Unusual clonal evolution involving 5q in a case of myelodysplastic syndrome with deletion 5q 31 treated with lenalidomide

Abstract

Unusual clonal evolution involving 5q in a case of myelodysplastic syndrome with deletion 5q 31 treated with lenalidomideLenalidomide is a very active drug in myelodysplastic syndrome with del (5q). We report such a patient treated with this drug who developed unusual complex cytogenetic abnormalities, which were elucidated by multi-FISH and FISH analysis as jumping translocations involving the long arm of chromosome 5, that resulted in an increase of 5q copies. This unusual findings is discussed in the context of resistance to lenalidomide observed in this patient. Haematologica. 2008 Feb; 93:(2) 315-316. DOI: 10.3324/haematol.11917 The 5q-syndrome, 1 is characterized by female predominance, refractory anemia with macrocytosis, normal or elevated platelet counts, frequent erythoblastopenia, abnormal monolobulated megakaryocytes, no excess of marrow blasts count, isolated del(5)(q13q33), rare progression to overt leukemia and prolonged survival.2 Lenalidomide (Revlimid; Celgene Corporation) is a thalidomide analogue with particular activity in MDS with del(5q), especially in the 5q-syndrome, leading to transfusion independence and cytogenetic response in over two-thirds of cases.3 We report a patient with the 5q-syndrome, who had resistance to lenalidomide treatment, associated to emergence of clonal evolution involving chromosome. /L, bone marrow examination showed 4% blasts and no further dysmegakaryopoeisis but persistent dyserythropoiesis. Karyotype showed 46, XX, del(5)(q31q35) in 22 out of 26 examined metaphases. The dose of lenalidomide was increased to 10 mg once daily, 3 weeks every month. After another four months, the red blood cell transfusion requirement remained unchanged and lenalidomide was stopped. Bone marrow examination revealed erythroid hyperplasia with megaloblastoid features, decrease in granulocytes, recurrence of typical dysmegakaryopoiesis, without excess of blasts.Cytogenetic examination showed a complex karyotype with del(5)(q31q35) associated with 2-4 derivative chromosomes consisting of the long arm of chromosome 5 and variable partners as short arm: 45-46,XX, del(4)(q21q35) [7],add(5)(p10) [5],+add(5)(p10)del (5) (Figure 1). Hybridization with EGRF1 probe, showed 3 spots in 45% of cells and 4 spots in 5%. Hybridization with centromeric probes (pGA-16 and pEDZ6, a gift from S. Romana, Hopital Necker Paris) confirmed the dicentric dic(5;6) in 30% of the cells. The patient died in December 2006 from lung infection.Our patient showed no erythroid response to lenalidomide and clonal cytogenetic evolution that was unusual in the 5q-syndrome. The cytogenetic evolution with numerous 5q derivatives resulting from unbalanced translocations between different partners had not, to our knowledge, been previously described, with chromosome 5. It suggests jumping translocations (JT) rarely described in different hematologic malignancies including lymphoma, myeloma, and AML or ALL.4,5 JT are characterized by relocalization of the same part of a donor chromosome to several recipient chromosomes, ...

Efficacy and safety of lenalidomide in patients with myelodysplastic syndrome with chromosome 5q deletion

“…One of the principal concerns that has arisen over the last several years is the incidence of increased clonal evolution and progression to AML in patients treated with lenalidomide [Eclache et al 2008;Gohring et al 2008;List et al 2006a]. In the MDS-003 trial, 16 patients progressed to a more advanced French-American-British (FAB) MDS subtype or AML and 24 developed new chromosomal abnormalities during the course of treatment [List et al 2006a].…”