Gary Gilliland John G Gribben

Introduction, 47 Methods for assessing the risk of therapy-related leukemia, 49

Risk factors for t-MDS/AML after autologous stem cell transplantation, 47 Approaches to minimizing the risk of t-MDS/AML, 52

Therapy-related AML is a clonal disorder, 48 Further reading, 52 More than one mutation is necessary to cause AML, 48

Introduction

Table 5.1 Criteria used to define t-MDS after ASCT at Dana-Farber Cancer Institute.

Significant marrow dysplasia in at least 2 cell lineages Peripheral cytopenia without alternative explanation Blast counts in marrow defined by FAB classification

A major complication of chemotherapy and radiotherapy for the treatment of cancer is the subsequent development of therapy-related myelodysplastic syndromes and secondary acute myelogenous leukemia (t-MDS/AML). Although devastating in their impact, t-MDS/AML allow the opportunity to study the development of malignancy since many such patients have serial blood and bone marrow samples available from the time of initial therapy to their subsequent diagnosis with leukemia. There is abundant evidence that t-MDS/AML are clonal disorders that are the consequence of acquired somatic mutations and confer a proliferative and/or survival advantage on hematopoietic progenitors. No single mutation or gene rearrangement appears to be sufficient for the development of tMDS/AML. Indeed, the identification of a single gene rearrangement or point mutation may not necessarily be predictive of its subsequent development. Methods for assessing risk are based on the presence of clonal abnormalities in hematopoietic cells, including standard cytogenetics, interphase fluorescence in situ hybridization (FISH), analysis for loss of heterozygosity (LOH), PCR for point mutations, and X-inactivation-based clonality assays. Each of these approaches has strengths and weaknesses, and they are discussed in more detail below.

The actuarial risk of developing therapy-related leukemia (t-MDS/AML) varies with the therapy used to treat the cancer. Although some agents are associated with particularly increased risk, in general the more intensive the therapy the higher the risk. The risk of the development of t-MDS/AML after high-dose chemoradiotherapy and autologous stem cell transplantation (ASCT) for lymphoma is substantial, ranging from 3% to as many as 24% of patients. In our own series of patients with non-Hodgkin's lymphoma who have undergone high-dose therapy and ASCT at the Dana-Farber

Cancer Institute, development of t-MDS/AML has emerged as the second most common cause of death, after relapse of disease, in these patients. On review of these cases, it became clear that strict criteria were required to make the diagnosis of secondary MDS. A number of patients have relative pan-cytopenia after ASCT and many patients have dysplastic features and cytogenetic abnormalities, but only 30% of these patients develop secondary MDS. The criteria that we use to define t-MDS are shown in Table 5.1. On the basis of these criteria, some patients initially reported to have developed t-MDS in the original report from this center have now been excluded, and it is of note that none of these patients have progressed to t-MDS or AML. The median time from highdose therapy to the development of t-MDS was 47 months, with a range from 12 to 129 months after ASCT. The actuarial risk of development of t-MDS in these patients is shown in Figure 5.1. The prognosis of these patients remains dismal and these patients have a median survival after diagnosis of less than 1 year.

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