A JAK2 Germline Genetic Variation Is Associated with Shortened Survival in Primary Myelofibrosis: Clinical and JAK2V617F Allele Burden Correlates of rs12343867 SNP Genotype in 132 Cases.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2895-2895 ◽  
Author(s):  
Ayalew Tefferi ◽  
Terra Lasho ◽  
Christy Finke ◽  
Kebede Hussein ◽  
Michelle Elliott ◽  
...  
Keyword(s):  
Mutant Allele ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Multivariable Analysis ◽  
Primary Myelofibrosis ◽  
Taqman Assay ◽  
Snp Analysis ◽  
Allele Burden ◽  
Mutational Status ◽  
Jak2v617f Allele Burden

Abstract Abstract 2895 Poster Board II-871 Background: Recent studies have reported a significant association between JAK2V617F acquisition and a specific JAK2 germline haplotype; rs12343867 (located at intron 14 of the JAK2 gene) is one of several SNPs that tag this haplotype. We performed rs12343867 SNP analysis in a consecutive cohort of patients with primary myelofibrosis (PMF) in order to study the clinical and laboratory correlates of the particular JAK2 haplotype and its effect on survival. Methods: Study patients were recruited form the Mayo Clinic database for PMF. Molecular studies were performed on DNA extracted from stored bone marrow. rs12343867 SNP genotyping was performed by a commercially available Taqman assay. Quantitative JAK2V617F analysis was done according to previously published methods. Standard statistical methods were used to test significance of associations between SNP genotype and other variables. Survival analysis was performed by the Kaplan-Meier method and comparisons made by the log-rank test. Cox regression model was used for multivariable analysis. Results: 132 patients with PMF were studied (median age 62, range 28-82; 82 males). Risk distribution according to the International Prognostic Scoring System (IPSS) for PMF were low in 39 (29%) patients, intermediate-1 in 41 (31%), intermediate-2 in 25 (20%) and high in 27 (20%). 77 (58%) patients were JAK2V617F positive; median mutant allele burden was 26% (range 1-85) and 21 patients displayed > 50% mutant allele burden. The rs12343867 genotype distributions were C/C 22%, C/T 44% and T/T 34% . The corresponding figures in JAK2V617F positive/negative cases were 31%/9%, 38%/53%, 31%/38% (p=0.01). Among the 21 patients with > 50% JAK2V617F allele burden, 14 (67%) displayed the C/C allele, 2 C/T and 5 T/T. The specific SNP genotype was not significantly affected by age (p=0.33), sex (p=0.46), leukocyte count (p=0.39), platelet count (p=0.09), or IPSS risk category (p=0.63). Patients were followed for a median of 54 months and during this period 73 (55%) deaths were documented. The T/T SNP genotype was significantly associated with shortened survival, compared to either C/C or C/T (p=0.001; Figure). Multivariable analysis showed this association to be independent of IPSS, JAK2V617F mutational status, age or sex. The adverse prognostic effect of the T/T genotype was also apparent when JAK2V617F negative (p=0.01) or positive (p=0.06) cases were analyzed separately. Conversely, JAK2 mutational status or allele burden did not affect survival in patients with T/T or C/C allele. Conclusion: The current study illustrates the non-random haplotype distribution of JAK2V617F in patients with PMF. More importantly, a non-JAK2 haplotype, tagged by the rs12343867 T allele, was associated with inferior survival that is not accounted for by IPSS or JAK2V617F mutational status. These findings, together with previous observations regarding shortened survival associated with low JAK2V617F allele burden, suggest the presence of molecular events in PMF that are more aggressive than JAK2V617F and not necessarily linked to the JAK2 haplotype. Disclosures: No relevant conflicts of interest to declare.

JAK2 Haplotype SNP Analysis in Essential Thrombocythemia: Clinical and JAK2V617F Allele Burden Correlates in 226 Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2893-2893
Author(s):  
Animesh D. Pardanani ◽  
Terra Lasho ◽  
Christy Finke ◽  
Kebede Hussein ◽  
Michelle Elliott ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Research Funding ◽  
Cox Regression ◽  
Myeloproliferative Neoplasms ◽  
Multivariable Analysis ◽  
Taqman Assay ◽  
Snp Analysis ◽  
Allele Burden ◽  
Mutational Status ◽  
Jak2v617f Allele Burden

Abstract Abstract 2893 Poster Board II-869 Background: A specific JAK2 germline haplotype has been associated with the occurrence of JAK2V617F in myeloproliferative neoplasms (MPN). Several SNPs, including rs12343867, tag this haplotype. We performed rs12343867 SNP analysis in a consecutive cohort of patients with essential thrombocythemia (ET) in order to study the clinical and JAK2V617F allele burden correlates of the particular SNP genotype. Methods: Study patients were recruited form the Mayo Clinic database for ET. Molecular studies were performed on DNA extracted from stored bone marrow. rs12343867 SNP genotyping was performed by a commercially available Taqman assay. Quantitative JAK2V617F analysis was done according to previously published methods. Standard statistical methods were used to test significance of associations between SNP genotype and other variables. Survival analysis was performed by the Kaplan-Meier method and comparisons made by the log-rank test. Cox regression model was used for multivariable analysis. Results: 226 patients with ET were studied (median age 57, range 14-91; 145 females). Median hemoglobin, leukocyte and platelet counts at initial diagnosis were 13.8 g/dL, 9.7 × 109/L and 1000 × 109/L, respectively. 118 patients (52%) were JAK2V617F positive and among them, 90 (76%) displayed JAK2V617F allele burden of < 10% (low allele burden group) and the median (range) mutant allele burden in the remaining 28 patients (higher allele burden group) was 12% (12-68). As expected, JAK2V617F-positive cases, compared to their mutation-negative counterparts, were older (p=0.006) and displayed higher hemoglobin (p=0.0001) and leukocyte (p<0.0001) counts and lower platelet (0.03) count. The rs12343867 genotype distributions were C/C 15%, C/T 53% and T/T 33% (expected frequency in the HapMap-CEU listed control population is ∼ 6%, 46% and 48%, respectively). The corresponding figures in JAK2V617F positive/negative cases were 17%%/11%, 53%/53%, 30%/36% (p=0.29). Unlike the case with JAK2V617F mutational status, rs12343867 SNP genotype did not correlate with age (p=0.69), hemoglobin level (p=0.47), leukocyte count (p=0.25) or platelet count (p=0.33). Patients were followed for a median of 7.4 years and during this period 56 (25%) deaths were documented. rs12343867 SNP genotype did not correlate with survival (Figure). Similarly, survival did not correlate with the presence or absence of JAK2V617F. However, patients with higher JAK2V617F allele burden displayed a shorter survival with borderline significance, during multivariable analysis that included age as a covariate. Conclusion: The current study shows the JAK2 haplotype enrichment in a large series of ET patients. However, the particular phenomenon was not significantly different between JAK2V617F positive and negative cases, which suggests specific haplotype association with the disease rather than the mutation. Consistent with this contention, rs12343867 genotype did not correlate with clinical or laboratory variables that typically associate with JAK2V617F mutational status. Furthermore, unlike the case with primary myelofibrosis, rs12343867 SNP genotype did not correlate with survival, an observation that is not surprising considering the lower level of complexity in molecular pathogenesis in ET compared to PMF. Disclosures: Pardanani: TargeGen: Research Funding; Cytopia: Research Funding. Off Label Use: Data from ongoing clinical trial will be presented. Tefferi:TargeGen: Research Funding.

Thrombotic Events in Primary Myelofibrosis: Prevalence and Prognostic Factors in 207 Consecutive Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3915-3915
Author(s):  
Michelle Elliott ◽  
Terra Lasho ◽  
Christy Finke ◽  
Animesh D. Pardanani ◽  
Ayalew Tefferi
Keyword(s):  
Platelet Count ◽  
Prognostic Factors ◽  
Mutant Allele ◽  
Primary Myelofibrosis ◽  
Hemoglobin Level ◽  
Snp Genotyping ◽  
Taqman Assay ◽  
Allele Burden ◽  
Vein Thrombosis ◽  
Jak2v617f Allele Burden

Abstract Abstract 3915 Poster Board III-851 Background Thromboembolic disease (TE) is a major cause of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET). There is limited information on the prevalence of TE in primary myelofibrosis (PMF) and associated prognostic factors. Methods Study patients were recruited form the Mayo Clinic database for PMF. Diagnosis was according to the 2001 WHO criteria. Clinical and laboratory information was collected at time of diagnosis and correlated with the occurrence of TE in general and arterial (AT) or venous (VT) thrombosis in particular. Leukocytosis was defined as a leukocyte count of > 10 × 109/L. Qualitative JAK2V617F analysis was done according to previously published PCR-based methods. In addition, a subset of the study patients underwent quantitative PCR for JAK2V617F and rs12343867 SNP genotyping (performed by a commercially available Taqman assay). All molecular studies were performed on stored bone marrow. Standard statistical methods were used to test significance of associations between thrombosis and other variables. Results 207 patients with PMF were studied (median age 62, range 28-87; 132 males). At presentation, the median (range) of hemoglobin (Hb), leukocytes (WBC) and platelets (plt) were 11 g/dl (6.4-15.4), 8.6 × 109/L (0.8-156.7) and 273 × 109/L (13-1916), respectively. Dupriez prognostic scores at diagnosis were low, intermediate and high in 57%, 33% and 10% of the patients, respectively. 130 (63%) patients were JAK2V617F positive. Among 73 patients in whom quantitative JAK2V617F analysis was performed, the mutation was not detected in 30 (41%) patients and the median mutant allele burden in the 43 mutation-positive patients was 28% (range 1-85). The same 73 patients had rs12343867 SNP genotyping performed that revealed C/C genotype in 14 (19%) patients, C/T in 34 (47%) and T/T in 25 (34%). At or before diagnosis, a total of 29 patients (14 %) had TE: 23 (11%) AT and 9 (4%) VT. The AT included acute coronary syndromes (ACS; n=19), transient ischemic attack/ cerebrovascular accidents (TIA/CVA; n=6) and peripheral arterial thrombosis (PAT; n=1). The VT included abdominal vein thrombosis (AVT; n=4), deep vein thrombosis/pulmonary embolism (DVT/PE; n=6) and dural sinus thrombosis (n=1). Several patients had more than one event and some both AT and VT. During follow-up, 22 (11%) patients experienced TE: 17 (8%) VT and 8 (4%) AT. The post-diagnosis VT included AVT (n=8), DVT/PE (n=13) and both DVT/PE and AVT (n=4). Post-diagnosis AT included CVA (n=4), TIA (n=1), ACS (n=2) and PAT (n=1). AT at or before diagnosis was associated with advanced age (p=0.003) but not with sex, leukocytosis, hemoglobin level, platelet count, JAK2 mutational status, JAK2 mutant allele burden or rs12343867 SNP genotype. VT at or before diagnosis also did not correlate with all these variables or age. These variables were also evaluated regarding their relationship with post-diagnosis AT, which showed significant associations with hemoglobin level (p=0.006), platelet count (p=0.04) and high JAK2V617F allele burden (0.03). The corresponding significant variables for post-diagnosis VT were leukocytosis (p=0.02) and high JAK2V617F allele burden (p=0.01). Of note, AT or VT at or before diagnosis did not predict post-diagnosis events. During multivariable analysis, only higher hemoglobin level predicted post-diagnosis AT. Conclusion The current study provides an accurate description of both arterial and venous thrombotic events in PMF. The association between higher hemoglobin and leukocyte counts at diagnosis and post-diagnosis occurrence, respectively, of arterial and venous thrombosis is similar to observations in patients with PV or ET and suggests a potential benefit from early institution of cytoreductive therapy for the appropriate patient groups. Disclosures: No relevant conflicts of interest to declare.

Low JAK2V617F Allele Burden in Primary Myelofibrosis, Compared to Either a Higher Allele Burden or Unmutated Status, Predicts Inferior Overall and Leukemia-Free Survival.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 676-676
Author(s):  
Ayalew Tefferi ◽  
Terra L. Lasho ◽  
Jocelin Huang ◽  
Christy Finke ◽  
Curtis A. Hanson ◽  
...  
Keyword(s):  
Leukocyte Count ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Primary Myelofibrosis ◽  
Older Age ◽  
World Health ◽  
Lower Quartile ◽  
Free Survival ◽  
Allele Burden ◽  
Mutational Status

Abstract Background : Two previous studies have reported significant but inconsistent associations between the presence of JAK2V617F in primary myelofibrosis (PMF) and older age at diagnosis, risk of thrombosis, higher leukocyte count, and inferior survival (Tefferi, et al. BJH2005;131:320, Campbell, et al. Blood2006;107:2098). The clinical relevance of V617F allele burden in PMF has not been previously studied. Methods : Diagnosis of PMF was based on the World Health Organization criteria and study eligibility included the availability of bone marrow-derived DNA that was collected either at time of diagnosis or within one year of diagnosis. Quantitative allele specific PCR was utilized to meaure V617F allele burden. Results I. V617F-positive vs. V617F-negative comparisons: A total of 199 patients (60% males; median age 61 years) were suitable for analysis of comparisons between mutation-positive and mutation-negative disease. The Dupriez prognostic scoring system (PSS) risk distributions were 61% low-risk, 31% intermediate-risk, and 8% high-risk. Hypercatabolic symptoms were present in 27% of the patients and ≥1% peripheral blood (PB) blasts in 37%. At a median follow-up of 23 months (range 0–266), 57 patients (29%) had died, 17 (9%) developed leukemic transformation (LT) and 10 (5%) experienced major thrombosis. V617F mutational frequency was 58%. Univariate analysis identified older age (p=0.0007), platelet count ≥ 100 x 109/L (p=0.05), and PB blast percentage < 3% (p=0.001) as being associated with a positive mutational status; all three variables sustained their significance during multivariable analysis. The presence of the mutation did not affect the incidence of thrombosis (p=0.78), overall survival (p=0.22) or leukemia-free survival (p=0.5). Results II. Clinical correlates of V617F allele burden: Quantitative measurement of V617F allele burden was performed in 129 patients that were divided into four groups: V617F-negative (n=53) and V617F-positive with mutant allele burden in the lower quartile (n=19), middle quartiles (n=38), or upper quartile (n=19) range (median and range of V617F allele burden ratio was 29% and 1% to 74%). Kaplan-Meier plots revealed significantly shortened overall (Figure; p = 0.0008) and leukemia-free (p = 0.01) survival for the lower quartile allele burden group; survival significance was sustained in a multivariable analysis that included the Dupriez PSS. Lower quartile allele burden was also associated with lower leukocyte count (p = 0.003) and presence of hypercatabolic symptoms (p=0.05). Thrombosis incidence was not affected by allele burden. Conclusions: In PMF, patients with a low V617F allele burden, compared to those with either undetectable (i.e. wild-type) or higher allele burden, display significantly shorter overall and leukemia-free survival. In contrast, the presence or absence of the mutation, by itself, does not result in distinct groups that differ significantly in terms of survival, LT, or incidence of thrombosis. These data suggest that a low V617F allele burden in PMF is a surrogate for the development of dominant V617F-negative subclones that are more likely to undergo LT. Figure Figure

Transfusion Need at Diagnosis or Its Development During the First Year of Diagnosis in Primary Myelofibrosis: Effect On Survival and Correlation with JAK2 and TET2 Mutational Status.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1909-1909
Author(s):  
Ayalew Tefferi ◽  
Sergio Siragusa ◽  
Rakhee Vaidya ◽  
Susan Schwager ◽  
Kebede Hussein ◽  
...  
Keyword(s):  
Median Survival ◽  
Conflicts Of Interest ◽  
Multivariable Analysis ◽  
Primary Myelofibrosis ◽  
First Year ◽  
Prognostic Impact ◽  
Mutational Status ◽  
Risk Patients ◽  
One Year

Abstract Abstract 1909 Poster Board I-932 Background: The International Prognostic Scoring System (IPSS) for primary myelofibrosis (PMF) utilizes five independent predictors of inferior survival; of these, a hemoglobin level <10 g/dL has the highest impact on survival (Cervantes et al. Blood 2009;113:2895). In the current study, we examined the additional prognostic impact of transfusion need at diagnosis or becoming transfusion-dependent in the first year of diagnosis. These events were also correlated with JAK2 or TET2 mutational status. Methods: Patients were selected from the Mayo Clinic PMF database based on availability of bone marrow histology and IPSS-relevant information at diagnosis and follow-up transfusion history at one year from diagnosis. WHO criteria were used for PMF diagnosis. Patients who underwent allogeneic hematopoietic cell transplantation were censored at time of transplant. Patient records were updated in July, 2009. Survival curves were constructed using the Kaplan-Meier method and compared by the log-rank test. Multivariable survival was analysed using Cox regression model. Results: A consecutive cohort of 254 patients was studied (median age 59 years; range 28-87; 159 males). IPSS risk category was low, intermediate (int)-1, int-2 and high in 75, 71, 62 and 46 patients, respectively. JAK2V617F was present in 118 (62%) of 192 patients and TET2 mutations in 6 (13%) of 45 patients evaluated. Transfusion need at diagnosis was documented in 62 patients whereas an additional 22 patients became transfusion-dependent during the first year of their diagnosis. The remaining 170 patients remained transfusion-independent for at least one year post-diagnosis. To date, 139 patients have died. In patients who are alive, median follow-up was 5.3 years. Median survivals in IPSS high, Int-2, Int-1 and low risk patients were, 3, 3.9, 6.8 and 12.8 years, respectively (p<0.0001). Median survival for patients requiring transfusions at diagnosis was similar to that of patients who became transfusion-dependent in their first year of diagnosis, and both were significantly shorter than the median survival seen in patients who remained transfusion-free during the first year post-diagnosis: 2.9, 2.2 and 9.7 years, respectively (p<0.0001; figure). Multivariable analysis confirmed the IPSS-independent prognostic value of transfusion status-based risk stratification. Neither JAK2 nor TET2 mutational status correlated with transfusion need. Conclusions: In PMF, becoming transfusion-dependent in the first year of diagnosis is prognostically as detrimental as requiring transfusions at initial presentation. These events are not affected by JAK2 or TET2 mutational status and confer an IPSS-independent adverse prognosis. The ability to identify Int-1 risk patients with shortened survival (Figure) holds major treatment implications. Disclosures: No relevant conflicts of interest to declare.

IPSS-Independent Cytogenetic Risk Categorization in Primary Myelofibrosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2909-2909 ◽  
Author(s):  
Kebede Hussein ◽  
Animesh D. Pardanani ◽  
Daniel van Dyke ◽  
Curtis A. Hanson ◽  
Ayalew Tefferi
Keyword(s):  
Median Survival ◽  
Prognostic Value ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Multivariable Analysis ◽  
Primary Myelofibrosis ◽  
Rank Test ◽  
International Prognostic Scoring System ◽  
Cytogenetic Abnormalities ◽  
Risk Categorization

Abstract Abstract 2909 Poster Board II-885 Background: Previous studies have identified sole abnormalities of del(20q) and del(13q) as prognostically favorable cytogenetic markers in primary myelofibrosis (PMF) (Tefferi et al. BJH 2001;113:763). A more recent study (Tam et al. Blood 2009;113:4171) confirmed these findings and suggested additional cytogenetic markers of prognosis. In the current study with larger numbers of informative patients studied at time of diagnosis, we wanted to validate these observations and examine the prognostic interaction between cytogenetic risk categorization and the International Prognostic Scoring System (IPSS). Methods: Patients with cytogenetic information at diagnosis were selected from the Mayo Clinic database of WHO-defined PMF. Specific cytogenetic categories were considered only in the presence of at least 5 informative patients; otherwise, they were included in the category of “other cytogenetic abnormalities”. Follow-up information was updated in July, 2009. Survival curves were prepared by the Kaplan-Meier method and compared by the log-rank test. Cox regression model was used for multivariable analysis. Results: 200 patients were studied (median age, 62 years; 63% males). The IPSS risk distributions were low in 66 patients, intermediate (int)-1 in 64, int-2 in 44 and high in 26. Cytogenetic findings at diagnosis were abnormal in 83 (42%) patients and included sole del(20q) in 21, complex (i.e. 3 or more abnormalities) in 13, sole del(13q) in 8, sole +8 in 7, sole +9 in 6, and other abnormalities in 28 patients. Median survivals in low, int-1, int-2 and high IPSS risk groups were 188, 71, 47 and 26 months, respectively (p < 0.0001). Median survival in patients with sole +9 was not reached and in those with sole del(13q), sole del(20q), normal karyotype, complex abnormalities and sole +8 was 112, 108, 80, 37 and 27 months, respectively, while it was 46 months for patients with other cytogenetic abnormalities (p = 0.01). Accordingly, sole abnormalities of +9, del(20q) and del(13q) were categorized as being favorable (n = 35) and complex abnormalities and sole +8 as unfavorable (n = 20); the respective median survivals were 112 and 34 months (p=0.002; Figure). Multivariable analysis confirmed the IPSS-independent prognostic value of cytogenetic risk categorization and the intra-IPSS risk prognostic distinction was most apparent in the int-1 group: median survival was 35 and 81 months in the presence of unfavorable or favorable cytogenetic markers, respectively (p=0.0009; Figure). Conclusion: The current study identifies sole +9, along with del(13q) and del(20q), as favorable and sole +8, along with complex abnormalities, as unfavorable cytogenetic markers of prognosis in PMF. Cytogenetic risk categorization in PMF has an IPSS-independent prognostic value that is important in patient selection for specific therapy. Disclosures: No relevant conflicts of interest to declare.

Decrease in JAK2V617F Allele Burden is Not a Prerequisite to Clinical Response in Patients with Polycythemia Vera (PV).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1908-1908 ◽  
Author(s):  
Richard T. Silver ◽  
Katherine Vandris ◽  
Joshua J. Goldman ◽  
Fernando Adriano ◽  
Y. Lynn Wang ◽  
...  
Keyword(s):  
Clinical Response ◽  
Polycythemia Vera ◽  
Mutant Allele ◽  
Conflicts Of Interest ◽  
Kappa Coefficient ◽  
Molecular Response ◽  
Allele Burden ◽  
Hematologic Response ◽  
Complete Hematologic Response ◽  
Jak2v617f Allele Burden

Abstract Abstract 1908 Poster Board I-931 Previous studies of patients (pts) with polycythemia vera (PV) treated with pegylated interferon (peg-IFNá-2a) have shown an 83% complete hematologic response associated with an 89% molecular response over a median of 11 months (Kiladjian et al. Blood. 2008. 112(8):3065-3072) implying a causative relationship between molecular and hematologic responses. Our data show pts treated with rIFNá-2b or non-rIFNá-2b agents achieve hematologic response despite the absence of a molecular response suggesting that a molecular change is not a prerequisite to hematologic response. Thirty pts diagnosed with PV by the criteria of the Polycythemia Vera Study Group (PVSG) were followed clinically and hematologically with serial quantified JAK2V617F allele burden determined at six-month intervals over a mean of 21.6 months (mos) (range: 6.0 – 56.4 mos). These pts were treated with rIFNá-2b ranging from 0.5 mu to 3.0 mu three times per week depending upon clinical response. Primary clinical endpoints were hematocrit (hct) ≤45% men, ≤42% women, and no need for phlebotomy (PHL). Molecular and hematologic responses were graded according to the criteria of Barosi et al. (Blood. 2009. 113(20):4829-4833): complete hematologic response (CHR: hct ≤45% without PHL, platelets '400×109/L, WBC ≤10×109/L, normal spleen size, asymptomatic); partial hematologic response (PHR: hct ≤45% without PHL or response in 3 or more of the CHR categories); no hematologic response (NHR: failure to meet the criteria of CHR or PHR); complete molecular response (CMR: reduction of JAK2V617F marker to undetectable levels); partial molecular response (PMR: ≥50% reduction in pts with '50% mutant allele burden at baseline, or ≥25% reduction in pts with >50% mutant allele burden at baseline; applicable only to pts with ≥10% baseline allele burden); and no molecular response (NMR: failure to meet the criteria of CMR or PMR). Of the 30 pts treated with rIFNá-2b, 14 had a CHR, 13 had a PHR and 3 had NHR. Of 14 pts who had a CHR, 4 had a PMR and 10 had NMR. Of thirteen pts who had a PHR, 1 had a PMR and 12 had NMR. All 3 pts who had NHR also had NMR. Based on these data, the statistical agreement between hematologic response and molecular response was poor (kappa coefficient = 0.06, P=0.17). We then examined the hematologic responses (HR: CHR+PHR) of 25 non-rIFNá-2b treated pts, which included PHL ± anagrelide (3 pts: 2 HR/NMR, 1 NHR/NMR), dasatinib (5 pts: 5 HR/NMR), imatinib (9 pts: 3 HR/PMR, 4 HR/NMR, 2 NHR/NMR), and hydroxyurea (8 pts: 1 CHR/PMR, 7 HR/NMR). The minimal molecular response to dasatinib and hydroxyurea is noteworthy. Likewise, there was poor statistical agreement between hematologic response and molecular response for non-rIFNá-2b treated patients (kappa coefficient = 0.05, P=0.21). Of all 55 pts (rIFNá-2b and non-rIFNá-2b), those 9 patients with a PMR had a hematologic response (7 CHR and 2 PHR). Of 46 NMR's, 40 pts (87%) had a hematologic response (16 CHR, 24 PHR). Thus, NMR did not exclude the possibility of achieving CHR. Regardless of therapy, we demonstrate poor agreement between hematologic and molecular responses for these drugs (all pts: kappa = 0.05, P=0.13). This suggests a difference in action between peg-IFNá-2a, shown to cause molecular and hematologic responses concurrently, and several drugs we examined leading to clinical response without necessarily changing JAK2V617F allele burden. In this regard, other parameters such as bone marrow morphology and new biological markers may be useful in reconciling the differences. In summary, we find that a hematologic response is not always accompanied by a molecular response in PV pts treated with either rIFNá-2b or some non-rIFNá-2b drugs. We thus conclude that a reduction in JAK2V617F allele burden is not always required for patients to achieve hematologic response, and that following the JAK2V617F biomarker may be drug-dependent and may not always be a reliable measure of response. This warrants the importance of the randomized trial planned to compare peg-IFNá-2a to the current standard of treatment, hydroxyurea. Disclosures: No relevant conflicts of interest to declare.

Normal Serum-Erythropoietin (S-epo) Level at Diagnosis of Polycythemia Vera (PV) Correlates with LowJAK2V617F Mutant Allele Burden and Indicates Mild Phenotype.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4978-4978
Author(s):  
Joshua J. Goldman ◽  
Katherine Vandris ◽  
Fernando Adriano ◽  
Michael Bourla ◽  
Richard T. Silver
Keyword(s):  
Polycythemia Vera ◽  
Mutant Allele ◽  
Conflicts Of Interest ◽  
Cell Mass ◽  
The Other ◽  
World Health ◽  
Mild Phenotype ◽  
Allele Burden ◽  
Serum Erythropoietin ◽  
Jak2v617f Allele Burden

Abstract Abstract 4978 A low serum-erythropoietin (S-epo) level is a minor criterion of the World Health Organization (WHO) recommendations for diagnosing polycythemia vera (PV) even though previous studies indicate that a normal level does not always rule out PV. We wished to determine whether a normal S-epo level correlates with a low JAK2V617F mutant allele burden and a low phlebotomy (PHL) rate, since the relationship between S-epo level, JAK2V617F allele burden, and PHL rate heretofore has not been reported. At diagnosis, we grouped the S-epo levels of 26 PV patients (pts) as follows: low (<5 U/l), normal (5-10 U/l), and high (>10 U/l). Of the 26 pts, 4 (15.4%) had normal S-epo levels, and 22 had low S-epo levels. The diagnosis of PV in pts with normal S-epo levels was made by quantitative JAK2V617F analysis and elevated Cr51 red cell mass (RCM). All pts had a bone marrow biopsy consistent with PV. We determined the number of phlebotomies required to maintain normal hematocrit (hct) levels ('42% women, '45% men) as an assessment of disease severity during the period prior to myelosuppressive therapy. We then examined the number of phlebotomies per year (PHL/yr) in relation to S-epo level at diagnosis. Of the 26 pts, 14 were treated with PHL-only for a mean of 15 months (mos) prior to beginning other therapies including anagrelide, hydroxyurea, imatinib, and rIFNa-2b. The number of PHL/yr were grouped into 4 categories: 0 (none), 1 – 5 (low), 6 – 10 (moderate), and >10 (high). Of the 14 pts, 3 had a normal S-epo level at diagnosis, all of whom had a low PHL requirement, median 3/yr. The other 11 pts had low S-epo levels at diagnosis and a median PHL requirement of 6/yr (7 moderate and 4 low). Thus, while a low S-epo level at presentation was usually associated with moderate PHL requirement, a normal S-epo level at diagnosis was always associated with a subsequently low PHL requirement during the period of observation (mean 15 mos). Of the 26 pts, 14 had quantitative JAK2 analyses done at diagnosis. The other 12 were diagnosed prior to 2002 and quantitative JAK2 determinations were not available. Of the 14 pts, 2 had a normal S-epo level and a low JAK2V617F mutant allele burden (1-25%). These 2 pts also had a low PHL requirement. Thus, these pts who had normal S-epo levels, had JAK2V617F allele burdens in the lowest quartile, and had low PHL rates. Of the remaining 12 pts, 5 had JAK2V617F allele burdens in the 2nd (25-50%) quartile, 5 in the 3rd (50-75%) quartile, and 1 each in the 1st and 4th quartiles. We conclude (1) as previously reported, about 15% of pts with PV present with normal S-epo levels at diagnosis, suggesting a limitation of this WHO criterion, and (2) those pts with a low JAK2V617F allele burden and a normal S-epo level required fewer PHL/yr, all suggesting a more benign phenotype. This may provide a useful prognostic tool for patients with PV. Disclosures No relevant conflicts of interest to declare.

scholarly journals The effects of mutational profiles on phenotypic presentation of myeloproliferative neoplasm subtypes in Bosnia: 18 year follow-up

2019 ◽  
Author(s):  
Amina Kurtovic-Kozaric ◽  
Erna Islamagic ◽  
Hana Komic ◽  
Nurija Bilalovic ◽  
Izet Eminovic ◽  
...  
Keyword(s):  
Clinical Features ◽  
Mutant Allele ◽  
Myeloproliferative Neoplasm ◽  
Gene Mutations ◽  
Primary Myelofibrosis ◽  
Patient Characteristics ◽  
Disease Evolution ◽  
Allele Burden ◽  
Mutational Status

The identification of mutually exclusive somatic mutations shared among myeloproliferative neoplasm (MPN) subtypes has provided a powerful tool for studying disease evolution. Clinical features, gene mutations, and survival over 18 years were analyzed in MPN patients. One hundred thirty-eight MPN patients were subcategorized according to MPN subtypes: essential thrombocythemia (ET, n = 41), polycythemia vera (PV, n = 56), primary myelofibrosis (PMF, n = 10), and MPN unclassified (MPN-U, n = 31). Patient characteristics included clinical parameters, overall survival, and mutational status of the JAK2, CALR, and MPL genes. We compared hematologic and clinical features of JAK2V617F-ET vs. CALR-mutated ET vs. JAK2V617F-PV patients. JAK2V617F-patients had higher values of erythrocytes, hemoglobin, and hematocrit compared to CALR-mutated patients (p < 0.05). The mutant allele burden in JAK2V617F-PV and JAK2V617F-ET patients directly correlated with erythrocyte, hemoglobin, and hematocrit values, but it inversely correlated with platelet count. Thus, mutant allele burden was an indicator of the clinical phenotype in JAK2V617F-MPN patients. OS was not affected by the mutational status. In general, mutated JAK2, CALR, and MPL genes left specific hematological signatures.

Correlations Between TET2 Mutation and Clinicohematologic Parameters in Myeloproliferative Neoplasms

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1455-1455
Author(s):  
Jung Sook Ha ◽  
Jae Hee Lee ◽  
Sung Gyun Park ◽  
Nam Hee Ryoo ◽  
Dong Suk Jeon ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Direct Sequencing ◽  
Jak2 V617f ◽  
Putative Tumor Suppressor Gene ◽  
Allele Burden ◽  
Frame Shift ◽  
Mutational Status ◽  
Tet2 Mutation ◽  
Disease Specific

Abstract Abstract 1455 Background: Since the acquired somatic mutation, JAK2 V617F, was discovered as a first molecular marker of myeloproliferative neoplasms (MPN), and it has been detected variably in each MPN subtypes. However, JAK2 V617F does not found in all of MPN cases and not necessarily specific to a particular clinicpathologic entity. Recently, mutation of the putative tumor suppressor gene, Ten-Eleven-Translocation-2(TET2), has been identified in MPN patients. However, the frequency of TET2 mutation or its relationship with JAK2 V617F mutation or pathologic function in MPN has not been concluded, yet. The aim of our study was to evaluate the frequency of TET2 in MPN patients, and whether there is any correlation of TET2 mutation with JAK2V617F mutation or the clinicohematologic parameters. Materials and Methods: Total 99 adult MPN patients (18 PV, 62 ET, 11 PMF and 8 MPN unclassified) whose bone marrow cells had been stored from 2007 to 2010 at point of first diagnosis were included in this study. Hematological diagnoses and subtyping were reconfirmed according to the 2008 WHO classification and clinicohematologic datas were collected from patient records. Direct sequencing for TET2(exon3–11) and JAK2 (exons 12 and 14) were performed using an ABI 3730XL DNA analyzer. The JAK2V617F allele burdens were determined by pyrosequencing for samples available and MPL was analyzed by allele-specific PCR. Results: The overall TET2 mutational frequency was 12.1%, and disease-specific mutational frequencies were 22.2% in PV, 9.7% in ET and 18.2% in PMF. The found mutations included 11 mutations, 7 frame-shift (p.Lys95AsnfsX18, p.Gln967AsnfsX40, p.Lys1022GlufsX4, p.Asp1314MetfsX49, p.Gln1534AlafsX43, p.Tyr1618LeufsX4, p.Leu1609GlufsX45), 1 nonsense (p.Gly1735X), 1 missense (Q599R) and 2 splicing mutations (c.3409+1G>T, c.4044+2insT). Those mutations most frequently involved exon 3(four mutations) and exon 11(four mutaions), and rarely intron 3, intron 8 and exon 7. None of the mutations were associated with a karyotypically apparent 4q24 rearrangement. All patients were also screened for JAK2 V617F, and the overall JAK2 V617F positive rate was 68%(94.4% in PV, 69.4% in ET, 45.5% in PMF and 37.5% in MPN, unclassified). All TET2 mutations occurred in JAK2 V617F positive cases. JAK2 exon12 mutation was not found in all patients. MPL W515L was found in one ET patient who also carried JAK2V617F, but not TET2 mutation. Information on JAK2 V617F allele burden was available in 78 patients. Considering all 99 patients, the patient age, hematologic indexes (leukocyte count, neutrophil fraction, lymphocyte fraction, monocyte fraction, Hb, Hct and platelet count), the frequency of organomegaly, marrow fibrosis or thrombotic/hemorrhagic complications were not different according to carrying TET2 mutation. However, TET2 mutation was more frequently found in JAK2 V617F carriers than non-carriers (P=0.008), but JAK2 V617F allele burden did not correlated with the presence of mutant TET2. When analysis was performed for each PV, ET, and PMF (no TET2 mutation in MPN-unclassifiable patients), correlation between TET2 and JAK2 V617F mutational status was not found in each subtypes (P=0.078 in PV, P=0.099 in ET and P=0.182 in PMF). However, the JAK2 V617F allele burden was significantly higher in PMF harboring TET2 mutation than PMF patients did not (88.0 ± 4.3% vs 19.1 ± 28.7%, P=0.034). In statistical analysis for the correlations of clinicohematologic parameters with TET2 mutation in each PV, ET and PMF patients, only a few statistically significant results were identified. The presence of TET2 mutation was correlated with high Hct in PMF (47.4 ± 5.4 vs 25.5 ± 6.2, P=0.037), and TET2 positive ET patients showed relatively higher frequency of organomegaly compared to ET patients without TET2 mutation (50% vs 19.6%, P=0.018). Conclusions: The overall and disease-specific frequencies of TET2 mutation in our study are similar with previous studies, and frame-shift mutation is the most frequent mutation type. There is no specific relationship between JAK2 V617F and TET2 mutation occurrence, but TET2 mutant PMF has higher JAK2 V617F allele burden than non-mutant. TET2 mutation is also associated with a higher Hct in PMF and higher frequency of organomegaly in ET. Larger scale studies involving more MPN patients are needed. Disclosures: No relevant conflicts of interest to declare.

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