Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias.

Detection of the FIP1L1-PDGFRA fusion gene or the corresponding cryptic 4q12 deletion supports the diagnosis of chronic eosinophilic leukemia (CEL) in patients with chronic hypereosinophilia. We retrospectively characterized 17 patients fulfilling WHO criteria for idiopathic hypereosinophilic syndrome (IHES) or CEL, using nested RT-PCR and interphase fluorescence in situ hybridization (FISH). Eight had FIP1L1-PDGFRA (+) CEL, three had FIP1L1-PDGFRA (-) CEL and six had IHES. FIP1L1-PDGFRA (+) CEL responded poorly to steroids, hydroxyurea or interferon-alpha, and had a high probability of eosinophilic endomyocarditis (n=4) and disease-related death (n=4). In FIP1L1-PDGFRA (+) CEL, palpable splenomegaly was present in 5/8 cases, serum vitamin B(12) was always markedly increased, and marrow biopsies revealed a distinctively myeloproliferative aspect. Imatinib induced rapid complete hematological responses in 4/4 treated FIP1L1-PDGFRA (+) cases, including one female, and complete molecular remission in 2/3 evaluable cases. In the female patient, 1 log reduction of FIP1L1-PDGFRA copy number was reached as by real-time quantitative PCR (RQ-PCR). Thus, correlating IHES/CEL genotype with phenotype, FIP1L1-PDGFRA (+) CEL emerges as a homogeneous clinicobiological entity, where imatinib can induce molecular remission. While RT-PCR and interphase FISH are equally valid diagnostic tools, the role of marrow biopsy in diagnosis and of RQ-PCR in disease and therapy monitoring needs further evaluation.

[A man with plasma cell dyscrasia and polyneuropathy due to POEMS syndrome]. / Een man met plasmaceldyscrasie en polyneuropathie door het POEMS-syndroom.

In a 52-year-old man with general malaise, muscle stiffness and weakness, POEMS-syndrome was diagnosed based on polyneuropathy, splenomegaly, lymphadenopathy, subclinical hypothyroidism and the presence of a monoclonal paraprotein with osteosclerotic lesions and an indurated skin (POEMS is an acronym for Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes). This is a rare systemic disease from the clinical spectrum of plasma cell dyscrasias with polyneuropathy. The clinical picture is broader and more pleomorphic than the acronym suggests. The possibility of a POEMS syndrome should be considered in the differential diagnosis of polyneuropathy in association with monoclonal gammopathy. Quite often it is associated with osteosclerotic myeloma or mixed osteoscleroticlytic lesions. The patient described was treated with high dose corticosteroids which were gradually decreased over the next three months, upon which a marked improvement could be seen. The general malaise subsided, as did the splenomegaly, and the skin became supple again.

Management of essential thrombocythemia during pregnancy with aspirin, interferon alpha-2a and no treatment. A comparative analysis of the literature.

It is advisable to treat essential thrombocythemia (ET) during pregnancy, because elevated platelet counts can lead to maternal and fetal complications. In order to establish which therapy is more favorable, we undertook a review of the literature. In addition to our own case, we found 27 reports which described 75 cases with 143 pregnancies. We discussed the complications of ET during pregnancy and postpartum, fetal outcome and the therapeutic strategies. Considering the clear risk of complications during pregnancy -- especially the occurrence of spontaneous abortion in the first trimester -- and the risk of intrauterine fetal death, we believe all patients should at least be treated with aspirin unless there is a contraindication. Platelet reduction with interferon-alpha (IFN-alpha) might be able to further reduce the complications of ET during pregnancy and to improve fetal outcome (data from 14 patients). After treatment with IFN-alpha, sufficient numbers of umbilical cord blood stem cells can be collected.

Natural killer (NK) cell leukaemia in a patient with a B cell non-Hodgkin's lymphoma.

We describe a 74-year-old woman with the diagnosis of natural killer (NK)-cell leukaemia and autoimmune pathology. Four years previously, a diffuse large B cell non-Hodgkin's lymphoma had been diagnosed and treated effectively. Although NK-cell leukaemia has been thought to be a distinct highly aggressive clinicopathological entity, our case shows no further evolution at the present time. As far as we know, this association has not been previously described in the literature.

Identification of four new translocations involving FGFR1 in myeloid disorders.

The 8p11 myeloproliferative syndrome (EMS) is associated with three translocations, t(8;13)(p11;q12), t(8;9)(p11;q33), and t(6;8)(q27;p11), that fuse unrelated genes (ZNF198, CEP110, and FOP, respectively) to the entire tyrosine kinase domain of FGFR1. In all cases thus far examined (n = 10), the t(8;13) results in an identical mRNA fusion between ZNF198 exon 17 and FGFR1 exon 9. To determine if consistent fusions are also seen in the variant translocations, we performed RT-PCR on four cases and sequenced the products. For two patients with a t(8;9), we found that CEP110 exon 15 was fused to FGFR1 exon 9. For two patients with a t(6;8), we found that FOP exon 5 (n = 1) or exon 7 (n = 1) was fused to FGFR1 exon 9. To determine if FGFR1 might be involved in other myeloid disorders with translocations of 8p, we developed a two-color FISH assay using two differentially labeled PAC clones that flank FGFR1. Disruption of this gene was indicated in a patient with a t(8;17)(p11;q25) and Ph-negative chronic myeloid leukemia in association with systemic malignant mast cell disease, a patient with acute myeloid leukemia with a t(8;11)(p11;p15), and two cases with T-cell lymphoma, myeloproliferative disorder, and marrow eosinophilia with a t(8;12)(p11;q15) and ins(12;8)(p11;p11p21), respectively. For the patient with the t(8;11), the chromosome 11 breakpoint was determined to be in the vicinity of NUP98. We conclude that 1) all mRNA fusions in EMS result in splicing to FGFR1 exon 9 but breakpoints in FOP are variable, 2) two-color FISH can identify patients with EMS, and 3) the t(8;17)(p11;q25), t(8;11)(p11;p15), t(8;12)(p11;q15), and ins(12;8)(p11;p11p21) are novel karyotypic changes that most likely involve FGFR1.