Addition of Venetoclax to Intensive Chemotherapy Yields Durable Responses in Younger Patients With High-Risk AML

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Longer follow-up of a phase II study of venetoclax combined with cladribine, idarubicin, and cytarabine (CLIA) as a front-line induction regimen for younger patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) shows a pattern of durable efficacy consistent with earlier reports, investigators reported at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition.1 The safety and activity are encouraging, and more studies will be conducted.

At a median follow-up of 22.5 months, the median duration of response was not yet reached in patients treated with this regimen. Estimated 12- and 24-month duration of response rates are 82.6% and 80.3%, respectively, in this high-risk group of younger patients. Median event-free survival was not reached.

“The goal of modifications to standard intensive therapy in AML is to improve activity, safety, and durability of response; to reduce early mortality; and to allow for transplant if indicated,” said lead author Patrick K.
Reville, MD, MPH
, Instructor in the Advanced Scholar Program at The University of Texas MD Anderson Cancer Center, Houston.

Patrick K. Reville, MD, MPH

Patrick K. Reville, MD, MPH

The CLIA regimen has improved induction response rates from 50% to 60% to the 70% to 80% range. Overall survival has also improved. Despite this, we need better induction regimens,” Dr. Reville told listeners.

“In this phase II study, the addition of venetoclax to CLIA in younger high-risk patients was highly effective. We found a composite complete response rate of 96%; a complete response rate of 85%; and a measurable residual disease [MRD]-negative rate of 90%. At a median follow-up of 25.3 months, the 24-month event-free survival was 68%, and median overall survival has not been reached. The 24-four-month overall survival is 71%,” he told the audience.

Speaking to the rationale for adding venetoclax, Dr. Reville said: “With the addition of venetoclax, we saw much higher rates of MRD-negative responses, deeper responses, and we were able to transition more patients to transplant with venetoclax. Our goal is to get patients MRD-negative prior to transplant.”

Study Details

To date, the phase II study has enrolled 67 patients with previously untreated high-risk AML (n = 60) or high-risk MDS (> 10 blasts or IPSS [International Prognostic Scoring System] > 2; n = 4). Three patients had a mixed phenotype. Patients were aged 65 or younger (median age, 48 years), had an Eastern Cooperative Oncology Group performance status less than 2, had received no previous therapy with venetoclax, and had adequate organ function. Patients with acute promyelocytic leukemia and core binding factor were excluded from the study. Approximately half of patients underwent emergency cytoreductive therapy.

A total of 55% had diploid cytogenetics; 18% had complex adverse cytogenetics. Ten percent had secondary AML, 8% had therapy-related AML, and 5% had treated secondary AML. European Leukemia Network (ELN) risk was classified as favorable in 25%, intermediate in 35%, and adverse in 40% of patients.

CLIA was given as induction and consolidation therapy. Venetoclax at 400 mg daily, without ramp-up, was given on days 2 to 8 with dose modifications for CYP3A4 inhibition. All patients received antimicrobial prophylaxis.

The primary endpoint of composite complete response rate was achieved in 96% of patients (complete response in 85% of patients plus complete response with incomplete hematologic recovery in 10%). At first response assessment by flow cytometry, 77% of patients achieved MRD negativity.

Patients received a median of two
venetoclax courses, and 70% of patients went on to receive transplant. One patient died at 4 weeks, and two died at 8 weeks.

Durable Response Rates

“Responses were preserved across key subgroups,” Dr. Reville reported. Composite complete response rates were 94% in ELN favorable-risk (n = 16), 95% in ELN intermediate-risk (n = 22), and 96% in ELN adverse-risk patients (n = 25); and 97% in patients with diploid cytogenetics (n = 36), 100% in those with other intermediate cytogenetics (n = 16), and 96% in those with complex/adverse cytogenetics (n = 12).

In patients with TP53 mutations (n = 3), the response rate was 67%. In patients with NPM1-mutated disease (n = 23), response rate was 96%. In those with FLT3-ITD–mutated disease (n = 14), response rate was 93%.

“Responses were durable,” Dr. Reville added.

Survival Outcomes

At 24 months, 71% of patients were leukemia-free, and 86% were leukemia-free at 12 months. Median overall survival was not yet reached at the time of the presentation.

“The event-free survival is highly encouraging and is similar in patients with FLT3 mutations and those who are FLT3 wild-type. In half the patients, a FLT3 inhibitor was added. Some patients had prolonged cytopenia with this regimen, and we no longer add a concomitant FLT3 inhibitor,” he said. “In patients with low allelic burden FLT3-ITD, we saw 100% response rate without the addition of a FLT3 inhibitor.”

“Patients who were classified as ELN favorable-risk experienced great outcomes. ELN intermediate- and adverse-risk patients had similar outcomes, which appeared to show improvements compared with historical expectations. Median event-free survival and overall survival were reached only in intermediate-risk patients,” he continued.

A landmark analysis at the median time to allogeneic stem cell transplantation of 3.3 months showed that receipt of transplant at first remission was significantly associated with improved overall survival (P = .036).

Adverse Events

The most common adverse events were infections; 73% developed febrile neutropenia, 78% had alanine transaminase elevations, and 58% had fatigue. More than 20% of patients experienced nausea, mucositis, and aspartate transaminase elevations. There were four patients who died during remission from infections while cytopenic.

Blood cell count recovery was not prolonged during cycles 1 and 2, but it was faster with cycle 1, he noted. For most patients, blood cell counts recovered within 5 weeks.

Discussion Points

During the discussion following his presentation, Dr. Reville was asked what happens to patients who relapse after venetoclax plus CLIA. “Luckily, relapses were uncommon in this study. At MD Anderson, we have access to many clinical trials, so for relapse post venetoclax, the best option [for our patients] is a clinical trial,” he said.

He explained that cladribine was selected for this study instead of fludarabine as the choice of purine analog added to the 7+3 regimen. “Cladribine is the only drug that improved survival in this setting,” Dr. Reville said.

“Most patients received two or three cycles of CLIA plus venetoclax. For those who didn’t go to transplant, we push toward maintenance, especially in patients who are indicated for transplant but for one reason or another can’t go to transplant,” he noted. 

DISCLOSURE: Dr. Reville reported no conflicts of interest.


1. Reville P, Kantarjian HP, Borthakur G, et al: Venetoclax combined with cladribine, idarubicin, cytarabine (CLIA) as induction therapy in patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome. 2022 ASH Annual Meeting and Exposition. Abstract 709. Presented December 11, 2022.

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