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Cancer Apr 2022
Topics: Blast Crisis; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
PubMed: 35133004
DOI: 10.1002/cncr.34119 -
Best Practice & Research. Clinical... Mar 2021Myeloproliferative neoplasm-blast phase (MPN-BP) is a form of acute leukemia which is distinct from de novo acute myeloid leukemia with each entity being characterized... (Review)
Review
Myeloproliferative neoplasm-blast phase (MPN-BP) is a form of acute leukemia which is distinct from de novo acute myeloid leukemia with each entity being characterized by specific complex cytogenetic abnormalities and myeloid gene mutational patterns. MPN-BP patients have a particularly dismal prognosis with a medium overall survival of 5.8 months with currently available therapies. Large-scale sequencing studies have unraveled the mutational landscape of the chronic MPNs and MPN-BP, demonstrating importance of clonal heterogeneity and the role of somatic mutations in disease progression and their use to determine patient outcomes. JAK inhibitors represent the standard of care for intermediate/high-risk MF patients and have been shown to improve clinical symptoms. However, this therapeutic approach leads to a modest reduction in the variant allele frequency of the known MPN driver mutations in most patients and does not substantially delay or prevent the evolution to MPN-BP. In this article, we will review molecular mechanisms driving the progression from chronic MPNs to a BP, the impact of genetic changes on MPN-BP evolution, and the role of clonal evolution in response to JAK inhibitor therapy and disease progression. We will also discuss our ongoing functional studies of cells responsible for the development of MPN-BP.
Topics: Blast Crisis; Clonal Evolution; Humans; Leukemia, Myeloid, Acute; Mutation; Myeloproliferative Disorders
PubMed: 33762108
DOI: 10.1016/j.beha.2021.101254 -
Blood Jul 2015This multicenter, randomized, open-label, phase 3 trial evaluated azacitidine efficacy and safety vs conventional care regimens (CCRs) in 488 patients age ≥65 years... (Comparative Study)
Comparative Study Randomized Controlled Trial
This multicenter, randomized, open-label, phase 3 trial evaluated azacitidine efficacy and safety vs conventional care regimens (CCRs) in 488 patients age ≥65 years with newly diagnosed acute myeloid leukemia (AML) with >30% bone marrow blasts. Before randomization, a CCR (standard induction chemotherapy, low-dose ara-c, or supportive care only) was preselected for each patient. Patients then were assigned 1:1 to azacitidine (n = 241) or CCR (n = 247). Patients assigned to CCR received their preselected treatment. Median overall survival (OS) was increased with azacitidine vs CCR: 10.4 months (95% confidence interval [CI], 8.0-12.7 months) vs 6.5 months (95% CI, 5.0-8.6 months), respectively (hazard ratio [HR] was 0.85; 95% CI, 0.69-1.03; stratified log-rank P = .1009). One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively (difference, 12.3%; 95% CI, 3.5%-21.0%). A prespecified analysis censoring patients who received AML treatment after discontinuing study drug showed median OS with azacitidine vs CCR was 12.1 months (95% CI, 9.2-14.2 months) vs 6.9 months (95% CI, 5.1-9.6 months; HR, 0.76; 95% CI, 0.60-0.96; stratified log-rank P = .0190). Univariate analysis showed favorable trends for azacitidine compared with CCR across all subgroups defined by baseline demographic and disease features. Adverse events were consistent with the well-established safety profile of azacitidine. Azacitidine may be an important treatment option for this difficult-to-treat AML population. This trial was registered at www.clinicaltrials.gov as #NCT01074047.
Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Blast Crisis; Female; Follow-Up Studies; Humans; International Agencies; Leukemia, Myeloid, Acute; Male; Neoplasm Staging; Prognosis; Prospective Studies; Survival Rate
PubMed: 25987659
DOI: 10.1182/blood-2015-01-621664 -
Hematology. American Society of... Dec 2021Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia (CML). With TKI therapy, the percentage of patients who progress to...
Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia (CML). With TKI therapy, the percentage of patients who progress to accelerated phase (AP) or blast phase (BP) CML has decreased from more than 20% to 1% to 1.5% per year. Although AP- and BP-CML occur in a minority of patients, outcomes in these patients are significantly worse compared with chronic phase CML, with decreased response rates and duration of response to TKI. Despite this, TKIs have improved outcomes in advanced phase CML, particularly in de novo AP patients, but are often inadequate for lasting remissions. The goal of initial therapy in advanced CML is a return to a chronic phase followed by consideration for bone marrow transplantation. The addition of induction chemotherapy with TKI is often necessary for achievement of a second chronic phase. Given the small population of patients with advanced CML, development of novel treatment strategies and investigational agents is challenging, although clinical trial participation is encouraged in AP and BP patients, whenever possible. We review the overall management approach to advanced CML, including TKI selection, combination therapy, consideration of transplant, and novel agents.
Topics: Blast Crisis; Disease Management; Disease Progression; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Middle Aged; Protein Kinase Inhibitors
PubMed: 34889372
DOI: 10.1182/hematology.2021000240 -
Hematology. American Society of... Nov 2018Myelofibrosis (MF) is the most aggressive form of Philadelphia chromosome-negative myeloproliferative neoplasm, and it is complicated by severe symptom burden,... (Review)
Review
Myelofibrosis (MF) is the most aggressive form of Philadelphia chromosome-negative myeloproliferative neoplasm, and it is complicated by severe symptom burden, thrombotic events, infections, cytopenias, and transformation to acute myeloid leukemia (AML). Ruxolitinib, the first-line therapy for symptomatic or intermediate- and high-prognostic risk MF, has improved overall survival for this population. However, approximately one-half of MF patients will discontinue ruxolitinib by the first few years of therapy due to a spectrum of resistance, intolerance, relapse, or progression to blast phase disease. Danazol, erythropoietin-stimulating agents, and spleen-directed therapies can be useful in the ruxolitinib-resistant setting. In the ruxolitinib-refractory or -intolerant setting, commercial and novel therapies, either alone or in combination with ruxolitinib, have shown clinical utility. For blast-phase MF, the recent advancements in available AML therapies have increased the options with targeted and more tolerable therapies. In this article, we will discuss our paradigm for the management of relapsed/refractory and blast-phase MF in the context of therapeutic advancements in both AML and MF.
Topics: Blast Crisis; Danazol; Hematologic Neoplasms; Humans; Primary Myelofibrosis; Recurrence; Rituximab
PubMed: 30504300
DOI: 10.1182/asheducation-2018.1.118 -
Annals of Medicine Dec 2023There is a lack of evidence regarding whether combination therapy of hypomethylating agents (HMAs) has better outcomes than HMA monotherapy in patients with Philadelphia... (Meta-Analysis)
Meta-Analysis Review
Efficacy and safety of combination therapies vs monotherapy of hypomethylating agents in accelerated or blast phase of Philadelphia negative myeloproliferative neoplasms: a systematic review and meta-analysis.
BACKGROUND
There is a lack of evidence regarding whether combination therapy of hypomethylating agents (HMAs) has better outcomes than HMA monotherapy in patients with Philadelphia chromosome-negative accelerated or blast phase myeloproliferative neoplasms (MPN-AP/BP).
MATERIALS AND METHODS
Pubmed, Embase, Web of Science and Cochrane library databases were searched for studies from inception of each database until 31 December 2021. Data extraction and synthesis were conducted following the PRISMA reporting guideline.
RESULTS
It was found that HMAs plus venetoclax therapy yielded a higher CR/CRi rate than HMAs alone [36% vs 19%, = .0204] and a higher CR rate than HMAs plus ruxolitinib [22% vs 8%, = .0313]. HMAs plus ruxolitinib combination showed a higher ORR than HMA monotherapy [45% vs 30%, = .0395], but there was no improvement in CR/CRi. The one-year and two-year OS rate for patients treated with HMAs plus venetoclx/ruxolitinib demonstrated a trend towards prolonged survival than HMAs alone [HMAs plus venetoclax: 24% vs 11%, = .1295 and 12% vs 3%, = .2357; HMAs plus ruxolitinib: 25% vs 11%, = .0774 and 33% vs 3%, = .051].
CONCLUSION
It was confirmed that HMA in combination with venetoclax is an effective and well-tolerated option in MPN-AP/BP patients in pre- as well as post-haematopoietic stem cell transplantation settings. HMA plus ruxolitinib therapy was revealed to be effective in patients with MPN-AP.Key MessagesCombination therapy with HMAs and venetoclax/ruxolitinib was associated with improved outcomes than HMAs alone in MPN-AP/BP patients.Further large-scale randomized controlled trials are needed to confirm regarding to the optimal treatment for this patient population.
Topics: Humans; Treatment Outcome; Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic
PubMed: 36644935
DOI: 10.1080/07853890.2022.2164611 -
Molecular Cancer Nov 2023Although the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance...
BACKGROUND
Although the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML.
METHODS
We generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3 CML patients.
RESULTS
We reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3 BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3 BP-CML patients had significantly less favorable prognosis than FLT3 patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3 BCR::ABL1 cells and mouse xenograft models.
CONCLUSION
Here, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies.
Topics: Animals; Mice; Humans; Blast Crisis; Fusion Proteins, bcr-abl; Drug Resistance, Neoplasm; Signal Transduction; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; fms-Like Tyrosine Kinase 3
PubMed: 37932786
DOI: 10.1186/s12943-023-01837-4 -
Pharmaceutical Biology Dec 2022Resistance to BCR-ABL tyrosine kinase inhibitor (TKI) is the cause of treatment failure in blast phase chronic myeloid leukaemia (BP-CML). Agents that act...
CONTEXT
Resistance to BCR-ABL tyrosine kinase inhibitor (TKI) is the cause of treatment failure in blast phase chronic myeloid leukaemia (BP-CML). Agents that act synergistically with BCR-ABL TKI are required to improve response.
OBJECTIVE
This work investigated the effects of stachydrine in CML.
MATERIALS AND METHODS
CML cells were treated with control or stachydrine at 20, 40 and 80 µM. Proliferation and apoptosis were examined after 72 h treatment. Combination studies were performed in four groups: control, TKI, stachydrine and the combination of stachydrine and TKI. Immunoblotting analysis was performed in CML cells after 24 h treatment.
RESULTS
Stachydrine inhibited K562 (IC 61 µM), KCL22 (IC 141 µM), LAMA84 (IC 86 µM), Ba/F3 T315I (IC 26 µM), Ba/F3 WT (IC 22 µM) and KU812 (IC 35 µM) proliferation, and induced apoptosis in these CML cell lines. Stachydrine significantly induced apoptosis, inhibited colony formation and self-renewal in BP-CML CD34 cells. The combination index of stachydrine and TKI combination was <1. Compared to TKI alone, the combination of stachydrine and TKI significantly induced more apoptosis and decreased colony formation in BP-CML CD34 cells. Stachydrine decreased phosphorylation levels of multiple receptor tyrosine kinases in CML cells.
DISCUSSION AND CONCLUSIONS
Our study is the first to demonstrate (1) the anticancer activity of stachydrine on primary patient cancer cells; (2) the inhibitory effects of stachydrine on cancer stem cells; (3) the synergism between stachydrine and other anticancer drugs.
Topics: Blast Crisis; Cell Line, Tumor; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Proline; Tyrosine
PubMed: 35348419
DOI: 10.1080/13880209.2022.2044862 -
Leukemia Apr 2021Blast-phase chronic myeloid leukemia (BP-CML) is associated with additional chromosomal aberrations, RUNX1 mutations being one of the most common. Tyrosine kinase...
Blast-phase chronic myeloid leukemia (BP-CML) is associated with additional chromosomal aberrations, RUNX1 mutations being one of the most common. Tyrosine kinase inhibitor therapy has only limited efficacy in BP-CML, and characterization of more defined molecular subtypes is warranted in order to design better treatment modalities for this poor prognosis patient group. Using whole-exome and RNA sequencing we demonstrate that PHF6 and BCORL1 mutations, IKZF1 deletions, and AID/RAG-mediated rearrangements are enriched in RUNX1 BP-CML leading to typical mutational signature. On transcriptional level interferon and TNF signaling were deregulated in primary RUNX1 CML cells and stem cell and B-lymphoid factors upregulated giving a rise to distinct phenotype. This was accompanied with the sensitivity of RUNX1 blasts to CD19-CAR T cells in ex vivo assays. High-throughput drug sensitivity and resistance testing revealed leukemia cells from RUNX1 patients to be highly responsive for mTOR-, BCL2-, and VEGFR inhibitors and glucocorticoids. These findings were further investigated and confirmed in CRISPR/Cas9-edited homozygous RUNX1 and heterozygous RUNX1 BCR-ABL positive cell lines. Overall, our study provides insights into the pathogenic role of RUNX1 mutations and highlights personalized targeted therapy and CAR T-cell immunotherapy as potentially promising strategies for treating RUNX1 BP-CML patients.
Topics: Binding Sites; Biomarkers, Tumor; Blast Crisis; Cell Line, Tumor; Combined Modality Therapy; Core Binding Factor Alpha 2 Subunit; Disease Management; Disease Susceptibility; Drug Resistance, Neoplasm; Flow Cytometry; Gene Deletion; Gene Editing; Humans; Ikaros Transcription Factor; Immunophenotyping; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Targeted Therapy; Mutation; Phenotype; Protein Binding; Signal Transduction; Transcriptome; Exome Sequencing
PubMed: 32782381
DOI: 10.1038/s41375-020-01011-5 -
Blood Advances Oct 2018There is a paucity of data regarding the impact of mutations on outcomes in accelerated-phase (AP) and blast-phase (BP) myeloproliferative neoplasms (MPNs). Moreover, it...
There is a paucity of data regarding the impact of mutations on outcomes in accelerated-phase (AP) and blast-phase (BP) myeloproliferative neoplasms (MPNs). Moreover, it is unknown whether mutational status affects survival, as seen in chronic-phase MPNs. Therefore, we performed a retrospective analysis of all patients treated at our institution with AP/BP MPNs (N = 122; AP = 14; BP = 108) to comprehensively describe the mutational profile and correlate with clinical outcomes. Targeted sequencing with a 54-gene panel was performed. Forty-four patients were treated with intensive therapy, 27 with nonintensive therapy, and 51 with best supportive care (BSC). The most common mutation was , occurring in 55% of subjects; was found in 13% of patients and in 6%. Thirty-two (26%) patients were triple negative. Other frequently mutated genes were (30%), (25%), (22%), (20%), and (17%). Mutations in 1, 2, 3, and ≥4 genes were seen in 15%, 13%, 25%, and 46% of patients, respectively. There was no difference in survival between patients treated with intensive vs nonintensive therapy, and the benefit of intensive therapy was limited to patients who were able to undergo transplantation. was the only individual mutation to correlate with shorter overall survival (hazard ratio, 1.89; = .03). In the multivariate analysis, mutated , ≥4 mutations, low albumin, increased peripheral blood blasts, ≥3 cytogenetic abnormalities, and BSC were associated with shorter survival. In conclusion, mutational data enhance the understanding of patients with AP/BP MPN who are likely to benefit from current therapeutic options.
Topics: Blast Crisis; Female; Humans; Male; Myeloproliferative Disorders; Treatment Outcome
PubMed: 30327374
DOI: 10.1182/bloodadvances.2018021469