Ilene Galinsky, BSN, MSN, ANP-C, discusses the evolution of targeted therapy in acute myeloid leukemia treatment, and how venetoclax plays into the treatment paradigm.
Targeted therapy has changed the treatment landscape for acute myeloid leukemia (AML), according to Ilene Galinsky, BSN, MSN, ANP-C, senior leukemia protocol research nurse practitioner at Dana-Farber Cancer Institute.
As Galinsky explained in an interview with Oncology Nursing News®, the first targeted therapy for AML was imatinib (Gleevac), which was tested in clinical trials in the late 1990s and approved in 2001.1 Later, in 2017, the FDA approved midostaurin (Rydapt) for the treatment of FLT3-positiveAML. This approval was supported by findings from the international RATIFY trial (NCT00651261), which demonstrated the efficacy of targeted therapy compared with placebo in this patient population.2
“That [trial] started a snowball effect of targeted therapy, either by mutations, or by flow cytometry markers like [with] gemtuzumab ozogamicin [Myolotarg],” Galinsky said. “Since that time, 7 or 8 drugs have been FDA approved [for pediatric and adult patients], all of which target a different aspect of the disease.”
The BCL2 inhibitor venetoclax (Venclexta) was approved by the FDA for adult patients with newly diagnosed AML aged 75 years or older and for patients who had preexisting conditions that precluded them from the use of intensive chemotherapy. This includes patients with an ECOG performance status of 2 or 3 and severe comorbidities including cardiac or hepatic impairment.3
The agent is approved at a dose of 400 mg daily in combination with azacitadine (Vidaza), decitabine, or low-dose cytarabine.3
Galinsky recently presented on the efficacy and practical treatment considerations with BCL2 inhibitors at the 47th Annual Oncology Nursing Society Congress. In an interview with Oncology Nursing News®, she discusses important considerations when prescribing venetoclax, and why the evolution of targeted therapy is significant for patients with AML.
Prescribing Considerations With BLC2 Inhibition
When prescribing or administering venetoclax, it is important to keep a patient’s disease burden top of mind, Galinsky said.
Venetoclax should not be initiated if a patient has a high white blood count and hydroxyurea should be used to achieve counts below 25,000 cells/μL. Further, tumor lysis syndrome, though rare, was observed during the ramp-up phase in the original clinical trials. Nurses, therefore, are encouraged to monitor laboratory tumor lysis counts, either in the inpatient or outpatient setting, 6 to 8 hours after administering venetoclax.
“The ramp-up period to get to that targeted dose is 3 days,” Galinsky said. “Once you are at that target dose, we check [labs] another time—24 hours later.”
Hydration can also be key in reducing the risk of tumor lysis syndrome and can be effectively achieved through either oral intake or intravenous (IV) fluid, she said. “You can put your patients on an antihyperuricemia agent such as allopurinol, or rasburicase [Elitek]. These are preventative measures [for] tumor lysis syndrome.”
Concomitant medications are another important factor to consider, Galinsky said.CYP3A4 inhibitors can affect the pharmacokinetics of venetoclax, she said. If a patient is receiving one of those drugs, dose modifications may be necessary to get the patient to their target venetoclax dose.
“Those are the important key factors to think about when you’re using venetoclax in AML. The other factor is we know that it causes myelosuppression just like a chemotherapy agent.”
A mid-cycle bone marrow biopsy is recommended between days 21 to 28 to dictate if—and when—the second 28-day cycle can begin.
If a patient is not in remission after 1 cycle, treatment should be continued despite low blood counts, and a second bone marrow biopsy should be repeated, she said. If a patient is in remission and has neutropenia, providers should wait until the patient has recovered to grade 1 or 2 neutropenia before initiating a second dose. If, following a second dose, neutropenia is persisting, providers should hold the dose and upon resuming prescribe a 21-day cycle instead of a 28-day cycle.
With the myelosuppression, patients also may be transfusion dependent until their counts normalize or respond to therapy. Therefore, Galinsky typically has her patients come in twice a week during their first month of therapy for laboratory assessments and possible transfusions.
If patients have neutropenia, there is an increased risk of infections and, in the VIALE-A trial (NCT02993523), there was an increased risk of pneumonia. Therefore, some providers prescribe either antifungals, or antibacterial prophylactic antibiotic therapy.
“In my institute, we do not do that,” Galinsky said. “It is not wrong to do that, but if you do, you have to be mindful when you’re adding an azole that you have to decrease the dose of venetoclax.”
Moreover, like with chemotherapy agents, gastrointestinal (GI) toxicities are common.
“With this therapy, [GI toxicities are] usually grade 1 or 2, and manageable with antiemetics, but some [individuals] do [experience] diarrhea, so antidiarrheal [medicines] can be used as well,” she explained.
Adjusting the timing of the dose can be an effective strategy as well, Galinsky continued.
“It is recommended to take [venetoclax] in the morning, but, in my experience, some [individuals] have found that they have less GI toxicities when they take it later in the day,” she said. “If they are not on a clinical trial, I let patients [experiment to find] what works best for them.”
Overall, it’s an exciting time to be working in AML, Galinsky concluded.
“In the past several years there have been changes in therapies that have [made them] less toxic and have improved overall survival in our patients with AML,” she said. “Prior to midostaurin, it didn’t matter what a patient’s molecular makeup was. You gave them induction chemotherapy and hoped for the best.
“Now we have the technology and the ability to find why there’s specific abnormalities, how to target those specific abnormalities, and how best to improve overall survival and quality of life.”
1. How imatinib transformed leukemia treatment and cancer research. National Cancer Institute. UpdatedApril 11, 2018. Accessed June 21, 2022. https://bit.ly/2FdcgWt
2. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi:10.1056/NEJMoa1614359
3. Venclexta. Prescribing information. AbbVie Inc; 2020. Accessed June 21, 2022. https://bit.ly/3ye5i2c