JAK2V617F, CALR, and MPL Mutations and Bone Marrow Histology in Patients with Essential Thrombocythaemia

2018 ◽  
Vol 140 (4) ◽  
pp. 234-239 ◽  
Author(s):  
Achille Pich ◽  
Ludovica Riera ◽  
Paola Francia di Celle ◽  
Eloise Beggiato ◽  
Giulia Benevolo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Value ◽  
Triple Negative ◽  
Morphological Changes ◽  
Gene Mutations ◽  
Essential Thrombocythaemia ◽  
Bone Marrow Histology ◽  
Marrow Cellularity ◽  
Morphological Patterns

Introduction: Mutations in the JAK2, CALR, and MPL genes have been shown to have prognostic value in essential thrombocythaemia (ET), but no clear association with morphological changes has been reported so far. We investigated the possible correlation between gene mutations and histopathological features in bone marrow (BM) biopsies of patients with ET. Methods: Marrow cellularity, fibrosis, and the number of total and dysmorphic megakaryocytes and clusters of megakaryocytes were compared to gene mutations in 90 cases of ET at diagnosis. Results: The JAK2V617F mutation was found in 58.9%, CALR in 28.9%, and MPL in 4.4% of the cases, and 7.8% were triple-negative. JAK2V617F-mutated ET showed a high BM cellularity, the lowest number of clusters of megakaryocytes and the highest number of dysmorphic megakaryocytes; CALR-mutated ET showed a reduced BM cellularity, many clusters of large megakaryocytes, and very few dysmorphic megakaryocytes; MPL-mutated ET showed the lowest BM cellularity, the highest number of clustered and large megakaryocytes, and the lowest number of dysmorphic megakaryocytes. Triple-negative ET cases had the highest BM cellularity. Conclusions: Distinct morphological patterns were associated with gene mutations in ET, supporting the classification of ET into different subtypes.

scholarly journals Histopathologic Characterization of Vexas Syndrome

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4656-4656
Author(s):  
Mohammad I. Barouqa ◽  
Aishwarya Ravindran ◽  
Dong Chen ◽  
Jennifer L Oliveira ◽  
Horatiu Olteanu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Morphological Changes ◽  
Gene Mutations ◽  
Relapsing Polychondritis ◽  
Inflammatory Disorder ◽  
Bone Marrow Biopsies ◽  
Oncology Research ◽  
Institutional Review ◽  
Hematopoietic Precursor

Abstract Introduction: VEXAS syndrome (vacuoles, E1 ubiquitin ligase, X-linked, autoinflammatory, somatic) is a newly recognized inflammatory disorder caused by somatic mutations in the UBA1 gene. Bone marrows from these patients reveal a range of morphological changes in hematopoietic precursor cells. In this study, we aim to assess the laboratory indices and morphologic spectrum of bone marrow pathology in VEXAS syndrome. Methods: We identified 16 cases of VEXAS syndrome. All cases had confirmed UBA1 mutation. We reviewed bone marrow biopsies corresponding to the date of diagnosis. This study was approved by the Mayo Clinic Institutional Review Board. Results: All patients were male with a median age of 73 years - associated autoimmune disorders included Sweet syndrome, inflammatory arthritis, relapsing polychondritis and granulomatosis with polyangiitis. 14/16 patients had anemia with median hemoglobin of 10.4 (Range: 6.7- 14.1 g/dL). 15/16 had macrocytosis with median MCV 110.4 (Range: 94.8- 123.1 /fL). 5/16 had thrombocytopenia with median platelet count 174 (Range: 20- 500 x10^9/L). 7/16 had leukopenia with median WBC 3.65 (Range: 2.4- 11.6 x10^9/ L). The ESR and CRP medians were 61.0 mm/hr and 81.5 mg/L, respectively. Karyotype was performed in 12 patients of which 11 were normal and the remaining case showed a complex karyotype. An NGS panel targeting the most frequent myeloid disorder associated gene mutations was negative in 10/15 cases. GS for myeloid mutations revealed pathogenic mutations in 5 patients, involving genes TET2 (2/5), DNMT3A (2/5), and TP53 (1/5). Conclusions: Bone marrow findings in VEXAS syndrome, in this series of 16 patients, are individually non-specific, yet when taken altogether in the overtly abnormal cases, are very suggestive when the clinical index of suspicion is high. In such scenarios, the combined clinical and bone marrow findings should prompt discussion and consideration for UBA1 mutation testing given the significant clinical implications for patient management and prognosis. Disclosures Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding. Warrington: Eli Lilly: Research Funding; Kiniksa: Research Funding.

Additional Prognostic Value of Bone Marrow Histology in Patients Subclassified According to the International Prognostic Scoring System for Myelodysplastic Syndromes

2003 ◽  
Vol 21 (2) ◽  
pp. 273-282 ◽  
Author(s):  
E. Verburgh ◽  
R. Achten ◽  
B. Maes ◽  
A. Hagemeijer ◽  
M. Boogaerts ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Scoring System ◽  
Lower Risk ◽  
Prognostic Value ◽  
Predictive Power ◽  
Intensive Therapy ◽  
International Prognostic Scoring System ◽  
Prognostic System ◽  
Bone Marrow Histology

Purpose: The most recent and powerful prognostic instrument established for myelodysplastic syndromes (MDS) is the International Prognostic Scoring System (IPSS), which is primarily based on medullary blast cell count, number of cytopenias, and cytogenetics. Although this prognostic system has substantial predictive power in MDS, further refinement is necessary, especially as far as lower-risk patients are concerned. Histologic parameters, which have long proved to be associated with outcome, are promising candidates to improve the prognostic accuracy of the IPSS. Therefore, we assessed the additional predictive power of the presence of abnormally localized immature precursors (ALIPs) and CD34 immunoreactivity in bone marrow (BM) biopsies of MDS patients. Patients and Methods: Cytogenetic, morphologic, and clinical data of 184 MDS patients, all from a single institution, were collected, with special emphasis on the determinants of the IPSS score. BM biopsies of 173 patients were analyzed for the presence of ALIP, and CD34 immunoreactivity was assessable in 119 patients. Forty-nine patients received intensive therapy. Results: The presence of ALIP and CD34 immunoreactivity significantly improved the prognostic value of the IPSS, with respect to overall as well as leukemia-free survival, in particular within the lower-risk categories. In contrast to the IPSS, both histologic parameters also were predictive of outcome within the group of intensively treated MDS patients. Conclusion: Our data confirm the importance of histopathologic evaluation in MDS and indicate that determining the presence of ALIP and an increase in CD34 immunostaining in addition to the IPSS score could lead to an improved prognostic subcategorization of MDS patients.

scholarly journals Prognostic value of integrated cytogenetic, somatic variation, and copy number variation analyses in Korean patients with newly diagnosed multiple myeloma

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246322
Author(s):  
Nuri Lee ◽  
Sung-Min Kim ◽  
Youngeun Lee ◽  
Dajeong Jeong ◽  
Jiwon Yun ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Copy Number ◽  
Prognostic Value ◽  
Gene Mutations ◽  
Median Number ◽  
Integrated Analysis ◽  
Driver Gene ◽  
Newly Diagnosed ◽  
1Q Gain

Background To investigate the prognostic value of gene variants and copy number variations (CNVs) in patients with newly diagnosed multiple myeloma (NDMM), an integrative genomic analysis was performed. Methods Sixty-seven patients with NDMM exhibiting more than 60% plasma cells in the bone marrow aspirate were enrolled in the study. Whole-exome sequencing was conducted on bone marrow nucleated cells. Mutation and CNV analyses were performed using the CNVkit and Nexus Copy Number software. In addition, karyotype and fluorescent in situ hybridization were utilized for the integrated analysis. Results Eighty-three driver gene mutations were detected in 63 patients with NDMM. The median number of mutations per patient was 2.0 (95% confidence interval [CI] = 2.0–3.0, range = 0–8). MAML2 and BHLHE41 mutations were associated with decreased survival. CNVs were detected in 56 patients (72.7%; 56/67). The median number of CNVs per patient was 6.0 (95% CI = 5.7–7.0; range = 0–16). Among the CNVs, 1q gain, 6p gain, 6q loss, 8p loss, and 13q loss were associated with decreased survival. Additionally, 1q gain and 6p gain were independent adverse prognostic factors. Increased numbers of CNVs and driver gene mutations were associated with poor clinical outcomes. Cluster analysis revealed that patients with the highest number of driver mutations along with 1q gain, 6p gain, and 13q loss exhibited the poorest prognosis. Conclusions In addition to the known prognostic factors, the integrated analysis of genetic variations and CNVs could contribute to prognostic stratification of patients with NDMM.

scholarly journals A Rare Case of Triple-Negative Essential Thrombocythemia in a Young Postsplenectomy Patient: A Diagnostic Challenge

2018 ◽  
Vol 2018 ◽  
pp. 1-5
Author(s):  
Tugce Akcan ◽  
Paolo Strati ◽  
Melissa Yan ◽  
Modupe Idowu
Keyword(s):  
Bone Marrow ◽  
Essential Thrombocythemia ◽  
Triple Negative ◽  
Myeloproliferative Neoplasms ◽  
Splenic Vein ◽  
Myeloproliferative Neoplasm ◽  
Diagnostic Challenge ◽  
Reactive Thrombocytosis ◽  
Vein Thrombosis ◽  
Bone Marrow Histology

The distinction between primary and reactive thrombocytosis by bone marrow histology is very important. Reactive thrombocytosis, the most common cause of thrombocytosis, can be expected in postsplenectomy states; however, close hematological evaluation of prolonged thrombocytosis is essential to identify patients who may have an underlying myeloproliferative neoplasm. We report a 37-year-old woman who was found to have portal, mesenteric, and splenic vein thrombosis with thrombocytosis, two months after she had a splenectomy for spontaneous splenic rupture. Other reactive conditions and myeloproliferative neoplasms (MPN) were excluded, and subsequently, the diagnosis of triple-negative essential thrombocythemia (ET) was established by bone marrow histology. This case of primary thrombocythemia following splenectomy in a young patient illustrates some of the diagnostic difficulties associated with postsplenectomy thrombocytosis. Continuing reports of anecdotal experiences in managing similar complex scenarios is essential and remains the only reference for clinicians facing these rare conditions.

scholarly journals A Retrospective Audit of the Use of Next-Generation Sequencing in the Management of Myelofibrosis Patients in North London Hospitals

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-14
Author(s):  
Ke Xu ◽  
Andrew Wilson ◽  
Elisabeth P. Nacheva ◽  
Temenuzhka Boneva ◽  
Rajeev Gupta
Keyword(s):  
Bone Marrow ◽  
Triple Negative ◽  
Primary Myelofibrosis ◽  
Pathogenic Mutation ◽  
Driver Mutations ◽  
Clonal Hematopoiesis ◽  
Myeloid Neoplasms ◽  
Pathogenic Mutations ◽  
Retrospective Audit

Background: Myelofibrosis (MF) is typically characterized by one of three classic driver mutations identified in the JAK2, CALR, and MPL genes. However, a small proportion of MF patients are triple negative and do not carry any of these driver mutations. In the latest WHO 2016 classification of myeloid neoplasms, the authors recommended further genetic testing in this subset of patients to confirm clonality 1. In MF, mutations in ASXL1, EZH2, IDH1, IDH2, SRSF2, U2AF predicted shorter survival and increased risk of leukemic transformation 2,3,4. The presence of one or more of these mutations defined a higher risk category termed high molecular risk (HMR) 4. In transplant eligible patients with HMR, early transplantation should be considered. The hematological malignancy diagnostic service (HMDS) at University College London Hospital (UCLH) serves 8 secondary or tertiary hospitals in North London. At our HMDS, transplant eligible patients with suspected MF are offered the TruSight Myeloid NGS (Illumina) with a panel of 54 genes. The panel is run on the MiSeq Illumina platform. All results are integrated by the oncogenomics multidisciplinary team (MDT). Aim: We evaluated the diagnostic, prognostic, and therapeutic utilization of 54 gene panel myeloid NGS in management of MF patients. Method: Eligible patients were those: (1) Aged >18 years at diagnosis of MF, with a diagnostic date between 1/1/2017 and 12/31/2019. (2) Availability of diagnostic bone marrow samples at HMDS at UCLH. Data was retrospectively collected from patients' medical records. Gene variance screening was performed as described before 5. Results: 67 patients were referred to HMDS at UCLH with suspected myelofibrosis between 1/1/2017 and 12/31/2019. 36 patients were included in this retrospective audit (94% [n= 34/36] with primary MF (PMF) and 6% [n=2/36] with secondary MF). The median age at MF diagnosis was 69 years (range 48-90 years). 55.5% patients (n=20/36) had JAK2 mutation, 13.8% (n=5/36) had CALR mutation, 5.5% (n=2/36) had MPL mutation, 27.3% (n=9/36) were negative for JAK2, CALR and MPL mutation (triple negative) by polymerase chain reaction (PCR). 24/36 patients had myeloid NGS. This includes 15/17 (88%) transplant eligible patients and 9/19 (47%) transplant ineligible patients. 12% patients (n=3/24) had no pathogenic mutations, 42% (n=10/24) had 1 pathogenic mutation, 21% (n=5/24) had 2 pathogenic mutations, 21% (n=5/24) had 3 pathogenic mutations, and 4% (n=1/24) had 4 mutations (Figure 1). The most commonly identified pathogenic mutation by NGS was JAK2 (42%), followed by ASXL1 (21%), SRSF2 (17%), TET2 (13%), CALR (13%). Other less frequent mutations were identified in U2AF1 (8%), SETBP1 (8%), MPL (4%), TP53 (4%), SF3B1 (4%), NRAS (4%), PHF6(4%), CUX1(4%), RUNX1 (4%), BCOR (4%) (Figure 2). 57% (n=4/7) triple negative patients showed evidence of clonal hematopoiesis by NGS. Compared with our standard PCR, NGS showed 88% concordance in identifying JAK2, MPL and CALR mutations. 12% mutations identified by PCR were not identified by NGS. No cryptic mutations were identified. 29% patients (n=7/24) had high molecular risk, of whom 4 were transplant eligible with a DIPSS-plus score of intermediate-2 or above. All of the 4 patients were referred for early Hematopoietic Stem Cell Transplant (HSCT). Despite early HSCT, 2 patients showed early relapse and disease progression of MF. Conclusion: Myeloid NGS showed clinical utility in diagnosis of MF through verifying clonal hematopoiesis in triple negative patients and refining clinical decisions relating to HSCT. References: 1.Arber DA, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391-2405 2.Vannucchi AM, et al. Mutations and prognosis in primary myelofibrosis. Leukemia 2013; 27:1861-1869 3.Guglielmelli P, et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia 2014; 28:1804-1810 4.Tefferi A, et al: MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis. JCO 2018; 36 :1769-1770 5.Nacheva E, et al. Absence of damaging effects of stem cell donation in unrelated donors assessed by FISH and gene variance screening. Bone Marrow Transplantation 2020; 55:1290-1296 Disclosures No relevant conflicts of interest to declare.

scholarly journals JAK2 or CALR Mutations Status and Bone Marrow Histology in Patients with Essential Thrombocythemia in Chinese

2020 ◽  
Author(s):  
xiupeng ye ◽  
Muhtar Yimamniyaz ◽  
Ye qiong LI ◽  
Jian MA ◽  
Shen BAO ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Essential Thrombocythemia ◽  
Gene Mutations ◽  
Median Number ◽  
High Power Field ◽  
Jak2 Mutation ◽  
Bone Marrow Histology ◽  
Calr Mutations ◽  
Lower Count ◽  
Calr Mutation

Abstract Objectives: To characterize the clinical, and bone marrow histopathological features of essential thrombocythemia (ET) with different gene mutations status of CALR and JAK2.Methods: 159 patients of ET were centrally analyzed from January 2016 to December 2019, including 59 cases with CALR mutation, 96 JAK2 mutation, 2 MPL mutation, and 2 cases were triple-negative (TN). Bone marrow pathology observation and determination were performed by 2 immobilized experienced morphological specialists.Results: Compared to ET with JAK2 mutation, patients with CALR mutation were younger (p=0.000), showed lower count of white blood cell (WBC) and level of hemoglobin (p=0.001, p=0.001), and higher count of platelet (p=0.001). In the bone marrow (BM) biopsy, the median number of megakaryocyte and clusters of megakaryocytes in each high power field (HPF) of vision in patients with CALR mutations were lower than JAK2 mutations patients (p=0.001, p=0.001), thrombotic events in two group was different (5% vs 11.5%) (p=0.03).Conclusion: In Chinese ET patients, patients with CALR mutations were younger, and had lower levels of Hb, and count of WBC, the lower thrombotic evens although with higher platelet counts than those with JAK2 mutation. Patients with JAK2 mutations had a higher median number of megakaryocytes and median number of clusters of megakaryocytes, the clinical significance is worth exploring.

Triple Negative Myeloproliferative Neoplasms (MPNs) Patients Show Low MPN10 Score and Lower Grades of Bone Marrow Fibrosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5477-5477
Author(s):  
Yasser Elnahass ◽  
Hossam K Mahmoud ◽  
Mervat Mattar ◽  
Omar Fahmy ◽  
Mohamed A. Samra ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Gene Mutation ◽  
Disease Burden ◽  
Triple Negative ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Gene Mutations ◽  
Janus Kinase ◽  
Driver Gene ◽  
The Impact

Abstract Introduction: The vast majority ofmyeloproliferative neoplasms (MPNs) patients are characterized by a molecular genetic background and by variable symptoms reflecting disease burden that may correlate with prognosis. Aim: To study the impact of triple negative status of driver gene mutations: Janus kinase 2 (JAK2), calreticulin (CALR) and myeloproliferative leukemia virus oncogene (MPL) on disease burden and its correlation with symptom severity (MPN10 score) and degree of bone marrow (BM) fibrosis in MPNs patients. Patients and Methods: MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) was assessed as median of 10 items: fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pains, abdominal discomfort, weight loss and fever. JAK2V617F and MPL W515exon 10 mutations were performed by allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) while CALR exon 9 insertion/deletion was detected by high-resolution melting (HRM) curve analysis. Results: 100 MPNs patients (54 males and 46 females): 18 polycythemia vera (PV), 41 essential thrombocythemia (ET), 24 primary myelofibrosis (PMF), 10 Post-ET/PV-myelofibrosis (post-ET/PV-MF) and 7 myelodysplastic/myeloproliferative neoplasms (MDS/MPN) were included. Median age at diagnosis was 55 years (17-75) and was lower in ET than PV and PMF patients; 44 (19-75) years vs. 56 (34-70) years and 56 (20-75) years, respectively (p=0.06). JAK2 mutation was positive in 15 (85%) PV patients, 14 (34%) ET patients, 15 (62%) PMF patients, 8(80%) post-ET/PV-MF patients and zero (0%) MDS/MPN patients (p<0.001). CALR mutation was positive in zero (0%) PV patients, 10 (24%) ET patients, 4 (17%) PMF patients, zero (0%) Post-ET/PV-MF patients and zero (0%) MDS/MPN patients (p<0.05). MPL mutation was positive in zero (0%) PV patients, 2 (5%) ET patients, 1(4%) PMF patients, zero (0%) Post ET/PV-MF patients and zero (0%) MDS/MPN patients. Twenty four/93 (26%) patients were triple negative; 15 ET (16%), 3 PV (3%), 6 PMF (6%). Median MPN10 score was 21 (4-45) in ET versus 37.5 (25-56) in PV, 54 (15-80) in PMF and 59 (45-75) in Post-ET/PV-MF (p<0.001). Median MPN10 score was 25 (10-50) in triple negative patients vs. 40 (4-80) in MPNs patients showing at least one driver mutation positivity (p<0.001). BM fibrosis was present in 6 (15%) patients with triple negative vs. 33 (85%) patients showing at least one molecular marker positivity (p=0.007). Out of 52 patients having splenomegaly; seven (13.5%) patients were triple negative vs. 45 (87%) patients with at least one gene mutation (p<0.001). Out of the 24 triple negative patients, 19 (80%), 4 (16%), 1 (3%) and 0(0%) had BM fibrosis grades 0, 1, 2 and 3 vs. 36 (52%), 7 (10%), 12 (17%), 14 (20%) out of 69 patients with at least one gene mutation, respectively (p=0.002). After a median follow-up period of 16 months (3-151), overall survival (OS) was 95%. OS in PV and ET patients was 100 % versus 83 % in PMF patients (p=0.08). OS in triple negative group was 100% versus 94% in the gene mutations group (p=0.387). Conclusion: Driver gene mutations show an impact on disease symptoms and burden. Triple negative MPNs patients in our cohort have significantly low MPN10 score and less BM fibrosis which may indicate a more indolent disease course. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Prefibrotic myelofibrosis: is this diagnosis valid?

Blood ◽  
2008 ◽  
Vol 111 (1) ◽  
pp. 1-2 ◽  
Author(s):  
LoAnn Peterson
Keyword(s):  
Bone Marrow ◽  
World Health Organization ◽  
Diagnostic Criteria ◽  
Essential Thrombocythemia ◽  
World Health ◽  
Substantial Variation ◽  
Bone Marrow Histology ◽  
The World ◽  
Health Organization

Wilkins and colleagues evaluate the utility of the World Health Organization (WHO) diagnostic criteria intended to separate cases previously classified as essential thrombocythemia (ET) into 2 groups: “true ET” and “prefibrotic myelofibrosis.” Focusing on bone marrow histology, the authors found substantial variation in classification of cases.

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