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Current Opinion in Hematology:
doi: 10.1097/MOH.0000000000000021
MYELOID DISEASE: Edited by Martin S. Tallman

Making sense of the myelodysplastic/myeloproliferative neoplasms overlap syndromes

Tiu, Ramon V.a,b,c,∗; Sekeres, Mikkael A.a,c,∗

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Author Information

aDepartment of Translational Hematology and Oncology Research

bCleveland Clinic Taussig Cancer Institute

cLeukemia Program, Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA

Both authors contributed equally to the writing of this article.

Correspondence to Mikkael A. Sekeres, MD, MS, Director, Leukemia Program, Professor of Medicine, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue R35, Cleveland, OH 44195, USA. Tel: +1 216 445 9353; fax: +1 216 636 0636; e-mail: sekerem@ccf.org

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Abstract

Purpose of review

Myelodysplastic/myeloproliferative neoplasms (MDS/MPNs), including chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, MDS/MPN-Unclassifiable, ring sideroblasts associated with marked thrombocytosis, and juvenile myelomonocytic leukemia, are clonal hematologic diseases characterized by myeloid dysplasia, proliferation, and absence of the molecular lesions BCR/ABL, PDGFRA, PDGFRB, and FGFR1. There are currently no US Food and Drug Administration approved therapies for all MDS/MPN subtypes. Advances in the understanding of the biologic and molecular drivers of these diseases will help in diagnosis, prognosis, and therapeutics. This review article summarizes the molecular aspects of MDS/MPNs and provides an overview of classic and emerging therapies.

Recent findings

Next generation sequencing has provided new insights into the genetic nature of MDS/MPNs. Molecular mutations such as TET2, CBL, SETBP1, CSF3R, and SF3B1 are relevant as diagnostic and prognostic biomarkers. Hematopoietic cell transplantation, although potentially curative, is applicable to only a small proportion of patients. Attempts to standardize response and outcomes criteria specific to MDS/MPN and clinical trials using novel agents focused on MDS/MPN patients are underway.

Summary

MDS/MPNs have clinicopathologic features of both MDS and MPN diseases. Emerging molecular data support the distinctive disease biology of each of these morphologic entities, and will serve as the foundation to develop effective therapeutics that can ameliorate disease-related complications and lead to better outcomes.

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INTRODUCTION

In 2001 the WHO introduced a new disease entity called myelodysplastic/myeloproliferative neoplasms (MDS/MPNs), encompassing diseases with overlapping phenotypic features of MDS and MPN. At clinical presentation, patients frequently manifest with cytopenias and dysplasia (MDS feature) and variable degrees of myeloproliferation of different cell lineages, frequently with extramedullary hematopoiesis (MPN feature). The four MDS/MPN disease subtypes includes chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), and MDS/MPN-Unclassifiable (MDS/MPN-U), which includes refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T) [1]. Diagnosis based on the 2008 WHO classification is heavily weighted on morphological criteria. Additional disease characteristics involving genetic data are obtained using metaphase cytogenetics, fluorescence in-situ hybridization (FISH), and polymerase chain reaction. Patients who belong to specific MDS/MPN subtypes have variable natural histories and outcomes incompletely addressed by current WHO classification schemes or by prognostic risk stratification systems like the International Prognostic Scoring System (IPSS) and revised IPSS, both of which exclude patients with white blood cell (WBC) counts more than 12 k/μl. Similarly, although MDS/MPN patients are treated with drugs developed for MDS or MPN, no therapeutic and outcomes response criteria have been developed specifically for the management of MDS/MPN patients. Furthermore, there are no US Food and Drug Administration approved therapies for any of the specific MDS/MPN subtypes. Molecular characterization of myeloid cancers have evolved with time and ease of gene discovery, made possible through the use of powerful and relatively more affordable next generation sequencing technologies. Our review will focus on the recent developments in molecular genetics in MDS/MPN and how they are shaping the way we understand adult MDS/MPN, the diagnostic and therapeutic strategies currently being used, and novel therapies that are being investigated in the management of adult MDS/MPN.

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CHRONIC MYELOMONOCYTIC LEUKEMIA: CLINICAL FEATURES/DIAGNOSIS

CMML is a clonal hematopoietic stem cell disorder, with a median age at diagnosis of 65–75 years old, a male predominance (1.5–3.1 : 1) [2] and diagnosed by an elevated absolute monocyte count (monocytosis) greater than 1 × 109/l in the peripheral blood that persist for more than 3 months. Most patients initially present with elevated WBC counts with or without concomitant anemia and thrombocytopenia. Clinical stigmata include fever, night sweats, weight loss, petechiae, and splenomegaly. The diagnosis is made based on the 2008 WHO classification criteria, with the distinction between CMML-1 and CMML-2 based on blast percentage. The bone marrow is typically hypercellular with granulocytic hyperplasia. Monocytic proliferation and dysplasia of at least one hematopoietic lineage can be observed. Reticulin fibrosis is present in 30% of patients (Table 1). Cytochemical and immunohistochemical (IHC) stains such as alpha-naphthyl acetate esterase, alpha-naphthyl butyrate esterase, and chloroacetate esterase are useful adjuncts in the identification of monocytes [3]. Flow cytometry, although not part of the diagnostic criteria, can be helpful in distinguishing CMML, CMML transforming to acute myeloid leukemia (AML), and acute myelomonocytic leukemia.

Table 1
Table 1
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Cytogenetics/acquired molecular mutations

There is no pathognomonic cytogenetic abnormality associated with CMML. Chromosomal abnormalities can be detected in 20–40% of CMML patients using conventional metaphase cytogenetics and FISH and have important prognostic value. The most commonly detected abnormalities are −7 and +8 (Table 1) [4]. Traditional metaphase cytogenetics techniques can be complemented by single nucleotide polymorphism arrays (SNP-A) karyotyping that can improve the detection of chromosomal lesions by 60% [5,6].

Molecular genetics has furthered our understanding of CMML biology. TET2 mutations are common and found in 49–61% of CMML patients. Other common mutations include ASXL1 (43–44%), DNMT3A (10%), UTX (8%), EZH2 (6–10%), IDH1/2 (4%), CBL (14–19%), RUNX1 (22%), and JAK2V617F (1–7%) [5]. Spliceosome mutations like SRSF2 (36–47%), U2AF1 (13%), and SF3B1 (6%) are also frequent [7,8], whereas SETBP1 is infrequent (4%) [9▪], as are mutations in FLT3-ITD and FLT3-TKD (0.95%) [10]. Point mutations in RAS genes [KRAS (7–11%) and NRAS (4–16%)], were identified as secondary events associated with poor prognosis, as are the presence of at least three genetic mutations. Some mutations are commonly associated: RAS with RUNX1[11], RUNX1 with FLT3, and NRAS and KRAS[12]. Molecular abnormalities used as biomarkers include TET2, for their relevance to survival outcomes [13], and TET2 and DNMT3A for responsiveness to hypomethylating therapy (HMT) [14▪▪].

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Treatment: pharmacologic therapy

Some CMML patients have indolent disease courses, whereas others progress quickly to leukemia. Patients requiring therapy, either for cytopenias, excess blasts or other evidence of advanced disease, or symptoms, are treated with drugs appropriated from MDS, AML, and MPN arsenals. HMT leads to overall response rates (ORR) of 40%, with survival of less than 2 years. Topotecan-based regimens or low-dose cytarabine can lead to complete remission rates of 27–40% with a similar survival. Etoposide and hydroxyurea can be used to alleviate symptoms. Hydroxyurea is usually suggested when patients have also enlarged spleen and high leukocyte counts. Given the dearth of available therapeutic options, clinical trials specifically directed toward patients with CMML are desperately needed. In rare cases, when abnormalities in PDGFRA, PDGFRB, or FGFR1 are identified, patients are best classified as myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1. Those with PDGFRA or PDGFRB rearrangements are usually responsive to tyrosine kinase inhibitors such as imatinib (Table 2) [15–28].

Table 2
Table 2
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Table 2
Table 2
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Hematopoietic cell transplantation

Many patients with CMML are not eligible for allogeneic hematopoietic cell transplantation (ALLO-HCT) due to high comorbidity risk scores and lack of suitable donors. The ideal regimen and timing of HCT for CMML is not known, and typically extrapolated from experience in MDS. Table 3 summarizes the results of ALLO-HCT in CMML [29–31]. A study of 18 CMML patients who received T-cell depleted transplants reported a 3-year overall survival (OS) of 31% and relapse incidence of 47% [32]. Another study evaluated HCT outcomes in a group of 85 CMML (CMML1/2: 57/26) patients transplanted with related (n = 38) or unrelated (n = 47) donors. The relapse incidence was 27% and progression-free survival was 38% at 10 years [33]. High-risk cytogenetics were associated with mortality. A recent retrospective study by Park et al.[34▪] investigated prognostic factors for outcome after HCT in 73 CMML patients. The 3-year OS and event free survival were 32 and 26%, respectively. Splenomegaly had a negative impact on both outcomes. One review of 197 CMML patients highlighted several HCT studies with long-term survival rates of 18–75% at 2–10 years and relapse rates at 2–4 years of 17–63% [35].

Table 3
Table 3
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ATYPICAL CHRONIC MYELOID LEUKEMIA, BCR-ABL1 NEGATIVE: CLINICAL FEATURES/DIAGNOSIS

Atypical CML (aCML) is rare, and epidemiologic dataare scarce. Like other MDS/MPNs, the median age at diagnosis is above 60 years. By definition, these patients are negative for the BCR-ABL mutation diagnostic of typical CML [36,37]. Although patients with aCML can have cytopenias at presentation, leukocytosis is common. Splenomegaly can be observed in 75% of cases. The diagnosis is based on 2008 WHO criteria (Table 1) [38]. Leukocytosis is an important diagnostic feature in aCML and is generally at least 13 × 109/l with neutrophilic precursors accounting for 10–20%, monocytes less than 10%, and basophils less than 2% of the WBC count. The presence of peripheral blood dysgranulopoiesis is common. Blasts may be present, but are usually less than 5%. Anemia and thrombocytopenia can occur with or without accompanying dysplasia. The bone marrow is hypercellular due to an increase of granulocytes/granulocytic precursors. Dysplasia of at least one lineage is commonly seen. The ratio of myeloid to erythroid precursors is high (10 : 1). Some patients have increased reticulin fibrosis. Cytochemistry, immunophenotyping, and IHC are nonspecific but can be helpful in excluding CMML [39].

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Cytogenetics/acquired molecular mutations

Chromosomal and molecular abnormalities are not specific to aCML, and may be found in other myeloid neoplasms. The most frequent chromosomal changes are +8 and deletion 20q; less common abnormalities include +13 and i17q [38,40]. SNP-A can detect cryptic chromosomal defects including uniparental disomy (UPD) of chromosome 11q [41]. NRAS and KRAS mutations may be found in one-third of patients [42]. JAK2V617F mutations are infrequently found in aCML [43–45]. Mutations in genes involved in epigenetic and proliferation pathways, such as TET2 and CBL were found in 30 and 8% of aCML patients, respectively [42,46]. U2AF1 mutations are also infrequent in aCML [47▪].

There was no specific molecular marker until the discovery of SETBP1 and CSF3R. Somatic mutations in SETBP1 have been found in 24% of aCML patients and are associated with worse survival [9▪]. Mutations in CSF3R, the gene encoding the receptor for colony-stimulating factor 3, have been identified and may be a diagnostic marker for aCML and chronic neutrophilic leukemia (CNL). Mutations were found in 16/27 (59%) of patients with aCML and CNL. Differential downstream signaling including SRC-TNK2 or JAK kinases produce different sensitivity to kinase inhibitors. Indeed, murine bone marrow cells transduced with different CSF3R mutations (S783fs and T618I) had different sensitivity to dasatinib [48▪▪,49].

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Treatment: pharmacologic therapy

Median survival in aCML is short, ranging 2–3 years. Clonal evolution to AML occurs in 20–45% [50]. Bleeding and infections are the primary causes of mortality. No standard-of-care treatments are available. Management with hydroxyurea palliates symptoms related to leukocytosis and splenomegaly, and is noncurative. ORRs are around 80%, lasting only 2–4 months [40]. Interferon (IFN)-α can produce nondurable complete remissions in isolated cases. In one aCML series, 14/26 (53.8%) patients were treated with IFN-α at a dose range of 3–6 × 106 units/day, with 43% of patients responding. Five patients had complete and one a partial hematologic response lasting 100+ months. Remaining patients received busulfan, low and high dose cytarabine with cisplatin, and fludarabine, but with low response rates [40].

Another option is pegylated-IFN (PEG-IFN-α2b). In a phase II study, aCML patients given PEG-IFN-α2b at a starting dose of 3 μg/kg/week achieved a 40% (2/5) complete remission rate. However, treatment duration was short, with a median of 37 months, due to toxicity [51]. A recent case report described the successful use of decitabine (20 mg/m2 × 5 days) in an aCML patient negative for PDGF, JAK2, and double mutant for CEBPA. The patient achieved hematologic responses after one cycle with an improvement in peripheral blood counts and a decrease in blasts after 3 cycles of treatment [52].

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Hematopoietic cell transplantation

Allogeneic HCT has been used successfully in one retrospective study of nine patients with aCML. Types of donors included HLA-identical siblings (n = 4), HLA-compatible unrelated (n = 4), and a twin brother (n = 1). Various conditioning regimens were used. After a median follow up of 55 months, all but one patient remained in complete remission, and the patient who received stem cells from his twin brother, after relapsing 19 months from his original transplant, was successfully salvaged using stem cells from the original donor. Acute and chronic graft-versus-host disease (grades II–IV) occurred in 63 and 100% of patients, respectively [53].

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MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS-UNCLASSIFIABLE AND RING SIDEROBLASTS ASSOCIATED WITH MARKED THROMBOCYTOSIS: CLINICAL FEATURES/DIAGNOSIS

MDS/MPN-U includes patients who do not fulfill diagnostic criteria at initial presentation for a specific subtype of MDS/MPN. The MDS/MPN-U is also highly heterogeneous. Included in this group is the provisional 2008 WHO entity RARS-T. The incidence of MDS/MPN-U and RARS-T is unknown. In one study, MDS/MPN-U that included RARS-T accounted for 12% of the total MDS and MDS/MPN cohort and 43% of the MDS/MPN cohort. RARS-T accounted for just 5% of the total MDS and MDS/MPN group and 17% of the MDS/MPN cohort. RARS-T is unique in patients diagnosed with MDS or MPN that later on acquire ring sideroblasts [54]. Molecular mutations (reviewed below) may be the driving event that explains the mixed feature of this disease. Leukocytosis, variable levels of anemia and platelet counts at least 450 × 109/l are common at disease presentation. Hepatosplenomegaly may also occur.

Most patients present with macrocytic anemia. The bone marrow is usually hypercellular with multilineage dysplasia. MPN-related features, including bone marrow fibrosis, may be seen. In the case of RARS-T, features of RARS (anemia, absence of peripheral blood blasts, dysplastic erythroid cells, presence of at least 15% ring sideroblasts in the bone marrow, and the presence of less than 5% bone marrow blasts) are accompanied by platelet counts of at least 450 × 109/l and the presence of atypical megakaryocytes. Immunophenotypic or IHC features are again nonspecific. Diagnostic criteria are summarized in Table 1.

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Cytogenetics/acquired molecular mutations

To date, no specific cytogenetic findings have been linked to MDS/MPN-U or RARS-T. Cytogenetic findings help in the exclusion of other similar diseases like CML, 5q- syndrome, and myeloid neoplasms with rearrangements of PDGFRA, PDGFRB, or FGFR1. SNP-A increases the chance of detecting chromosomal lesions in MDS/MPN-U and RARS-T [6]. Novel lesions including gains and losses in chromosome 2p and 5q and UPDs in 1p, 2p, 3q, 6p, 8p, and 10p were reported [55]. The findings of molecular mutations in JAK2V617F (60%) and MPLW515L (23%) in patients with RARS-T link this disease more closely to classical MPN than MDS. ASXL1 and LNK gene mutations are uncommon [56], whereas TET2 mutations were found in 5/19 (26%) of patients with RARS-T [57]. Mutations in DNMT3A were found in 17% of RARS-T [56]. SF3B1 mutations, found in 68% of RARS patients, occur in 81% of RARS-T, emphasizing the close association of splicesome abnormalities and the ring sideroblast phenotype [58▪,59].

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Treatment

As with other overlap disorders, the treatment for patients with MDS/MPN-U and RARS-T derive from therapies used for MDS or MPN, guided by symptoms and/or cytopenias. Prognosis is quite variable, further compounded by inadequate representation in commonly used prognostic scoring systems, including the IPSS and revised IPSS. A scoring system based on 92 patients with unclassifiable MDS or MDS/MPN diseases identified absolute neutrophil counts, lactate dehydrogenase levels, hemoglobin levels, and percentage of peripheral blood blasts as important prognostic factors in these disease subtypes [60]. Growth factors (erythropoiesis and granulocyte stimulating agents) can alleviate cytopenias, whereas leukocytosis can be managed with cytoreductive therapies. Lenalidomide can eradicate the JAK2 mutant clone [61]. ALLO-HCT remains the only potentially curative treatment modality.

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NOVEL THERAPEUTIC AGENTS IN MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS

New pharmacologic agents are currently being investigated in various myeloid neoplasms and may be useful in MDS/MPN. The primary goals of treatment are to ameliorate cytopenias, symptoms related to hepatosplenomegaly, constitutional symptoms, leukemia transformation, and other disease-related features like fibrosis. Viable targets include the TGF-β, P38 MAPK, JAK-STAT, MPL, BCL-2, spliceosome, lysyl-oxidase-like-2, and farnesyl transferase pathways (Table 4).

Table 4
Table 4
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CONCLUSION

MDS/MPN represents a class of diseases with distinct clinical features, natural history, and disease biology. Altogether novel genomic technologies have helped in the clarification of the clonal nature of these diseases. Mutations in SF3B1, SETBP1, and CSF3R may be specific for some of these myeloid neoplasms and will be an important part of future diagnostic criteria, whereas molecular mutations in TET2 and DNMT3A genes are important in predicting for better response to HMT therapy in MDS, MDS/MPN, and AML. Standardized response and outcomes criteria specific to MDS/MPN patients are needed, though, for this distinct disease group, along with clinical trials designed specifically to enroll MDS/MPN patients. The evolving knowledge of disease biology provided by the discovery of new molecular markers in these disorders may help shape the way decision making is made in MDS/MPN and in the identification of new therapeutic targets that can improve patient outcomes.

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Acknowledgements

The authors would like to thank Dr Valeria Visconte for her careful review of the manuscript.

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Conflicts of interest

M.A.S. serves on advisory boards for Celgene and Amgen.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

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47▪. Makishima H, Visconte V, Sakaguchi H, et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood. 2012; 119:3203–3210.

An important study illustrating the overall frequency of spliceosome gene mutations like SF3B1, SRSF2, U2AF1 in MDS and MDS/MPN and their association with survival outcomes.


48▪▪. Maxson JE, Gotlib J, Pollyea DA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med. 2013; 368:1781–1790.

This study reported another possible candidate oncogene in aCML and CNL. Mutations in CSF3R were highly prevalent (59%) in both diseases.


49. Pardanani A, Lasho TL, Laborde RR, et al. CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia. Leukemia. 2013; 27:1870–1873.

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52. Mao L, You L, Yang M, et al. The first case of decitabine successfully in treatment of atypical chronic myeloid leukemia with CEBPA double mutation. Chemotherapy. 2013; 2:114

53. Koldehoff M, Beelen DW, Trenschel R, et al. Outcome of hematopoietic stem cell transplantation in patients with atypical chronic myeloid leukemia. Bone Marrow Transplant. 2004; 34:1047–1050.

54. Schmitt-Graeff A, Thiele J, Zuk I, Kvasnicka HM. Essential thrombocythemia with ringed sideroblasts: a heterogeneous spectrum of diseases, but not a distinct entity. Haematologica. 2002; 87:392–399.

55. Szpurka H, Jankowska AM, Makishima H, et al. Spectrum of mutations in RARS-T patients includes TET2 and ASXL1 mutations. Leuk Res. 2010; 34:969–973.

56. Visconte V, Makishima H, Jankowska A, et al. SF3B1, a splicing factor is frequently mutated in refractory anemia with ring sideroblasts. Leukemia. 2012; 26:542–545.

57. Flach J, Dicker F, Schnittger S, et al. Mutations of JAK2 and TET2, but not CBL are detectable in a high portion of patients with refractory anemia with ring sideroblasts and thrombocytosis. Haematologica. 2010; 95:518–519.

58▪. Visconte V, Rogers HJ, Singh J, et al. SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes. Blood. 2012; 120:3173–3186.

SF3B1, a splicing factor gene, is mutated in 60–81% of patients with RARS and RARS-T. This study was the first experimental evidence demontrating the association between SF3B1 mutations and ring sideroblast phenotype.


59. Visconte V, Tabarroki A, Rogers HJ, et al. SF3B1 mutations are infrequently found in nonmyelodysplastic bone marrow failure syndromes and mast cell diseases but, if present, are associated with the ring sideroblast phenotype. Haematologica. 2013; 98:e105–e107.

60. Liu Y, Tabarroki A, Visconte V, et al. A prognostic scoring system for unclassifiable MDS and MDS/MPN [abstract]. Blood (ASH Annual Meeting Abstracts). 2012; 120:1701

61. Huls G, Mulder AB, Rosati S, et al. Efficacy of single-agent lenalidomide in patients with JAK2 (V617F) mutated refractory anemia with ring sideroblasts and thrombocytosis. Blood. 2010; 116:180–182.

Keywords

diagnosis; genetics; myelodysplastic/myeloproliferative neoplasms

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

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