Objective: To evaluate the clinical characteristics and prognostic factors of patients with Philadelphia-negative myeloproliferative neoplasm-accelerated phase/blast phase (MPN-AP/BP) . Methods: A total of 67 patients with MPN-AP/BP were enrolled from February 2014 to December 2021 at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences. Their clinical features and prognostic factors were analyzed retrospectively. Results: ① Sixty-seven patients with MPN-AP/BP with a median age of 60 (range, 33-75) years, including 31 males (46.3% ) and 36 females (53.7% ) , were analyzed. Forty-eight patients progressed from primary myelofibrosis (PMF) , and 19 progressed from other myeloproliferative neoplasms (MPNs) , which included polycythemia vera, essential thrombocythemia, and MPN unclassifiable. Patients who progressed from PMF had higher lactate dehydrogenase (LDH) levels than those who progressed from other MPNs (925.95 vs. 576.2 U/L, P=0.011) , and there were higher proportions of patients who progressed from PMF with splenomegaly (81.4% vs. 57.9% , P=0.05) , a myelofibrosis grade of ≥2 (93.6% vs. 63.2% , P=0.004) , and a shorter duration from diagnosis to the transformation to AP/BP (28.7 vs. 81 months, P=0.001) . ② JAK2V617F, CALR, and MPLW515 were detected in 41 (61.2% ) , 13 (19.4% ) , and 3 (4.5% ) patients, respectively, whereas 10 (14.9% ) patients did not have any driver mutations (triple-negative) . Other than driver mutations, the most frequently mutated genes were ASXL1 (42.2% , n=27) , SRSF2 (25% , n=16) , SETBP1 (22.6% , n=15) , TET2 (20.3% , n=13) , RUNX1 (20.3% , n=13) , and TP53 (17.2% , n=11) . The ASXL1 mutation was more enriched (51.1% vs. 21.1% , P=0.03) , and the median variant allele fraction (VAF) of the SRSF2 mutation (median VAF, 48.8% vs. 39.6% ; P=0.008) was higher in patients who progressed from PMF than those who progressed from other MPNs. ③ In the multivariate analysis, the complex karyotype (hazard ratio, 2.53; 95% confidence interval, 1.06-6.05; P=0.036) was independently associated with worse overall survival (OS) . Patients who received allogeneic stem cell transplantation (allo-HSCT) (median OS, 21.3 vs. 3 months; P=0.05) or acute myeloid leukemia-like (AML-like) therapy (median OS, 13 vs. 3 months; P=0.011) had significantly better OS than those who received supportive therapy. Conclusion: The proportions of patients with PMF-AP/BP with splenomegaly, myelofibrosis grade ≥2, a higher LDH level, and a shorter duration from diagnosis to the transformation to AP/BP were higher than those of patients with other Philadelphia-negative MPN-AP/BP. The complex karyotype was an independent prognostic factor for OS. Compared with supportive therapy, AML-like therapy and allo-HSCT could prolong the OS of patients with MPN-AP/BP.
Male ; Female ; Humans ; Adult ; Middle Aged ; Aged ; Blast Crisis/drug therapy* ; Primary Myelofibrosis/genetics* ; Prognosis ; Splenomegaly ; Retrospective Studies ; Myeloproliferative Disorders/genetics* ; Mutation ; Leukemia, Myeloid, Acute ; Janus Kinase 2/genetics*

OBJECTIVETodelineate the clinical and genetic features of a patient with myeloproliferative neoplasm (MPN) in association with PDGFRA and EVI1 genes rearrangements.

METHODSClinical data of the patient was collected. Conventional cytogenetics, fluorescence in situ hybridization (FISH) and nested PCR were carried out for the patient.

RESULTSThe patient has featured recurrent rash, joint pain, and intermittent fever. Laboratory tests showed hyperleukocytosis and marked eosinophilia. Physical examination revealed splenomegaly. His karyotype was 46,XY,t(3;5)(q26;q15)[6]/46,XY[10]. FISH assay showed that both PDGFRA and EVI1 genes were rearranged. Molecular studies of the mRNA suggested that there was a in-frame fusion between exon 12 of the PDGFRA gene and exon 9 of the FIP1L1 gene. Imatinib was initiated at a dosage of 200 mg, and after 10 months, the signal of the FIP1L1-PDGFRA fusion gene was undetectable in bone marrow sample. However, the expression of EVI1 mRNA was stable, with no significant difference found between the patient and 10 healthy controls.

CONCLUSIONMPN in association with PDGFRA and EVI1 genes rearrangements have unique clinical and genetic features. Genetic testing is helpful for early diagnosis. Imatinib may be effective for the treatment.

Antineoplastic Agents ; therapeutic use ; Base Sequence ; Chromosome Banding ; Chromosomes, Human, Pair 3 ; genetics ; Chromosomes, Human, Pair 5 ; genetics ; DNA-Binding Proteins ; genetics ; Gene Rearrangement ; Humans ; Imatinib Mesylate ; therapeutic use ; In Situ Hybridization, Fluorescence ; Karyotyping ; MDS1 and EVI1 Complex Locus Protein ; Male ; Myeloproliferative Disorders ; drug therapy ; genetics ; Proto-Oncogenes ; genetics ; Receptor, Platelet-Derived Growth Factor alpha ; genetics ; Transcription Factors ; genetics ; Translocation, Genetic ; Treatment Outcome ; Young Adult

Polycythemia vera, essential thrombocythemia, and primary myelofibrosis are collectively known as 'Philadelphia-negative classical myeloproliferative neoplasms (MPNs).' The discovery of new genetic aberrations such as Janus kinase 2 (JAK2) have enhanced our understanding of the pathophysiology of MPNs. Currently, the JAK2 mutation is not only a standard criterion for diagnosis but is also a new target for drug development. The JAK1/2 inhibitor, ruxolitinib, was the first JAK inhibitor approved for patients with intermediate- to high-risk myelofibrosis and its effects in improving symptoms and survival benefits were demonstrated by randomized controlled trials. In 2011, the Korean Society of Hematology MPN Working Party devised diagnostic and therapeutic guidelines for Korean MPN patients. Subsequently, other genetic mutations have been discovered and many kinds of new drugs are now under clinical investigation. In view of recent developments, we have revised the guidelines for the diagnosis and management of MPN based on published evidence and the experiences of the expert panel. Here we describe the epidemiology, new genetic mutations, and novel therapeutic options as well as diagnostic criteria and standard treatment strategies for MPN patients in Korea.
Antineoplastic Agents/*therapeutic use ; Asian Continental Ancestry Group/genetics ; Humans ; Janus Kinase 2/*antagonists & inhibitors/genetics/metabolism ; Molecular Targeted Therapy ; Mutation ; Myeloproliferative Disorders/diagnosis/drug therapy/enzymology/ethnology/genetics ; Protein Kinase Inhibitors/*therapeutic use ; Republic of Korea/epidemiology ; Risk Factors ; Signal Transduction/drug effects ; Treatment Outcome

OBJECTIVESTo evaluate the efficacy and safety of imatinib mesylate (imatinib) for myeloproliferative neoplasm (MPN) patients with eosinophilia.

METHODSEight MPN patients with eosinophilia and positive FIP1L1-PDGFR alpha gene and one CEL, NOS were treated with 100 mg or 400 mg/d imatinib orally.

RESULTSHematological remission (HR) rate was 100%, including complete HR (CHR) rate 87.5%, and partial remission (PR) rate 12.5% with a median follow-up of 16 (6.0 -26.0 ) months. Complete molecular remission (cMR) rate was 85.7%. The median time of FIP1L1-PDGFR alpha fusion gene becoming negative was 4 (1.5 - 8) months. Three patients withdrew imatinib after getting cMR. After a median follow-up of 12 months, all the 3 patients remained in CHR. The main adverse effect of imatinib was mild myelosuppression occurring in 37.5% of patients in a median time of 6 (4 - 9) days after treatment.

CONCLUSIONImatinib in treatment of MPN with eosinophilia and positive FIP1L1-PDGFR alpha gene patients can induce high hematologic and molecular remission. The adverse effects of imatinib are mild and tolerable.

Adult ; Aged ; Benzamides ; Eosinophilia ; complications ; Follow-Up Studies ; Humans ; Imatinib Mesylate ; Male ; Middle Aged ; Myeloproliferative Disorders ; complications ; drug therapy ; genetics ; Oncogene Proteins, Fusion ; genetics ; Piperazines ; therapeutic use ; Pyrimidines ; therapeutic use ; Receptor, Platelet-Derived Growth Factor alpha ; genetics ; Treatment Outcome ; Young Adult ; mRNA Cleavage and Polyadenylation Factors ; genetics

No abstract available.
Adult ; Alleles ; Fusion Proteins, bcr-abl/*genetics ; Heterozygote ; Humans ; Hydroxyurea/*therapeutic use ; Janus Kinase 2/*genetics ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis ; Leukocytes, Mononuclear/pathology ; Leukocytosis/diagnosis ; Male ; Middle Aged ; Mutation ; Myeloproliferative Disorders/drug therapy/*genetics ; Phenotype ; Splenomegaly/diagnosis ; Thrombocytosis/diagnosis ; Translocation, Genetic