A Phase I study has shown improved response rates among a specific subset of older patients with acute myeloid leukemia treated with oral lenalidomide, a molecular analog of thalidomide first approved in 2005 for treating myelodysplastic syndromes (MDS), and then one year later for myeloid leukemia.
Treatment in elderly patients is often discouraged due to the high potential for severe side effects, but a study by researchers from the Southwest Oncology Group (SWOG), published online May 10 in Blood (doi:10.1182/blood-2011-02-337303), found “modest” improvement in response and remission in a handful of older patients who have the specific genetic defect of chromosome 5q deletion or del(5q).
Elderly patients received 50 mg of oral lenalidomide for 28 days as induction therapy, and 10 mg daily for 21 days during a second 28-day cycle as maintenance therapy, until there was disease progression or unacceptable toxicity. The patients, who were on average 74 years old, responded well to treatment, and some achieved complete remission. On average, patients who responded to treatment survived for two or three months, but some survived longer.
“This is the largest study specifically in older patients with 5q deletion,” noted the corresponding author, Mikkael A. Sekeres, MD, Director of the Leukemia Program at the Cleveland Clinic Taussig Cancer Institute and Chair of the Hematology/Oncology Pharmacy and Therapeutics Committee there. “The difference is that in earlier studies there has been no clinical response.”
Lenalidomide inhibits tumor necrosis factor and is often used in conjunction with dexamethosone in patients with relapsing or refractory multiple myeloma.
The researchers initially recruited 37 male and female patients age 60 to 94, but only 14 patients (38%) completed induction therapy. All of the patients had prior MDS, and 81% had pretreatment cytogenetic evaluation. Six patients had isolated del(5q), one had del(5q), and seven had del(5q) identified locally.
Recruiting older AML patients is often difficult, said Dr. Sekeres, OT's Clinical Advisoroy Editor for Hematology/Oncology. Many patients are unwilling to undergo experimental treatment at that age or are concerned with potentially debilitating side effects.
Of the 14 patients completing induction therapy, only eight remained in treatment long enough to start the maintenance regimen. Among them, five had partial or complete responses, two with isolated del(5q) and three with complex cytogenetics.
The relapse-free survival time in these patients was five months, vs two months for the entire population, and median overall survival was 15 months. Three of the five patients had disease relapse by month five, one patient died 15 months after experiencing a complete response without relapse, and a fifth patient was alive without relapse 19 months after achieving partial remission during maintenance therapy.
Seven died during induction therapy, eight patients had disease progression, seven had nonfatal adverse events, and one patient entered hospice care and stopped treatment.
There were three deaths from adverse events; one respiratory, one cardiac, and one associated with febrile neutropenia, believed to have been caused by treatment. One patient also died of an induction-related adverse respiratory event 34 days after the study began.
“What we have seen is pretty impressive,” said Dr. Sekeres. “This is not that big a response, but it was achieved with oral medication, and we feel it solidly provides evidence for the next phase of research: using lenalidomide with cytotoxic chemotherapy.”
Such a study is already under way by French researchers participating in Groupe Francophone Des Myelodysplasies (GFM) trials. Early results in 48 patients, presented as an abstract at last year's American Society of Hematology Annual Meeting (Ades et al, Abstract 508), showed complete remission in 50% of treated AML patients and in 66% of MDS patients.
Dr. Sekeres said that together with researchers at H. Lee Moffitt Cancer Center, he is in the process of recruiting patients for a similar study in the United States.
Elihu Estey: Truly Significant?
However, asked his opinion for this article, Elihu H. Estey, MD, Professor of Medicine in the Division of Hematology at the University of Washington School of Medicine and a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center, questioned whether the response benefits really denote a “modestly beneficial effect,” as the researchers stated.
“With any new drug it is important to know two things: whether an experimental drug is active and whether its activity is beneficial in terms of extending the quantity or quality of patients' lives. This study indicates that lenalidomide is clearly active and thus possibly worth combining with other drugs, but this is different from saying that lenalidomide was beneficial for the patients. Most importantly it is very plausible that the patients might have lived as long or longer had they not received lenalidomide.”
Dr. Estey added that new drugs frequently touted as being promising in early studies subsequently fail efficacy or safety benchmarks in subsequent trials—for example, data show, he noted, that only one of 38 drugs considered promising is currently approved and being used clinically five years after a review of them was presented as an abstract at the ASH meeting, and the same is the case for peer-reviewed papers.
The reasons for these false positive findings, he and colleagues found in a 2010 study (Walter RB, Estey EH, Larson RA, et al: Shortcomings in the clinical evaluation of new drugs: acute myeloid leukemia as paradigm. Blood 2010;116:2420-2428) and for “intrinsic” inefficiencies in the sequence of clinical drug testing, include a lack of control groups, patient heterogeneity, selection bias, and choice of end points.
“I think the important point with this new study is that we need to put it in perspective. The findings are medically interesting without yet being of real clinical importance.”
Similarly, Farhad Ravandi, MD, of the Department of Leukemia at the University of Texas MD Anderson Cancer Center, said he is “luke-warm” about the findings and noted that the high doses used in the study carry significant risk of toxicities, especially cytopenia.
“Future studies in larger groups treated uniformly, preferably at academic cancer centers, might one day show some benefit. But we have to wait and see what develops,” he said.
Next Step: Phase 3
Dr. Sekeres agreed that still to be demonstrated is an improvement in quality or quantity of life in older adults with the del (5q) lesion, but that those endpoints can be assessed only in a Phase 3 study, which can be justified only if a drug demonstrates activity in an earlier Phase study.
“Clearly, lenalidomide has activity in AML, and our study lays the groundwork to justify that type of study,” he said.