Publication Only: Myelodysplastic syndromes - Clinical
MDS del(5q) is a distinct MDS subgroup with an isolated interstitial 5q deletion involving 5q31, characterized by bone marrow erythroid hyperplasia, hypolobated megakaryocytes and refractory anemia. The phenotype is due to haplo-insufficiency of multiple genes. Heterozygous loss of the RPS14 gene on 5q leads to activation of p53 in the erythroid lineage and the macrocytic anemia characteristic of the 5q- syndrome. The megakaryocytic and platelet phenotype of the 5q- syndrome has been attributed to heterozygous deletion of miR145 and miR146a. The haploinsufficient gene expression is known to sensitize cells to lenalidomide therapy. Lenalidomide also co-stimulates T cells through degradation of interleukin 2 expression repressors (Gandhi et al., Br J Haematol 2014) and has been found to activate cytotoxic T and NK cells (Kerdivel et al., Leukemia 2018).
The current treatment standard in MDS del(5q), where severe anemia is usually the main clinical problem, is after erythropoietin refractoriness or failure, lenalidomide taken 10 mg per day in 21/28-day cycles. An erythroid response is reached in 76% after a median of 4,6 weeks. A complete cytogenetic remission (CCyR) has been reported in 45%. Lenalidomide is continued until relapse of red blood cell (RBC) transfusion dependence or progression of disease, which may mean several years of treatment. Stem cells harboring del(5q) have, however, been detected even in patients in CCyR.
Rare MDS del(5q) cases have been reported with persistent RBC transfusion independence (RBC-TI) even after discontinuing lenalidomide. RBC- TI lasting several years has been described in eight patients in CCyR for at least 6 months during lenalidomide before stopping (Giagounidis et al., Leukemia 2012).
Lenalidomide has been associated with long-term adverse effects such as development of secondary malignancies and possible selection of resistant clones, especially clones with TP53 mutation, predisposing to AML progression. Therefore, possible beneficial effects of temporary or sequential lenalidomide treatment have been suggested.
We describe five MDS del(5q) patients with prolonged RBC-TI after interruption of lenalidomide use (Table).
The clinical data was retrospectively collected from records of available patients in Finland.
All the still living patients (1,2, 4 and 5) had normal hemoglobin levels at the time of analysis. Some of the patients had an inflammatory reaction temporally closely associated with lenalidomide initiation (erythrodermia, myocarditis, pruritic eczema after the second lenalidomide initiation in patient 3). In addition, patient 2 had pre-existing rheumatoid arthritis. In patient 5, the interleukin 2 receptor concentration measured during the acute erythrodermic phase was as high as 6080 kU/l, and also a temporary plasma cell clone in the bone marrow of the patient was detected. The clinical course and various immunological features/reaction models will be analyzed in blood and bone marrow samples collected from the most recent patient 5.
A limited lenalidomide exposure may result in prolonged transfusion free time in MDS del(5q) patients. This beneficial response might be associated with an early immune reaction inducing long-term suppression of the disease clone. Acute inflammatory events in patients could represent development of a host-versus-malignancy effect. Prospective clinical trials in MDS del(5q) with lenalidomide interruption for instance after hemoglobin level normalization or at CCyR, and close follow-up, are warranted.