Contents
13.1 Introduction . . . 135
13.2 Synchronous Malignancies . . . 135
13.3 Metachronous Malignancies . . . 136
13.3.1 Chemotherapy . . . 136
13.3.2 Hemopoietic Cell Transplantation . 136 13.3 Conclusions . . . 136
References . . . 136
Introduction
Second malignancies, defined as new malignancies that develop as a consequence of therapy, are not a frequent complication in patients with myelodysplastic syn- drome (MDS). For one, patients with less advanced or low-risk MDS are generally managed conservatively, and do not receive cytotoxic chemotherapy or irradia- tion, the two modalities most frequently associated with the induction of secondary malignancies. Secondly, pa- tients with more advanced or high-risk MDS, who may receive cytotoxic therapy in the non-transplant setting, usually are not cured of MDS and have a short life ex- pectancy. Thus, on the basis of the time course alone, these patients are unlikely to manifest second (treat- ment-related) malignancies.
The situation is different for patients who are cured of MDS by hematopoietic cell transplantation (HCT).
These patients received chemotherapy or irradiation
(or both) as conditioning for HCT and may have experi- enced graft-versus-host disease (GvHD), all factors that have been associated with new malignancies (Curtis et al. 1997, 1999; Flowers and Deeg 2004; Friedman et al.
2004). Some of these patients have now been followed for two decades, a risk period of sufficient length to al- low for at least a preliminary assessment.
To what extent genetic predisposition and poly- morphism of genes, especially in xenobiotic pathways, are relevant for both the initial diagnosis of MDS, and the chances for a secondary malignancy remains to be determined. Of greater relevance appears to be the pre- sentation of secondary MDS as a malignancy following therapy for other disorders (Metayer et al. 2003); these cases account for maybe 10±15% of all cases of MDS (see Chapter 3).
13.2
Synchronous Malignancies
Many reported series include cases where patients pre- sented with ªmarrow failureº and were subsequently di- agnosed as having MDS as well as another, generally lymphoid malignancy, including chronic lymphocytic leukemia, non-Hodgkin lymphoma, multiple myeloma, hairy cell leukemia or other. These observations again raise the question of the role of underlying genetic fac- tors, but no systematic studies addressing these possib- ilities are currently available. In addition, these observa- tions raise the question of the effect of the location of the mutagenic lesion relative to the steps in stem cell differentiation on the clinical presentation.
Second Malignancies
H. Joachim Deeg
13.3
Metachronous Malignancies
13.3.1Chemotherapy
Recent observations in patients with MDS treated with CC-5013 (Revlimid) show that some patients, in partic- ular those with a 5q± syndrome, who achieve hemopoi- etic and even cytogenetic responses, may indeed devel- op new clonal cytogenetic abnormalities. The mecha- nism leading to those abnormalities and the clinical rel- evance are currently not clear. However, the observa- tions are somewhat reminiscent of those in patients with chronic myeloid leukemia treated with imatinib.
As with all clonal (non-constitutional) abnormalities, close monitoring appears to be indicated.
13.3.2
Hemopoietic Cell Transplantation
Numerous analyses of the development of post-trans- plant malignancies have been reported, although not specifically for patients with a primary diagnosis of MDS. Curtis et al. (1997) analyzed results in 19,229 pa- tients (including 643 with MDS or myeloproliferative disorders), 97.2% of whom had received allogeneic HCT and who had been observed for 5±30 years. The ra- tio of observed/expected tumors was 2.7 (P<0.001);
among patients surviving beyond 10 years, the risk was 8.3 times that of the population at large. The cumu- lative incidence was 6.7% at 15 years. Elevated in partic- ular were the risks for malignant melanoma, cancers of the buccal cavity, liver, brain, thyroid, bone, and con- nective tissue. Higher doses of total body irradiation (TBI) were associated with solid tumors, and male sex and chronic GvHD with squamous cell carcinoma of the oral cavity and skin.
Patients were also at risk for post-transplant lym- phoproliferative disorders. The risk was highest during the first 5 months after transplantation. The cumulative incidence was 1% (Curtis et al. 1999). The risk for early occurring lymphoproliferative disorders was strongly associated (P<0.0001) with transplants from unrelated
or human leukocyte antigen (HLA) non-identical do- nors, T-cell depletion of donor marrow, the use of poly- clonal or monoclonal anti-T-cell antibody preparations to prevent or treat acute GvHD, the development of acute GvHD, and the use of TBI in the conditioning reg- imen. Late onset lymphomas were associated with ex- tensive chronic GvHD (P=0.01).
13.3
Conclusions
Thus, second malignancies have not been a major prob- lem in patients with MDS. The occurrence of new malig- nancies is most likely related to conditioning and trans- plant-related problems, but a contribution of genetic factors can, at present, neither be proven nor disproven.
References
Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Soci G, Travis LB, Horo- witz MM, Witherspoon RP, Hoover RN, Sobocinski KA, Fraumeni JF Jr, Boice JD Jr, Schoch HG, Sale GE, Storb R, Travis WD, Kolb H-J, Gale RP, Passweg JR (1997) Solid cancers after bone marrow trans- plantation. N Engl J Med 336:897±904
Curtis RE, Travis LB, Rowlings PA, Soci G, Kingma DW, Banks PM, Jaffe ES, Sale GE, Horowitz MM, Witherspoon RP, Shriner DA, Weisdorf DJ, Kolb H-J, Sullivan KM, Sobocinski KA, Gale RP, Hoover RN, Frau- meni JF Jr, Deeg HJ (1999) Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study.
Blood 94:2208±2216
Flowers MED, Deeg HJ (2004) Delayed complications after hemato- poietic cell transplantation. In: Blume KG, Forman SJ, Appelbaum FR (eds) Thomas' hematopoietic cell transplantation. Blackwell Publishing Ltd., Oxford, UK, pp 944±961
Friedman DL, Leisenring W, Schwartz JL, Deeg HJ (2004) Second ma- lignant neoplasms following hematopoietic stem cell transplanta- tion. Int J Hematol 79:229±234
Metayer C, Curtis RE, Vose J, Sobocinski KA, Horowitz MM, Bhatia S, Fay JW, Freytes CO, Goldstein SC, Herzig RH, Keating A, Miller CB, Ne- vill TJ, Pecora AL, Rizzo JD, Williams SF, Li CY, Travis LB, Weisdorf DJ (2003) Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-con- trol study. Blood 101:2015±2023
136 Chapter 13 ´ Second Malignancies
