The approval of venetoclax in combination with hypomethylating agents (HMAs) or low-dose cytarabine provides significant benefit for older adults with newly diagnosed acute myeloid leukemia (AML). But the therapy also comes with a specific set of challenges that clinicians are learning to tackle.

Venetoclax (Venclexta, AbbVie/Genentech) has been a “huge medical breakthrough and a much-welcomed addition” to AML therapy, one of the most aggressive leukemias, said Sara Kim, PharmD, BCOP, a senior clinical oncology pharmacy specialist at Northwell Health, in New York. With the lowest survival rate for all leukemia types, AML is particularly deadly in older populations: Among patients 75 years of age or older, the five-year overall survival (OS) rate is only 2.7%, compared with 10.8% among those diagnosed between 65 and 74 years of age and 26.3% among those aged 50 to 64 years.

Originally granted provisional approval in 2018 under the FDA’s accelerated pathway for adults with AML who are at least 75 years of age or have comorbidities that preclude use of intensive induction chemotherapy, venetoclax received full approval for this indication in October 2020.

The oral BCL-2 protein inhibitor showed only modest activity as a single agent in the relapsed/refractory setting, but when combined with existing backbone therapies used among newly diagnosed older AML patients who are typically considered not suitable for intensive chemotherapy, it turned out to be a powerhouse (Blood Adv 2019;3[24]:4326-4335). In this setting, “venetoclax plus an HMA, such as azacitidine or decitabine, has a 70% complete response rate in clinical trials and is a great option for older patients and/or patients with comorbidities who may not be a candidate for an intensive induction therapy with 7+3,” Dr. Kim said. (The 7+3 regimen consists of seven days of continuous cytarabine infusion, along with an anthracycline drug, either daunorubicin or idarubicin, on each of the first three days as a short IV bolus or IV push.)

The clinical trials leading to its approval also found that venetoclax extended OS, with a median OS of 14.7 months in patients receiving the combination compared with 9.6 months among those who received azacitidine alone.

But the treatment comes with the cost of profound cytopenia for many patients, including neutropenia and neutropenia-related infections. “In the trials, up to 47% required interruption of venetoclax, most frequently from persistent cytopenia at the end of the first cycle. Managing cytopenia so that our patients can continue therapy without much interruption in between cycles is one of the main challenges that clinicians have faced with this therapy,” said Dr. Kim.

Venetoclax dosing is given in a 28-day cycle, beginning with a ramp-up phase consisting of 100, 200 and 400 mg given on days 1, 2 and 3, respectively; for day 4 and beyond, the venetoclax dose is 400 mg per day when given in combination with azacitidine or decitabine and 600 mg per day when given in combination with low-dose cytarabine. A bone marrow (BM) biopsy/aspirate usually is performed after cycle 1 (around day 28) to assess for treatment response. Recent publications, however, recommend performing a day 21 BM biopsy/aspirate and holding venetoclax if complete remission has been achieved, to allow for blood count recovery.

In the VIALE-A study leading to venetoclax’s approval in this setting, the majority of responding patients in the venetoclax plus azacitidine arm required dosing modifications to manage cytopenia, most commonly delays between cycles or within-cycle reductions of venetoclax (Blood 2020;136[suppl 1]:51-53).

Dose Reductions, Extended Timing

Dose reduction options can involve either venetoclax, HMA or both, said Molly Schiffer, PharmD, BCOP, a hematology/oncology clinical pharmacist at Yale New Haven Health’s Smilow Cancer Center, in Connecticut. “In our center, we will more frequently reduce the dosage or frequency of the hypomethylating agent, but I have seen this done with both agents to reduce the myelosuppression. Often our providers will extend the cycles to be approximately five- to six-week cycles instead of changing any doses to allow more time for count recovery. In my experience, sometimes when you hold dosing for a week, that can help patients recover their counts before starting the next cycle.”

Several major cancer centers have published their experience and recommendations for managing cytopenia during venetoclax combination therapy for AML. Investigators at Roswell Park Cancer Institute, for example, described their protocol in a report in Hematology, ASH Education Program (2020;2020[1]:57-66) (Table).

Table. Managing Cytopenia During Venetoclax Combination Therapy for AML
The main features of Roswell Park Cancer Institute’s protocol for managing cytopenia in patients with acute myeloid leukemia being treated with venetoclax combination therapy include:
Blood counts three times weekly to daily.
Neutropenic prophylaxis, with dose reductions of venetoclax for azole antifungals as needed.
At day 21, if BM biopsy reveals no evidence of AML, hold venetoclax and start granulocyte colony-stimulating factor if counts are low. Await count recovery to start the next cycle, and consider decreasing the venetoclax from 28 days to seven to 21 days, or reducing the hypomethylating agent by 33% to 50%.
If AML persists at day 21, continue venetoclax dosing and start cycle 2 on day 29 with no delay. Continue the second cycle and repeat BM biopsy between day 21 and 28 of the cycle.
AML, acute myeloid leuakemia; BM, bone marrow Source: Hematology Am Soc Hematol Educ Program. 2020;2020(1):57-66.

A Balancing Act

In a 2019 publication in Leukemia, Brian Jonas, MD, PhD, an associate professor of medicine (hematology) at the University of California, Davis, and Daniel Pollyea, MD, the clinical director of leukemia services at the University of Colorado Medicine, in Aurora, noted that they have treated many patients with venetoclax-based regimens who are in long-term remission and are cytopenic but have no notable clinical consequences from their counts (2019;33[12]:2795-2804).

“We have found that for the majority of patients, cytopenias can be successfully managed,” they noted. “Primarily, until a response is assessed, we strongly advocate continuing this regimen with aggressive supportive care and discourage treatment interruption or dose reductions in either therapy. Those who regularly treat AML are accustomed to the principle that initial therapy, whether it is intensive or less intensive, mandates this approach. This should extend even more so to venetoclax-based regimens, with their high-response rates, rapid remissions and low early death rates (3%), which translates to a lower risk: benefit ratio than conventional therapies.”

When to Pause

For patients who have achieved a morphologic remission and have failed to achieve count recovery, they recommended a pause of up to 14 days from both therapies. “We find that G-CSF [granulocyte colony-stimulating factor] support can rapidly correct neutropenia in many cases,” they noted. On the other hand, for patients in whom residual disease remains and for whom more therapy may be beneficial, they argue for starting the next cycle without delay and withholding G-CSF support until complete remission has been achieved.

“We’re still learning to figure out the best approach to deliver this regimen to minimize the risk of complications related to significant treatment-related BM suppression, while optimizing efficacy of the therapy. It is all about a balancing act,” Dr. Kim said. “There are no hard-and-fast rules. We have to tailor each cycle to how the patient is tolerating the therapy. Younger patients, of course, tolerate it better, but we are now treating patients in their 70s and 80s, and we really have to personalize the scheduling of these therapies so that they can tolerate them and continue to benefit.”

—Gina Shaw

Drs. Kim and Schiffer reported no relevant financial disclosures.