Clinical phenotype in systemic mastocytosis (SM) is markedly variable, which complicates prognostication and decision making regarding the choice and timing of therapy. In a retrospective study of ...342 consecutive adult patients with SM seen at the Mayo Clinic between 1976 and 2007, disease subdesignation according to the World Health Organization (WHO) proposal was indolent (ISM) in 159 (46%), with associated clonal hematologic non–mast cell lineage disease (SM-AHNMD) in 138 (40%), aggressive (ASM) in 41 (12%), and mast cell leukemia in 4 (1%). KITD816V was detected in bone marrow–derived DNA by allele-specific polymerase chain reaction (PCR) in 68% of 165 patients evaluated (ISM, 78%; ASM, 82%; SM-AHNMD, 60%; P = .03); JAK2V617F was detected in 4%, all in SM-AHNMD. Compared with those with nonindolent SM, life expectancy in ISM was superior and not significantly different from that of the age- and sex-matched US population. In addition, multivariable analysis identified advanced age, weight loss, anemia, thrombocytopenia, hypoalbuminemia, and excess bone marrow blasts as independent adverse prognostic factors for survival. The current study validates the prognostic relevance of the WHO subclassification of SM and provides additional information of value in terms of both risk stratification and interpretation of clinical presentation and laboratory results.
Copper deficiency is an established cause of hematological abnormalities but is frequently misdiagnosed. Copper deficiency can present as a combination of hematological and neurological abnormalities ...and it may masquerade as a myelodysplastic syndrome. We reviewed the records of patients with hypocupremia and hematologic abnormalities identified between 1970 and 2005. Patients with hypocupremia unrelated to copper deficiency (e.g. Wilson’s disease) were excluded. Forty patients with copper deficiency and hematological abnormalities were identified. Ten patients (25%) had undergone bariatric (weight reduction) surgery and an additional 14 patients (35%) had undergone surgery on the gastrointestinal tract, most commonly gastric resection. In 12 cases, no cause for copper deficiency was identified. Anemia and neutropenia were the most common hematologic abnormalities identified and the majority of the patients also had neurologic findings, most commonly due to myeloneuropathy. Abnormalities observed on bone marrow examination including vacuoles in myeloid precursors, iron‐containing plasma cells, a decrease in granulocyte precursors and ring sideroblasts may be valuable clues to the diagnosis. Copper deficiency is an uncommon but very treatable cause of hematologic abnormalities.
Summary
Leucocytosis (leucocyte count >15 × 109/l) was recently associated with thrombosis in polycythaemia vera (PV). This study sought the prognostic relevance of leucocytosis for survival and ...leukaemic or fibrotic transformation. Amongst 459 patients with PV seen at our institution in recent years (median age, 60 years; 56% males), 146 deaths and 88 leukaemic (n = 34) or fibrotic (n = 54) transformations were documented. Arterial or venous thrombosis occurred in 14% and 9% of patients at diagnosis and in 25% and 15% during follow‐up, respectively. Multivariate analysis identified the advanced age (P < 0·0001), leucocytosis (leucocyte count ≥15 × 109/l; P = 0·0006) and arterial thrombosis at diagnosis (P = 0·01) as independent predictors of inferior survival. In the absence of the first two risk factors, median survival was projected at 272 months as opposed to 108 months in the presence of both risk factors (P < 0·0001). Leucocytosis was also identified as an independent predictor of both leukaemic transformation and venous thrombosis during follow‐up. Time‐to‐event analysis did not disclose a significant association between single or multiple cytotoxic drug exposure and either leukaemic or fibrotic transformation. The current study highlighted the prognostic relevance of leucocytosis on various aspects of the disease in PV.
To define associated clinical conditions, pathology, natural history, and treatment outcome of nonhepatosplenic extramedullary hematopoiesis (NHS-EMH).
We retrospectively reviewed the medical charts ...of all patients identified as having NHS-EMH from 1975 to 2002. Diagnosis was made by tissue biopsy, fine-needle aspiration biopsy, or radionuclide bone marrow scanning.
We identified 27 patients with antemortem diagnosis of NHS-EMH. The most common associated condition and disease site were myelofibrosis with myeloid metaplasia (MMM) (in 18 patients 67%) and the vertebral column (in 7 patients 26%; all involving the thoracic region), respectively. At the time of diagnosis of NHS-EMH, concurrent splenic EMH (in 22 patients 82%; 15 56% had undergone splenectomy) and red blood cell transfusion dependency (in 12 patients 44%) were prevalent. Of the 27 patients, 9 (33%) required no specific therapy. Specific therapy was radiation (in 7 patients with a 71% response rate) and surgical excision (in 6 patients with a 67% response). Treatment-associated complications were limited to surgery. Radiation therapy was not used in the non-MMM group, but low-dose radiation therapy was used in the MMM group for paraspinal or intraspinal EMH (median dose, 1 Gy; range, 1-10 Gy), pleural or pulmonary disease (median dose, 1.25 Gy; range, 1.00-1.50 Gy), and abdominal or pelvic disease (median dose, 2.02 Gy; range, 1.50-4.50 Gy). Median survival after the diagnosis of NHS-EMH was 13 months in the MMM group and 21 months in the non-MMM group.
This retrospective study suggests that NHS-EMH is rare, is often associated with MMM, and preferentially affects the thoracic spinal region. Asymptomatic disease may require no specific treatment, whereas symptomatic disease is best managed with low-dose radiation therapy.
Imatinib mesylate (Gleevec), a small molecule inhibitor of abl, kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, has been reported to be effective in the treatment of ...hypereosinophilic syndrome (HES) and a rare eosinophilia-associated chronic myeloid disorder (eos-CMD) characterized by the t(5;12)(q33;p13) cytogenetic abnormality. In the current study, we sought to confirm the preliminary observations in HES as well as evaluate the therapeutic value of imatinib in eos-CMD that is not associated with t(5;12)(q33;p13). Five patients with HES (all men, median age = 46 years) and 2 with eos-CMD (both men, aged 45 and 58 years) were treated with imatinib at a starting dose of 100 to 400 mg/day. Cytogenetic studies showed no evidence of either the bcr-abl translocation or t(5;12)(q33;p13) in any patient. Screening of exons encoding the intracellular catalytic domains and extracellular ligand binding domains of PDGFRβ (exons 2-23) and c-kit (exons 1-21) in 6 patients demonstrated mostly previously known polymorphisms. At a median follow-up of 17 weeks (range, 10-33 weeks), 2 patients with HES and 1 with eos-CMD have achieved complete clinical remission and 1 additional patient with HES has achieved a partial remission. In contrast to previous observations, all 4 responding patients had elevated serum interleukin-5 levels. Although the drug was well tolerated in most patients, a previously unrecognized treatment toxicity of acute left ventricular dysfunction occurred in a responding patient with HES within the first week of treatment. Myocardial biopsy revealed eosinophilic infiltration and degranulation, and the cardiogenic shock was reversed with the prompt institution of corticosteroid therapy.
Survival in primary myelofibrosis (PMF) is predicted by several prognostic scoring systems (PSSs); the most widely recognized is that of Dupriez. Two other PSSs, Cervantes and Mayo, were recently ...reported as being more useful in younger patients. The current study compares these 3 PSSs among all age groups.
The Mayo Clinic PMF database was queried to identify a consecutive series of patients in whom pretreatment bone marrow and complete blood count (CBC), obtained within 6 months of diagnosis, were available for review.
Among 334 study patients (median age, 57 years), median survival was 70 months. Multivariable analysis of all 6 adverse prognostic factors utilized in the aforementioned PSSs (ie, hemoglobin <10 g/dL, leukocyte count <4 or >30 x 10(9)/L, constitutional symptoms, circulating blasts > or = 1%, platelet count <100 x 10(9)/L, absolute monocyte count > or = 1 x 10(9)/L) identified all but platelet count as being significant. The Mayo PSS, which is based on the 4 CBC-derived parameters (ie, hemoglobin, platelet, leukocyte, and monocyte counts), displayed a better hazard ratio profile compared with the other 2 PSSs in identifying long-lived patients as well as delineating intermediate-risk disease category. The latter effect was even more pronounced in patients younger than age 60 years.
The Mayo PSS for survival in PMF is an objective CBC-derived prognostic model that might be superior in its performance over that of either the Dupriez and Cervantes PSSs.
Summary
C‐terminal somatic mutations in nucleophosmin (NPM), a nucleolar shuttling protein that binds p53 and p19Arf, were recently described in karyotypically normal acute myeloid leukaemia (AML). ...We analysed primary marrow samples from 150 patients with various chronic myeloid disorders for mutations in the NPM1 gene encoding NPM. NPM1 mutations (tetranucleotide duplication) were detected in three patients, all of whom had chronic myelomonocytic leukaemia (CMML) and a short (<1 year) survival, with rapid progression to overt AML. All other patients were NPM1‐wild type in the region analysed. In conclusion, C‐terminal NPM mutations are uncommon in chronic myeloid neoplasia, but if present may represent an evolving leukaemic clone.
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