Hematopoietic stem cell (HSC) transplantation may improve outcomes of patients with hematologic malignancies not curable with conventional therapies. In some clinical settings, transplantation represents the only curative option. The feasibility and efficacy of this approach in older patients are undefined, since this population has been excluded from nearly all clinical trials. Advances in supportive care, HSC harvesting, and safer conditioning regimens have made this therapy available to patients well into their 6th and 7th decades of life. Recent evidence suggests that elderly patients with good performance status and no comorbidities could, in fact, not only survive the transplant with reasonable risk, but also benefit in the same measure as younger patients.
The median age at presentation for hematologic disorders such as leukemia, myelodysplasia, lymphoma, and myeloma is over 60 years. Newer targeted therapeutic approaches have led to promising results in these maladies, particularly in the initial treatment approach.[2-4] Respectable remission rates have been achieved for about half of the patients treated. Despite the improved remission rates, patients with these diseases still relapse. Elderly patients (conventionally defined as those over the age of 60 years old) have a higher risk of relapse of their disease. Factors such as abnormal cytogenetics and other intrinsic genetic changes in the cells are more commonly seen in this elderly group, leading to poorer outcomes compared to their younger counterparts. The presence of these features has limited the usefulness of salvage chemotherapy once the patient has relapsed or experienced disease progression.
Transplantation has been the mainstay of therapy for patients with relapsed and/or high-risk hematologic disorders. This approach has mainly been used in patients under the age of 60. Outcomes using autologous transplant are superior to standard therapy in the treatment of relapsed aggressive lymphoma. In myeloma, where advances in up-front therapies have improved overall survival, transplantation has been a useful approach in advanced disease. Early superiority was proven over traditional chemotherapeutic approaches for patients with myeloma. Despite not being curative for most of these patients, single and tandem transplant have provided long-term disease-free and overall survival in a small group of patients. Allogeneic transplant is the only therapy with a chance of cure for relapsed acute myeloid leukemia and for patients with high-risk (International Prognostic Scoring System intermediate-2 and high) myelodysplasia.
Challenges in Older Patients
The biggest obstacle to overcome has been the overwhelming bias against transplantation in this "elderly" group of patients. Concerns about regimens that are too toxic immediately posttransplant or that could lead to later sequelae have limited referrals of these patients to transplant centers. Furthermore, multiple regimens of chemotherapy prior to a transplant referral can lead to a self-fulfilling prophecy of poorer outcomes, from inadequate collection of hematopoietic stem cells to poorer-risk patients being transplanted.
Bringing the patient to transplant earlier allows for the appropriate use of dose-intense strategies when there is a better chance of cure. Advances in the pretransplant conditioning regimens and supportive care posttransplantation have reduced treatment-related mortality to acceptable levels. Based on improvements in the procedure, including the efficient procurement of hematopoietic stem cells, the use of growth factors, and the improved antibiotic and antifungal armamentarium, most transplant centers have increased their upper age limit from 40 to 70–80 years old.
In "Hematopoietic Stem Cell Transplantation in the Elderly," Ballester et al have summarized past and more current experiences and outcomes using transplantation in elderly patients. The lack of randomized trials have made it more difficult to draw firm conclusions, but improved trends noted in treatment-related mortality, progression-free survival, and overall survival prove the promise of this approach in the elderly cohort.
Moreover, adjustments in dose intensity-whether it be from a nonmyeloablative, reduced-intensity, or fully ablative approach-allow for therapy to fit the risk profile of the patient and the disease. Targeting levels of the conditioning regimes allows for precise doses of therapy to be delivered when it counts the most. The "one-size-fits-all" approach that was used previously in the transplant setting is no longer appropriate. Improvements in the posttransplant care of complications such as infections and graft-vs-host disease have also led to improvements in survival.
As the authors have rightfully noted, we have learned over the past 30 years that age in and of itself does not predict for a poorer outcome. Current knowledge of existing comorbid factors that influence the outcome of transplant are now known and allow for better patient selection by the transplant team. The favorable outcomes demonstrated in patients with hematologic disorders have demonstrated that despite the concerns about performing stem cell transplants in older patients, the outcomes are no better or worse than in similarly risk-stratified younger patients.
As newer targeted agents become available, patients will be in better shape prior to being referred to transplant. Not having endured multiple cycles of traditional chemotherapy, and not being burdened by multiple infections from prior neutropenia, will improve the status of patients undergoing transplant. Further study of alternative transplant conditioning regimens in elderly patients will improve long-term outcomes. In the future, expanding the transplant approach should be considered to treat other disorders such as chronic lymphocytic leukemia, mantle cell lymphoma, and acute lymphoblastic leukemia.
-Hugo F. Fernandez, MD
1. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence-SEER 9 Regs Limited-Use, Nov 2006 Sub (1973-2004), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch. Released April 2007, Based on the November 2006 submission.
2. Richardson PG, Sonneveld P, Schuster MW, et al: Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed multiple myeloma. Br J Haematol 137:429-435, 2007 .
3. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002.
4. Silverman LR, Demakos EP, Peterson BL, et al: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the Cancer and Leukemia Group B. J Clin Oncol 20:2429-2440, 2002.
5. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 333:1540-1545, 1995.
6. Deeg HJ, Storer BE, Boeckh M, et al: Reduced incidence of acute and chronic graft-versus-host disease with the addition of thymoglobulin to a targeted busulfan/cyclophosphamide regimen. Biol Blood Marrow Transplant 12:573-584, 2006.
7. Sorror ML, Maris MB, Storb R, et al: Hematopoietic cell transplantation (HCT)-specific comorbidity index: A new tool for risk assessment before allogeneic HCT. Blood 106:2912-2919, 2005.