September 17, 2018
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Chemotherapy combination appears safe for elderly patients with acute myeloid leukemia

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Tapan M. Kadia

Treatment with the combination of cladribine and low-dose cytarabine alternating with decitabine appeared safe and effective among older patients with newly diagnosed acute myeloid leukemia, according a single-arm, open-label phase 2 study.

“There has been, for a long time, a desire to develop lower intensity but effective therapies for older patients with AML,” Tapan M. Kadia, MD, associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “These therapies should provide clinical benefit and reduce the risk for early mortality and toxicity.”

Options include hypomethylating agents — such as azacytidine or decitabine (Dacogen, Otsuka) — which are well tolerated. However, response rates and survival outcomes remain inferior compared with standard approaches in younger patients.

“The current study was undertaken to study a new lower-intensity regimen that maintained tolerability and safety, but provided improved efficacy,” Kadia said.

Kadia and colleagues studied 118 patients aged 60 years or older with previously untreated AML or high-risk myelodysplastic syndrome from a single center.

Inclusion criteria included adequate organ function and an ECOG performance status of 2 or less. Forty-eight (41%) patients had an adverse karyotype, 20 (17%) had therapy-related AML, 18 (15%) had secondary AML and 20 (17%) had TP53 mutations.

Patients received cladribine — a purine nucleoside — plus low-dose cytarabine for two 28-day cycles alternating with decitabine for two 28-day cycles, for up to 18 cycles.

Induction therapy during cycle 1 included 5 mg/m2 IV cladribine over 1 to 2 hours on days 1 through 5 and 20 mg cytarabine subcutaneously twice daily on days 1 through 10. Patients who achieved remission during the induction phase received consolidation therapy with 5 mg/m2 IV cladribine on days 1 through 3 and 20 mg cytarabine subcutaneously twice daily on days 1 through 10, alternating with 20 mg/m2 IV decitabine on days 1 through 5.

DFS served as the primary endpoint.

Median follow-up was 37.2 months.

Researchers observed a median DFS of 10.8 months (interquartile range [IQR], 5.4-25.9).

Sixty-eight percent of patients achieved an objective response, with 58% achieving a complete response and 9% achieving a complete response with incomplete count recovery.

Median OS was 13.8 months (IQR, 6.9-28.6).

Researchers reported a 1-year OS rate of 64% (95% CI, 52-71) and 2-year OS rate of 28% (95% CI, 20-38).

Among 38 patients with a diploid karyotype, 84% achieved objective response, with a median OS of 19.9 months (IQR, 13.8–41.2) and a 1-year OS rate of 82% (95% CI, 70-96).

Researchers observed inferior outcomes among patients with adverse karyotypes (ORR, 50%; OS, 10.5 months [IQR, 2.7-15.9]) and TP53 mutation (ORR, 40%; OS, 8.9 months [IQR, 3.6-18.1]).

“Subgroup analysis by karyotype and molecular subtypes showed further differentiation in outcomes,” Kadia said. “The complete response rates and OS in this study for older and unfit patients was similar to what has been achieved with intensive chemotherapy in larger population-based studies of older adults (with less toxicity). The regimen is mostly delivered as an outpatient with drugs that are easily accessible and available — off patent and low cost.”

The treatment regimen appeared well-tolerated, with one (1%) death reported in the first 4 weeks and eight (7%) deaths reported within the first 8 weeks.

The most common nonhematological grade 3 or worse adverse events included infection (75%), elevated total bilirubin (22%), rash (11%) and nausea (11%).

Future studies should assess this regimen in large groups and in community settings, according to Kadia.

“Additionally, with the advent of newer small molecule drugs in the treatment of leukemia, it would be compelling to switch the chemotherapy backbone from hypomethylating agents (as is currently done) to a cladribine and [low-dose cytarabine alternating with decitabine] backbone for combination studies, he added. “We can then see whether this can even further build on the improved outcomes seen with hypomethylating agent-based combinations.”

In an accompanying editorial, Norbert Vey, MD, PU-PH, professor in hematology and head of the leukemias treatment unit at Institut Paoli-Calmettes in France, highlighted directions and concerns with future research among elderly patients with AML.

“The investigators propose to validate their results in randomized trials using a single-agent hypomethylating agent control arm. However, the regimen of cladribine plus low-dose cytarabine alternating with decitabine might be too toxic for patients more frail than those included in this study,” he wrote.

“The time might have come to change old thinking that divides the elderly patient population into fit and unfit, and to compare this regimen with intensive therapies in fit, elderly patients,” Vey added. “Whatever the strategy followed, there is a need for the development of active backbones and more complex but tolerable multiagent combinations using new targeted agents.” – by Cassie Homer

For more information:

Tapan M. Kadia , MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: tkadia@mdanderson.org.

Disclosures: The authors report no relevant financial disclosures. Vey reports personal fees from Celgene and Janssen.