged survival.

“Patients of very advanced age in their 80s or 90s are understandably perceived to be, and may indeed be, frailer with more age-related end-organ dysfunction than younger patients in their late 60s or 70s,” said author Justin Watts, MD, of University of Miami Sylvester Comprehensive Cancer Center. “We showed that venetoclax plus an HMA is safe, feasible, and has high response rates and can extend survival even in octo- and nonagenarians with AML.”

Dr. Watts and colleagues looked at outcomes for 154 patients aged 80 or older with AML who received VEN-HMA between March 2015 and April 2022. Median age of the patients was 82. More than half (53%) of patients had European Leukemia Net 2017 adverse-risk AML; another third had intermediate-risk disease.

The starting dose of VEN-HMA was determined by the treating physicians and accounted for CYP3A4 drug interaction dose adjustments. The majority of patients (67%) received the standard dose and schedule of venetoclax (400 mg [78%] for 28 days [77%]) and HMA (azacitidine 75 mg/m2 for seven days [95%] and decitabine 20 mg/m2 for five days [100%]).

Median follow-up was 7.7 months. Twenty-three percent of patients remained in remission, and 20% were still on VEN-HMA at last follow-up. Composite complete remission (CRc) rate was 57% overall and 73% for patients with newly diagnosed AML without prior myelodysplastic syndromes (MDS). Response rates were lower among patients with prior HMA treatment.

Median overall survival (OS) was 8.1 months overall, but it was prolonged at 13.2 months among patients who achieved CRc compared with 4.1 months in non-responders (p<0.001).

“About 25% of the 154 patients on study had prolonged survival of two years or more, with some in sustained remission for several years, and about another 25% of patients on study achieved remission with clear clinical benefit and more time with their families,” Dr. Watts said.

Patients with newly diagnosed AML without a prior MDS diagnosis did exceptionally well given their age, especially if they achieved an initial response, and patients with NPM1-mutated AML did remarkably well with a CRc rate of 82% and median OS not reached if they were otherwise favorable risk.

FLT3-ITD and RAS pathway mutations did not confer worse survival, Dr. Watts noted. Patients with FLT3-ITD-mutated disease had numerically longer OS compared with FLT3-ITD wild-type disease (median 12.2 vs. 7.8 months), and those with any RAS pathway mutation had similar survival to those without a RAS pathway mutation (median 9.1 vs. 7.8 months).

“Patients with a prior MDS diagnosis and/or TP53 mutation did poorly, and in such patients, a dose reduction — particularly in venetoclax duration — should be strongly considered as soon as the first cycle,” Dr. Watts said.

Notably, all patients who responded benefited from a reduction in venetoclax duration to 14 days. A landmark analysis from time CRc was achieved showed that receipt of venetoclax for 14 days or fewer had an improved OS, with a median of 24.0 months.

Finally, multivariable analysis showed that in addition to TP53 mutation (hazard ratio [HR] = 1.96), prior MDS (HR=1.72), intermediate risk (HR=3.56), adverse risk (HR=3.31), and ECOG performance status of 3 or greater were associated with inferior OS (HR=3.57; 95% CI 1.35-9.45; p=0.010). Dr. Watts noted that the use of the VEN-HMA regimen is a “a patient-by-patient decision and also depends on patient preference and fitness, family and social support, and the underlying AML subtype and genetic classification.”

These patient-by-patient decisions may include dose reductions and cycle extensions to help ensure tolerability over the long term, the researchers noted in their discussion. As an example, patients in this study who achieved CRc had a median final dose and duration of 200 mg venetoclax for 21 days every 35 days. Additionally, receipt of a shorter duration of venetoclax did not affect OS.

One limitation of the analysis was the relatively short median follow-up of 7.7 months, which Dr. Watts noted was limited due to both the retrospective nature of the study and the advanced age of patients, a large proportion of whom had adverse-risk disease. Notably, 35% of patients in the study had AML with a TP53 mutation and/or complex karyotype, which was associated with very short survival. Median follow-up was notably longer in surviving patients (18.6 months), highlighting the durability of outcomes in a subset of patients.

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Madarang E, Lykon J, Zhao W, et al. Venetoclax and hypomethylating agents in octo- and nonagenarians with acute myeloid leukemia [published online ahead of print, 2024 May 9]. Blood Neoplasia. doi: 10.1016/j.bneo.2024.100016.

Perspectives

The landmark VIALE-A study established VEN-HMA as the standard of care for patients with newly diagnosed AML who are not eligible for intensive chemotherapy.1 Intensive chemotherapy is generally not administered in those older than 80, so unless patients are unable to tolerate VEN-HMA because of frailty or have other targeted mutations, this combination is generally the go-to regimen for older adults.

In VIALE-A, the median age was 76 (range = 49-91), and 61% were 75 years or older, so the oldest-old individuals were included. Nonetheless, we know that patients enrolled on clinical trials are generally healthier than those not on trials. Therefore, studies evaluating regimens in the real world are important. In this study by Watts et al. of older patients (median = 82 years, range = 80-92) treated with VEN-HMA, the CRc rate was 57% in the whole sample, 73% among patients with newly diagnosed AML without prior MDS, and 48% in those with prior MDS (65% in VIALE-A). Median OS was 10.2 and 6.4 months, respectively (14.7 months in VIALE-A). Early mortality appeared to be mostly due to disease progression.

Some retrospective studies have suggested that initial reduction of venetoclax duration (7-21 days) may not influence outcomes.2–4 This study supported that those receiving 14 to 21 days of venetoclax had similar response to those receiving 28 days, though those receiving seven or fewer days had lower response. On multivariate analysis, 14 or fewer days (vs. >14 days) of venetoclax was associated with better OS (HR=2.47; p<0.001). What is most interesting was that following achievement of CRc, those receiving 14 or fewer days of treatment had improved OS (median 24 vs. 8 months).

This study reinforces that reducing initial venetoclax duration is a reasonable approach (7-21 days; exact duration is still to be determined), especially for those who are frail. In addition, subsequent dose reductions are expected and should be considered, especially if patients have achieved remission. More studies are needed to determine how venetoclax should be dosed based on disease characteristics. An adapted approach based on frailty, disease characteristics, and patient preferences is a critical area for this population.

Kah Poh (Melissa) Loh, MBBCh BAO, MS
University of Rochester Medical Center
James P. Wilmot Cancer Institute
Rochester, New York

COI Disclosure: Dr. Loh has received honoraria from Pfizer and has served as a consultant for Pfizer and Seagan.

References

  1. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629.
  2. Karrar O, Abdelmagid M, Rana M, et al. Venetoclax duration (14 vs. 21 vs. 28 days) in combination with hypomethylating agent in newly diagnosed acute myeloid leukemia: comparative analysis of response, toxicity, and survival. Am J Hematol. 2024;99(2):E63-E66.
  3. Aiba M, Shigematsu A, Suzuki T, et al. Shorter duration of venetoclax administration to 14 days has same efficacy and better safety profile in treatment of acute myeloid leukemia. Ann Hematol. 2023;102(3):541-546.
  4. Willekens C, Chraibi S, Decroocq J, et al. Reduced venetoclax exposition to seven days of azacitidine is efficient in treatment-naïve patients with acute myeloid leukemia. Blood. 2022;140(Suppl 1):537-538.

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