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Remitting Activity of Lenalidomide in Treatment-Induced Myelodysplastic Syndrome

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Remitting Activity of Lenalidomide in Treatment-Induced Myelodysplastic Syndrome Letters to the Editor 1576 products was significantly higher (greater than 2-fold) than the 2Department of Leukemia, University of Texas MD Anderson morphologic mast cell counts, which suggested the presence of Cancer Center, Houston, TX, USA KIT mutation in non-mast cell components. Table 1 summarizes E-mail: [email protected] the demographics, BM myeloid cell counts, KIT mutation levels and final disease classification. Review of clinical features and References pathological material revealed coexisting AHNMCD in all five discordant cases. Among the remaining 11 cases in which 1 Akin C, Jaffe ES, Raffeld M, Kirshenbaum AS, Daley T, Noel P et al. percentage of mutated KIT PCR product was roughly equal to or An immunohistochemical study of the bone marrow lesions of less than the number of mast cells, three had associated mild systemic mastocytosis: expression of stem cell factor by lesional eosinophilia, two had associated CMML and the rest were mast cells. Am J Clin Pathol 2002; 118: 242–247. morphologically consistent with pure MCDs. There was striking 2 Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG et al. female predominance among the pure MCD and MCD with Somatic c-KIT activating mutation in urticaria pigmentosa and isolated eosinophilia cases (9 of 10) compared to the male aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet 1996; 12: 312–314. predominance in MCD with AHNMCD cases (6/6 male, Po 3 Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, 0.002). For all 39 patients in the study, KIT mutation was Suzuki Y et al. Identification of a point mutation in the catalytic detected much more frequently in MCD with ANMHD domain of the protooncogene c-kit in peripheral blood compared with those cases in which KIT mutation was mononuclear cells of patients who have mastocytosis with an not detected by either pyrosequencing or D816V qPCR (1/26, associated hematologic disorder. Proc Natl Acad Sci USA 1995; 92: 1 CMML). 10560–10564. 4 Taylor ML, Sehgal D, Raffeld M, Obiakor H, Akin C, Mage RG et al. We show here that a routine quantitative pyrosequencing Demonstration that mast cells, T cells, and B cells bearing the assay for KIT codon 816, while not sensitive enough to detect activating kit mutation D816V occur in clusters within the marrow mutation in unsorted samples of MCD with minimal (o5%) of patients with mastocytosis. J Mol Diagn 2004; 6: 335–342. marrow involvement, can readily highlight those cases of MCD 5 Garcia-Montero AC, Jara-Acevedo M, Teodosio C, Sanchez ML, associated with an associated KIT mutation-bearing myeloid or Nunez R, Prados A et al. KIT mutation in mast cells and other bone eosinophilic component. The quantitative nature of pyrosequen- marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) cing, however, provides a rapid method to help recognize cases in a series of 113 patients. Blood 2006; 108: 2366–2372. of MCD-AHNMD and differentiate them from pure MCD. Given 6 Valent P, Metcalfe DD, Horny H-P, Parwaresch RM, Li CY, Bennett the differential sensitivity of MCD with different molecular JM et al. Mastocytosis. In: Jaffe ES, Harris N, Stein H & Vardiman JW abnormalities to kinase inhibitors, quantitative molecular (eds) Tumours of Hematopoietic and Lymphoid Tissues. IARC Press: classification methods for KIT mutation detection will also be Lyon, France, 2001, 292–302. essential to establish the molecular correlates of response of 7 Nordstrom T, Ronaghi M, Forsberg L, de Faire U, Morgenstern R, 8 Nyren P. Direct analysis of single-nucleotide polymorphism on MCD subtypes to novel targeted therapeutic agents. double-stranded DNA by pyrosequencing. Biotechnol Appl Bio- chem 2000; 31 (Pt 2): 107–112. W Zhao1, CE Bueso-Ramos1, S Verstovsek2, BA Barkoh1, 1 1 8 Schittenhelm MM, Shiraga S, Schroeder A, Corbin AS, Griffith D, AA Khitamy and D Jones Lee FY et al. Dasatinib (BMS-354825), a dual SRC/ABL kinase 1 Division of Pathology and Laboratory Medicine, Department inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, of Hematopathology, University of Texas MD Anderson and activation loop mutant KIT isoforms associated with human Cancer Center, Houston, TX, USA and malignancies. Cancer Res 2006; 66: 473–481. Remitting activity of lenalidomide in treatment-induced myelodysplastic syndrome Leukemia (2007) 21, 1576–1578; doi:10.1038/sj.leu.2404677; extracorporeal perfusional chemotherapy with mitomycin-C, published online 29 March 2007 interleukin-2, epirubicin, etoposide, 5–fluorouracil, leucovorin and methotrexate. He has remained in a sustained complete remission from the adenocarcinoma. However, he developed Lenalidomide (Revlimid, Celgene) is an immunomodulatory mild thrombocytopenia in 2001, followed by progressive agent with both erythropoetic and cytogenetic remitting activity anemia and thrombocytopenia in early 2006. By February in patients with primary myelodysplastic syndrome (MDS) 2006, he had a hemoglobin level of 8.8 g/dl with a white blood associated with interstitial deletion of chromosome 5q. MDS cell count of 2400/ml and platelet count of 54 000/l. Bone secondary to chemotherapy or ionizing radiation is historically marrow aspirate and biopsy were performed in March 2003 associated with an aggressive natural history and unfavorable demonstrating a relatively hypocellular marrow with trilineage prognosis with resistance to standard therapeutic agents.1 Here dysplasia and a myeloid/erythroid ratio of 1:1.2. The myeloblast we report two patients with secondary MDS and deletion 5q count was 15% with rare ringed sideroblasts and cytogenetic who achieved hematologic or cytogenetic responses following studies demonstrated a 5q 13–33 deletion in 20 of 23 treatment with lenalidomide. metaphases analyzed. He initially received treatment with In the first case, a seventy-four-year-old male with secondary recombinant erythropoietin 10 000 units three times a week MDS was initially diagnosed in June 1999 with adenocarcinoma without improvement and was dependent on red blood cell of the gastroesophageal junction. He underwent esophagectomy transfusion. A repeat bone marrow biopsy performed in April with gastric pull through and surgical staging of T3 N1 M0 2006 showed no change in medullary blast percentage (16%) or disease (six of nine lymph nodes involved). He received 45 Gy karyotype. The patient started treatment with lenalidomide at a post-operative radiotherapy and aggressive local regional dose of 10 mg daily in June 2006. He received treatment for 10 Leukemia Letters to the Editor 1577 consecutive days followed by a 7-day treatment hiatus for As summarized in Table 2, the patient’s platelet count started pruritic rash before resuming lenalidomide at 5 mg daily dose. to decline in July 2006 and treatment with lenalidomide 10 mg After 2 months of treatment, he experienced a progressive rise in daily was initiated on 20 July 2006. His baseline white blood hemoglobin level (44 g/dl increase) and moderate improve- cell count was 3000/ml, hemoglobin level of 10.4 g/dl and ment in platelet count (Table 1). He has been maintained on platelet count 82 000/ml. Lenalidomide was continued for 30 5 mg daily dose thereafter. Bone marrow aspirate and biopsy days, during which time the platelet count after an initial drop repeated on 22 August 2006 showed no evidence of residual recovered to over 100 000/ml for the first time in 5 months. A dysplasia with 0% blasts and cytogenetic studies demonstrating repeat bone marrow evaluation on 31 August 2006 showed a a normal male karyotype in each of the 20 metaphases analyzed. normocellular marrow with erythroid hyperplasia, decreased His latest red blood cell transfusion was administered on June granulopoiesis and increased megakaryopoiesis. Cytogenetic 2006 with the most recent complete blood count recorded on 22 analysis revealed clonal evolution with new abnormalities December 2006 showing a white blood cell count of 2300/ml with including 7qÀ, 17pÀ and 12pÀ. No increased blast population 53% neutrophils, hemoglobin level of 12.4 gm/dl with an MCV of was identified. A matched unrelated donor was identified and 104 and a platelet count of 99 000/ml. the patient received an unrelated donor transplant in September Next, a 50-year-old male patient with treatment-related MDS 2006. He remains without any evidence of relapse from his and a previous history of chemotherapy for follicular lymphoma MDS. followed by autologous stem cell transplantation was treated Lenalidomide has proven efficacy in the treatment of primary with lenalidomide. The diagnosis of stage IV-B follicular non- MDS and was approved by the Food and Drug Administration Hodgkin lymphoma (NHL) was made in November 2002. He (FDA) in the United States in December 2005 for the treatment received treatment with a Southwest Oncology Group (SWOG) of transfusion-dependent, low or intermediate-1 risk MDS with protocol including cyclophosphamide, adriamycin, vincristine chromosome 5q deletion. Approximately 70% of patients with and prednisone (CHOP) followed by iodine (I131) tositumomab MDS and deletion 5q as the sole chromosomal abnormality in May 2003. He achieved complete remission, but relapsed in treated on the MDS-001 and MDS-003 trials achieved major November 2004 and received treatment with rituximab, hematologic and cytogenetic response.2,3 Response rates in ifosfamide, carboplatin and etoposide (RICE) for three cycles. patients with complex karyotype, which is characteristic of Peripheral blood stem cells were mobilized with AMD3100 and treatment-induced MDS, was not significantly different from granulocyte colony-stimulating factor. On 16 July 2005, he patients with an isolated 5q deletion. The presence of one or underwent a conditioning regimen with cyclophosphamide and more chromosomal abnormalities portends a more unfavorable a total body irradiation followed by autologous stem cell rescue. prognosis in MDS with deletion 5q. However, in the MDS-003 He engrafted promptly, however, thrombocytopenia persisted at trial, overall survival showed no significant difference when both 100 and 180 days after the procedure.
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