Efficacy of lenalidomide in myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and an extreme platelet count

Abstract Lenalidomide is efficient in reducing red blood cell transfusion dependency and markedly lowering platelet counts in MDS/MPN‐RS‐T in the context of major platelet counts.


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DIVOUX et al. mutations in exon 10 of MPL (myeloproliferative leukemia) or in exon 9 of CALR (calreticulin) and (b) a high rate of splicing factor 3B subunit 1 (SF3B1) mutations, responsible for the myelodysplastic component of the disease. [2][3][4][5][6] Thus, MDS/MPN-RS-T is now considered as an independent entity. 1 The risk of thrombosis is higher in MDS/MPN-RS-T than in MDS-RS patients without a high platelet count and this thrombotic risk often leads clinicians to use cytoreductive agents known to reduce the platelet count in almost 33% of cases. 2 However, the use of cytoreductive agents is frequently interrupted, due to the worsening of cytopenia, especially anemia. The management and treatment of this disease are currently based on thrombosis risk stratification. When platelet count is <1000 × 10 9 /L, Patnaik and Tefferi 7 recommend stratifying patients according to two thrombosis risk factors: age > 60 years and prior arterial or venous thrombosis. Patients with no risk factors should be treated with low-dose aspirin or observation alone in JAK2 V617F -negative diseases with absence of thrombotic risk factors. Patients with 1 or 2 risk factors should be treated with low-dose aspirin. Cytoreductive therapy with hydroxyurea is only recommended in case of high thrombotic risk. Lenalidomide is an immunomodulatory agent frequently used in low-risk myelodysplastic syndromes. 8 In this context, it is considered as third-line treatment, in case of hydroxyurea failure associated with anemia. In case of a high platelet count >1000 × 10 9 /L, aspirin may exacerbate bleeding, cytoreductive therapy often worsens anemia and lenalidomide use is not suggested. Lenalidomide has been tested in published MDS/MPN-RS-T cases, with conflicting results. [9][10][11][12][13][14][15] Here, we report our experience using lenalidomide on two patients with JAK2 V617Fnegative MDS/MPN-RS-T, one of them presenting with a major thrombocytosis.

| CASES HISTORY
The first patient was a 78-year-old woman (Patient 1, Table 1), with a complete blood count (CBC) showing hemoglobin level at 85 g/L, persistent thrombocytosis (platelet count: 743 × 10 9 /L) and a leukocyte count at 6.4 × 10 9 /L. The bone marrow aspirates revealed erythroid hyperplasia with myelodysplastic features and 64% ring sideroblasts, no blast cells, associated with atypical megakaryocytes, leading to the diagnosis of MDS/MPN-RS-T, according to the revised 2016 world health organization classification's criteria. 1 Bone marrow cytogenetics showed a normal 46XX karyotype. A Lys700Glu SF3B1 mutation was noted, without JAK2 V617F , MPL exon 10 or CALR mutations. Blood transfusions were performed for one year but, in order to avoid relying on red blood cell transfusions, a treatment with lenalidomide (5 mg daily, 21/28 days) was started resulting in the decrease of platelet count from 686 × 10 9 /L (start of treatment) to 150 × 10 9 /L, associated with an improvement in hemoglobin levels from 80 to 100 g/L over      Figure 1A), and no transfusion was required in the subsequent 47 weeks since the hemoglobin level was above 90 g/L. However, due to the subsequent decrease in the hemoglobin level, RBC transfusions were later reinitiated, but with a lower frequency (2 units of RBC every 2 months), in association with lenalidomide. In other words, over the 20 months of treatment with lenalidomide, the RBC requirements were drastically reduced. However, grade IV neutropenia was observed (granulocytes: 0.5 × 10 9 /L), without any infectious disease, but leading to treatment stop. The second patient was a 58-year-old woman (Patient 2, Table 1) whose initial CBC showed hemoglobin 114 g/L, platelet count 710 × 10 9 /L, leukocytes 7.4 × 10 9 /L. Bone marrow aspirate showed erythroid hyperplasia with myelodysplastic features, no excess of blasts and 24% ring sideroblasts associated with atypical megakaryocytes, leading to the diagnosis of MDS/MPN-RS-T. 1 Bone marrow cytogenetics showed a normal karyotype. A watch-and-wait strategy was initiated, but due to a marked increase in the platelet count > 2000 × 10 9 /L, hydroxyurea (500 mg/d and then 1000 mg/d) was started. It worsened the anemia to 108 g/L and then to 84 g/L, leading to a weekly use of erythropoietin. After 18 months, hydroxyurea was stopped due to (a) its adverse effects on hemoglobin level and (b) the observation of irregular elevated platelet counts ranging from 1700 × 10 9 /L to 3622 × 10 9 /L. After a drop of platelet count at 1700 × 10 9 /L, a new increase was observed at 3106 × 10 9 /L leading to the start of a lenalidomide treatment (5 mg daily, 21/28 days), secondarily increased to 10 mg daily (21/28 days) since very well tolerated. A marked decrease in the platelet count from 3106 to 760 × 10 9 /L was noted, while hemoglobin level raised up from 102 to 118 g/L ( Figure 1B). However, for this patient, erythropoietin treatment was maintained every 2 weeks in combination with lenalidomide. Four years after the beginning of lenalidomide therapy, platelet F I G U R E 1 Course of blood counts for the two patients treated with lenalidomide: A, Patient 1; B, Patient 2. The left y-axis represents the platelet counts (10 9 /L), and the right y-axis represents hemoglobin level (g/L). The x-axis represents the follow-up (in days)
Informed consent for publication was obtained from both patients.

| DISCUSSION
In conclusion, this two-case experiment with more than 3-year follow-up shows the efficacy of lenalidomide in normalizing (Patient 1) or markedly reducing (Patient 2) the platelet count and allowing independency from RBC transfusion in MDS/MPN-RS-T. To our best knowledge, ten MDS/ MPN-RS-T cases have been published so far ( Table 2). [9][10][11][12][13][14][15] The efficacy of lenalidomide was constant in early stages, except for one case of advanced disease with rapid evolution in myelofibrosis and bone marrow failure. 10 Efficacy of lenalidomide in reducing platelet count has been observed in 3 published cases ( Table 2, patients 1, 7, and 10), 9,14,15 in the context of moderately elevated platelet counts.
Our second case is striking, since it shows that lenalidomide induced a significant decrease in platelet count, even starting from very high counts (up to 3106 × 10 9 /L), along with an increase in hemoglobin level. So far, the efficacy of lenalidomide has never been shown in MDS/MPN-RS-T with such a high platelet count. It highlights the interest of lenalidomide as an alternative treatment for MDS/MPN-RS-T, including when they present with a major platelet count. Prospective trials are still needed to confirm those encouraging results, but because of rarity of the disease, such trials are very difficult to perform.