Search

Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is characterized by anemia, ring sideroblast erythroid precursors, and persistent thrombocytosis. Case reports suggest lenalidomide may be effective in treating MDS/MPN-RS-T. We evaluated a large series of patients with MDS/MPN-RS-T to compare hematological improvement (HI) response rates among different drug therapies including lenalidomide. We identified 167 patients with MDS/MPN-RS-T. Among the patients tested, 84% had SF3B1 mutations and 43% had JAK2 V617F mutations. The median OS for the cohort was 81 months. Overall, 76 patients (46%) received erythropoiesis-stimulating agents (ESAs), 47 patients (28%) received lenalidomide, and 45 patients (27%) received hypomethylating agents (HMAs). The HI rates were 58%, 53%, and 24%, respectively. The median duration of treatment was 11 months for lenalidomide compared to 6 months for HMAs. Rates of HI improvement were higher in patients with MDS/MPN-RS-T treated with ESAs or lenalidomide, in comparison to those treated with HMAs.

Patients presenting with thrombocytosis require thorough clinical and laboratory evaluation to determine whether they suffer from essential thrombocythemia or another myeloproliferative disorder. This distinction becomes increasingly relevant as targeted agents become available to treat specific myeloproliferative diseases. Cytogenetic testing plays a major role in this analysis. This study presents a patient with Philadelphia chromosome positive (Ph + ) thrombocytosis and a cryptic der(9q)t(5;9)t(9;22) not found by conventional cytogenetics, whose disease progressed within 2 years to typical myeloblastic crisis of CML. It discusses the entity of Ph + ET, the utility of molecular cytogenetic testing in the diagnosis of this unusual disease entity and the importance of cytogenetic testing in the prognosis of ET.

Thrombocytosis is a rare finding in acute myeloblastic leukemia (AML). Here, we describe a patient with AML who relapsed with marked thrombocytosis. The patient was initially diagnosed as having AML (M4) with a low platelet count. The patient was started on combination chemotherapy including high-dose etoposide and achieved complete remission. However, the patient relapsed six months later with an extremely high platelet count (72.5 x 10(4)/microl). Cytogenetic analysis at relapse revealed the development of t(2;14)(p13;q32). Despite the repeated combination chemotherapy, the patient died with progressive disease. This case suggests that the additional chromosomal aberration t(2;14)(p13;q32) may be related to abnormal thrombocytosis in AML.

Thrombopoietin (TPO) is implicated as a primary regulator of megakaryopoiesis and thrombopoiesis through binding to the cytokine receptor c-Mpl (the product of the c-mpl-proto-oncogene). In addition to its physiologic role, the TPO-c-mpl system has been suggested to participate in the pathophysiology of essential thrombocythemia (ET) which is a clonal disorder characterized by a sustained elevation of the circulating platelet count and bone-marrow hyperplasia with excessive proliferation of megakaryocytes. Recent studies have demonstrated that serum TPO levels are slightly elevated or within normal range in ET patients, whereas serum TPO levels tend to be inversely correlated with platelet mass. Flow cytometric, Western blot, and Northern blot analyses have revealed that the expression of platelet c-Mpl is strikingly reduced in all of patients with ET, possibly due to the decreased expression of c-mpl mRNA. These results suggest that normal or slightly elevated levels of serum TPO in ET patients may be attributable to the impaired uptake and catabolism of TPO owing to the low c-Mpl expression. Furthermore, immunoblotting with anti-phosphotyrosine antibody showed that no aberrant protein-tyrosine phosphorylation was observed in platelets of ET patients before treatment with TPO, and the levels of TPO-induced protein-tyrosine phosphorylation, including c-Mpl-tyrosyl phosphorylation, roughly paralleled those of c-Mpl expression, suggesting that c-Mpl-mediated signaling pathway was not constitutively activated in platelets of ET patients. Although activating mutation in the TPO gene, which leads to overexpression of TPO mRNA, has been reported in familial thrombocythemia, these results suggest that TPO-c-Mpl system may not be directly linked to pathogenesis of sporadic ET.

The breakpoints on chromosome 22 in CML occur within a 5.8 kb region called the Major breakpoint cluster region (M-bcr). DNA mapping within the M-bcr region was performed in 41 long term followed Ph1-positive CML patients using the Southern blot technique. The purpose of this study was to determine whether localization of M-bcr breakpoint correlates with the length of chronic phase of the disease, blastic crisis lineage and thrombocytosis at the time of initial diagnosis. Our results fail to indicate any correlation between breakpoint localization and duration of chronic phase, blastic crisis lineage and platelet count at diagnosis.

Cytogenetic investigations have distinguished at least 3 distinct clinical-cytogenetic syndromes of hematopoietic malignancy with structural rearrangement of 3q. The majority of cases have breakpoints at both 3q21 and 3q26, frequently associated with monosomy 7, abnormal thrombopoiesis, and adverse outcome. Cases with only one of these breakpoints may have milder features of the syndrome. A subgroup with t(3q;5q) occurs in younger patients, occasionally with megakaryocytic dysplasia but rarely having thrombocytosis. The t(3;21) is encountered in secondary leukemias or after chemotherapy of myeloproliferative disorders. The genetic deregulations associated with each of these syndromes involve distinct genes on 3q. The majority of cases of acute leukemias with 3q rearrangements have a poor prognosis and do not respond to current modes of therapy.