Regimen may improve cell transplantation outcomes for older adults with blood, bone marrow cancers

November 01, 2011

CHICAGO - Older patients with advanced hematologic malignancies, such as leukemia and lymphoma, who received a conditioning regimen that included minimal-intensity radiation therapy prior to allogeneic (genetically different) hematopoietic cell transplantation (HCT; receipt of bone marrow or stem cells transplant) had survival and progression-free survival outcomes suggesting that this treatment approach may be a viable option for older patients with these malignancies, according to a study in the November 2 issue of JAMA.

"Increasing age has been historically implicated in higher mortality after high-dose allogeneic HCT for patients with hematologic malignancies [cancers of the blood or bone marrow]. Such transplants are preceded by intense, cytotoxic [toxic to cells] conditioning regimens aimed at reducing tumor burden. The risk of organ toxicities has limited the use of high-dose regimens to younger patients in good medical condition. Therefore, age cutoffs of 55 to 60 years have been in place for decades for high-dose HCT. This excluded the vast majority of patients from allogeneic HCT, given that median [midpoint] ages of patients at diagnoses of most hematologic malignancies range from 65 to 70 years," according to background information in the article.

To address this limitation, a nonmyeloablative (an approach using lower doses of chemotherapy and/or radiation that does not lead to eradication of all bone marrow cells prior to stem cell transplant) conditioning regimen for allogeneic HCT was developed. The regimen relies on graft-vs.-tumor effects to cure cancer and consists of the chemotherapy drug fludarabine and a low dose of total-body irradiation before HCT and a course of immunosuppression. "This regimen has allowed extension of allogeneic HCT to a previously unserved population of older or medically infirm patients," the authors write.

Mohamed L. Sorror, M.D., M.Sc., of the Fred Hutchinson Cancer Research Center, Seattle, and colleagues analyzed the outcomes of older patients with advanced hematologic malignancies who received minimally toxic nonmyeloablative allogeneic HCT. From 1998 to 2008, 372 patients ages 60 to 75 years (median age, 64 years) were enrolled in prospective clinical HCT trials at 18 collaborating institutions using conditioning with low-dose total body irradiation alone or combined with fludarabine, before related (n = 184) or unrelated (n = 188) donor transplants. They also received postgrafting immunosuppression therapy. The primary outcomes measured for the study were overall and progression-free survival.

As of June 23, 2010, 133 of the 372 patients were alive, with a median follow-up of 55 months. Overall, disease progression or relapse has been the most common cause of death (n = 135). Nonrelapse deaths occurred among 104 patients, mainly due to infections, graft-vs.-host disease (GVHD), and multi-organ failure. Five-year rates of overall survival and progression-free survival were 35 percent and 32 percent, respectively. The overall 5-year cumulative incidence of relapse was 41 percent.

Cumulative incidences for nonrelapse mortality at 5 years were comparable among the 3 age groups (27 percent for patients ages 60-64 vs. 26 percent for those ages 65-69 vs. 31 percent for those 70 or older). Five-year rates of overall survival were 38 percent for patients ages 60 through 64, 33 percent for those ages 65 through 69, and 25 percent for those 70 years or older.

Also, comorbid conditions and risks for disease relapse, but not increasing age, were associated with worse outcomes. More than half of the older patients were never hospitalized, and two-thirds of survivors experienced eventual resolution of their chronic GVHD with return to normal or near-normal physical function.

"While there is much room for improvement, particularly with regard to relapse, these results are encouraging given the poor outcomes with nontransplantation treatments, especially for patients with high-risk acute myeloid leukemia, fludarabine-refractory chronic lymphocytic leukemia, or progressive lymphoma. The older population is increasing; demographic changes in the United States suggest that 20 percent of the population will be 65 years or older by 2030. Furthermore, increases of up to 77 percent in the number of newly diagnosed hematologic malignancies among the older population are expected to occur in the next 20 years. Greater age is also associated with increased medical comorbid conditions. Thus, establishing treatment options with curative outcomes and near-normal long-term physical function have become an important future goal for older patients with hematologic malignancies," the authors write.

(JAMA. 2011;306[17]:1874-1883. Available pre-embargo to the media at www.jamamedia.org)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Overcoming the Age Barrier in Hematopoietic Stem Cell Transplantation

In an accompanying editorial, Shin Mineishi, M.D., of the University of Michigan, Ann Arbor, Mich., comments on the findings of this study.

"Development and refinement of reduced-intensity, nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) has been an important accomplishment in HSCT over the last 15 years. As reported by Sorror et al, even among patients aged 60 through 75 years overall survival, progression-free survival, and other outcomes now appear almost comparable to those in younger patients. Although age alone should no longer be considered a limiting factor for allogeneic HSCT, more questions have been raised, and more problems need to be resolved for achieving optimal outcomes for older patients receiving allogeneic HSCT."

(JAMA. 2011;306[17]:1918-1920. Available pre-embargo to the media at www.jamamedia.org)

Editor's Note: Please see the article for additional information, including financial disclosures, funding and support, etc.
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