Hematologic and Cytogenetic Response to Lenalidomide Therapy in an 82 Year Old Female with Acute Myeloid Leukemia (AML) Arising from JAK2V617F Positive, del(5)(q13q33) Myelodysplastic Syndrome (MDS).
Authors: Mesa Ruben A. , Tefferi Ayalew , Steensma David P. 
Published: April 2020

Background: Lenalidomide (Revlimid; Celgene Co. New Jersey, USA) has ameliorated cytopenias and induced cytogenetic responses in patients with MDS, especially those with del(5)(q13q33)) (List et. al. NEJM2005;352:549–57)., and myelofibrosis with myeloid metaplasia with del(5)(q13q33) (Tefferi et. al. Blood 2006 epub). However, no data exist regarding lenalidomide efficacy in patients with del(5)(q13q33) who have progressed to AML.

Case: An 82 year old woman presented to our institution with a several year history of MDS associated with mild anemia, thrombocytosis, and isolated del(5)(q13q33). She had required no prior MDS-specific therapy, and had suffered no thrombohemorrhagic complications. Subsequently, in response to worsening anemia (hemoglobin 9.9 g/dL), leukopenia (1.5 × 109/L), and neutropenia (0.45 × 109/L), with the appearance of peripheral circulating blasts (2%), a bone marrow was obtained. The marrow demonstrated minimally differentiated AML (AML-M0) with 34% blasts and trilineage dysplasia. Karyotypic analysis showed 11 of 20 metaphases containing the del(5)(q13q33), while allele specific PCR demonstrated the presence of JAK2V617F.

Therapy: After discussion of the therapeutic alternatives with the patient (including the high risk and likelihood of failure with conventional induction chemotherapy with AML that arises in the context of MDS in an elderly patient (median survival 3–4 weeks - DeLima et. al. Br J Haem1996;93:89), and the responses reported with lenalidomide for patients with interstitial chromosome 5q deletions and MDS, she elected to begin lenalidomide at a dose of 10mg/day. She tolerated the agent well, without any adverse effects. After three months of treatment, she had normal peripheral blood counts, and no evidence of circulating blasts. A repeat marrow exam showed a slightly hypercellular marrow with 5% blasts, improved granulocyte maturation, and a completely normal female karyotype (&gt;20 metaphases counted). This would be considered a partial response by the International Working Group for Acute Myeloid Leukemia (Cheson et. al. JCO2003;21:4642–49). After two additional months of lenalidomide the patient had evidence of disease progression, with recurrent leukopenia, thrombocytopenia, and 10% blasts in the marrow. Additionally, karyotype showed clonal progression, with 10/30 metaphases having the del (5) (q13q33), and 7 of them with multiple other structural abnormalities including loss of 17p. Alternative therapy was initiated.

Discussion: To our knowledge, this is the first report of lenalidomide monotherapy resulting in achievement a solid 5 month partial remission in an elderly patient with high risk AML . The patient reported a high quality of life during this time, and was free of transfusions, hospitalization, and infection. The co-existence of the JAK2V617F mutation, a finding more commonly associated with myeloproliferative disorders, is an additional intriguing aspect to this case. JAK2V167F has been described in 6.2% MDS patients with del(5)(q13q33) (Ingram et. al. Leukemia 2006 April 16), and the clinical significance is unknown.

Conclusions: Few agents offer legitimate therapeutic benefit to elderly patients with secondary AML. Lenalidomide may have activity as monotherapy against AML arising from del(5q)-associated chronic myeloid disorders. However, the apparent ability of the disorders to undergo clonal evolution suggests that combination or sequential therapy of lenalidomide with other novel or traditional agents should be explored.