Late Second Malignancies in Lymphoma Marrow Transplant Survivors
Late Second Malignancies in Lymphoma Marrow Transplant Survivors
Abstract & Commentary
William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC, is Editor for Clinical Oncology Alert
Synopsis: In a retrospective analysis of a relatively large cohort of non-Hodgkin’s lymphoma patients transplanted after a standardized conditioning regimen of cyclophosphamide and total body irradiation with B-cell purged autologous bone marrow, there was a 21% incidence of second neoplasms at 10 years. Myelodysplasia/acute myelogenous leukemia (MDS/AML) accounted for about half of these, and other hematological neoplasia or solid tumors accounted for the remainder. Whereas the incidence of MDS/AML appeared to plateau at 10 years, solid tumors continue to be recognized with each succeeding year.
Source: Brown JR, et al. J Clin Oncol. 2005;23:2208-2214.
Myelodysplasia (MDS) and acute Myelogenous Leukemia (AML) are known to occur in a fraction of patients following autologous bone marrow transplantation (ABMT), but the development of solid tumors in this setting has not been fully characterized. Brown and colleagues have performed a retrospective review of 605 patients who underwent ABMT at the Massachusetts General Hospital between 1982 and 1997. During this period, a uniform conditioning program was employed, including both cyclophosphamide and total-body irradiation followed by the infusion of autologous bone marrow that had been purged in vitro with anti-B cell monoclonal antibody.
The review was accomplished by questionnaire completed by the referring oncologist. From this, it was learned that 42 solid tumors, 6 non-MDS hematological malignancies, 39 non-melanoma skin cancers and 68 cases of MDS/AML were observed at a median follow-up of 9.5 years. Using a cumulative incidence model in which death was considered a competing risk it was estimated that the 10-year incidence of second malignancy was 21% with 10.0% non-MDS malignancies and that the projected incidence of all malignancies at 15 years is 29%. The principal risk factor for second malignancy was found to be older age at ABMT (P = .0002).
Comment by William B. Ershler, MD
MDS/AML is a known consequence of combined modality therapy,1,2 and appears in this series to be similar to that observed in patients cured of Hodgkin’s disease, with MDS/AML developing in a subset up until approximately 10 years after treatment, but not thereafter. In contrast, as true also for patients cured of Hodgkin’s disease, solid tumors continue to rise at a rate of approximately 1% per year without any evidence that the incidence plateaus.3,4
Once again, it is curious that age figures as a prominent risk factor. For example, there was a 15% incidence of second malignancies in patients 19 to 37 years at the time of ABMT compared with a 31% incidence in patients aged 51 to 66 years (P = 0.0002). A similar age-associated risk for the development of second malignancies has been reported (9,13,26), but in at least one series that included pediatric patients, the risk was found highest in those who were transplanted in the first decade of life.5,6 Why older recipients are particularly susceptible is unknown, but this probably relates to those other factors which predispose older patients to cancer in general (accumulated somatic mutations, declining DNA repair mechanisms, etc).
It is also curious that the current report did not clearly implicate radiation exposure in inducing non-MDS second malignancies. This is a controversial area, particularly in the realm of Hodgkin’s disease, where many have advocated a reduced role for XRT in upfront treatment based upon reported evidence of higher late complications of patients treated with combined modality or XRT alone.
This is a well-conducted review highlighting a problem that will be increasingly apparent over the next several years, as ABMT-treated long-term non-Hodgkin’s lymphoma survivors increase in number. To summarize, this series found a 21% rate of second malignant neoplasms at 10-year follow-up, approximately evenly divided between solid malignancies and MDS/AML. These malignancies have been responsible for the death of 9.6% of the patients, due primarily to the very poor treatment success of MDS/AML, but with increasing recent deaths due to solid tumors. New approaches, using autologous stem cells and novel conditioning regimens, are under investigation. Oncologists following patients after transplant need to maintain surveillance indefinitely, such that new malignancies are recognized with sufficient time to provide effective therapy.
References
- Darrington DL, et al. J Clin Oncol. 1994;12:2527-2534.
- Friedberg JW, et al. J Clin Oncol. 1999;17:3128-3135.
- Nyandoto P, et al. Int J Radiat Oncol Biol Phys. 1998; 42:373-378.
- van Leeuwen FE, et al. J Clin Oncol. 1994;12:312-325.
- Curtis RE, et al. N Engl J Med. 1997;336:897-904.
- Bhatia S, et al. J Clin Oncol. 2001;19:464-471.
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