-
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Apr 2023To evaluate the clinical characteristics and prognostic factors of patients with Philadelphia-negative myeloproliferative neoplasm-accelerated phase/blast phase...
To evaluate the clinical characteristics and prognostic factors of patients with Philadelphia-negative myeloproliferative neoplasm-accelerated phase/blast phase (MPN-AP/BP) . 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. 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 . 576.2 U/L, =0.011) , and there were higher proportions of patients who progressed from PMF with splenomegaly (81.4% . 57.9% , =0.05) , a myelofibrosis grade of ≥2 (93.6% . 63.2% , =0.004) , and a shorter duration from diagnosis to the transformation to AP/BP (28.7 . 81 months, =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% , =27) , SRSF2 (25% , =16) , SETBP1 (22.6% , =15) , TET2 (20.3% , =13) , RUNX1 (20.3% , =13) , and TP53 (17.2% , =11) . The ASXL1 mutation was more enriched (51.1% . 21.1% , =0.03) , and the median variant allele fraction (VAF) of the SRSF2 mutation (median VAF, 48.8% . 39.6% ; =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; =0.036) was independently associated with worse overall survival (OS) . Patients who received allogeneic stem cell transplantation (allo-HSCT) (median OS, 21.3 . 3 months; =0.05) or acute myeloid leukemia-like (AML-like) therapy (median OS, 13 . 3 months; =0.011) had significantly better OS than those who received supportive therapy. 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.
Topics: Male; Female; Humans; Adult; Middle Aged; Aged; Blast Crisis; Primary Myelofibrosis; Prognosis; Splenomegaly; Retrospective Studies; Myeloproliferative Disorders; Mutation; Leukemia, Myeloid, Acute; Janus Kinase 2
PubMed: 37356995
DOI: 10.3760/cma.j.issn.0253-2727.2023.04.003 -
American Journal of Hematology Nov 2021
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Myelomonocytic, Chronic; Male; Middle Aged; Sulfonamides; Treatment Outcome
PubMed: 34428328
DOI: 10.1002/ajh.26334 -
Blood Nov 2018The classic Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) are a heterogeneous group of hematopoietic stem-cell diseases, characterized by... (Review)
Review
The classic Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) are a heterogeneous group of hematopoietic stem-cell diseases, characterized by activated JAK/STAT signaling and significant phenotypic mimicry, including a propensity for evolution to myeloid blast phase disease. Effective therapeutic options are limited for patients with Ph MPNs in the blast phase (MPN-BP), and allogeneic stem-cell transplantation is the only known cure. Our increasing understanding of the molecular pathogenesis of this group of diseases, coupled with the increasing availability of targeted agents, has the potential to inform new subset-specific therapeutic approaches. Ultimately, progress in MPN-BP will hinge on prospective clinical and translational investigations with the goal of generating more effective treatment interventions. This case-based review highlights the molecular and clinical heterogeneities of MPN-BP and incorporates a treatment algorithm that underscores the importance of a personalized approach to this challenging group of diseases.
Topics: Aged; Antineoplastic Agents; Blast Crisis; Disease Management; Female; Humans; Male; Middle Aged; Myeloproliferative Disorders; Philadelphia Chromosome; Stem Cell Transplantation
PubMed: 30333119
DOI: 10.1182/blood-2018-03-785907 -
Proceedings of the National Academy of... Mar 2021Despite advances that have improved the treatment of chronic myeloid leukemia (CML) patients in chronic phase, the mechanisms of the transition from chronic phase CML to...
Despite advances that have improved the treatment of chronic myeloid leukemia (CML) patients in chronic phase, the mechanisms of the transition from chronic phase CML to blast crisis (BC) are not fully understood. Considering the key role of miR-15/16 loci in the pathogenesis of myeloid and lymphocytic leukemia, here we aimed to correlate the expression of miR-15a/16 and miR-15b/16 to progression of CML from chronic phase to BC. We analyzed the expression of the two miR-15/16 clusters in 17 CML patients in chronic phase and 22 patients in BC and in 11 paired chronic phase and BC CML patients. BC CMLs show a significant reduction of the expression of miR-15a/-15b/16 compared to CMLs in chronic phase. Moreover, BC CMLs showed an overexpression of miR-15/16 direct targets such as Bmi-1, ROR1, and Bcl-2 compared to CMLs in chronic phase. This study highlights the loss of both miR-15/16 clusters as a potential oncogenic driver in the transition from chronic phase to BC in CML patients.
Topics: Adult; Blast Crisis; Disease Progression; Female; Gene Expression Regulation, Leukemic; Genetic Loci; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; MicroRNAs; Middle Aged; Polycomb Repressive Complex 1; Proto-Oncogene Proteins c-bcl-2; Receptor Tyrosine Kinase-like Orphan Receptors
PubMed: 33836616
DOI: 10.1073/pnas.2101566118 -
Haematologica Sep 2023
Topics: Humans; Blast Crisis; Myeloproliferative Disorders; Nitriles; Mutation
PubMed: 36794509
DOI: 10.3324/haematol.2022.282627 -
Cancer Nov 2017Outcomes in patients with chronic myeloid leukemia in blast phase (CML-BP) are historically dismal. Herein, the authors sought to analyze the characteristics, prognostic...
BACKGROUND
Outcomes in patients with chronic myeloid leukemia in blast phase (CML-BP) are historically dismal. Herein, the authors sought to analyze the characteristics, prognostic factors, and survival outcomes in patients with CML-BP in the tyrosine kinase inhibitor (TKI) era.
METHODS
A total of 477 patients with CML-BP were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics that were predictive of survival. Overall survival and failure-free survival were assessed. Optimal cutoff points for specific parameters were identified using classification and regression tree (CART) analysis.
RESULTS
The median age of the patients was 53 years (range, 16-84 years) and 64% were male. Approximately 80% of patients initially were diagnosed in the chronic phase of CML at a median of 41 months (range, 0.7-298 months) before transformation to CML-BP. De novo CML-BP occurred in 71 patients. Approximately 72% of patients received TKI therapy before CML-BP. The initial therapy for CML-BP included a TKI alone (35%), a TKI with chemotherapy (46%), and non-TKI therapies (19%). The median overall survival was 12 months and the median failure-free survival was 5 months. In multivariate analysis, myeloid immunophenotype, prior TKI, age ≥58 years, lactate dehydrogenase level ≥1227 IU/L, platelet count < 102 K/μL, no history of stem cell transplantation, transition to BP from chronic phase/accelerated phase, and the presence of chromosome 15 aberrations predicted for a significantly increased risk of death. Achievement of major hematologic response and/or complete cytogenetic response to first-line treatment was found to be predictive of better survival. The combination of a TKI with intensive chemotherapy followed by stem cell transplantation appeared to confer the best outcome.
CONCLUSIONS
Patients with CML-BP continue to pose a therapeutic challenge, have dismal outcomes, and require newer treatment approaches. Cancer 2017;123:4391-402. © 2017 American Cancer Society.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blast Crisis; Cohort Studies; Female; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Prognosis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Risk Factors; Survival Analysis; Young Adult
PubMed: 28743165
DOI: 10.1002/cncr.30864 -
JCO Oncology Practice Jul 2020Ruxolitinib improves splenomegaly and other disease-related symptoms in patients with myelofibrosis, but over time, many patients lose this benefit. It is difficult to... (Review)
Review
Ruxolitinib improves splenomegaly and other disease-related symptoms in patients with myelofibrosis, but over time, many patients lose this benefit. It is difficult to determine whether this is due to resistance or intolerance to the drug; thus, we have used the more inclusive term of ruxolitinib failure. The survival of patients with myelofibrosis after ruxolitinib failure is poor but varies significantly by the pattern of the failure, underlining the need for a clinically appropriate classification. In this review, we propose diagnostic guidance for early recognition of the pattern of ruxolitinib failure and we recommend treatment options. The most frequent patterns of ruxolitinib failure are loss or failure to obtain a significant reduction in splenomegaly or symptom response, and the development or persistence of clinically significant cytopenias. Ruxolitinib dose modification and other ancillary therapies are sometimes helpful, and splenectomy is a palliative option in selected cases. Stem-cell transplantation is the only curative option for these patterns of failure, but its restricted applicability due to toxicity highlights the importance of ongoing clinical trials in this area. Recent approval of fedratinib by the US Food and Drug Administration provides an alternative option for patients with suboptimal or loss of spleen response. The transformation of myelofibrosis to accelerated or blast phase is an infrequent form of failure with an extremely poor prognosis, whereby patients who are ineligible for transplantation have limited treatment options.
Topics: Blast Crisis; Canada; Humans; Nitriles; Primary Myelofibrosis; Pyrazoles; Pyrimidines; United States
PubMed: 32134707
DOI: 10.1200/JOP.19.00506 -
Experimental Hematology Jan 2019After initially successful chemotherapy, relapse frequently jeopardizes the outcome of patients with acute leukemia. Because of their adverse characteristics of... (Review)
Review
After initially successful chemotherapy, relapse frequently jeopardizes the outcome of patients with acute leukemia. Because of their adverse characteristics of self-renewal and dormancy, leukemia stem cells have been hypothesized to play a critical role in resistance to antiproliferative chemotherapy and the development of relapse. The high abundance of stem-like cells in acute lymphoblastic leukemia (ALL), however, suggests that not all leukemia-initiating cells carry these adverse characteristics, complicating the biological characterization of relapse-inducing cells in this malignancy. Here, we review sources of therapy resistance and relapse in acute leukemias, which include tumor cell plasticity and reversible characteristics. We discuss the development of patient-derived mouse models that are genetically engineered to mimic long-term dormancy and minimal residual disease in patients. These models allow the tracking and functional characterization of patient-derived ALL blasts that combine the properties of long-term dormancy, treatment resistance, and stemness. Finally, we discuss possible therapeutic avenues to target the functional plasticity of leukemia-initiating cells in ALL.
Topics: Animals; Blast Crisis; Cell Tracking; Humans; Mice; Mice, Mutant Strains; Neoplasm, Residual; Neoplasms, Experimental; Neoplastic Stem Cells; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence
PubMed: 30261200
DOI: 10.1016/j.exphem.2018.09.006 -
American Journal of Hematology Sep 2022In most patients with chronic myeloid leukemia (CML) clonal cells can be kept under control by BCR::ABL1 tyrosine kinase inhibitors (TKI). However, overt resistance or...
In most patients with chronic myeloid leukemia (CML) clonal cells can be kept under control by BCR::ABL1 tyrosine kinase inhibitors (TKI). However, overt resistance or intolerance against these TKI may occur. We identified the epigenetic reader BRD4 and its downstream-effector MYC as growth regulators and therapeutic targets in CML cells. BRD4 and MYC were found to be expressed in primary CML cells, CD34 /CD38 leukemic stem cells (LSC), and in the CML cell lines KU812, K562, KCL22, and KCL22 . The BRD4-targeting drug JQ1 was found to suppress proliferation in KU812 cells and primary leukemic cells in the majority of patients with chronic phase CML. In the blast phase of CML, JQ1 was less effective. However, the BRD4 degrader dBET6 was found to block proliferation and/or survival of primary CML cells in all patients tested, including blast phase CML and CML cells exhibiting the T315I variant of BCR::ABL1. Moreover, dBET6 was found to block MYC expression and to synergize with BCR::ABL1 TKI in inhibiting the proliferation in the JQ1-resistant cell line K562. Furthermore, BRD4 degradation was found to overcome osteoblast-induced TKI resistance of CML LSC in a co-culture system and to block interferon-gamma-induced upregulation of the checkpoint antigen PD-L1 in LSC. Finally, dBET6 was found to suppress the in vitro survival of CML LSC and their engraftment in NSG mice. Together, targeting of BRD4 and MYC through BET degradation sensitizes CML cells against BCR::ABL1 TKI and is a potent approach to overcome multiple forms of drug resistance in CML LSC.
Topics: Animals; Blast Crisis; Cell Cycle Proteins; Cell Line, Tumor; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Nuclear Proteins; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Stem Cells; Transcription Factors
PubMed: 35794848
DOI: 10.1002/ajh.26650 -
Acta Haematologica 2020Philadelphia chromosome-positive (Ph+) advanced leukemias, including acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) in myeloid blast phase (MBP), have...
BACKGROUND
Philadelphia chromosome-positive (Ph+) advanced leukemias, including acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) in myeloid blast phase (MBP), have poor outcomes. Venetoclax has shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKI) in preclinical studies. However, clinical activity of venetoclax and TKI-based regimens is unknown.
METHODS
We conducted a retrospective study on patients with Ph+ AML (n = 7) and CML-MBP (n = 9) who received venetoclax combined with TKI-based regimens at our institution.
RESULTS
Median patient age was 42 years, and the median number of prior therapy cycles was 5 (range 2-8). Nine patients received decitabine-based, and 7 received intensive chemotherapy-based regimens. Ten patients (63%) received ponatinib. The overall response rate (ORR) in 15 evaluable patients was 60% (1 complete remission [CR], 6 CR with incomplete hematologic recovery [CRi], 1 morphologic leukemia-free state, and 1 partial response). The ORR was 43% in Ph+ AML and 75% in CML-MBP. The median overall survival (OS) for all patients was 3.6 months, for AML OS was 2.0 months, and for CML-MBP OS was 10.9 months. The median relapse-free survival for AML and CML-MBP was 3.6 and 3.9 months, respectively. Compared to nonresponders, patients achieving CR/CRi had higher baseline Ph+ metaphases and BCR-ABL1 PCR.
CONCLUSIONS
Combination therapy of venetoclax with TKI-based regimens shows encouraging activity in very heavily pretreated, advanced Ph+ leukemias, particularly CML-MBP.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Female; Fusion Proteins, bcr-abl; Humans; Imidazoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Middle Aged; Protein Kinase Inhibitors; Pyridazines; Retrospective Studies; Sulfonamides; Survival Rate
PubMed: 32289808
DOI: 10.1159/000506346