Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

• Published in: Haematologica (Roma) 2011-07, Vol.96 (7), p.963-971
• Main Authors: MÖLLGARD, Lars, SAFT, Leonie, JÄDERSTEN, Martin, KJELDSEN, Lars, LINDER, Olle, NILSSON, Lars, VESTERGAARD, Hanne, PORWIT, Anna, GRØNBAEK, Kirsten, LINDBERG, Eva Hellström, TREPPENDAHL, Marianne Bach, DYBEDAL, Ingunn, NØRGAARD, Jan Maxwell, ASTERMARK, Jan, EJERBLAD, Elisabeth, GARELIUS, Hege, DUFVA, Inge Hogh, JANSSON, Monika
• Format: Article
• Language: English
• Subjects: acute myeloid leukemia; Aged; Aged, 80 and over; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Base Sequence; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Chromosome Aberrations; Chromosomes, Human, Pair 5 - genetics; Clinical Medicine; Dermatologi och venerologi, klinisk genetik, invärtesmedicin; Dermatology and venerology,clinical genetics, internal medicine; Female; Gene Expression Regulation, Leukemic; Haematology; Hematologi; Hematologic and hematopoietic diseases; Hematology; Humans; Internal medicine; Invärtesmedicin; Klinisk medicin; lenalidomide; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical and Health Sciences; Medical sciences; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Middle Aged; mutation; Mutation - genetics; myelodysplastic syndrome; Myelodysplastic Syndromes - drug therapy; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - mortality; Oncogene Protein p21(ras) - genetics; Oncogene Protein p21(ras) - metabolism; Original; P53; P53 mutation; Thalidomide - administration & dosage; Thalidomide - adverse effects; Thalidomide - analogs & derivatives; Treatment Outcome; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; WT1 Proteins - genetics; WT1 Proteins - metabolism
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2010.039669

Patients with chromosome 5 abnormalities and high-risk myelodysplastic syndromes or acute myeloid leukemia have a poor outcome. We hypothesized that increasing doses of lenalidomide may benefit this group of patients by inhibiting the tumor clone, as assessed by fluorescence in situ hybridization for del(5q31). Twenty-eight patients at diagnosis or with relapsed disease and not eligible for standard therapy (16 with acute myeloid leukemia, 12 with intermediate-risk 2 or high-risk myelodysplastic syndrome) were enrolled in this prospective phase II multicenter trial and treated with lenalidomide up to 30 mg daily for 16 weeks. Three patients had isolated del(5q), six had del(5q) plus one additional aberration, 14 had del(5q) and a complex karyotype, four had monosomy 5, and one had del(5q) identified by fluorescence in situ hybridization only. Major and minor cytogenetic responses, assessed by fluorescence in situ hybridization, were achieved in 5/26 (19%) and 2/26 (8%) patients, respectively, who received one or more dose of lenalidomide, while two patients achieved only a bone marrow response. Nine of all 26 patients (35%) and nine of the ten who completed the 16 weeks of trial responded to treatment. Using the International Working Group criteria for acute myeloid leukemia and myelodysplastic syndrome the overall response rate in treated patients with acute myeloid leukemia was 20% (3/15), while that for patients with myelodysplastic syndrome was 36% (4/11). Seven patients stopped therapy due to progressive disease and nine because of complications, most of which were disease-related. Response rates were similar in patients with isolated del(5q) and in those with additional aberrations. Interestingly, patients with TP53 mutations responded less well than those without mutations (2/13 versus 5/9, respectively; P=0.047). No responses were observed among 11 cases with deleterious TP53 mutations. Our data support a role for higher doses of lenalidomide in poor prognosis patients with myelodysplastic syndrome and acute myeloid leukemia with deletion 5q. (Clinicaltrials.gov identifier NCT00761449).