Late Onset of Secondary AML with 5q- in CLL with 13q- Abnormality; Coexistence of the Two Neoplastic Clones and the Therapeutic Potential of Lenalidomide.

Abstract 4394

Therapy-related acute myeloid leukemia (AML) and myelodysplastic syndrome (t-AML/MDS) are common after alkylating agents. t-AML/MDS related to alkylating agents are associated with monosomies or deletions of the long arm of chromosomes 5 and 7.

Among patients with chronic lymphocytic leukemia (CLL), the potential for disease transformation to diffuse aggressive non-Hodgkin's lymphoma (Richter's syndrome) or the evolution to prolymphocytic leukemia is well known. However, the development of therapy related myelodysplastic syndrome (t-MDS) or t-AML is uncommon. In most trials, an incidence rate of 1% has been reported. We describe here a patient who developed t-AML twentyone years after treatment with chlorambucil and fludarabine for CLL, carrying a typical CLL-associated Chromosomal abnormality (CA), associated with a typical AML-related CA.

In 1988 a 42-year-old man was found to have B-cell CLL (Binet stage B). Examination of the marrow showed infiltration by small lymphoid cells that expressed CD5, CD19, CD23, and weak surface immunoglobulin with lambda light chain restriction. The residual hematopoiesis was otherwise normal in morphology. During subsequent years he received courses of therapy with chlorambucil and fludarabine which resulted in partial remission. In June 2009 he developed pancytopenia (WBC 11.4×10e9/L, PMN 0.1×10e9/L, Hgb 7.7g/dL, PLT 26×10e9/L). Physical examination showed small, diffuse lymphadenopaties and splenomegaly. Peripheral blood film examination and immunophenotype were consistent with diagnosis of CLL. Bone marrow examination showed trilineage myelodisplasia with 25% blasts and 62% lymphocytes that expressed CD5, CD19, CD23 and sIg lambda, confirming the diagnosis of concurrent AML with multilineage dysplasia and CLL. Cytogenetic analysis showed a hyperdiploid karyotype with a number of chromosomes comprised between 47 and 55. FISH analysis of bone marrow showed del 5q in 50% of nuclei and biallelic deletion of 13q14 in 70% of nuclei. FISH analysis on peripheral blood confirmed deletion 13q14 in 80% of nuclei, and del 5q in 10% of nuclei; trisomy of 18 in 50% of nuclei was also present.

Although patients with CLL have an increased risk for the development of second malignancies, solid tumors are most common. With regard to second hematologic malignancies, the risk of multiple myeloma in patients with CLL is increased 10-fold over the incidence of myeloma in the general population. However, AML develops in 1% or fewer of patients with CLL, despite the frequent and long-term use of alkylating agents for therapy, the older age of many of these patients, and their relatively long survival with this disease process. In a retrospective review by Robertson et al of 1,374 CLL patients who received care at the M.D. Anderson Cancer Center from 1972 to 1992, only three cases of MDS or AML were found. Seventy-two percent of these patients had received prior alkylator therapy. Anecdotal cases of myelodysplasia or AML occurring in untreated patients with CLL have been reported, as have cases of concomitant diagnoses of CLL and AML, although these are quite uncommon. These cases of secondary leukemia were generally refractory to therapy, with a median survival after diagnosis of approximately 1 month. Lenalidomide (Revlimid) is an immunomodulatory drug that yields a high frequency of erythroid, pathologic, and cytogenetic response in patients with myelodysplastic syndromes (MDS) with an interstitial deletion of the long arm of chromosome 5 (del 5q). Responses of AML with del 5q are also reported. Whether both the diseases will respond to this drug it is matter to prospectively investigate in these cases.