Venetoclax for Older Patients With AML? 'Remarkable' Response

Alexander M. Castellino, PhD

January 18, 2018

Elderly patients with acute myeloid leukemia (AML) urgently need effective treatment options. Hope may be on the horizon for these patients after results from an early-phase trial showed "remarkable" results with a combination of venetoclax (Venclexta, AbbVie/Genentech) and hypomethylating agents (decitabine or  azacitidine).

The phase 1b study was published online January 12 in Lancet Oncology.

"Venetoclax in combination with hypomethylating agents seems to be a well-tolerated regimen with low early mortality and promising anti-leukaemic activity in elderly, treatment-naive patients with acute myeloid leukaemia," write the authors, headed by Daniel A. Pollyea, MD, from the University of Colorado School of Medicine, Aurora.

The study was conducted in 57 elderly patients with AML, median age of 75 years, for whom intensive chemotherapy was not an option.

The results show that 61% patients achieved complete remission (CR) or complete remission with incomplete marrow recovery (CRi). Nine of these patients went on to receive allogeneic stem cell transplants while in remission, suggesting that venetoclax with decitabine or azacitidine may provide a bridge to a curative strategy.  

This result is "remarkable for several reasons," comment Carsten Müller-Tidow, MD, and Richard F. Schlenk, MD, from Heidelberg University, Germany, writing in an accompanying commentary.  This 61% CR rate is double that seen in the past with single-agent decitabine or azacitidine in similar patients, and venetoclax has "manageable toxicity," they note.

Why Venetoclax Provides Promise for Elderly Patients With AML

Dr Müller-Tidow and Dr Schlenk also provide some background on why this study is noteworthy. In contrast to other hematologic malignancies, new treatment options for improving survival and the hope of a cure are not available for patients with AML, they point out.

 "Survival in this disease has remained dismal, especially in elderly patients with acute myeloid leukaemia not eligible for intensive induction chemotherapy," they write. And although hypomethylating medicines, such as azacitidine and decitabine, have shown substantial activity in older patients, they do not cure the disease. Less than 30% of patients achieve a clinical response, median survival is less than 1 year, and neither drug is curative, they point out.

This phase 1b study provides hope for patients who need one. While venetoclax has changed the treatment landscape for patients with chronic lymphocytic leukemia, single-agent venetoclax shows limited activity in AML, Dr Müller-Tidow and Dr Schlenk note. But they add that "based on the favourable toxicity profile of venetoclax, combination strategies are a very compelling option."

However, Dr Müller-Tidow and Dr Schlenk note that with the short follow-up of this study, the venetoclax combinations used in the study induce remissions in induction but are less effective in relapse prevention. "Cure of this disease requires the induction of clinical remission followed by further treatment strategies to maintain remission," they comment. They pointed out that several patients within the trial proceeded to transplantation, "the most effective post-remission treatment." For patients who are not candidates for this treatment strategy, other means of targeting relapse are needed.

"Venetoclax might ultimately be an important part in a comprehensive treatment concept of acute myeloid leukaemia with other drugs and treatment approaches," Dr Müller-Tidow and Dr Schlenk write.

Details of the Study

The study was conducted in newly diagnosed patients with histologically confirmed AML who were age 65 years or older, had a projected life expectancy of at least 12 weeks, and were ineligible for standard induction chemotherapy as determined by the investigator.

Patients with favorable-risk cytogenetics or active central nervous system involvement were excluded.

The study included a dose-escalation phase and enrolled three groups (A to C) of patients — each group with four cohorts of at least three patients in each. Oral administration of venetoclax started on day 2, with a mandated daily ramping in venetoclax dose to the final dose for that cohort. In cohorts 1 to 4, venetoclax was started at a dose of 20 mg, 50 mg, 100 mg, and 100 mg, respectively, on day 2, to reach the final dose of 400 mg, 800 mg, 800 mg, and 1200 mg on day 6. The final dose was then provided for the rest of the 28-day cycle.

In group A, decitabine 20 mg/m2 was given intravenously on days 1 to 5 of each cycle. In group B, azacitidine 75 mg/m2 was given intravenously or subcutaneously on days 1 to 7 of each cycle. Treatment continued until disease progressed or intolerable side effects occurred.

Group C patients were enrolled for a drug-drug interaction study, the details of which have already been published (Clin Ther. 2017;39:359-367). In this group, the study evaluated the combination of venetoclax plus posaconazole, an antifungal agent, and decitabine.

All patients received prophylaxis against tumor lysis syndrome, starting 72 hours before venetoclax dosing. Tumor lysis syndrome was monitored before dosing and 6 hours and 12 hours after dosing for each dose escalation and 24, 48, and 72 hours after the administration of the maximum venetoclax dose. All patients also received supportive care measures and were able to receive prophylactic nonazole antifungal agents as per institution protocol.

Primary endpoints were safety, pharmacokinetics, and determining the phase 2 dose of venetoclax.

Venetoclax Safety in Elderly Patients With AML

Of 57 patients enrolled, 45 were in groups A (n = 23) and B (n = 22). Twelve patients were in group C.

Median follow-up for the total trial population was 12.4 months. Median age was 75 years, 21 (37%) patients had poor-risk cytogenetics, and 8 (14%) had an antecedent hematologic disorder.

Venetoclax was well tolerated in this elderly AML patient population, the authors report, with low early mortality. Patients in groups A and B showed similar safety profiles.

The 30-day and 60-day mortality rates were 7% and 16%, respectively, and were associated with causes such as sepsis, bacteremia, lung infection, and respiratory failure. According to Dr Pollyea and colleagues, these rates are lower than would be expected in an age-matched population receiving intensive therapy and similar to those seen with decitabine or azacitidine monotherapy.

Thrombocytopenia (47%), febrile neutropenia (42%), and neutropenia (40%) were the most common grade 3/4 adverse events, which were associated with dose interruptions in 51% of patients. Venetoclax dose reductions, also due to treatment-emergent adverse events, were reported in 17%, 14%, and 8% of patients in groups A, B, and C, respectively.

Grade 1/2 gastrointestinal events and cytopenias were the most common treatment-emergent adverse events in all groups. Of note, patient cohorts receiving 1200 mg venetoclax had frequent gastrointestinal events, including nausea (82%), diarrhea (64%), constipation (55%), and vomiting (45%), which restricted continuous dosing and led to dose reductions and dose interruptions.

No laboratory or clinical events of tumor lysis syndrome, such as those experienced with venetoclax in chronic lymphocytic leukemia, were seen in this study. This potential risk was mitigated by the requirement that all patients have a white cell count of 25 × 109/L. In addition, no dose-limiting toxicities were reported. Although the maximum tolerated dose was not reached, the experience with the 1200-mg dose lead to recommending venetoclax 800 mg as the phase 2 dose.

The drug-drug interaction study showed that the concomitant use of venetoclax (a CYP3A substrate) and posaconazole (a strong CYP3A inhibitor) increased venetoclax maximum plasma concentration by about seven times. Hence, in patients receiving prophylaxis with posaconazole, the venetoclax dose needs to be reduced by about 75%, the authors note.

However, patients in groups A and B did not receive antifungal azoles but alternate antifungal drugs, which are not CYP3A inhibitors and are also effective.

Efficacy of Venetoclax in Elderly Patients With AML

Clinical efficacy endpoints were similar across all groups. CR and CRi rates were 61% for group A, 59% for group B, and 67% for group C. Median time to CR/CRi was 1.0, 1.2, and 0.9 months for groups A, B, and C, respectively.

Similar rates were reported for patients with AML who had intermediate-risk (66%) and poor-risk (52%) cytogenetics. Responses were also reported for patients.   

Survival was not assessed separately for group C. Median overall survival was 12.3 months for all patients, 15.2 months for groups A and B, 15.2 months for group A, and 14.2 months for group B.

Best Partner for Venetoclax Still to Be Determined

This is the first study to assess the efficacy and safety of venetoclax in combination with decitabine or azacitidine in elderly patients with newly diagnosed AML. The study continues with an expansion phase, so more patients will be treated with these venetoclax combinations.

However, Dr Müller-Tidow and Dr Schlenk point out that venetoclax is also being evaluated with other drugs for AML, such as cytarabine.

They contend that venetoclax is emerging as a serious contender for the treatment of AML. "Ultimately, the best treatment approach still needs to be established," they conclude.    

The editorialists also comment that for physicians who treat elderly patients with AML, the choice between intensive chemotherapy and palliative treatment is important. "Effective induction of clinical remission without the toxicity of intensive chemotherapy might eventually pave the way to overcome this dualistic approach and shift the focus on subsequent treatment strategies to eradicate leukaemic stem cells," they write.

The study was funded by AbbVie and Genentech. Financial disclosures for all authors appears at the end of the paper. Dr Pollyea reports funding from Pfizer and Agios and has been on advisory boards for Pfizer, Curis, Takeda, Servier, Celgene, Jazz, Gilead, Pharmacyclics, and Alexion. Several study authors are employees of AbbVie. Dr M ü ller-Tidow reported receiving grants, personal fees, and nonfinancial support from Celgene. Dr Schlenk reported grants from AstraZeneca, PharmaMar, Amgen, and Chugai; grants and personal fees from Novartis and Pfizer; and personal fees from Janssen, Daiichi Sankyo, and AROG.

Lancet Oncol. Published online January 12, 2018. Abstract, Comment

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