A Heterogeneous Response Pattern to Interferon-alpha2 with Induction of a Significant Decrease in the Calreticulin Mutant Allele Burden in a Subset of Patients with Essential Thrombocythemia and Primary Myelofibrosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4057-4057
Author(s):  
Sabrina Cordua ◽  
Lasse Kjaer ◽  
Morten Orebo Holmström ◽  
Niels Pallisgaard ◽  
Vibe Skov ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Mutant Allele ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Allele Burden ◽  
Travel Grant ◽  
Ifn Treatment

Abstract Introduction The discovery of mutations in the calreticulin (CALR) gene in the majority of JAK2 -V617F negative patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) (Klampfl et al., 2013; Nangalia et al., 2013) has improved the diagnostic accuracy considerably, and most recently distinct clinical and hematological characteristics according to mutational status have been described (Park et al., 2015). The perspective is to personalize and optimize treatment according to the molecular and clinical landscape. This may be achieved by obtaining more information on responses in myeloproliferative neoplasms (MPN) to existing treatment strategies as assessed by the allele burden. Mutations in the CALR gene have proven to play a major role in oncogenic and immunologic processes (Lu, Weng, & Lee, 2015). In this context, it is highly relevant to explore the effectiveness of interferon-alpha2 (IFN) in reducing the CALR -mutated clone. Until now, only one paper has reported a decrease in allele burden in two patients during IFN treatment (Cassinat, Verger, & Kiladijan, 2014). The objective of this report is to expand current knowledge on this important topic by describing the mutant CALR allele burden over time in a larger group of IFN-treated patients. Method Clinical data were collected retrospectively from a single institution on all IFN-treated CALR positive MPN patients with sequential determinations of the mutant allele burden. Type 1 and type 2 mutations were initially identified by a previously published fragment analysis (Klampfl et al 2013). We have developed a Taqman qPCR assay for precise determination of the mutant allele burden of type 1 and type 2 mutations. Stored DNA was subsequently analysed to increase follow-up time. Results Twenty-one patients were included. Fifteen patients had a diagnosis of PMF; 7 of these were diagnosed with prefibrotic myelofibrosis. Six patients had ET. The type 1 and 2 mutations were found in 15 and 6 patients, respectively. Median age was 60 years (range 42-79) and the sex ratio (M/F) was 8/13. Fifteen patients (71%) were in ongoing treatment with IFN, whereas treatment was discontinued in 6 (29%) because of side effects. Median time of IFN treatment was 756 days (range 42-3927). The IFN prescribed was either subcutaneous injection of Pegasys® (median: 45 microgram (ug) per week), PegIntron® 25-50 ug per week, or Multiferon® 3 x 3 million IU per week. Median follow up time since the first CALR measurement was 756 days (range 294-2108). Fourteen patients (67%) maintained an unchanged allele burden during follow up; 1 patient (5%) presented a temporary decrease (from 39% to 27% in allele burden) but increased to the initial level within months while still on IFN treatment (presumably due to low compliance); 1 patient (5%) displayed an increase in allele burden during transformation to acute myelogenous leukemia (Figure 1); and 5 patients (24%) exhibited a marked decrease in allele burden (median decrease: 32%, range 18-45) during treatment with IFN (Figure 2). All 5 patients with decreasing allele burden (Table 1) normalized their platelet counts within a median time of 5 weeks (range 4-20) after initiating treatment with IFN. Conclusion Using a novel sensitive assay for the CALR mutant allele burden, we have demonstrated and substantiated the effectiveness of IFN to reduce the allele burden in a larger series of CALR positive patients with PMF and ET. Importantly, we report for the first time on highly heterogeneous response patterns. Our observation of one fourth of the CALR positive patients responding to treatment with IFN strongly suggests that IFN significantly influences the CALR mutational load. Further clinical and molecular studies are urgently needed to explore the mechanisms behind the heterogeneous response patterns and the clinical implications in regard to clonal evolution and disease progression in non-responding patients. We are currently analysing these issues to assess the definite role of IFN in future treatment strategies in CALR positive MPN patients. Table 1. Patients responding to interferon-alpha2 Characteristics Number/median (range) Patients 5 Age, years 53 (42-62) Sex (M/F) 1/4 Diagnosis- Essential thrombocythemia- Primary myelofibrosis- Prefibrotic myelofibrosis 221 Calreticulin mutation type- type 1- type 2 50 Duration of interferon-alpha2 treatment, days 960 (177-2790) Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Cordua: Janssen-Cilag: Other: travel grant. Off Label Use: interferon alpha2 for myeloproliferative neoplasms. Holmström:La Roche Ltd: Other: travel grant. Pallisgaard:Qiagen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Speakers Bureau; Bristol Meyer Squibb: Speakers Bureau; Novartis: Other: travel grant, Research Funding, Speakers Bureau; Roche: Other: travel grant. Hasselbalch:Novartis: Research Funding.

Sequential Analysis By Next Generation Sequencing of 18 Genes in Polycythemia Vera and Essential Thrombocythemia Reveals a Association Between Mutational Status and Clinical Outcome after 3-Year Follow-up

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2808-2808
Author(s):  
Damien Luque Paz ◽  
Aurelie Chauveau ◽  
Caroline Buors ◽  
Jean-Christophe Ianotto ◽  
Francoise Boyer ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Jak2 V617f Mutation ◽  
Poor Prognostic Factor ◽  
Disease Evolution ◽  
Allele Burden ◽  
V617f Mutation

Abstract Introduction Myeloproliferative neoplasms (MPN) are molecularly characterized by driver mutations of JAK2, MPL or CALR. Other somatic mutations may occur in epigenetic modifiers or oncogenes. Some of them have been shown to confer a poor prognosis in primary myelofibrosis, but their impact is less known in Polycythemia Vera (PV) and Essential Thrombocythemia (ET). In this study, we investigated the mutational profile using NGS technology in 50 JAK2 V617F positive cases of MPN (27 PV and 23 ET) collected at the time of diagnosis and after a 3 year follow-up (3y). Patients and Methods All patients were JAK2 V617F positive and already included in the prospective cohort JAKSUIVI. All exons of JAK2, MPL, LNK, CBL, NRAS, NF1, TET2, ASXL1, IDH1 and 2, DNMT3A, SUZ12, EZH2, SF3B1, SRSF2, TP53, IKZF1 and SETBP1 were covered by an AmpliseqTM custom design and sequenced on a PGM instrument (Life Technologies). CALR exon 9 mutations were screened using fragment analysis. Hotspots that mutated recurrently in MPN with no sequencing NGS coverage were screened by Sanger sequencing and HRM. A somatic validation was performed for some mutations using DNA derived from the nails. The increase of a mutation between diagnosis and follow-up has been defined as a relative increase of twenty percent of the allele burden. An aggravation of the disease at 3y was defined by the presence of at least one of the following criteria: leukocytosis >12G/L or immature granulocytes >2% or erythroblasts >1%; anemia or thrombocytopenia not related to treatment toxicity; development or progressive splenomegaly; thrombocytosis on cytoreductive therapy; inadequate control of the patient's condition using the treatment (defined by at least one treatment change for reasons other than an adverse event). Results As expected, the JAK2 V617F mutation was found in all patients with the use of NGS. In addition, we found 27 other mutations in 10 genes out of the 18 genes studied by NGS (mean 0.54 mutations per patient). Overall, 29 of 50 patients had only the JAK2 V617F mutation and no other mutation in any of the genes analysed. No CALR mutation was detected. Nine mutations that were not previously described in myeloid malignancies were found. The genes involved in the epigenetic regulation were those most frequently mutated: TET2, ASXL1, IDH1, IDH2 and DNMT3A. In particular, TET2 mutations were the most frequent and occurred in 20% of cases. There was no difference in the number or in the presence of mutations between PV and ET. At 3y, 4 mutations appeared in 4 patients and 15 out of 50 patients (9 PV and 6 ET) were affected by an allele burden increase of at least one mutation. At 3y, 24/50 patients suffered an aggravation of the disease as defined by the primary outcome criterion (16 PV and 8 ET). The presence of a mutation (JAK2 V617Fomitted) at the time of the diagnosis was significantly associated with the aggravation of the disease (p=0.025). Retaining only mutations with an allele burden greater than 20%, the association with disease aggravation is more significant (p=0.011). Moreover, a mutation of ASXL1, IDH1/2 or SRSF2, which is a poor prognostic factor in primary myelofibrosis, was found in 8 patients, all having presented an aggravation of their disease (p=0.001). Only 4 patients had more than one somatic mutation other than JAK2 V617F and all of them also had an aggravation at 3y (p=0.046). In this cohort, appearance of a mutation at 3y was not associated with the course of the disease. Conversely, the increase of allele burden of at least one mutation was associated with an aggravation (p=0.019). Discussion and conclusion Despite the short follow-up and the limited number of patients, this study suggests that the presence of additional mutations at the time of the diagnosis in PV and TE is correlated to a poorer disease evolution. The increase of mutation allele burden, which reflects clonal evolution, also seems to be associated with the course of the disease. These results argue for a clinical interest in large mutation screening by NGS at the time of the diagnosis and during follow-up in ET and PV. Disclosures Ugo: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: ASH travel.

scholarly journals A Novel Pathogenic CALR Exon 9 Mutation in a Patient with Essential Thrombocythemia

2019 ◽  
Vol 51 (3) ◽  
pp. 306-309
Author(s):  
Jee-Soo Lee ◽  
Ho Young Kim ◽  
Miyoung Kim ◽  
Young Kyung Lee
Keyword(s):  
Essential Thrombocythemia ◽  
Frameshift Mutation ◽  
Myeloproliferative Neoplasms ◽  
Case Reports ◽  
Individual Case ◽  
First Case ◽  
Exon 9 ◽  
Calr Mutations

Abstract The clinical phenotypes and prognoses of CALR-mutant myeloproliferative neoplasms depend on the mutation type. The 2 most common mutations, type 1 (52-bp deletion) and type 2 (5-bp insertion), account for 85% of CALR-mutated neoplasms. The former confers a myelofibrotic phenotype, and the latter is associated with a low risk of thrombosis and an indolent clinical course. Individual case reports for patients with novel pathogenic CALR mutations are rare. Herein, we present the first case in the literature, to our knowledge, of a 63-year old ethnic Korean man with essential thrombocythemia who was diagnosed with a novel +1-bp frameshift mutation in CALR, which was predicted to exhibit a type 2–like phenotype.

The Clinical Phenotype of Patients with Essential Thrombocythemia Harboring MPL 515W>L/K Mutation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 678-678 ◽  
Author(s):  
Alessandro M. Vannucchi ◽  
Elisabetta Antonioli ◽  
Alessandro Pancrazzi ◽  
Paola Guglielmelli ◽  
Simonetta Di Lollo ◽  
...  
Keyword(s):  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Mutant Allele ◽  
Clinical Phenotype ◽  
Primary Myelofibrosis ◽  
Allele Burden ◽  
Long Term Stability ◽  
Blood Smears ◽  
Significant Difference ◽  
Systemic Symptoms

Abstract A 515W>L/K mutation in MPL (MPLmut) has been described in 5–10% of patients (pts) with myelofibrosis (Pikman Y, PloS Med 2006), possibly associated with JAK2617V>F allele. Among 217 subjects with primary myelofibrosis, the 18 MPLmut pts presented a more severe anemic phenotype than MPL wild-type (MPLWT) pts (Guglielmelli P, BJH 2007). MPL 515W>L mutation has been reported also in 4 pts with essential thrombocythemia (ET) (1%) (Pardanani A, Blood 2006). We have collected 13 MPLmut pts in an unselected series of 273 ET pts according to WHO criteria (4.7% of total) to evaluate whether MPL mutation associated with unique clinical characteristics and eventually whether MPLmut ET pts should be re-classified as having WHO pre-fibrotic myelofibrosis. A novel quantitative real-time PCR assay for 515W>L and 515W>K allele in granulocyte DNA has been designed; detection limit was 0.01% for W>L allele and 0.1% for W>K allele. Six pts were 515W>L and seven were 515W>K; 1 pt with W>L and 4 pts with W>K allele had only mutant allele. Mean mutant allele burden was 44(+/−25)% and 59(+/−21)% for W>L and W>K, respectively. Seven MPLmut pts (53%) also harbored JAK2617V>F allele, as compared to 164/260 of MPLWT (63%); they were 2/6 pts with 515W>L and 5/7 with 515W>K. Mean 617V>F allele burden was significantly lower in MPLmut (11+/− 9%) than MPLWT pts (24+/− 17%; P=0.03). There was no difference in age or gender, but median disease duration was longer in MPLmut pts (110 vs 57 months, P=0.001). At diagnosis, platelet count was significantly higher in MPLmut pts (1,113+/− 438x109/L vs 864+/− 302x109/L; P=0.02), while hemoglobin, serum ferritin, LDH level, and leukocyte count were not statistically different. Frequency of pts presenting endogenous erythroid colonies or PRV-1 over-expression was similar among MPLmut (37% and 44%, respectively) or MPLWT pts (48% and 43%). There was no difference in splenomegaly, systemic symptoms, major thrombosis (30% vs 21%) or hemorrhages (8% vs 6%) between MPLmut and MPLWT pts. However, pts with microvessel disease were significantly more frequent among MPLmut (77% vs 34%, P=0.002). Bone marrow (BM) biopsy at diagnosis of MPLmut pts was reviewed in a blinded fashion among 30 random biopsies from MPLWT ET pts. There was no significant difference in total cellularity, erythoid or myeloid lineage beteween MPLWT and MPLmut pts. Megakaryocyte hyperplasia was prominent in MPLmut pts, with Mks being either scattered or in loose clusters similarly to MPLWT pts. However, in addition to typical large Mks, MPLmut pts displayed a discrete number of small-size vWF and/or CD61-pos Mks. BM fibrosis quantification (revised EUMNET criteria) revealed grade 0–1 fibrosis in all but one MPLmut pts, who presented grade 1–2. Finally, there was no evidence of leukoerythroblastosis in blood smears. One pt died after 11 yrs of major thrombosis, none evolved to myelofibrosis. Overall, these data indicate that prevalence of MPL mutation in ET may be higher (5%) than previously reported, but the mutation per se does not associate with a unique clinical phenotype, a part for a higher platelet count and greater occurrence of microvessel symptoms. Increased number of small-size Mks was observed in BM biopsy, but the whole hystologic pattern, as well as long-term stability of disease, did not support alternative diagnosis of pre-fibrotic myelofibrosis.

Calreticulin Mutation Is Associated with Milder Disease in Patients with Post Essential Thrombocythemia Myelofibrosis (PET-MF) Compared with JAK2V617F Mutation: A Study from the AGIMM Group

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3179-3179
Author(s):  
Paola Guglielmelli ◽  
Giada Rotunno ◽  
Giada Brogi ◽  
Annalisa Pacilli ◽  
Costanza Bogani ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Allele Burden ◽  
Risk Of Death ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Calr Mutations ◽  
The Impact ◽  
Calr Mutation

Abstract Background: Mutations in the gene calreticulin (CALR) were recently discovered in 60-80% of patients (pts) with primary myelofibrosis (PMF) and essential thrombocythemia (ET) who were un-mutated for JAK2V617F and MPLW515. CALR mutated PMF pts had better overall survival (OS) compared with JAK2V617F or MPLW515 mutated while in ET CALR mutations were associated with lower incidence of thrombosis although the effect on survival was not significant. Conversely, there is no information concerning the impact of CALRmutation on disease phenotype and prognosis in post-essential thrombocythemia myelofibrosis (PET-MF). Aims: The aim of the study was to assess whether CALR mutational status and/or allele burden had clinical and/or prognostic relevance in PET-MF compared with JAK2, MPLmutated or triple-negative (TN) pts. Methods: ET and PET-MF were diagnosed by 2008 WHO and IWG-MRT criteria respectively; all pts provided an informed consent. Genotyping for CALR, JAK2V617F and MPLW515 was performed in granulocytes using allele specific RTQ-PCR (JAK2, MPL), capillary electrophoresis and direct sequencing (CALR, MPL). The prognostic value of the molecular variables with regard to OS was estimated by the Kaplan-Meier method and Cox regression. Results: A series of 147 PET-MF pts from 4 Italian centres was collected. Pts median age was 63y. Median follow up from PET diagnosis was 3.2y (0.07-18.8y) and the median time from ET to PET diagnosis was 11.6y (0.9-30.6y). Death occurred in 38 pts (26%) and 14 pts (9.5%) developed acute leukemia (AML). The median OS in the entire series calculated from PET-MF diagnosis was 10.9y (7.1-14.7y). Frequency of mutations was: CALR 16%, JAK2V617F 77%; MPLW515 4.3%; TN 2.8%. The frequency of CALR mutations in PET-MF patients was superimposable to that observed in a control group of 576 ET patients from our Institution (15.5%) and slightly lower compared with other series (20-25%). Type of CALRmutations was: 59.6% type 1, 23.1%, type 2, 17.3% others, significantly different (P=0.023) from ET: 46% type 1, 38% type 2, 16% others. Median CALR allele burden in PET-MF was 56% (20%-100%) with no significant differences in the CALR mutation subtypes (57.5% in type 1, 47.5% in type 2 and 45.0% in others); however, the median mutant allele burden of CALR-mutated PET-MF patients was significantly higher than in ET patients (33%, range 2%-52%; n=100) (P<0.03) suggesting a role for mutated allele accumulation in evolution to PET-MF. Similarly, the median V617F allele burden in JAK2 mutated patients was 50.5% (range 5-100%) significantly greater than the value (24%; range, 1-87%) (P=0.02) in ET pts, confirming previous data that evolution to PET-MF is associated with accumulation of mutated JAK2allele. We then compared hematological and clinical characteristics of the patients who were categorized according to their JAK2V617F, MPLW515 and CALR mutation status. There was no statistically significant difference among the unique patient mutational groups regarding age, hemoglobin, leukocyte and platelet count, peripheral blasts, LDH, circulating CD34+ cells, abnormal karyotype, grade of bone marrow fibrosis and cellularity, and pruritus. However, JAK2+ pts showed an increased rate of large (>10 cm) splenomegaly (28.6% vs 14% in CALR+, 7.1 in MPL+ and 25% in TN pts; P=0.02) and constitutional symptoms (50% vs 18.8% in CALR+, 45% in MPL+ and 12.5% in TN pts; P=0.002). The interval from ET to PET-MF was significantly longer in CALR+ pts (14.5y) compared with JAK2+ (10.2y) and TN patients (11.0y; P=0.04 for both) and similar to MPL+ (14y). There was a reduced rate of death (13.5%) in CALR+ compared with JAK2+ (30.6%), MPL+ (21.4%) and TN (66.7%) pts (P=0.005), although Kaplan Meier estimates did not reach a statistically significant difference. Finally, there were less AML transformation in CALR+ pts (1.9%) compared with JAK2+ (13.9%), MPL+(7.1%) and TN (22.2%) (P=0.04). Conclusion: These results show that CALR mutation is associated with delayed transformation of ET to PET-MF, a milder disease in terms of splenomegaly and symptom burden and a reduced risk of death compared with JAK2V617F PET-MF pts and more in general with MPL mutated and TN pts.In addition, similar to findings in primary MF and unlike in ET, PET-MF is characterized by prevalence of type 1 CALR mutations. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Contemporary Approach to CALR-Positive Myeloproliferative Neoplasms

2021 ◽  
Vol 22 (7) ◽  
pp. 3371
Author(s):  
Tanja Belčič Mikič ◽  
Tadej Pajič ◽  
Samo Zver ◽  
Matjaž Sever
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Molecular Genetic ◽  
Diagnostic Algorithm ◽  
Primary Myelofibrosis ◽  
Cellular Mechanisms ◽  
Cellular Effects ◽  
Prognostic Importance ◽  
Calr Mutations

CALR mutations are a revolutionary discovery and represent an important hallmark of myeloproliferative neoplasms (MPN), especially essential thrombocythemia and primary myelofibrosis. To date, several CALR mutations were identified, with only frameshift mutations linked to the diseased phenotype. It is of diagnostic and prognostic importance to properly define the type of CALR mutation and subclassify it according to its structural similarities to the classical mutations, a 52-bp deletion (type 1 mutation) and a 5-bp insertion (type 2 mutation), using a statistical approximation algorithm (AGADIR). Today, the knowledge on the pathogenesis of CALR-positive MPN is expanding and several cellular mechanisms have been recognized that finally cause a clonal hematopoietic expansion. In this review, we discuss the current basis of the cellular effects of CALR mutants and the understanding of its implementation in the current diagnostic laboratorial and medical practice. Different methods of CALR detection are explained and a diagnostic algorithm is shown that aids in the approach to CALR-positive MPN. Finally, contemporary methods joining artificial intelligence in accordance with molecular-genetic biomarkers in the approach to MPN are presented.

scholarly journals The Germline JAK2 GGCC (46/1) Haplotype and Survival Among 414 Molecularly-Annotated Patients with Primary Myelofibrosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1761-1761
Author(s):  
Ayalew Tefferi ◽  
Terra L. Lasho ◽  
Christy Finke ◽  
Mythri Mudireddy ◽  
Natasha Szuber ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Genetic Risk ◽  
Triple Negative ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Version 2.0 ◽  
Survival Effect

Abstract Background: We have long introduced the concept of host genetic variations in the phenotypic diversity of myeloproliferative neoplasms (MPN) (Blood 2008;111:2785). Previous studies have established an association between JAK2 mutations in myeloproliferative neoplasms (MPN) and the germline GGCC (46/1) haplotype, which constitutes a string of single nucleotide polymorphisms (SNPs) near the JAK2 gene that are inherited together on chromosome 9p (reviewed recently;Int J Mol Sci. 2018; 19: 1152). In 2010, we reported an association between shortened survival in primary myelofibrosis (PMF) and nullizygosity for the JAK2 46/1 haplotype (Leukemia 2010; 24:105), although our findings were not confirmed in another study (Leukemia 2010; 24:1533). Others have reported an association with splanchnic vein thrombosis, that was not accounted for by JAK2 mutations (Ann Hematol 2014;93:1845). In the current study, we have increased the number of informative cases to 414 (from 130 reported in 2010), in order to revisit with the phenotypic and prognostic relevance of the JAK2 46/1 haplotype in PMF. Methods : Study patients were recruited from the Mayo Clinic, Rochester, MN, USA. Diagnoses PMF and its leukemic transformation were confirmed by both clinical and bone marrow examinations, in line with the 2016 World Health Organization criteria (Blood. 2016;127:2391). Screening for the JAK2 46/1 haplotype included rs12343867 SNP genotyping, as previously detailed (Leukemia 2010; 24:105), and using a commercially available TaqMan SNP genotyping assay (Applied Biosystems Inc., Foster City, CA, USA). Statistical analyses considered clinical and laboratory data collected at the time of initial PMF diagnosis or Mayo Clinic referral point. Conventional statistics was used for confirming phenotypic associations and calculation of overall (OS) and leukemia-free (LFS) survival. The JMP® Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for all calculations. Results: 414 patients with PMF (median age 63 years; 63% males) were included in the current study; among 324 evaluable cases, MIPSS70+ version 2.0 risk distribution was 18% very high risk, 41% high risk, 19% intermediate risk, 18% low risk and 4% very low risk. Driver mutation distribution was 63% JAK2, 17% type 1-like CALR, 3% type 2-like CALR, 7% MPL and 10% triple-negative. JAK2 46/1 haplotype was documented in 69% of the study patients, including 25% in homozygous and 44% in heterozygous state. Driver mutation frequency in patients homozygous/heterozygous/nullizygous for the 46/1 haplotype was 78%/60%/56% JAK2, 10%/20%/18% type 1-like CALR, 3%/2%/5% type 2-like CALR, 4%/8%/7% MPL and 6%/10%/14% triple-negative (p=0.02). The three 46/1 haplotype groups were phenotypically mostly similar, with the exception of platelet count (p=0.02) and leukocyte count (p=0.003), which were both higher with homozygous 46/1 haplotype. In univariate analysis, nullizygosity for the JAK2 46/1 haplotype was associated with inferior overall survival (HR 1.5, 95% CI 1.1-1.9; figure 1a); this survival effect was most pronounced in JAK2 mutated cases (figure 1b; p<0.001), as opposed to CALR/MPL mutated cases (figure 1c; p=0.48) or triple-negative cases (figure 1d; p=0.27). Multivariable analysis that included age and other genetic risk factors, including karyotype, driver mutational status and presence of high molecular risk mutations, such as ASXL1 and SRSF2, confirmed the independent prognostic contribution of nullizygosity for the 46/1 haplotype (p=0.02; HR 1.4, 95% CI 1.1-1.8). Nullizygosity for 46/1 also remained significant in the context of the recently unveiled genetics-based prognostic model, GIPSS (genetically-inspired prognostic scoring system) (p=0.04) (Leukemia.2018 doi: 10.1038/s41375-018-0107-z), but not in the context of MIPSS70+ version 2.0 (karyotype and mutation-enhanced international prognostic scoring system for transplant-age patients) (p=0.4). (JClinOncol.2018 doi: 10.1200/JCO.2018.78.9867). Leukemia-free survival was not affected by the 46/1 haplotype (p=0.6). Conclusions: The current study confirms the association of nullizygosity for the JAK2 GGCC (46/1) haplotype with inferior survival in PMF, primarily in JAK2-mutated cases; the observed survival effect was independent of currently acknowledged genetic risk factors, including karyotype and high molecular risk mutations. 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.

A form of Autoimmune Diabetes in Adults Named LADA – An Update on Essential Features and Controversies

2019 ◽  
Vol 15 (3) ◽  
pp. 172-173 ◽  
Author(s):  
Valdemar Grill ◽  
Bjørn O. Åsvold
Keyword(s):  
Genetic Background ◽  
Clinical Utility ◽  
Autoimmune Diabetes ◽  
Classical Type ◽  
Phenotypic Characteristics ◽  
Latent Autoimmune Diabetes ◽  
The Impact

Latent Autoimmune Diabetes in the Adult, LADA has been investigated less than “classical” type 1 and type 2 diabetes and the criteria for and the relevance of a LADA diagnosis has been challenged. Despite the absence of a genetic background that is exclusive to LADA, this form of diabetes displays phenotypic characteristics that distinguish it from other forms of diabetes. LADA is heterogeneous in terms of the impact of autoimmunity and lifestyle factors, something that poses problems as to therapy and follow-up perhaps particularly in those with marginal positivity. Yet, there appears to be clear clinical utility in classifying individuals as LADA.

scholarly journals Serum urate and cardiovascular events in the DCCT/EDIC study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alicia J. Jenkins ◽  
Barbara H. Braffett ◽  
Arpita Basu ◽  
Ionut Bebu ◽  
Samuel Dagogo-Jack ◽  
...  
Keyword(s):  
Cardiovascular Events ◽  
Serum Urate ◽  
Continuous Variable ◽  
Major Adverse Cardiovascular Events ◽  
Normal Range ◽  
The Metabolic Syndrome ◽  
Routine Measurement

AbstractIn type 2 diabetes, hyperuricemia is associated with cardiovascular disease (CVD) and the metabolic syndrome (MetS), but associations in type 1 diabetes (T1D) have not been well-defined. This study examined the relationships between serum urate (SU) concentrations, clinical and biochemical factors, and subsequent cardiovascular events in a well-characterized cohort of adults with T1D. In 973 participants with T1D in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC), associations were defined between SU, measured once in blood collected 1997–2000, and (a) concurrent MetS and (b) incident ‘any CVD’ and major adverse cardiovascular events (MACE) through 2013. SU was higher in men than women [mean (SD): 4.47 (0.99) vs. 3.39 (0.97) mg/dl, respectively, p < 0.0001], and was associated with MetS features in both (men: p = 0.0016; women: p < 0.0001). During follow-up, 110 participants (11%) experienced “any CVD”, and 53 (5%) a MACE. Analyzed by quartiles, SU was not associated with subsequent CVD or MACE. In women, SU as a continuous variable was associated with MACE (unadjusted HR: 1.52; 95% CI 1.07–2.16; p = 0.0211) even after adjustment for age and HbA1c (HR: 1.47; 95% CI 1.01–2.14; p = 0.0467). Predominantly normal range serum urate concentrations in T1D were higher in men than women and were associated with features of the MetS. In some analyses of women only, SU was associated with subsequent MACE. Routine measurement of SU to assess cardiovascular risk in T1D is not merited.Trial registration clinicaltrials.gov NCT00360815 and NCT00360893.

Insulin Dose Adjustment Following Bariatric Surgery, a Review of Available Literature

2021 ◽  
pp. 193229682110288
Author(s):  
Lynn E. Kassel ◽  
Jessica J. Berei ◽  
Jamie M. Pitlick ◽  
Joel E. Rand
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Bariatric Surgery ◽  
Type 2 Diabetes Mellitus ◽  
Dose Adjustment ◽  
Insulin Dose ◽  
Appraisal Tool

Bariatric surgery is a known and effective treatment for type 2 diabetes mellitus. Patients with type 1 diabetes mellitus and exogenous insulin-requiring type 2 diabetes mellitus require adjusted insulin dosing after surgery to avoid hypoglycemia. This review describes insulin dose adjustments following a variety of bariatric procedures. After searching the available literature and assessing for eligibility, 8 articles were included. The Johns Hopkins Research Evidence Appraisal Tool for literature appraisal was used. The results of this review reveal insulin dose adjustment varies based upon surgical procedure type and time of follow-up from the procedure.

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