Efficacy of Lenalidomide in Myelodysplastic/Myeloproliferative Neoplasms with Ring Sideroblasts

Background: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) with ring sideroblasts and thrombosis (MDS/MPN-RS-T), include the dysplastic features of Refractory Anemia with Ring Sideroblasts (RARS) and the myeloproliferative features of essential thrombocythemia (ET) and are characterized by a high rate (50%) of JAK2 V617F mutations or rarely by the presence of mutations in exon 10 of the MPL (myeloproliferative leukemia) gene or in exon 9 of the calreticulin gene. We previously demonstrated that RARS-T differed from RARS and ET from a clinical, biological and prognostic point of view and that the presence of high rates of splicing factor 3B subunit 1 (SF3B1) mutations in RARS-T and the absence of these mutations in ET strengthened the hypothesis that RARS-T was a distinct entity. We also reported in a large series of patients (n=200) that the risk of thrombosis was higher in RARS-T than in RARS patients without a high platelet count, leading clinicians to reduce the platelet count in almost 33% of RARS-T patients. However, due to the presence of anemia, the use of the cytoreductive agents usually used in ET is limited since they worsen the cytopenia. This explains why it is difficult to treat patients who harbor both anemia and thrombocytosis.

Lenalidomide, an immunomodulatory agent frequently used in low-risk MDS, has very rarely been tested in MDS/MPN-RS-T patients, with conflicting results.

Objective : To test the effect of Lenalidomide on MDS/MPN-RS-T

Patients: Here, we report our experience using lenalidomide in two women who presented with JAK2 V617F negative MDS/MPN-RS-T.

Results: The first patient was a 78 year-old woman, with a complete blood count (CBC) showing hemoglobin 80 g/L, platelet count 686 G/L and leukocytes 6 G/L. The second was a 58 year-old woman whom initial CBC showed hemoglobin 113 g/L, platelet count 1,600 G/L, leukocytes 8.2 G/L. In both cases the bone marrow aspirates showed erythroid hyperplasia with myelodysplasic features and 64% and 24% of ring sideroblasts respectively, associated with marked dysmegakaryopoiesis, leading to the diagnosis of MDS/MPN-RS-T. No excess of blast cells was noted. Bone marrow cytogenetics showed in both cases a normal 46XX karyotype. A Lys700Glu SF3B1 mutation was noted for one patient (not tested for the second), without the JAK2 V617F or MPL exon10 or CALR mutations.

In the first patient, blood transfusions were initiated for one year, however, due to an increase in dependence on red blood cell transfusions, treatment with lenalidomide (5 mg daily 21/28days) was started and led to a decrease in the platelet count from 686 to 220 G/L associated with an regular improvement in hemoglobin levels from 80 to 100 g/L within the first 28 weeks of lenalidomide (only 6 units of red blood cells were transfused along this period). Finally, no transfusion was required in the subsequent 47 weeks since the hemoglobin level was above 90 g/L. However, due to a low hemoglobin level, red blood cell transfusions were reinitiated, but with a lower frequency (2 units of red blood cells every 2 months), in association with lenalidomide. Altogether, over the 20 months of treatment with lenalidomide, the red blood cell requirement was drastically reduced. However, grade IV neutropenia was observed (granulocytes 0.5 G/L) but without any infectious disease, leading to stop the treatment.

In the second patient, a watch-and-wait strategy was initiated, but due to an increase in the platelet count > 2,000 G/L, hydroxyurea (500 mg/day) was started, worsening the anemia to 108 g/l then 84 g/l leading to the use of erythropoietin once/week. Hydroxyurea was then stopped due to its adverse effects on hemoglobin, leading to the increase in the platelet count to 3,622 G/L. A treatment with lenalidomide (5 mg daily 21/28days) was then started and secondarily improved to 10 mg daily 21/28days since very well tolerated. A marked decrease in the platelet count was noted, from 3,622 to 985 G/L whereas hemoglobin level rised up from 92 to 115 g/L. Off note, for this patient erythropoietin treatment was maintained every 2 weeks in combination with lenalidomide.

Conclusion: This two-cases experience confirms the partial efficacy of lenalidomide in MDS/MPN-RS-T in normalizing (case 1) or markedly reducing (case 2) the platelet count and allowing of independence from blood transfusion (at least for 10 months in case 1).