Hairy cell leukemia and variant in Taiwan: report of a variant case and literature review.

Hairy cell leukemia (HCL) is characterized by leukemic cells with abundant "hairy" cytoplasm, strong cytoplasmic positivity for tartrate-resistant acid phosphatase (TRAP), characteristic immunophenotype and sensitivity to treatment with purine nucleoside analogs. HCL-variant (HCL-v) encompasses chronic B-cell leukemias resembling classical HCL but exhibiting variant cytomorphology, variant immunophenotype and resistance to conventional HCL therapy. We present the case of a 67-year-old Taiwanese male with HCL-v who had leukocytosis and splenomegaly. His hairy leukemic cells were weakly positive for TRAP and expressed CDllc and CD103 but not CD25. He received oral chemotherapy with chlorambucil and in complete hematological remission in 9 months but relapsed 2 months later. Literature review revealed 9 cases of HCL and 3 cases of HCL-v including current case from Taiwan. All patients were adults with splenomegaly. The HCL patients had a significantly higher frequency of leukopenia (p = 0.024) and monocytopenia (p = 0.008) and a lower frequency of leukocytosis (p = 0.018) than HCL-v patients. All 8 HCL patients responded favorably to 2-chlorodeoxyadenosine with or without splenectomy. The 3 HCL-v patients had leukocytosis and received chemotherapy with variable outcome. HCL and HCL-v are rare in Taiwan and their pathological and immunophenotypical features were not fully characterized. A multimodality approach incorporating hematological findings, cytomorphology, histopathology, cytochemistry, complete immunophenotyping and clinical features is needed to identify and characterize such cases in Taiwan.

Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903.

A multicenter Eastern Cooperative Group (ECOG) phase 2 trial assessed whether adding prednisone to lenalidomide would improve previously reported responses in persons with myelofibrosis (MF). Forty-eight subjects with anemia (42 evaluable) received lenalidomide, 10 mg/d, with a 3-month low-dose prednisone taper. Ten subjects received 3 months, and 25 received 6 months of therapy. Myelosuppression was the main toxicity with 88% with ≥ grade 3 hematologic toxicity and 45% ≥ grade 3 nonhematologic toxicity. There were responses in 10 subjects (23%) using the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)-defined clinical improvement of anemia in 8 (19%) and/or decreased spleen size in 4 (10%). Serial bone marrow analysis showed no resolution of disease-related fibrosis or angiogenesis. With a median follow-up of 2.3 years, 23 subjects are alive. Lenali-domide and prednisone for myelofibro-sis evaluated through a multicentered-cooperative group mechanism is only modestly active and myelosuppre-sive. This study was registered at http://clinicaltrials.gov as NCT00227591.

Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine.

Cytoreductive therapy in systemic mastocytosis (SM) includes several drugs whose individual merit has not been well characterized. We retrospectively studied 108 Mayo Clinic patients who met the 2008 WHO diagnostic criteria for SM and received at least one cytoreductive drug. The numbers of patients who were evaluable for response to treatment with interferon-alpha with or without prednisone (IFN-alpha), hydroxyurea (HU), imatinib mesylate (IM) or 2-chlorodeoxyadenosine (2-CdA) were 40, 26, 22, and 22, respectively. The corresponding overall (major) response rates, according to recently published consensus criteria, were 53% (18%), 19% (0%), 18% (9%), and 55% (37%). The respective overall response rates in indolent SM, aggressive SM and SM associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD) were 60%, 60%, 45% for IFN-alpha, 0, 0, 21% for HU, 14%, 50%, 9% for IM and 56%, 50%, 55% for 2-CdA. The absence of mast cell mediator release symptoms in IFN-alpha-treated patients and presence of circulating immature myeloid cells in 2-CdA-treated patients predicted inferior response. TET2 mutational status did not influence treatment response. Although the major response rates with these four cytoreductive agents were still suboptimal and HU was mainly used in patients with SM-AHNMD, the current study favors 2-CdA or IFN-alpha as first-line current therapy in SM and identifies patients who are likely to respond to such therapy.

Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies.

The prognostic heterogeneity of the World Health Organization category of "systemic mastocytosis with associated clonal hematologic nonmast cell lineage disease" (SM-AHNMD) has not been systematically validated by primary data. Among 138 consecutive cases with SM-AHNMD, 123 (89%) had associated myeloid neoplasm: 55 (45%) myeloproliferative neoplasm (SM-MPN), 36 (29%) chronic myelomonocytic leukemia, 28 (23%) myelodysplastic syndrome (SM-MDS), and 4 (3%) acute leukemia. Of the myeloid subgroups, SM-MPN displayed a 2- to 3-fold better life expectancy (P = .003), whereas leukemic transformation was more frequent in SM-MDS (29%; P = .02). The presence of eosinophilia, although prevalent (34%), was prognostically neutral, and the overall results were not affected by exclusion of FIP1L1-PDGFRA-positive cases. We conclude that it is clinically more useful to consider specific entities, such as SM-MPN, systemic mastocytosis with chronic myelomonocytic leukemia, SM-MDS, and systemic mastocytosis with-acute leukemia, rather than their broad reference as SM-AHNMD.

Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors.

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.

Risk factors for leukemic transformation in patients with primary myelofibrosis.

BACKGROUND: Previous prognostic studies in primary myelofibrosis have focused on risk factors for overall survival and have resulted in the establishment of several prognostic scoring systems. However, to the authors' knowledge, information regarding risk factors for leukemic transformation in primary myelofibrosis is limited. METHODS: The current retrospective study examined clinical variables at the time of diagnosis and specific treatment modalities for their effect on leukemic transformation in 311 patients with primary myelofibrosis who were seen at the Mayo Clinic. RESULTS: Univariate analysis of parameters at the time of diagnosis revealed a significant association between inferior leukemia-free survival and a peripheral blood blast percentage>or=3 (P<.0001), a platelet count<100x10(9)/L (P=.004), a monocyte count>or=1x10(9)/L (P=.02), the presence of hypercatabolic symptoms (P=.03), a low hemoglobin level (P=.04), and a high leukocyte count (P=.04). The first 2 parameters were found to maintain their statistical significance during multivariate analysis. Neither leukemia-free nor overall survival was found to be affected by the presence of <3% peripheral blood blasts or JAK2V617F mutation. The evaluation of treatment effect on leukemic transformation unexpectedly revealed a significant and independent association with previous therapy with either erythropoiesis-stimulating agents (P=.004) or danazol (P=.007), even when the aforementioned prognostic indicators at the time of diagnosis were added as covariates to the multivariate model. In contrast, leukemia-free survival was not found to be affected by a treatment history with hydroxyurea, thalidomide, or other drugs. CONCLUSIONS: A peripheral blood blast percentage>or=3 and/or a platelet count<100x10(9)/L at the time of diagnosis were found to be strong and independent predictors of leukemic transformation in patients with primary myelofibrosis. The unexpected association between leukemic transformation and a history of treatment with erythropoiesis-stimulating agents or danazol requires validation by prospective studies.

Pruritus in polycythemia vera is associated with a lower risk of arterial thrombosis.

Among 418 patients with polycythemia vera seen at our institution and in whom pruritus history was recorded, the presence of pruritus at diagnosis was documented in 131 (31%) and its absence in 287 (69%). Pruritus was less frequently reported by smokers (12% vs. 24%; P = 0.004) and diabetics (5% vs. 11%; P = 0.04). The presence of pruritus was associated with a lower rate of arterial thrombosis, both at diagnosis (8% vs. 17%; P = 0.01) and during follow-up (16% vs. 30%; P = 0.003). Multivariable analysis revealed that these associations were independent of other risk factors for thrombosis. High JAK2V617F allele burden clustered with pruritus (P = 0.002) but did not affect thrombosis rates.

Hematological manifestations of copper deficiency: a retrospective review.

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.

20+ yr without leukemic or fibrotic transformation in essential thrombocythemia or polycythemia vera: predictors at diagnosis.

OBJECTIVES: The current study identified patients with either essential thrombocythemia (ET) or polycythemia vera (PV) who have survived for at least 20 yr without the development of either acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) or myelofibrosis (MF) and compared their presenting features with those in whom these complications occurred in the first 10 yr of disease. METHODS: The study patients were selected from an institutional database of 1061 patients with either ET (n = 603) or PV (n = 458). In both instances, three distinct groups were delineated and their presenting features compared; group A included patients who have remained AML/MDS/MF free after a minimum follow-up of 20 yr; groups B and C included patients who developed either AML/MDS or MF, respectively, in the first decade of their disease. RESULTS: The respective number of patients who fulfilled the above-mentioned criteria for inclusion in groups A, B and C were 40, 12 and 8 for ET and 23, 18 and 12 for PV. In ET, compared with both groups B and C, group A displayed significantly fewer patients with less than normal hemoglobin level (P < 0.0001 and =0.02) or male sex (P = 0.005 and 0.05), respectively. On multivariable analysis, only anemia sustained its significance. A similar analysis in PV revealed an association between group B and leukocytosis using a leukocyte count threshold of either 10 or 15 x 10(9)/L (P = 0.02). CONCLUSION: The current study identifies PV patients with leukocytosis and ET patients with anemia as the most likely to undergo leukemic or fibrotic transformation.

Cytogenetic studies at diagnosis in polycythemia vera: clinical and JAK2V617F allele burden correlates.

The prognostic significance of cytogenetic findings at diagnosis in polycythemia vera (PV) was investigated in a retrospective series of 137 patients. Cytogenetics were normal in 117 patients (85%) and displayed a -Y abnormality in five patients (7% of male patients), and other chromosomal abnormalities in 15 patients (11%). The most frequent cytogenetic anomalies were trisomy 8 (n = 4), trisomy 9 (n = 2), deletion 20q (n = 2) and chromosomal 1 abnormalities (n = 2). Parameters that were significantly associated with abnormal cytogenetics included age > or = 60 yr (P = 0.02), but not JAK2V617F allele burden, thrombosis, hemorrhage, leukemic/fibrotic transformation, or survival. We conclude that cytogenetic anomalies occur infrequently at PV diagnosis and do not confer an adverse outcome.

Plasmablastic cytomorphologic features in plasma cell neoplasms in immunocompetent patients are significantly associated with EBV.

Multiple myeloma (MM) is rarely associated with Epstein-Barr virus (EBV) irrespective of HIV status, in contrast with its morphologic mimic, plasmablastic lymphoma, which occurs mainly in immunocompromised patients with frequent EBV association. Among 58 consecutive immunocompetent patients, we found plasmablastic cytomorphologic features in 2 of 4 with plasmacytomas and 14 (26%) of 54 with MM. Of the tumors, 4 (7%; 1 plasmacytoma and 3 MMs) were EBV-encoded RNA (EBER)-positive with plasmablastic cytomorphologic features in 3. The patient with plasmacytoma was disease free for 75 months, and the remaining 3 patients with MM died at 15, 74, and 97 months, respectively; the median survival of patients with EBER- MM was 12 months. EBV+ tumors were associated with plasmablastic cytomorphologic features and high labeling indices. Rare EBER+ plasmablastic plasma cell tumors exist in immunocompetent patients. These tumors may have been driven by EBV to gain the plasmablastic cytomorphologic features and high proliferation fraction. A large cohort study is needed to clarify the prognostic impact of EBV on immunocompetent patients with MM.

Leucocytosis in polycythaemia vera predicts both inferior survival and leukaemic transformation.

Leucocytosis (leucocyte count >15 x 10(9)/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 x 10(9)/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.

Validation and comparison of contemporary prognostic models in primary myelofibrosis: analysis based on 334 patients from a single institution.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Clinical correlates of JAK2V617F allele burden in essential thrombocythemia.

BACKGROUND: JAK2V617F occurs in approximately 50% of patients with essential thrombocythemia (ET). Qualitative studies of mutation analysis have previously reported an association between JAK2V617F and advanced age, higher hemoglobin level, higher leukocyte count, and lower platelet count. A possible association with thrombotic complication has also been considered. METHODS: Allele-specific, quantitative polymerase chain reaction (PCR) analysis for JAK2V617F was performed in 176 patients with ET using genomic DNA from archived bone marrow, which was collected within 1 year (n=72 patients), between 1 and 5 years (n=64 patients), or after 5 years (n=40 patients) of diagnosis. RESULTS: JAK2V617F was detected in 96 patients (55%), in whom mutant allele burden ranged from 1% to 100% (median, 6.3%). Neither mutational frequency (P=.37) nor mutant allele burden (P=.62) was affected by the timing of bone marrow sample collection. The presence of JAK2V617F was found to be significantly associated with higher hemoglobin level (P<.0001), lower platelet count (P=.001), higher leukocyte count (P=.008), increased incidence of venous thrombosis occurring after diagnosis (P=.02), and older age at diagnosis (P=.03). All but age retained significance in multivariable analysis. In mutation-positive patients (n=96 patients), JAK2V617F allele burden clustered between 1% and 22% in 94 cases, in whom it correlated directly and significantly with platelet and leukocyte counts, palpable splenomegaly at diagnosis, and venous thrombosis occurring after diagnosis. The latter 2 associations remained significant with the inclusion of the remaining 2 outlier cases with 100% mutant allele burden; in addition, an association with male gender became evident. CONCLUSIONS: JAK2V617F allele burden imparts additional phenotypic effects in ET.

Thalidomide therapy in adult patients with myelodysplastic syndrome. A North Central Cancer Treatment Group phase II trial.

BACKGROUND: Thalidomide has shown promise for the treatment of patients with myelodysplastic syndrome. The current prospective multicenter study examined the efficacy and toxicity of thalidomide in adult patients with myelodysplastic syndrome. METHODS: Using the International Prognostic Scoring System (IPSS), patients were stratified into 2 groups: favorable (IPSS score, 0-1.0) or unfavorable (IPSS score, 1.5-3.5). Seventy-two patients (42 of whom were favorable and 30 of whom were unfavorable) received a starting dose of oral thalidomide of 200 mg daily. The dose was increased by 50 mg per week to a targeted maximum daily dose of 1000 mg. RESULTS: According to the International Working Group response criteria for myelodysplastic syndrome, 1 patient in the unfavorable group achieved a partial remission with a complete cytogenetic response. Overall, 2 patients (5%) in the favorable group and 4 patients (14%) in the unfavorable group experienced either a hematologic improvement or a partial response. The most frequent Grade 3 or 4 (grading was based on the National Cancer Institute's Common Toxicity Criteria [version 2.0]) nonhematologic adverse events were fatigue (24%), infection (19%), neuropathy (13%), dyspnea (8%), and constipation (7%). CONCLUSIONS: Thalidomide alone, at the schedule and dose levels used in the current study, is not a safe and viable therapeutic option for patients with myelodysplastic syndrome. Limited efficacy and increased toxicity were observed in the current Phase II trial.

B-cell chronic lymphocytic leukemia: correlation of clinical stages with angiogenic cytokine expression.

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of non-cycling B cells in lymphatic and extralymphatic tissues. Earlier studies had validated that angiogenesis was increased in B-CLL. Increased serum concentrations of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) connote a poor prognosis in early-stage B-CLL. Early progression is also related to transforming growth factor-beta (TGF-beta), which inhibits B-cell proliferation and immunoglobulin production. The authors investigated the expression of CD34, VEGF, bFGF, and TGF-beta and their receptors in different stages of B-CLL by analyzing bone marrow samples from 23 patients (11 with Rai stages 0-II; 12 with stages III or IV). TGF-beta2 was expressed more strongly in stages 0 to II than in stages III or IV (P=0.03). There was no significant difference in the intensity of CD34, TGF-beta1, VEGF, and bFGF and their receptors between stages 0 to II and stages III or IV. Staining showed bFGF expression to be stronger than VEGF expression (P=0.001). Results did not confirm an association between the intensity of angiogenesis and B-CLL stage. The expression of TGF-beta2 was stronger in early-stage disease and may help slow disease progression.

C-terminal nucleophosmin mutations are uncommon in chronic myeloid disorders.

C-terminal somatic mutations in nucleophosmin (NPM), a nucleolar shuttling protein that binds p53 and p19(Arf), 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.

Respective clustering of unfavorable and favorable cytogenetic clones in myelofibrosis with myeloid metaplasia with homozygosity for JAK2(V617F) and response to erythropoietin therapy.

BACKGROUND: Patients who have myelofibrosis with myeloid metaplasia (MMM) display recurrent, albeit nonspecific cytogenetic abnormalities that are diverse prognostically. For the current study, the authors explored the relation between specific cytogenetic clones and JAK2(V617F) mutational status in patients with MMM and the effects on treatment response to erythropoietin (Epo). METHODS: Concomitantly collected blood granulocytes and bone marrow were processed for JAK2(V617F) mutation analysis and cytogenetic studies, respectively. Genomic DNA was amplified by polymerase chain reaction, and fluorescent dye chemistry sequencing was performed by using the same primers that were used for amplification. RESULTS: Among 105 study patients, cytogenetic abnormalities were detected in 47 patients (45%), and the JAK2(V617F) mutation was detected in 52 patients (50%). Comparison of mutational frequencies between favorable (normal, sole 13q-, or 20q- clones; n = 70 patients) and unfavorable (all other abnormalities; n = 35 patients) cytogenetic categories revealed a significantly different incidence of homozygous JAK2(V617F) between them (9% vs. 23%, respectively; P = .04). Furthermore, the mutant allele coexisted with several recurrent cytogenetic lesions. Among 25 patients who received Epo either alone (n = 17 patients) or in combination with hydroxyurea (n = 8 patients), 4 patients (16%) achieved a response, and none of them were homozygous for JAK2(V617F). Conversely, a response was more likely (P = .0001) in the presence of favorable cytogenetic abnormalities (i.e., 3 of 4 responders carried sole 13q- or 20q- clones). CONCLUSIONS: Unfavorable and favorable cytogenetic clones in MMM clustered with homozygosity for JAK2(V617F) and treatment response to Epo-based therapy, respectively.