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ABSTRACT: Truncation mutations of the receptor cytoplasmic domain for colony stimulating factor 3 (CSF3R) are frequently seen in severe congenital neutropenia whereas activating missense mutations affecting the extracellular domain (exon 14) have been described in hereditary neutrophilia and chronic neutrophilic leukemia (CNL). In order to clarify mutational frequency, specificity and phenotypic associations, we sequenced CSF3R exons 14-17 in 54 clinically suspected cases of CNL (n=35) or atypical chronic myeloid leukemia (aCML; n=19). Central review of these cases confirmed WHO-defined CNL in 12 patients, monoclonal gammopathy (MG)-associated CNL in 5 and WHO-defined aCML in 9. A total of 14 CSF3R mutations were detected in 13 patients, including 10 with CSF3RT618I (exon 14 mutation). CSF3RT618I occurred exclusively in WHO-defined CNL with a mutational frequency of 83% (10 of 12 cases). CSF3R mutations were not seen in aCML or MG-associated CNL. CSF3RT618I was also absent among 170 patients with primary myelofibrosis (PMF; n=76) or chronic myelomonocytic leukemia (CMML; n=94). SETBP1 mutational frequencies in WHO-defined CNL, aCML, CMML and PMF were 33%, 0%, 7% and 3%, respectively. Four CSF3RT618I-mutated cases co-expressed SETBP1 mutations. We conclude that CSF3RT618I is a highly sensitive and specific molecular marker for CNL and should be incorporated into current diagnostic criteria.Leukemia accepted article preview online, 22 April 2013; doi:10.1038/leu.2013.122.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2013; · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2013; · 8.30 Impact Factor
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M M Patnaik,
E Padron,
R R Laborde,
T L Lasho,
C M Finke, C A Hanson,
J M Hodnefield,
R A Knudson,
R P Ketterling,
A Al-Kali,
A Pardanani,
N A Ali,
R S Komroji,
A Tefferi
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ABSTRACT: We evaluated the prognostic relevance of several clinical and laboratory parameters in 226 Mayo Clinic patients with chronic myelomonocytic leukemia (CMML):152 (67%) males and median age 71 years. At a median follow-up of 15 months, 166 (73%) deaths and 33 (14.5%) leukemic transformations were documented. In univariate analysis, significant risk factors for survival included anemia, thrombocytopenia, and increased levels of white blood cells, absolute neutrophils, absolute monocytes (AMC), absolute lymphocytes, peripheral blood (PB) and bone marrow (BM) blasts and presence of circulating immature myeloid cells (IMC). Spliceosome component (P=0.4) and ASXL1 mutations (P=0.37) did not impact survival. On multivariable analysis, increased AMC (>10 × 10(9)/L, RR 2.5, 95% CI 1.7-3.8), presence of circulating IMC (RR 2.0, 95% CI 1.4-2.7), decreased hemoglobin (<10 g/dl; RR 1.6, 99% CI 1.2-2.2), and decreased platelet count (<100 × 10(9)/L; RR 1.4, 99% CI 1.0-1.9) remained significant. Using these four risk factors, a new prognostic model for overall (high-risk RR 4.4, 95% CI 2.9-6.7; intermediate-risk RR 2.0, 95% CI 1.4-2.9) and leukemia-free survival (high-risk RR 4.9, 95% CI 1.9-12.8; intermediate-risk RR 2.6, 95% CI 1.1-5.9) performed better than other conventional risk models and was validated in an independent cohort of 268 CMML patients.Leukemia (2013) accepted article preview online, 27 March 2013; doi:10.1038/leu.2013.88.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2013; · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2013; · 8.30 Impact Factor
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J Moreira,
K G Rabe,
J R Cerhan,
N E Kay,
J W Wilson,
T G Call,
J F Leis,
D F Jelinek,
S M Schwager,
D A Bowen, C A Hanson,
S L Slager,
T D Shanafelt
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ABSTRACT: Although the risk of progression from monoclonal B-cell lymphocytosis (MBL) to chronic lymphocytic leukemia (CLL) has been well characterized, it is unknown whether other common complications associated with CLL, such as increased risk of infection, occurs in individuals with MBL. We used the Mayo CLL database to identify cohorts of individuals with newly diagnosed MBL (n=154) or newly diagnosed CLL (n=174) who resided within 50 miles of Mayo Clinic. A cohort of 689 adult patients seen for a general medical examination who resided within 50 miles of Mayo clinic and who enrolled in a case-control study of non-Hodgkin lymphoma (NHL) was used as a comparison cohort. Hospitalization with infection was more common among individuals with MBL (25/154; 16.2%), and CLL (32/174; 18.4%) than controls (18/689; 2.6%). On pooled multivariable Cox proportional hazards analysis of all 1017 patients (controls, MBL and CLL), male sex (hazards ratio (HR)=2.3; P=0.002), major co-morbid health problems (HR=1.7, P=0.04), the presence of CLL (HR=3.2, P<0.001), treatment for progressive CLL (HR=2.4, P=0.001) and the presence of MBL (HR=3.0, P=0.001) were independently associated with risk of hospitalization for infection. These results suggest the risk of serious infection in clinical MBL is substantially greater than the risk of progression requiring treatment.Leukemia advance online publication, 10 August 2012; doi:10.1038/leu.2012.187.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2012; · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2012; · 8.30 Impact Factor
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A Tefferi,
A Pardanani,
N Gangat,
K H Begna, C A Hanson,
D L Van Dyke,
D Caramazza,
A M Vannucchi,
E Morra,
M Cazzola,
A Pereira,
F Cervantes,
F Passamonti
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2012; 26(6):1439-41. · 8.30 Impact Factor
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ABSTRACT: Unlike the case with acute myeloid leukemia, there is limited information on the prognostic impact of isocitrate dehydrogenase (IDH) mutations in myelodysplastic syndromes (MDS). In the current study of 277 patients with MDS, IDH mutations were detected in 34 (12%) cases: 26 IDH2 (all R140Q) and 8 IDH1 (6 R132S and 2 R132C). Mutational frequency was 4% (2 of 56) in refractory anemia with ring sideroblasts, 12% (16 of 130) in refractory cytopenia with multilineage dysplasia, 14% (2 of 14) in MDS-unclassifiable, 14% (6 of 42) in refractory anemia with excess blasts (RAEB)-1 and 23% (8 of 35) in RAEB-2. Normal karyotype was noted in all but one IDH1-mutated cases and 13 IDH2-mutated cases. Multivariable analysis identified presence of mutant IDH1 (P=0.0004; hazard ration 4.0, 95% confidence interval 1.9-8.8), revised International Prognostic Scoring System risk category (P<0.0001), and red cell transfusion need (P=0.002) as independent predictors of inferior survival. In a similar multivariable analysis, mutant IDH1 was the only variable associated with shortened leukemia-free survival (P=0.001; hazard ration 7.0, 95% confidence interval 2.3-20.8). The presence of IDH2R140Q did not affect the overall (P=0.54) or leukemia-free (P=0.81) survival. The current study suggests a powerful adverse prognostic effect for mutant IDH1 in MDS.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2012; 26(1):101-5. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2011; 26(5):1135-7. · 8.30 Impact Factor
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ABSTRACT: Recent studies suggest a powerful prognostic value for plasma cytokine levels in primary myelofibrosis (interleukin (IL)-2R, IL-8, IL-12, IL-15 and C-X-C motif chemokine 10 (CXCL10)) and large-cell lymphoma (IL-2R, IL-8, IL-10, IL-12, CXCL9 and CXCL10). To examine the possibility of a similar phenomenon in myelodysplastic syndromes (MDS), we used multiplex enzyme-linked immunosorbent assay to measure 30 plasma cytokines in 78 patients with primary MDS. Compared with normal controls (n = 35), the levels of 19 cytokines were significantly altered. Multivariable analysis identified increased levels of CXCL10 (P<0.01), IL-7 (P = 0.02) and IL-6 (P = 0.07) as predictors of shortened survival; the survival association remained significant when the Cox model was adjusted for the International Prognostic Scoring System, age, transfusion-need or thrombocytopenia. MDS patients with normal plasma levels of CXCL10, IL-7 and IL-6 lived significantly longer (median survival 76 months) than those with elevated levels of at least one of the three cytokines (median survival 25 months) (P<0.01). Increased levels of IL-6 were associated with inferior leukemia-free survival, independent of other prognostic factors (P = 0.01). Comparison of plasma cytokines between MDS (n = 78) and primary myelofibrosis (n = 127) revealed a significantly different pattern of abnormalities. These observations reinforce the concept of distinct and prognostically relevant plasma cytokine signatures in hematological malignancies.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2011; 26(4):693-9. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2011; 26(2):373-6. · 8.30 Impact Factor
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M C Lanasa,
S D Allgood,
S L Slager,
S S Dave,
C Love,
G E Marti,
N E Kay, C A Hanson,
K G Rabe,
S J Achenbach, [......],
L Z Rassenti,
J F Leis,
J P Gockerman,
S S Strom,
T G Call,
M Glenn,
J R Cerhan,
M C Levesque,
J B Weinberg,
N E Caporaso
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ABSTRACT: Monoclonal B-cell lymphocytosis (MBL) is a hematologic condition wherein small B-cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and 'CLL-like' MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. In all, 91 unique MBL clones were detected: 73 CLL-like MBL (CD5(+)CD20(dim)sIg(dim)), 11 atypical MBL (CD5(+)CD20(+)sIg(+)) and 7 CD5(neg) MBL (CD5(neg)CD20(+)sIg(neg)). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70 and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on seven CLL-like MBL, and showed activation of B-cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2011; 25(9):1459-66. · 8.30 Impact Factor
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D Caramazza,
T L Lasho,
C M Finke,
N Gangat,
D Dingli,
R A Knudson,
S Siragusa, C A Hanson,
A Pardanani,
R P Ketterling,
A Tefferi
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 12/2010; 24(12):2120-2. · 8.30 Impact Factor
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ABSTRACT: Monosomal karyotype (MK) refers to the presence of two or more distinct autosomal monosomies or a single monosomy associated with a structural abnormality. In acute myeloid leukemia, MK has been shown to be prognostically worse than an otherwise complex karyotype. The current study examines whether the same holds true for myelodysplastic syndromes (MDS). A total of 127 MDS patients (median age 70 years) with a complex karyotype were considered; 106 (83%) met the above-stipulated criteria for MK and 21 (17%) had a complex karyotype without monosomies. Survival was significantly inferior in patients with MK compared with those with a complex karyotype without monosomies (P=0.01; HR 1.9, 95% confidence interval (95% CI), 1.1-3.3). Multivariable analysis identified MK (P=0.002), advanced age (P=0.0004) and bone marrow blast percentage (0.04) as independent risk factors for survival. There was no difference in survival among MK patients further substratified by the presence or absence of monosomy 7 and/or monosomy 5. Although not statistically significant, leukemia-free survival was also worse with MK compared with complex karyotype without monosomies (P=0.09; HR 2.7, 95% CI 0.8-9.0). MK in MDS identifies a prognostically worse subgroup of patients with a complex karyotype, regardless of whether monosomy 7 or 5 is part of the MK component.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2010; 25(2):266-70. · 8.30 Impact Factor
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M M Patnaik,
T L Lasho,
C M Finke,
N Gangat,
D Caramazza,
S G Holtan,
A Pardanani,
R A Knudson,
R P Ketterling,
D Chen,
J D Hoyer, C A Hanson,
A Tefferi
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ABSTRACT: The 2008 World Health Organization (WHO) criteria were used to identify 88 consecutive Mayo Clinic patients with 'myelodysplastic syndrome with isolated del(5q)' (median age 74 years; 60 females). In all, 60 (68%) patients were followed up to the time of their death. Overall median survival was 66 months; leukemic transformation was documented in five (5.7%) cases. Multivariable analysis identified age >or=70 years (P=0.01), transfusion need at diagnosis (P=0.04) and dysgranulopoiesis (P=0.02) as independent predictors of shortened survival; the presence of zero (low risk), one (intermediate risk) or >or=2 (high risk) risk factors corresponded to median survivals of 102, 52 and 27 months, respectively. Janus kinase 2 (JAK2), thrombopoietin receptor (MPL), isocitrate dehydrogenase 1 (IDH1) and IDH2 mutational analysis was performed on archived bone marrows in 78 patients; JAK2V617F and MPLW515L mutations were shown in five (6.4%) and three (3.8%) patients, respectively, and did not seem to affect phenotype or prognosis. IDH mutations were not detected. Survival was not affected by serum ferritin and there were no instances of death directly related to iron overload. The current study is unique in its strict adherence to WHO criteria for selecting study patients and providing information on long-term survival, practical prognostic factors, baseline risk of leukemic transformation and the prevalence of JAK2, MPL and IDH mutations.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2010; 24(7):1283-9. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2010; 24(4):881-4. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2010; 24(5):1092-4. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2010; 24(4):859-60. · 8.30 Impact Factor
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ABSTRACT: The germline JAK2 haplotype 46/1, tagged by the 'C' allele of single-nucleotide polymorphism (SNP) rs12343867 (C/T), has been associated with JAK2V617F (VF)-positive myeloproliferative neoplasms. SNP rs12343867 was genotyped using bone marrow DNA in 226 consecutive patients with essential thrombocythemia (ET) with concomitant analysis of VF allele burden. The incidence of the 46/1-linked C allele was significantly higher in ET (genotype: CC 15%, CT 52%, TT 33%; C-allele frequency: 41%) than in population controls (P<0.01). Genotype distributions were similar among VF-positive/VF-negative patients (genotype: CC 18/11%, CT 52/53%, TT 30/36%; C-allele: 44/38%; P=0.29). Haplotype 46/1 frequency was remarkably similar when comparing VF-negative patients to those with <10% VF allele burden, but significantly higher in the presence of >10% VF allele burden (genotype: CC 11/13/38%, CT 53/56/38%, TT 36/31/24%; C-allele frequency: 38/41/57%; P<0.01). The clinical features of 46/1-positive and -negative ET were indistinguishable, including blood counts, rate of thrombosis/disease transformation and survival. We conclude that JAK2 haplotype 46/1 confers susceptibility to developing ET independent of VF mutational status and does not seem to further affect the clinical phenotype or prognosis.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2009; 24(1):110-4. · 8.30 Impact Factor
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ABSTRACT: A common JAK2 germline haplotype (46/1) has been associated with JAK2V617F (VF)-positive myeloproliferative neoplasms. The rs12343867 SNP (C/T) tags this haplotype. A total of 130 patients (77 VF-positive) with primary myelofibrosis (PMF) were analyzed for this informative SNP, using bone marrow-derived DNA. The observed 46/1 C allele frequencies in VF-positive (50%) and VF-negative (36%) patients were both significantly higher than expected in population controls (P<0.01). Genotype distributions in VF-positive/VF-negative patients were CC 31%/9%, CT 38%/53% and TT 31%/38% (P=0.01). CC genotype/C-allele frequencies in patients with <20% VF mutation burden (12%/37%) were similar (P=0.95) to those seen in VF-negative patients (9%/36%), but were significantly lower (P<0.01) than those seen in the presence of >50% mutation burden ( approximately 67%/71%). The rs12343867 genotype did not correlate with the International Prognostic Scoring System (IPSS) score or karyotype. Unexpectedly, the TT genotype was associated with shortened survival (P<0.01), which was not accounted for by IPSS score or VF allele burden. We conclude that JAK2 germline genetic variation affects disease susceptibility, and possibly survival, in PMF, regardless of VF mutational status. Allelic distortion from acquired uniparental disomy contributes to the appearance of a more pronounced effect on disease susceptibility in VF-positive patients, when studying clonally affected tissue.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2009; 24(1):105-9. · 8.30 Impact Factor
