Will a Novel Combination Become Standard for AML?

News
Article

A study in The Lancet Haematology suggests this combination could become first-line for elderly or unhealthy patients with newly diagnosed AML.

Alternating a combination of cladribine and low-dose cytarabine with decitabine could someday be front-line treatment for elderly or unhealthy patients with newly diagnosed acute myeloid leukemia (AML), according to a recent study published in The Lancet Haematology.

“Development of low-intensity regimens with less toxicity and good efficacy has been a priority for the treatment of elderly and unfit adults with AML,” wrote the authors, led by Tapan M. Kadia, MD, associate professor at the University of Texas MD Anderson Cancer Center in Houston.

Front-line therapy for elderly or unhealthy patients with AML yields poor outcomes and severe toxicity. Although hypomethylating agents, such as azacytidine and decitabine, are associated with better outcomes than supportive care alone, they provide lower response rates and survival benefits when compared with standard approaches in younger or healthier patients.

In a previous study, Kadia et al assessed a regimen of clofarabine-a similar but different drug from cladribine-plus low-dose cytarabine cycles alternating with decitabine in elderly patients with newly diagnosed AML. Of 118 patients evaluated, 79 attained a complete response with or without recovery of platelets, with a median overall survival of 18.5 months in responders.

Based on these results, the investigators hypothesized that this combination would be safer and more clinically effective than current approaches using hypomethylating agents. They completed a single-arm, open-label, phase II trial assessing 118 patients aged 60 years and older who had untreated AML or high-risk myelodysplastic syndrome with adequate organ function and an Eastern Cooperative Oncology Group performance status of 2 or lower. The primary endpoint was disease-free survival. Secondary endpoints included overall survival, proportion of patients achieving complete response, proportion of patients achieving response, toxicity, and induction mortality.

The median disease-free survival was 10.8 months, and the median overall survival was 13.8 months. In total, 80 patients (68%) attained objective response, with 69 (58%) attaining complete response. The combination was well-tolerated by patients.

If these results are confirmed by a future phase III trial, Kadia and colleagues posited that the combination could proffer an alternative to status quo hypomethalating agents, thus possibly becoming the “de-facto standard low-intensity backbone for AML,” with better clinical outcomes.

“The combination of cladribine and low-dose cytarabine alternating with decitabine appears to be a safe and highly effective regimen for the treatment of elderly or unfit patients with newly diagnosed AML,” concluded the researchers. “Further testing of this regimen is warranted, and could help to provide a new, effective option for reduced-intensity therapy in this population.”

“These results are exciting, as this regimen represents a potential much-improved alternative upfront regimen for this difficult-to-treat patient population, which is increasing over time due to overall aging of our population,” Eunice S. Wang, MD, professor of oncology at the University of Buffalo Jacobs School of Medicine and Biomedical Sciences, told Cancer Network. “However, many questions remain. Similarly high response rates of 60% to 70% have previously been reported in other phase II trials of older unfit AML patients, only to be followed by negative phase III multi-center trials.”

“The list of therapeutic failures include the polo kinase inhibitor, volasertib; the antibody drug conjugate, SGN33; the mTOR inhibitor, rapamycin; and recently, SGI-110 (guadecitabine),” continued Wang. “[These failures] highlight the intrinsic difficulty of developing new agents in this biologically and clinically heterogeneous population.”

Dr. Wang also noted several other potential issues with the Kadia et al study. “It is not clear from Kadia’s trial whether the benefits of therapy arise from cladribine, cytarabine, or decitabine,” she said. “Recently, the novel combination of the BCL-2 inhibitor venetoclax plus low-dose chemotherapy (cytarabine or a hypomethylating agent) has garnered much attention for upfront therapy of the same elderly unfit AML patient population. This regimen has the advantage of containing two drugs (one of which is oral) [that] clinicians are already familiar with and therefore may be more appealing than the three-drug protocol presented here.”

Catherine Lai, MD, MPH, director of leukemia and an assistant professor at Georgetown University Medical Center's Lombardi Comprehensive Cancer Center, said the results are promising, but agreed the regimen may be more complicated to administer than existing therapy. "Overall, the study showed good response rates and overall survival using a modification to the standard decitabine regimen. For patients that would typically be given a hypomethylating agent alone, this is an improved alternative, albeit more cumbersome to administer," Lai told Cancer Network. "Consideration for this regimen must account for quality of life, side effect profile, and [the] patient’s ability to receive low-dose cytarabine twice daily for 10 days," she said.

Recent Videos
Investigators are currently evaluating mosunetuzumab in relapsed disease or comparing it with rituximab in treatment-naïve follicular lymphoma.
Compared with second-generation tyrosine kinase inhibitors, asciminib was better tolerated in patients with chronic myeloid leukemia.
Bulkiness of disease did not appear to impact PFS outcomes with ibrutinib plus venetoclax in the phase 2 CAPTIVATE study.
Greater direct access to academic oncologists may help address challenges associated with a lack of CAR T education in the community setting.
Certain bridging therapies and abundant steroid use may complicate the T-cell collection process during CAR T therapy.
Educating community practices on CAR T referral and sequencing treatment strategies may help increase CAR T utilization.
Harmonizing protocols across the health care system may bolster the feasibility of giving bispecifics to those with lymphoma in a community setting.
Establishment of an AYA Lymphoma Consortium has facilitated a process to better understand and address gaps in knowledge for this patient group.
Adult and pediatric oncology collaboration in assessing nivolumab in advanced Hodgkin lymphoma facilitated the phase 3 SWOG S1826 findings.
Treatment paradigms differ between adult and pediatric oncologists when treating young adults with lymphoma.
Related Content