scholarly journals A rare atypical chronic myeloid leukemia BCR-ABL1 negative with concomitant JAK2 V617F and SETBP1 mutations: a case report and literature review

2020 ◽  
Vol 11 ◽  
pp. 204062072092710
Author(s):  
Tianqi Gao ◽  
Changhui Yu ◽  
Si Xia ◽  
Ting Liang ◽  
Xuekui Gu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Targeted Therapy ◽  
Next Generation Sequencing ◽  
Myeloid Leukemia ◽  
Jak2 V617f ◽  
Next Generation ◽  
Bone Marrow Fibrosis ◽  
Atypical Chronic Myeloid Leukemia ◽  
Generation Sequencing ◽  
Marrow Fibrosis

Atypical chronic myeloid leukemia (aCML) BCR-ABL1 negative is a rare myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) for which no standard treatment currently exists. The advent of next-generation sequencing has allowed our understanding of the molecular pathogenesis of aCML to be expanded and has made it possible for clinicians to more accurately differentiate aCML from similar MDS/MPN overlap syndrome and MPN counterparts, as MPN-associated driver mutations in JAK2, CALR, or MPL are typically absent in aCML. A 55-year old male with main complaints of weight loss and fatigue for more than half a year and night sweats for more than 2 months was admitted to our hospital. Further examination revealed increased white blood cells, splenomegaly, and grade 1 bone marrow fibrosis with JAK2 V617F, which supported a preliminary diagnosis of pre-primary marrow fibrosis. However, in addition to JAK2 V617F (51.00%), next-generation sequencing also detected SETBP1 D868N (46.00%), ASXL1 G645fs (36.09%), and SRSF2 P95_R102del (33.56%) mutations. According to the 2016 World Health Organization diagnostic criteria, the patient was ultimately diagnosed with rare aCML with concomitant JAK2 V617F and SETBP1 mutations. The patient received targeted therapy of ruxolitinib for 5 months and subsequently an additional four courses of combined hypomethylating therapy. The patient exhibited an optimal response, with decreased spleen volume by approximately 35% after therapy and improved symptom scores after therapy. In diagnosing primary bone marrow fibrosis, attention should be paid to the identification of MDS/MPN. In addition to basic cell morphology, mutational analysis using next-generation sequencing plays an increasingly important role in the differential diagnosis. aCML with concomitant JAK2 V617F and SETBP1 mutations has been rarely reported, and targeted therapy for mutated JAK2 may benefit patients, especially those not suitable recipients of hematopoietic stem cell transplants.

Refining Triage to Polycythaemia Vera or Primary Myelofibrosis Based on Targeted Molecular Profiling By Clinical Next Generation Sequencing

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4076-4076
Author(s):  
Song Jinming ◽  
Mohammad Omar Hussaini ◽  
Haipeng Shao ◽  
Eric Padron ◽  
Jeffrey E Lancet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Next Generation Sequencing ◽  
Gene Mutation ◽  
Research Funding ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Next Generation ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Potential Biomarkers

Abstract Background: Primary myelofibrosis (PMF) and polycythemia vera (PV) are myeloproliferative neoplasms (MPN) that can both share a similar bone marrow morphology with panmyelosis and fibrosis, posing a diagnostic challenge, particularly when the differential is between cellular phase of PMF and PV, or fibrotic PMF and post-PV myelofibrosis. Despite advances in genomic analysis, limited information is known regarding their differences in genetic profile/signature. It has been well known that constitutive tyrosine kinase activation due to JAK2 V617F mutation is seen in both PV and PMF. MPL and CALR mutations do segregate with PMF but may not be found in all cases. Accordingly, we analyzed next generation sequencing (NGS) data to look for potential biomarkers that may further aid in distinguishing these two entities. Design: The IRB approved study intended to recruit patients with diagnosis of PMF and PV who have myeloid gene mutation profiles available. Clinical information and molecular data from both a CLIA certified reference laboratory and our institution from May 2011 to June 2015 were retrieved. Cases with other myeloid neoplasms were excluded. The gene mutation profiles by Next Generation sequencing (NGS) and conventional karyotyping were acquired and compared. Clinicopathologic features including disease progression, degree of fibrosis in bone marrow, percentage of blasts, bone marrow cellularity, and circulating blood count (CBC) are correlated. Student t-test was used for numerical variables and Chi square (x2) test was used for categorical variables. Results: Of the 62 patients qualified in the study, 36 patients were diagnosed with PMF (Age 68.5 ± 12.2, M:F ratio of 1:1) and 26 patients with PV (Age 66.5 ± 11.9, M:F ratio of 1.6). The majority of patients (34/36 PMF and 26/26 PV) showed persistent disease with only two PMF patients progressing to acute myeloid leukemia (AML). In accordance with prior reports, JAK2 V617F mutation was more prevalent in PV (23/26, 88%) than in PMF (17/36, 47%)(p<0.05), while MPL mutation was found in PMF (5/36, 14%) but not in PV (0/26) (p<0.001). Overall, PMF patients tended to have more non JAK2 mutations (mean = 1.6 ± 1) than PV patients (mean= 0.54 ± 0.65) (p = 0.005), even though the PV patients tended to have a longer history of disease. Interestingly, ASXL1 mutations (mainly frame-shift, reportedly pathologic) appear to be more prevalent in PMF (28%) than in PV (8%) patients (p = 0.058). SRSF2 mutations were found in 14% of PMF patients but absent in all 26 PV patients (p=0.068). Mutations in a subset of other analyzed genes (TET2, EZH2, IDH2, and CUX1) were also more frequent in PMF than in PV patients (25% vs 15%, 8% vs 0%, 8% vs 0%, and 6% vs 0%, respectively), but not statistically significant due to limited number of cases. The highest number of mutations (n=4) was in a case of PMF that progressed to AML, suggesting a 'dosage' effect of driver mutations on outcomes similar to that described in MDS. The other patient that progressed from PMF to AML harbored JAK2, ASXL1, SRSF2 mutations along with del(20q). ASXL1 mutation was associated with del(20q) in 4/62 cases, all of which were PMF patients including the case that has progressed to AML. JAK2 mutation was associated with del(20q) in 7 out of the 62 cases, 6 (86%) of which were PMF patients. No gene mutations were uniquely associated with degree of fibrosis, blast count, cellularity, white blood cell counts, hemoglobin, or platelet counts. Conclusion: Our results indicate that PMF patients tend to have more non JAK2 mutations (e.g., ASXL1, SRSF2) than PV. Furthermore, the mutations, including JAK2 mutations, are more likely to be associated with del(20q) in PMF patients. Our findings provide insight into the genetic landscape of PMF and PV and offer potential biomarkers that may be helpful to distinguish between these entities, thus benefiting patient stratification for clinical practice. Disclosures Lancet: Seattle Genetics: Consultancy; Pfizer: Research Funding; Boehringer-Ingelheim: Consultancy; Kalo-Bios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding. Komrokji:Celgene: Consultancy, Research Funding; Incite: Consultancy; Novartis: Speakers Bureau; GSK: Research Funding.

scholarly journals Targeted next-generation sequencing of circulating cell-free DNA vs bone marrow in patients with acute myeloid leukemia

2020 ◽  
Vol 4 (8) ◽  
pp. 1670-1677
Author(s):  
Nicholas J. Short ◽  
Keyur P. Patel ◽  
Maher Albitar ◽  
Miguel Franquiz ◽  
Rajyalakshmi Luthra ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Next Generation Sequencing ◽  
Myeloid Leukemia ◽  
Next Generation ◽  
Cell Free Dna ◽  
Targeted Next Generation Sequencing ◽  
Free Dna ◽  
Generation Sequencing ◽  
Acute Myeloid

Abstract Circulating cell-free DNA (ccfDNA) allows for noninvasive peripheral blood sampling of cancer-associated mutations and has established clinical utility in several solid tumors. We performed targeted next-generation sequencing of ccfDNA and bone marrow at the time of diagnosis and after achieving remission in 22 patients with acute myeloid leukemia (AML). Among 28 genes sequenced by both platforms, a total of 39 unique somatic mutations were detected. Five mutations (13%) were detected only in ccfDNA, and 15 (38%) were detected only in bone marrow. Among the 19 mutations detected in both sources, the concordance of variant allelic frequency (VAF) assessment by both methods was high (R2 = 0.849). Mutations detected in only 1 source generally had lower VAF than those detected in both sources, suggesting that either method may miss small subclonal populations. In 3 patients, sequencing of ccfDNA detected new or persistent leukemia-associated mutations during remission that appeared to herald overt relapse. Overall, this study demonstrates that sequencing of ccfDNA in patients with AML can identify clinically relevant mutations not detected in the bone marrow and may play a role in the assessment of measurable residual disease. However, mutations were missed by both ccfDNA and bone marrow analyses, particularly when the VAF was &lt;10%, suggesting that ccfDNA and bone marrow may be complementary in the assessment and monitoring of patients with AML.

Mutational profiling of acute myeloid leukemia with normal cytogenetics in Brazilian patients: the value of next-generation sequencing for genomic classification

2017 ◽  
Vol 65 (8) ◽  
pp. 1155-1158 ◽  
Author(s):  
Thiago Rodrigo de Noronha ◽  
Miguel Mitne-Neto ◽  
Maria de Lourdes Chauffaille
Keyword(s):  
Acute Myeloid Leukemia ◽  
Next Generation Sequencing ◽  
Myeloid Leukemia ◽  
Regulation Of Gene Expression ◽  
Uniparental Disomy ◽  
Driver Mutations ◽  
Next Generation ◽  
Normal Cytogenetics ◽  
Generation Sequencing ◽  
Acute Myeloid

Karyotype (KT) aberrations are important prognostic factors for acute myeloid leukemia (AML); however, around 50% of cases present normal results. Single nucleotide polymorphism array can detect chromosomal gains, losses or uniparental disomy that are invisible to KT, thus improving patients’ risk assessment. However, when both tests are normal, important driver mutations can be detected by the use of next-generation sequencing (NGS). Fourteen adult patients with AML with normal cytogenetics were investigated by NGS for 19 AML-related genes. Every patient presented at least one mutation:DNMT3Ain nine patients;IDH2in six;IDH1in three;NRASandNPM1in two; andTET2,ASXL1,PTPN11, andRUNX1in one patient. No mutations were found inFLT3,KIT,JAK2,CEBPA,GATA2,TP53,BRAF,CBL,KRAS,andWT1genes. Twelve patients (86%) had at least one mutation in genes related with DNA methylation (DNMT3A,IDH1,IDH2,andTET2), which is involved in regulation of gene expression and genomic stability. All patients could be reclassified based on genomic status and nine had their prognosis modified. In summary, NGS offers insights into the molecular pathogenesis and biology of cytogenetically normal AML in Brazilian patients, indicating that the prognosis could be further stratified by different mutation combinations. This study shows a different frequency of mutations in Brazilian population that should be confirmed.

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