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International Journal of Molecular... Apr 2019Myeloproliferative neoplasms represent a heterogenous group of disorders of the hematopoietic stem cell, with an intrinsic risk of evolution into acute myeloid leukemia.... (Review)
Review
Myeloproliferative neoplasms represent a heterogenous group of disorders of the hematopoietic stem cell, with an intrinsic risk of evolution into acute myeloid leukemia. The frequency of leukemic evolution varies according to myeloproliferative neoplasms subtype. It is highest in primary myelofibrosis, where it is estimated to be approximately 10-20% at 10 years, following by polycythemia vera, with a risk of 2.3% at 10 years and 7.9% at 20 years. In essential thrombocythemia, however, transformation to acute myeloid leukemia is considered relatively uncommon. Different factors are associated with leukemic evolution in myeloproliferative neoplasms, but generally include advanced age, leukocytosis, exposure to myelosuppressive therapy, cytogenetic abnormalities, as well as increased number of mutations in genes associated with myeloid neoplasms. The prognosis of these patients is dismal, with a medium overall survival ranging from 2.6-7.0 months. Currently, there is no standard of care for managing the blast phase of these diseases, and no treatment to date has consistently led to prolonged survival and/or hematological remission apart from an allogeneic stem cell transplant. Nevertheless, new targeted agents are currently under development. In this review, we present the current evidence regarding risk factors, molecular characterization, and treatment options for this critical subset of myeloproliferative neoplasms patients.
Topics: Animals; Biomarkers; Blast Crisis; Bone Marrow; Cell Transformation, Neoplastic; Chromosome Aberrations; Combined Modality Therapy; Disease Progression; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Mutation; Myeloproliferative Disorders; Risk Factors
PubMed: 31013941
DOI: 10.3390/ijms20081839 -
Archives of Pathology & Laboratory... Dec 2016- Inv(3)(q21q26)/t(3;3)(q21;q26.2) is the most common form of genetic abnormality of the so-called 3q21q26 syndrome. Myeloid neoplasms with 3q21q26 aberrancies include... (Review)
Review
CONTEXT
- Inv(3)(q21q26)/t(3;3)(q21;q26.2) is the most common form of genetic abnormality of the so-called 3q21q26 syndrome. Myeloid neoplasms with 3q21q26 aberrancies include acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and blast crisis of myeloproliferative neoplasms. Recent advances on myeloid neoplasms with inv(3)/t(3;3) with regard to clinicopathologic features and novel molecular or genomic findings warrant a comprehensive review on this topic.
OBJECTIVE
- To review the clinicopathologic features and molecular as well as genomic alterations in myeloid neoplasms with inv(3)/t(3;3).
DATA SOURCES
- The data came from published articles in English-language literature.
CONCLUSIONS
- At the clinicopathologic front, recent studies on MDS with inv(3)/t(3;3) have highlighted their overlapping clinicopathologic features with and similar overall survival to that of inv(3)/t(3;3)-harboring AML regardless of the percentage of myeloid blasts. On the molecular front, AML and MDS with inv(3)/t(3;3) exhibit gene mutations, which affect the RAS/receptor tyrosine kinase pathway. Furthermore, functional genomic studies using genomic editing and genome engineering have shown that the reallocation of the GATA2 distal hematopoietic enhancer to the proximity of the promoter of ectopic virus integration site 1 (EVI1) without the formation of a new oncogenic fusion transcript is the molecular mechanism underlying these inv(3)/t(3;3) myeloid neoplasms. Although the AML and MDS with inv(3)/t(3;3) are listed as a separate category of myeloid malignancies in the 2008 World Health Organization classification, the overlapping clinicopathologic features, similar overall survival, and identical patterns at the molecular and genomic levels between AML and MDS patients with inv(3)/t(3;3) may collectively favor a unification of AML and MDS with inv(3)/t(3;3) as AML or myeloid neoplasms with inv(3)/t(3;3) regardless of the blast count.
Topics: Animals; Blast Crisis; Chromosome Inversion; Chromosomes, Human, Pair 3; DNA-Binding Proteins; Female; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute; MDS1 and EVI1 Complex Locus Protein; Male; Molecular Diagnostic Techniques; Myelodysplastic Syndromes; Myeloproliferative Disorders; Oncogene Proteins, Fusion; Pathology, Clinical; Prognosis; Protein Domains; Proto-Oncogenes; Transcription Factors; Translocation, Genetic
PubMed: 27628325
DOI: 10.5858/arpa.2016-0059-RA -
Journal of Hematology & Oncology Jun 2021The natural course of untreated chronic myeloid leukemia (CML) is progression to an aggressive blast phase. Even in the current era of BCR-ABL1 tyrosine kinase...
BACKGROUND
The natural course of untreated chronic myeloid leukemia (CML) is progression to an aggressive blast phase. Even in the current era of BCR-ABL1 tyrosine kinase inhibitors (TKIs), the outcomes of blast phase CML remain poor with no consensus frontline treatment approach.
METHODS
We retrospectively analyzed the response rates and survival outcomes of 104 consecutive patients with myeloid blast phase CML (CML-MBP) treated from 2000 to 2019 based on 4 different frontline treatment approaches: intensive chemotherapy (IC) + TKI (n = 20), hypomethylating agent (HMA) + TKI (n = 20), TKI alone (n = 56), or IC alone (n = 8). We also evaluated the impact of TKI selection and subsequent allogeneic stem cell transplant (ASCT) on patient outcomes.
RESULTS
Response rates were similar between patients treated with IC + TKI and HMA + TKI. Compared to treatment with TKI alone, treatment with IC/HMA + TKI resulted in a higher rate of complete remission (CR) or CR with incomplete count recovery (CRi) (57.5% vs 33.9%, p < 0.05), a higher complete cytogenetic response rate (45% vs 10.7%, p < 0.001), and more patients proceeding to ASCT (32.5% vs 10.7%, p < 0.01). With a median follow-up of 6.7 years, long-term outcomes were similar between the IC + TKI and HMA + TKI groups. Combination therapy with IC/HMA + TKI was superior to therapy with TKI alone, including when analysis was limited to those treated with a 2nd/3rd-generation TKI. When using a 2nd/3rd-generation TKI, IC/HMA + TKI led to lower 5-year cumulative incidence of relapse (CIR; 44% vs 86%, p < 0.05) and superior 5-year event-free survival (EFS; 28% vs 0%, p < 0.05) and overall survival (OS; 34% vs 8%, p = 0.23) compared to TKI alone. Among patients who received IC/HMA + TKI, EFS and OS was superior for patients who received a 2nd/3rd generation TKI compared to those who received imatinib-based therapy. In a landmark analysis, 5-year OS was higher for patients who proceeded to ASCT (58% vs 22%, p = 0.12).
CONCLUSIONS
Compared to patients treated with TKI alone for CML-MBP, treatment with IC + TKI or HMA + TKI led to improved response rates, CIR, EFS, and OS, particularly for patients who received a 2nd/3rd-generation TKI. Combination therapy with IC + TKI or HMA + TKI, rather than a TKI alone, should be considered the optimal treatment strategy for patients with CML-MBP.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Blast Crisis; Disease Progression; Female; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Protein Kinase Inhibitors; Retrospective Studies; Stem Cell Transplantation; Survival Analysis; Treatment Outcome; Young Adult
PubMed: 34130720
DOI: 10.1186/s13045-021-01106-1 -
Clinical Lymphoma, Myeloma & Leukemia Jul 2022Up to 20% of patients with myeloproliferative neoplasms (MPN) will progress to blast phase (MPN-BP). Outcomes are dismal, with intensive chemotherapy providing little...
INTRODUCTION
Up to 20% of patients with myeloproliferative neoplasms (MPN) will progress to blast phase (MPN-BP). Outcomes are dismal, with intensive chemotherapy providing little benefit. Low-intensity therapy is preferred due to better tolerability, but the prognosis remains poor. Allogeneic stem cell transplant (AHSCT) is still the only potential for long term survival.
PATIENTS AND METHODS
To better evaluate the initial treatment approach in MPN-BP, we performed a single-institution retrospective analysis of 75 patients with MPN-BP treated at Moffitt Cancer Center between 2001 and 2021. Patients were stratified by initial treatment: best supportive care (BSC), hypomethylating agent (HMA)-based therapy or intensive chemotherapy (IC).
RESULTS
Median overall survival (mOS) for the entire cohort was 4.8 months (BSC 0.8 months, HMA 4.7 months, and IC 11.4 months). Among IC patients, improved survival was evident in those that received AHSCT (mOS 40.8 months vs. 4.9 months, p < .01). Most patients that underwent AHSCT were initially treated with IC (p < .01). All patients that underwent AHSCT had achieved complete response (CR) or CR with incomplete hematological recovery (CRi). On multivariate analysis, factors associated with improved survival were receipt of therapy (HMA or IC) (P = .017), CR/CRi (P = .037) and receipt of AHSCT (p < .001).
CONCLUSION
We show that active treatment with IC improves survival, but it is mostly tied to receipt of AHSCT. IC is a reasonable approach in appropriate patients as it can provide an effective bridge to AHSCT. Other treatment strategies such as molecularly targeted therapy and novel agents are desperately needed.
Topics: Blast Crisis; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Myeloproliferative Disorders; Remission Induction; Retrospective Studies
PubMed: 35241387
DOI: 10.1016/j.clml.2022.01.015 -
Blood Cancer Journal Oct 2022While the clinical impact of mutations in the ABL1 gene on response to therapy in chronic phase chronic myeloid leukemia (CP-CML) is well established, less is known...
While the clinical impact of mutations in the ABL1 gene on response to therapy in chronic phase chronic myeloid leukemia (CP-CML) is well established, less is known about how other mutations affect prognosis. In a retrospective analysis, we identified 115 patients with CML (71 chronic, 15 accelerated and 29 blast phase) where targeted next-generation sequencing of genes recurrently mutated in myeloid leukemias was performed. ASXL1 was the most frequently mutated gene in the chronic (14%) and accelerated phase (40%) CML patients, whereas RUNX1 (20%) was the most common mutation in blast phase. Compared with wild-type ASXL1, CP-CML with mutant ASXL1 was associated with worse event-free survival (EFS) (median of 32.8 vs 88.3 months; P = 0.002) and failure-free survival (median of 13.8 vs 57.8 months; P = 0.04). In a multivariate analysis, ASXL1 mutation was the only independent risk factor associated with worse EFS in chronic phase CML with a hazard ratio of 4.25 (95% CI 1.59-11.35, P = 0.004). In conclusion, mutations in ASXL1 are associated with worse outcomes when detected in chronic phase CML.
Topics: Humans; Prognosis; Retrospective Studies; Blast Crisis; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mutation; Leukemia, Myeloid; Repressor Proteins
PubMed: 36307398
DOI: 10.1038/s41408-022-00742-1 -
Nature Communications Sep 2023The mechanisms underlying the transformation of chronic myeloid leukemia (CML) from chronic phase (CP) to blast crisis (BC) are not fully elucidated. Here, we show lower...
The mechanisms underlying the transformation of chronic myeloid leukemia (CML) from chronic phase (CP) to blast crisis (BC) are not fully elucidated. Here, we show lower levels of miR-142 in CD34CD38 blasts from BC CML patients than in those from CP CML patients, suggesting that miR-142 deficit is implicated in BC evolution. Thus, we create miR-142 knockout CML (i.e., miR-142BCR-ABL) mice, which develop BC and die sooner than miR-142 wt CML (i.e., miR-142BCR-ABL) mice, which instead remain in CP CML. Leukemic stem cells (LSCs) from miR-142BCR-ABL mice recapitulate the BC phenotype in congenic recipients, supporting LSC transformation by miR-142 deficit. State-transition and mutual information analyses of "bulk" and single cell RNA-seq data, metabolomic profiling and functional metabolic assays identify enhanced fatty acid β-oxidation, oxidative phosphorylation and mitochondrial fusion in LSCs as key steps in miR-142-driven BC evolution. A synthetic CpG-miR-142 mimic oligodeoxynucleotide rescues the BC phenotype in miR-142BCR-ABL mice and patient-derived xenografts.
Topics: Animals; Humans; Mice; Blast Crisis; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Leukemia, Myeloid, Chronic-Phase; MicroRNAs; Stem Cells
PubMed: 37658085
DOI: 10.1038/s41467-023-41167-z -
JCI Insight Apr 2022Chronic myeloproliferative neoplasms (MPN) frequently evolve to a blast phase (BP) that is almost uniformly resistant to induction chemotherapy or hypomethylating...
Chronic myeloproliferative neoplasms (MPN) frequently evolve to a blast phase (BP) that is almost uniformly resistant to induction chemotherapy or hypomethylating agents. We explored the functional properties, genomic architecture, and cell of origin of MPN-BP initiating cells (IC) using a serial NSG mouse xenograft transplantation model. Transplantation of peripheral blood mononuclear cells (MNC) from 7 of 18 patients resulted in a high degree of leukemic cell chimerism and recreated clinical characteristics of human MPN-BP. The function of MPN-BP ICs was not dependent on the presence of JAK2V617F, a driver mutation associated with the initial underlying MPN. By contrast, multiple MPN-BP IC subclones coexisted within MPN-BP MNCs characterized by different myeloid malignancy gene mutations and cytogenetic abnormalities. MPN-BP ICs in 4 patients exhibited extensive proliferative and self-renewal capacity, as demonstrated by their ability to recapitulate human MPN-BP in serial recipients. These MPN-BP IC subclones underwent extensive continuous clonal competition within individual xenografts and across multiple generations, and their subclonal dynamics were consistent with functional evolution of MPN-BP IC. Finally, we show that MPN-BP ICs originate from not only phenotypically identified hematopoietic stem cells, but also lymphoid-myeloid progenitor cells, which were each characterized by differences in MPN-BP initiating activity and self-renewal capacity.
Topics: Animals; Blast Crisis; Hematopoietic Stem Cells; Humans; Leukocytes, Mononuclear; Mice; Mutation; Myeloproliferative Disorders
PubMed: 35259128
DOI: 10.1172/jci.insight.156534 -
Genes Mar 2022The Philadelphia (Ph+) chromosome, t(9;22)(q34;q11.2), originates from a chimeric gene called and is present in more than 90% of CML patients. Most patients with CML...
The Philadelphia (Ph+) chromosome, t(9;22)(q34;q11.2), originates from a chimeric gene called and is present in more than 90% of CML patients. Most patients with CML express the protein p210 and, with a frequency lower than 5%, express rare isoforms, the main one being p190. In the transition from the chronic phase to the blast phase (BP), additional chromosomal abnormalities, such as the presence of the double Ph+ chromosome, are revealed. Of the 1132 patients analyzed via molecular biology in this study, two patients (0.17%) showed the co-expression of the p210 and p190 isoforms for the transcript, with the concomitant presence of a double Ph+ chromosome, which was observed via conventional cytogenetics and confirmed by fluorescent in situ hybridization. The /% p210 and p190 ratio increased in these two patients from diagnosis to progression to blast crisis. To our knowledge, this is the first report in the literature of patients who co-expressed the two main transcript isoforms and concomitantly presented Ph+ chromosome duplication. The evolution from the chronic phase to BP often occurs within 5 to 7 years, and, in this study, the evolution to BP was earlier, since disease-free survival was on average 4.5 months and overall survival was on average 9.5 months. The presence of the p190 transcript and the double Ph+ chromosome in CML may be related to the vertiginous progression of the disease.
Topics: Blast Crisis; Fusion Proteins, bcr-abl; Humans; In Situ Hybridization, Fluorescence; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Protein Isoforms
PubMed: 35456386
DOI: 10.3390/genes13040580 -
Leukemia & Lymphoma Jul 2014Despite vast improvements in the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) in chronic phase (CP), advanced stages of CML, accelerated... (Review)
Review
Despite vast improvements in the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) in chronic phase (CP), advanced stages of CML, accelerated phase or blast crisis, remain notoriously difficult to treat. Treatments that are highly effective against CML-CP produce disappointing results against advanced disease. Therefore, a primary goal of therapy should be to maintain patients in CP for as long as possible, by (1) striving for deep, early molecular response to treatment; (2) using tyrosine kinase inhibitors that lower risk of disease progression; and (3) more closely observing patients who demonstrate cytogenetic risk factors at diagnosis or during treatment.
Topics: Blast Crisis; Disease Management; Disease Progression; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Accelerated Phase; Neoplasm Staging; Prognosis; Treatment Outcome
PubMed: 24050507
DOI: 10.3109/10428194.2013.845883 -
Leukemia May 2024Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the...
Management and outcome of patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era - analysis of the European LeukemiaNet Blast Phase Registry.
Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.
Topics: Humans; Blast Crisis; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Registries; Protein Kinase Inhibitors; Middle Aged; Male; Adult; Female; Aged; Young Adult; Transplantation, Homologous; Europe; Hematopoietic Stem Cell Transplantation; Prognosis; Adolescent; Treatment Outcome; Survival Rate; Disease Management; Follow-Up Studies; Tyrosine Kinase Inhibitors
PubMed: 38548962
DOI: 10.1038/s41375-024-02204-y