-
Hematology. American Society of... Dec 2022The BCR-ABL-negative myeloproliferative neoplasms (MPNs) have a variable risk of progressing to accelerated- or blast-phase MPN (MPN-AP/MPN-BP), defined by the presence...
The BCR-ABL-negative myeloproliferative neoplasms (MPNs) have a variable risk of progressing to accelerated- or blast-phase MPN (MPN-AP/MPN-BP), defined by the presence of 10% to 19% and more than or equal to 20% myeloid blasts in the peripheral blood or bone marrow, respectively. The molecular processes underlying the progression to MPN-AP/MPN-BP are becoming increasingly understood with the acquisition of additional mutations in epigenetic modifiers (eg, ASXL1, EZH2, TET2), TP53, the Ras pathway, or splicing factors (eg, SRSF2, U2AF1), having been described as important steps in this evolutionary process. At least partially driven by the enrichment of these high-risk molecular features, the prognosis of patients with MPN-BP remains inferior to other patients with acute myeloid leukemia, with a median overall survival of 3 to 6 months. Allogeneic hematopoietic cell transplantation remains the only potentially curative therapeutic modality, but only a minority of patients are eligible. In the absence of curative intent, therapeutic strategies or palliative treatment with hypomethylating agents as monotherapy or in combination with ruxolitinib or venetoclax can be considered. Several novel agents are in various stages of clinical development but are not available for routine use at this point, highlighting the need for ongoing research and the prioritization of clinical trial enrollment when feasible.
Topics: Humans; Myeloproliferative Disorders; Blast Crisis; Prognosis; Leukemia, Myeloid, Acute; Mutation
PubMed: 36485103
DOI: 10.1182/hematology.2022000341 -
International Journal of Laboratory... May 2018This review focuses on how image processing and machine learning can be useful for the morphological characterization and automatic recognition of cell images captured... (Review)
Review
INTRODUCTION
This review focuses on how image processing and machine learning can be useful for the morphological characterization and automatic recognition of cell images captured from peripheral blood smears.
METHODS
The basics of the 3 core elements (segmentation, quantitative features, and classification) are outlined, and recent literature is discussed. Although red blood cells are a significant part of this context, this study focuses on malignant lymphoid cells and blast cells.
RESULTS
There is no doubt that these technologies may help the cytologist to perform efficient, objective, and fast morphological analysis of blood cells. They may also help in the interpretation of some morphological features and may serve as learning and survey tools.
CONCLUSION
Although research is still needed, it is important to define screening strategies to exploit the potential of image-based automatic recognition systems integrated in the daily routine of laboratories along with other analysis methodologies.
Topics: Blast Crisis; Blood Cells; Clinical Laboratory Techniques; Humans; Image Processing, Computer-Assisted; Lymphocytes; Machine Learning
PubMed: 29741258
DOI: 10.1111/ijlh.12818 -
Blood Jun 2004Chronic myelogenous leukemia (CML) evolves from a chronic phase characterized by the Philadelphia chromosome as the sole genetic abnormality into blast crisis, which is... (Review)
Review
Chronic myelogenous leukemia (CML) evolves from a chronic phase characterized by the Philadelphia chromosome as the sole genetic abnormality into blast crisis, which is often associated with additional chromosomal and molecular secondary changes. Although the pathogenic effects of most CML blast crisis secondary changes are still poorly understood, ample evidence suggests that the phenotype of CML blast crisis cells (enhanced proliferation and survival, differentiation arrest) depends on cooperation of BCR/ABL with genes dysregulated during disease progression. Most genetic abnormalities of CML blast crisis have a direct or indirect effect on p53 or Rb (or both) gene activity, which are primarily required for cell proliferation and survival, but not differentiation. Thus, the differentiation arrest of CML blast crisis cells is a secondary consequence of these abnormalities or is caused by dysregulation of differentiation-regulatory genes (ie, C/EBPalpha). Validation of the critical role of certain secondary changes (ie, loss of p53 or C/EBPalpha function) in murine models of CML blast crisis and in in vitro assays of BCR/ABL transformation of human hematopoietic progenitors might lead to the development of novel therapies based on targeting BCR/ABL and inhibiting or restoring the gene activity gained or lost during disease progression (ie, p53 or C/EBPalpha).
Topics: Animals; Blast Crisis; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
PubMed: 14982876
DOI: 10.1182/blood-2003-12-4111 -
Blood Advances Oct 2020Myeloproliferative neoplasms (MPN) that have evolved into accelerated or blast phase disease (MPN-AP/BP) have poor outcomes with limited treatment options and therefore...
Myeloproliferative neoplasms (MPN) that have evolved into accelerated or blast phase disease (MPN-AP/BP) have poor outcomes with limited treatment options and therefore represent an urgent unmet need. We have previously demonstrated in a multicenter, phase 1 trial conducted through the Myeloproliferative Neoplasms Research Consortium that the combination of ruxolitinib and decitabine is safe and tolerable and is associated with a favorable overall survival (OS). In this phase 2 trial, 25 patients with MPN-AP/BP were treated at the recommended phase 2 dose of ruxolitinib 25 mg twice daily for the induction cycle followed by 10 mg twice daily for subsequent cycles in combination with decitabine 20 mg/m2 for 5 consecutive days in a 28-day cycle. Nineteen patients died during the study follow-up. The median OS for all patients on study was 9.5 months (95% confidence interval, 4.3-12.0). Overall response rate (complete remission + incomplete platelet recovery + partial remission) was 11/25 (44%) and response was not associated with improved survival. We conclude that the combination of decitabine and ruxolitinib was well tolerated, demonstrated favorable OS, and represents a therapeutic option for this high-risk patient population. This trial was registered at www.clinicaltrials.gov as #NCT02076191.
Topics: Blast Crisis; Decitabine; Humans; Nitriles; Pyrazoles; Pyrimidines; Treatment Outcome
PubMed: 33104796
DOI: 10.1182/bloodadvances.2020002119 -
Hematology. American Society of... Nov 2018The use of multiagent combination chemotherapy regimens results in cure rates of >90% for children and ∼40% for adults with acute lymphoblastic leukemia (ALL) but is... (Review)
Review
The use of multiagent combination chemotherapy regimens results in cure rates of >90% for children and ∼40% for adults with acute lymphoblastic leukemia (ALL) but is associated with extensive toxicity and disappointingly low efficacy in relapsed patients. ALL blast cells express several surface antigens, including CD20, CD22, and CD19, which represent valuable targets for immunotherapy. Monoclonal antibodies, antibody-drug conjugates, and bispecific T-cell-engaging antibodies targeting these antigens offer novel mechanisms of action. Within the last several years, the anti-CD20 antibody rituximab has been added to chemotherapy for newly diagnosed patients <60 years with CD20 pre-B ALL and significantly improved the 2-year event-free survival from 52% to 65%. In adults with relapsed or refractory CD22 ALL, the antibody-drug conjugate inotuzumab ozogamicin resulted in a complete response rate of 81% and median overall survival of 7.7 months with reduced toxicity compared with standard chemotherapy. Similarly, the bispecific T-cell-engaging antibody blinatumomab yielded a complete response rate of 44% and a median overall survival of 7.7 months in an extensively treated ALL population. Moreover, ∼80% of ALL patients in complete remission with evidence of minimal residual disease (MRD) achieved a complete MRD response following treatment with blinatumomab. These results highlight the tremendous promise of antibody-based treatment approaches for ALL. Ongoing and future research is critical to further define the role of the various immunotherapies in the frontline treatment of ALL. Additional challenges include the optimal sequencing of the available antibodies in the relapsed setting as well as their integration with stem cell transplant and chimeric antigen receptor T-cell therapy.
Topics: Antibodies, Bispecific; Antigens, CD; Antineoplastic Agents, Immunological; Blast Crisis; Disease-Free Survival; Humans; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Survival Rate
PubMed: 30504286
DOI: 10.1182/asheducation-2018.1.9 -
Haematologica Feb 2022Cancer treatment is constantly evolving from a one-size-fits-all towards bespoke approaches for each patient. In certain solid cancers, including breast and lung, tumor... (Review)
Review
Cancer treatment is constantly evolving from a one-size-fits-all towards bespoke approaches for each patient. In certain solid cancers, including breast and lung, tumor genome profiling has been incorporated into therapeutic decision-making. For chronic phase chronic myeloid leukemia (CML), while tyrosine kinase inhibitor therapy is the standard treatment, current clinical scoring systems cannot accurately predict the heterogeneous treatment outcomes observed in patients. Biomarkers capable of segregating patients according to outcome at diagnosis are needed to improve management, and facilitate enrollment in clinical trials seeking to prevent blast crisis transformation and improve the depth of molecular responses. To this end, gene expression (GE) profiling studies have evaluated whether GE signatures at diagnosis are clinically informative. Patient material from a variety of sources has been profiled using microarrays, RNA sequencing and, more recently, single-cell RNA sequencing. However, differences in the cell types profiled, the technologies used, and the inherent complexities associated with the interpretation of genomic data pose challenges in distilling GE datasets into biomarkers with clinical utility. The goal of this paper is to review previous studies evaluating GE profiling in CML, and explore their potential as risk assessment tools for individualized CML treatment. We also review the contribution that acquired mutations, including those seen in clonal hematopoiesis, make to GE profiles, and how a model integrating contributions of genetic and epigenetic factors in resistance to tyrosine kinase inhibitors and blast crisis transformation can define a route to GE-based biomarkers. Finally, we outline a four-stage approach for the development of GE-based biomarkers in CML.
Topics: Biomarkers; Blast Crisis; Epigenesis, Genetic; Gene Expression; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors
PubMed: 34615339
DOI: 10.3324/haematol.2021.279317 -
Cancer Mar 2016Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by... (Review)
Review
Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by often debilitating constitutional symptoms and splenomegaly, bone marrow fibrosis and resultant cytopenias, extramedullary hematopoiesis, risk of leukemic transformation, and shortened survival. Post-polycythemia vera and post-essential thrombocythemia myelofibrosis represent similar entities, although some differences are being recognized. Attempts to classify patients with myelofibrosis into prognostic categories have been made since the late 1980s, and these scoring systems continue to evolve as new information becomes available. Over the last decade, the molecular pathogenesis of MPNs has been elucidated considerably, and the Janus kinase (JAK) 1/2 inhibitor ruxolitinib is the first drug specifically approved by the US Food and Drug Administration to treat patients with intermediate-risk and high-risk myelofibrosis. This article reviews the evolution of prognostic criteria in myelofibrosis, emphasizing the major systems widely in use today, as well as recently described, novel systems that incorporate emerging data regarding somatic mutations. Risk factors for thrombosis and conversion to MPN blast phase also are discussed. Finally, the practical usefulness of the current prognostic classification systems in terms of clinical decision making is discussed, particularly within the context of some of their inherent weaknesses. Cancer 2016;122:681-692. © 2015 American Cancer Society.
Topics: Age Factors; Blast Crisis; Clinical Decision-Making; Hemoglobins; Humans; Leukocyte Count; Primary Myelofibrosis; Prognosis; Risk Factors; Thrombosis
PubMed: 26717494
DOI: 10.1002/cncr.29842 -
International Journal of Molecular... Nov 2021Chronic Myeloid Leukemia (CML) is a rare malignant proliferative disease of the hematopoietic system, whose molecular hallmark is the Philadelphia chromosome (Ph). The... (Review)
Review
Chronic Myeloid Leukemia (CML) is a rare malignant proliferative disease of the hematopoietic system, whose molecular hallmark is the Philadelphia chromosome (Ph). The Ph chromosome originates an aberrant fusion gene with abnormal kinase activity, leading to the buildup of reactive oxygen species and genetic instability of relevance in disease progression. Several genetic abnormalities have been correlated with CML in the blast phase, including chromosomal aberrations and common altered genes. Some of these genes are involved in the regulation of cell apoptosis and proliferation, such as the epidermal growth factor receptor () tumor protein p53 (), or Schmidt-Ruppin A-2 proto-oncogene (); cell adhesion, e.g., catenin beta 1 (); or genes associated to TGF-β, such as SKI like proto-oncogene (), transforming growth factor beta 1 () or transforming growth factor beta 2 (); and TNF-α pathways, such as Tumor necrosis factor () or Nuclear factor kappa B subunit 1 (). The involvement of miRNAs in CML is also gaining momentum, where dysregulation of some critical miRNAs, such as miRNA-451 and miRNA-21, which have been associated to the molecular modulation of pathogenesis, progression of disease states, and response to therapeutics. In this review, the most relevant genomic alterations found in CML will be addressed.
Topics: Biomarkers, Tumor; Blast Crisis; ErbB Receptors; Genomic Instability; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Proto-Oncogene Proteins pp60(c-src); Reactive Oxygen Species; Transforming Growth Factor beta1; Tumor Suppressor Protein p53; beta Catenin
PubMed: 34830398
DOI: 10.3390/ijms222212516 -
Journal of Cancer Research and... 2020The rationale of this study is to reveal the statistics of pediatric chronic myeloid leukemia (CML) patients. (Clinical Trial)
Clinical Trial
BACKGROUND
The rationale of this study is to reveal the statistics of pediatric chronic myeloid leukemia (CML) patients.
SUBJECTS AND METHODS
It is a retrospective analysis conducted to assess pediatric CML data from January 1998 to December 2014. There are 65 (3.2%) pediatric CML patients out of entire 2008 patients of CML. Data were analyzed regarding epidemiological characteristics, clinical presentations, response and side effects of imatinib, event-free survival, and overall survival of the pediatric CML patients.
RESULTS
The median age of diagnosis was 11.84 years, and 76.9% patients were male and 23.07% patients were female. Sixty (92.3%) patients were in CML-chronic phase, 3 (4.6%) patients in CML-accelerated phase, and 2 (3.07%) patients in CML-blastic crisis. Most common initial symptoms and signs are weakness (60.0%), abdominal pain (55.38%), splenomegaly (100%), and hepatomegaly (86.5%). 67.3% of patients have white blood counts <100 × 10/L and 92.3% had platelets >150 × 10/L. In the initial months of 2002, imatinib was available and utilized in 54 patients. Of 54 patients, complete hematological response at 3 months, partial cytogenetic response at 6 months, complete cytogenetic response at 12 months, and major molecular response (MMR) at 18 months were 77.77%, 59.2%, 48.14%, and 40.74%, respectively. MMR at 36 months was 62.96% ( n = 34). Most common imatinib-related side effects are gastrointestinal upset and myelosuppression.
CONCLUSION
Pediatric CML in India is comparable with Western countries regarding epidemiological characteristic, clinical presentations, and tolerance of imatinib. As there is a paucity of universal literature regarding pediatric CML (especially data from Southeast Asian region), this article may fill up that space.
Topics: Adolescent; Antineoplastic Agents; Blast Crisis; Child; Child, Preschool; Disease-Free Survival; Female; Humans; India; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Protein Kinase Inhibitors; Retrospective Studies; Treatment Outcome
PubMed: 32362619
DOI: 10.4103/jcrt.JCRT_833_15 -
Blood Advances Feb 2018Among 248 consecutive patients with blast phase myeloproliferative neoplasm (MPN-BP), DNA collected at the time of blast transformation was available in 75 patients...
Among 248 consecutive patients with blast phase myeloproliferative neoplasm (MPN-BP), DNA collected at the time of blast transformation was available in 75 patients (median age, 66 years; 64% men). MPN-BP followed primary myelofibrosis in 39 patients, essential thrombocythemia in 20 patients, and polycythemia vera in 16 patients. A myeloid neoplasm-relevant 33-gene panel was used for next-generation sequencing. Driver mutation distribution was 57%, 20%, 9%, and triple-negative 13%. Sixty-four patients (85%) harbored other mutations/variants, including 37% with ≥3 mutations; most frequent were 47%, 19%, 17%, 16%, 15%, and 13%; relative mutual exclusivity was expressed by , , , , , and mutations. Paired chronic-blast phase sample analysis was possible in 19 patients and revealed more frequent blast phase acquisition of , , , , , and mutations/variants. In multivariable analysis, and mutations/variants were associated with shorter survival duration; respective hazard ratios (HRs) (95% confidence interval [CI]) were 2.1 (95% CI, 1.1-3.8) and 3.0 (95% CI, 1.1-6.6). An all-inclusive multivariable analysis confirmed the prognostic relevance of mutations (HR, 1.9; 95% CI, 1.5-5.5) and also showed additional contribution from a treatment strategy that includes transplant or induction of complete or near-complete remission (HR, 0.3; 95% CI, 0.2-0.5). The current study points to specific mutations that might bear pathogenetic relevance for leukemic transformation in MPN and also suggest an adverse survival effect of mutations.
Topics: Adult; Aged; Aged, 80 and over; Blast Crisis; Cell Transformation, Neoplastic; Core Binding Factor Alpha 2 Subunit; Female; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Mutation; Myeloproliferative Disorders; Neoplasms
PubMed: 29467191
DOI: 10.1182/bloodadvances.2018015875