Lenalidomide in High-Risk Myelodysplastic Syndrome and Acute Myelogenous Leukemia Associated with Chromosome 5 Abnormalities.

Background: Treatment with lenalidomide produces remarkable responses in patients with myelodysplastic syndrome and deletion 5q 31 (5q-) cytogenetic abnormality; transfusion independence in 67% of patients, major cytogenetic responses in 44% and a median duration of response of 115.9 weeks (List et al. Abstract #251; Blood: 108). Responses have been reported in few patients with MDS and complex karyotype as well. Since chromosome 5 abnormality is considered to be an early genetic event, we designed a phase 2 study of lenalidomide in patients with high-risk MDS and relapsed/refractory acute myelogenous leukemia (AML) with any chromosome 5 abnormality.

Method: The dose of lenalidomide was 25 mg/day, orally for 21 days with 7 days rest (28 day cycle). For patient with platelet count < 50,000/μl, the starting dose is 15 mg/day orally for 21 days with 7 days rest (28 day cycle). Dose interruptions/reductions are planned for ≥ grade3 neutrpenia with fever or ≥ grade 4 neutropenia (for patients starting with absolute neutrophil count [ANC] >1000/μl) and for grade 3 thrombocytopenia (for patients starting with platelet count ≥ 50,000/μl).

Results: Eleven patients out of this 30 patient study have been treated so far; 6 with AML and 5 with MDS. All patients with AML and 2 patients with MDS had previous therapy. Median age is 63 years (range, 44 to 80 years). Nine patients had complex karyotypic abnormality and 2 patients had single additional chromosomal abnormality (+8 in one and 11q abnormality in another) along with 5q deletion. One patient with AML (previously treated with decitabine) and with karyotypic abnormality of trisomy 8 in addition to 5q deletion, achieved complete remission after 3 cycles of therapy. Another patient had reduction in bone marrow blasts from 21 to 5%, but could not continue lenalidomide due to profound thrombocytopenia complicated by gastrointestinal bleeding and eventually had disease progression. Four (4/6) patients with a platelet count of ≥ 30,000/μl and 5 (5/6) patients with ANC of ≥500/μl at study entry experienced worsening cytopenias. No grade 3/4 non-hematological toxicities were seen. One patient in CR currently remains on study. Reasons off study include disease progression (8 patients), stem cell transplant (1 patient) and one patient died while on study from sustained pancytopenia, infection and multiorgan failure.

Conclusion: The role of lenalidomide in the treatment of high-risk MDS and AML with chromosome 5 and additional karyotypic abnormalities needs to be defined in the context of clinical trials. Future studies are needed to examine lower doses with or without growth factor support.