ALLO Transplants And Second Malignancies
ALLO Transplants And Second Malignancies
Abstract & Commentary
By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
Synopsis: The risk for solid tumor development in prior recipients of allogeneic hematopoietic stem cells at the Leukemia/Bone Marrow Transplantation Program of British Columbia was found to be 3.1% at ten years of follow up. Older recipients (40 years and older) and those who received their graft from female donors were particularly susceptible. Extended follow up will be needed to assess more fully the magnitude of second cancers among transplant recipients.
Source: Gallagher G, Forrest DL. Second solid cancers after allogeneic hematopoietic stem cell transplantation. Cancer. 2007;109:84-92.
Improvements in outcomes after transplantation have resulted in increased long-term survival, and now there is concern that marrow recipients, cured of their primary disease have more frequent or accelerated chronic diseases that are more typically seen in late life. Gallagher and Forrest reviewed the case files of 926 consecutive patients who received allogeneic hematopoietic stem cell transplant (allo-HCST) between the years 1985 and 2003 at the Leukemia/Bone Marrow Transplantation Program of British Columbia (Vancouver). Twenty-eight patients developed 30 solid malignancies at a median of 6.8 years after allo-HSCT for a 10-year cumulative incidence of 3.1% (95% confidence interval [CI], 2-5%; all solid tumors) and 2.3% (95% CI 1-4%, excluding basal cell carcinoma and carcinoma in situ of the cervix). The risk ratio of developing a second solid malignancy after allografting, compared with the general population of British Columbia, adjusted for age and sex, was 1.85 (95% CI, 1.04-3.06; P = 0.019). The variables examined with regard to developing a second malignancy included: age at the time of transplant (< 40 years vs > 40 years), sex, diagnosis (AML vs ALL vs CML vs MDS vs lymphoma vs other), interval between diagnosis and transplant (< 6 months vs > 6 months), history of prior radiotherapy, donor age (< 40 years vs > 40 years). HLA disparity between donor and recipient, type of transplantation (related vs unrelated), conditioning regimen (TBI-based vs chemotherapy only), source of stem cells (bone marrow vs peripheral blood), year of transplant (before or after 1995), whether the stem cells underwent T-cell depletion, the presence of acute graft vs host disease (GVHD), and the presence of chronic GVHD. Of these, in univariate analysis only, recipient age at the time of allo-HCST (P = 0.02) and donor sex (P = 0.005) were significant risk factors. These same factors (age > 40 years at time of transplant [P = 0.005], and having a female donor [P = 0.0008]) were risk factors for developing a second solid cancer after multivariate analysis.
The pattern for increased risk based upon recipient age was examined by additional subgroup multivariate analysis. Compared to those less than 30 years, for those aged 30-40 years at the time of transplant, the relative risk (RR) was 2.06, and for those 40 years, 4.75 (P = 0.005). Compared with the general population, the RR for those aged < 40 years and those > 40 years at allo-HCST was 3.42 (95% CI, 1.37-7.05; P = .005) and 1.32 (95% CI, 0.57-2.61, P = 0.26), respectively.
The 10 year cumulative incidence of developing a second solid cancer in patients who received a graft from a female donor and a male donor was 4.6% (95% CI, 2.5-7.6%) and 1.8% (95% CI, 0.8-3.8%), respectively (P = 0.008). The influence of sex matching on second cancer risk (donor/recipient: M/M, M/F, F/F, F/M) was examined in both univariate and multivariate analysis. As mentioned, having a female donor was associated with a significant risk (RR, 3.8; P = 0.0008). This risk was particularly high when the recipient of a female graft was a male (RR: M/M, 1.0; M/F, 0.97; F/F, 1.87; F/M, 4.7; P = 0.005).
Commentary
It is a testament to the procedural advances in stem cell transplantation that we are now facing long-term consequences. The 39% estimated 10-year disease free survival of the approximate 1000 patients transplanted in Vancouver between 1985 and 2003 reflects the remarkable advances in transplant biology and supportive care made possible by prior decades of careful laboratory and clinical investigation. Now, we are becoming increasingly aware of the risk of second cancers over the long-term in patients cured of their primary disease by transplantation.1, 2 Retrospective analysis, such as this from Vancouver, can provide clues as to where to focus to better understand and ultimately intervene to reduce second malignancy risk.
One might have the impression that the estimates from Vancouver are low. The experience with Hodgkin's disease and solid tumor risk (ie, in contrast to myelodysplasia or leukemia risk) would suggest a long latency period and thus extended surveillance beyond ten years, and perhaps for life. In fact, for Hodgkin's disease, the risk of second malignancy increases at a rate of approximately 1%/year, indefinitely.3, 4 Thus, the relatively short follow up for the Vancouver transplant patients (of the 420 alive at the time of report, the median duration of follow up was 7.0 years, and only 30% of these were out beyond 10 years) would allow prediction that the rate of solid tumor development in this cohort could increase significantly over the next decades.
That age was found to be an independent risk factor comes as no surprise. Older patients are theoretically more likely to harbor pre-malignant lesions that might accelerate with the intense preparative regimens involved in transplantation, or age-sensitive host factors, such as DNA repair mechanisms might render the older recipient more susceptible.5 However, if the marrow procedure itself is associated with carcinogenesis, it might be expected that solid tumor incidence in the younger recipients will catch up to that of the older cohort, but only after a longer latency, well in excess of what is currently available in the Vancouver series.
The unexpected finding of an increased risk when the donor is female had not been previously reported, and if confirmed from data at other marrow transplant centers, warrants in-depth analysis.
Thus, Gallagher and Forrest have presented an excellent summary of second tumor risk observed at their transplant center. The estimated rate of 3.1% at ten years of follow-up significantly exceeds what would be observed in the general population (age and sex matched) but probably is a harbinger of an even greater risk after longer follow up. However, it is important to remember that the incidence of these solid tumors would not be a concern for those leukemia patients not transplanted, as the great majority will have died years before from their primary disease. Second malignancies in this setting are an unwanted but not unexpected complication of prior life-saving treatment. It is inherent upon us now to identify the modifiable risks and reduce them, as possible.
References
1. Baker KS, et al. J Clin Oncol. 2003;21(7):1352-1358.
2. Curtis RE, et al. The New England journal of medicine. 1997;336(13):897-904.
3. Longo DL. Radiation therapy in the treatment of Hodgkin's disease—do you see what I see? Journal of the National Cancer Institute. 2003;95(13):928-929.
4. van Leeuwen FE, et al. Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin's disease. Journal of the National Cancer Institute. 2003;95(13):971-980.
5. Evans MK, et al. Mutation research. 1994;314(3):221-231.
The risk for solid tumor development in prior recipients of allogeneic hematopoietic stem cells at the Leukemia/Bone Marrow Transplantation Program of British Columbia was found to be 3.1% at ten years of follow up.Subscribe Now for Access
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