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Hematology. American Society of... Dec 2016T-cell acute lymphoblastic leukemia (T-ALL) is biologically distinct from its B lymphoblastic (B-ALL) counterpart and shows different kinetic patterns of disease... (Review)
Review
T-cell acute lymphoblastic leukemia (T-ALL) is biologically distinct from its B lymphoblastic (B-ALL) counterpart and shows different kinetic patterns of disease response. Although very similar regimens are used to treat T-ALL and B-ALL, distinctions in response to different elements of therapy have been observed. Similar to B-ALL, the key prognostic determinant in T-ALL is minimal residual disease (MRD) response. Unlike B-ALL, other factors including age, white blood cell count at diagnosis, and genetics of the ALL blasts are not independently prognostic when MRD response is included. Recent insights into T-ALL biology, using modern genomic techniques, have identified a number of recurrent lesions that can be grouped into several targetable pathways, including Notch, Jak/Stat, PI3K/Akt/mTOR, and MAPK. With contemporary chemotherapy, outcomes for de novo T-ALL have steadily improved and now approach those observed in B-ALL, with approximately 85% 5-year event-free survival. Unfortunately, salvage has remained poor, with less than 25% event-free and overall survival rates for relapsed disease. Thus, current efforts are focused on preventing relapse by augmenting therapy for high-risk patients, sparing toxicity in favorable subsets and developing new approaches for the treatment of recurrent disease.
Topics: Blast Crisis; Disease-Free Survival; Humans; MAP Kinase Signaling System; Neoplasm Proteins; Neoplasm, Residual; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Survival Rate
PubMed: 27913532
DOI: 10.1182/asheducation-2016.1.580 -
British Journal of Haematology Dec 2022Despite the success of BCR-ABL-specific tyrosine kinase inhibitors (TKIs) such as imatinib in chronic phase (CP) chronic myeloid leukaemia (CML), patients with blast... (Review)
Review
Despite the success of BCR-ABL-specific tyrosine kinase inhibitors (TKIs) such as imatinib in chronic phase (CP) chronic myeloid leukaemia (CML), patients with blast phase (BP)-CML continue to have a dismal outcome with median survival of less than one year from diagnosis. Thus BP-CML remains a critical unmet clinical need in the management of CML. Our understanding of the biology of BP-CML continues to grow; genomic instability leads to acquisition of mutations which drive leukaemic progenitor cells to develop self-renewal properties, resulting in differentiation block and a poor-prognosis acute leukaemia which may be myeloid, lymphoid or bi-phenotypic. Similar advances in therapy are urgently needed to improve patient outcomes; however, this is challenging given the rarity and heterogeneity of BP-CML, leading to difficulty in designing and recruiting to prospective clinical trials. This review will explore the treatment of BP-CML, evaluating the data for TKI therapy alone, combinations with intensive chemotherapy, the role of allogeneic haemopoietic stem cell transplantation, the use of novel agents and clinical trials, as well as discussing the most appropriate methods for diagnosing BP and assessing response to therapy, and factors predicting outcome.
Topics: Humans; Blast Crisis; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Prospective Studies; Imatinib Mesylate; Protein Kinase Inhibitors
PubMed: 35866251
DOI: 10.1111/bjh.18370 -
Blood Cancer Journal Jul 2023Leukemic transformation in myeloproliferative neoplasms (MPN), also referred to as "blast-phase MPN", is the most feared disease complication, with incidence estimates... (Review)
Review
Leukemic transformation in myeloproliferative neoplasms (MPN), also referred to as "blast-phase MPN", is the most feared disease complication, with incidence estimates of 1-4% for essential thrombocythemia, 3-7% for polycythemia vera, and 9-13% for primary myelofibrosis. Diagnosis of MPN-BP requires the presence of ≥20% circulating or bone marrow blasts; a lower level of excess blasts (10-19%) constitutes "accelerated phase" disease (MPN-AP). Neither "intensive" nor "less intensive" chemotherapy, by itself, secures long-term survival in MPN-BP. Large-scale retrospective series have consistently shown a dismal prognosis in MPN-BP, with 1- and 3-year survival estimates of <20% and <5%, respectively. Allogeneic hematopoietic stem cell transplant (AHSCT) offers the possibility of a >30% 3-year survival rate and should be pursued, ideally, while the patient is still in chronic phase disease. The value of pre-transplant bridging chemotherapy is uncertain in MPN-AP while it is advised in MPN-BP; in this regard, we currently favor combination chemotherapy with venetoclax (Ven) and hypomethylating agent (HMA); response is more likely in the absence of complex/monosomal karyotype and presence of TET2 mutation. Furthermore, in the presence of an IDH mutation, the use of IDH inhibitors, either alone or in combination with Ven-HMA, can be considered. Pre-transplant clearance of excess blasts is desired but not mandated; in this regard, additional salvage chemotherapy is more likely to compromise transplant eligibility rather than improve post-transplant survival. Controlled studies are needed to determine the optimal pre- and post-transplant measures that target transplant-associated morbidity and post-transplant relapse.
Topics: Humans; Blast Crisis; Retrospective Studies; Neoplasm Recurrence, Local; Myeloproliferative Disorders; Polycythemia Vera; Mutation; Chronic Disease
PubMed: 37460550
DOI: 10.1038/s41408-023-00878-8 -
Acta Haematologica 2021Myeloproliferative neoplasms (MPNs) can transform into blast phase MPN (leukemic transformation; MPN-BP), typically via accelerated phase MPN (MPN-AP), in ∼20-25% of... (Review)
Review
BACKGROUND
Myeloproliferative neoplasms (MPNs) can transform into blast phase MPN (leukemic transformation; MPN-BP), typically via accelerated phase MPN (MPN-AP), in ∼20-25% of the cases. MPN-AP and MPN-BP are characterized by 10-19% and ≥20% blasts, respectively. MPN-AP/BP portend a dismal prognosis with no established conventional treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole modality associated with long-term survival.
SUMMARY
MPN-AP/BP has a markedly different mutational profile from de novo acute myeloid leukemia (AML). In MPN-AP/BP, TP53 and IDH1/2 are more frequent, whereas FLT3 and DNMT3A are rare. Higher incidence of leukemic transformation has been associated with the most aggressive MPN subtype, myelofibrosis (MF); other risk factors for leukemic transformation include rising blast counts above 3-5%, advanced age, severe anemia, thrombocytopenia, leukocytosis, increasing bone marrow fibrosis, type 1 CALR-unmutated status, lack of driver mutations (negative for JAK2, CALR, or MPL genes), adverse cytogenetics, and acquisition of ≥2 high-molecular risk mutations (ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1Q157). The aforementioned factors have been incorporated in several novel prognostic scoring systems for MF. Currently, elderly/unfit patients with MPN-AP/BP are treated with hypomethylating agents with/without ruxolitinib; these regimens appear to confer comparable benefit to intensive chemotherapy but with lower toxicity. Retrospective studies in patients who acquired actionable mutations during MPN-AP/BP showed positive outcomes with targeted AML treatments, such as IDH1/2 inhibitors, and require further evaluation in clinical trials. Key Messages: Therapy for MPN-AP patients represents an unmet medical need. MF patients, in particular, should be appropriately stratified regarding their prognosis and the risk for transformation. Higher-risk patients should be monitored regularly and treated prior to progression to MPN-BP. MPN-AP patients may be treated with hypomethylating agents alone or in combination with ruxolitinib; also, patients can be provided with the option to enroll in rationally designed clinical trials exploring combination regimens, including novel targeted drugs, with an ultimate goal to transition to transplant.
Topics: Allografts; Blast Crisis; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Mutation; Myeloproliferative Disorders; Neoplasm Proteins
PubMed: 33882481
DOI: 10.1159/000512929 -
Leukemia Mar 2023Treatment of chronic myeloid leukemia has improved significantly with the introduction of tyrosine kinase inhibitors (TKIs), and treatment guidelines based on numerous... (Review)
Review
Treatment of chronic myeloid leukemia has improved significantly with the introduction of tyrosine kinase inhibitors (TKIs), and treatment guidelines based on numerous clinical trials are available for chronic phase disease. However for CML in the blast phase (CML-BP), prognosis remains poor and treatment options are much more limited. The spectrum of treatment strategies for children and adolescents with CML-BP has largely evolved empirically and includes treatment principles derived from adult CML-BP and pediatric acute leukemia. Given this heterogeneity of treatment approaches, we formed an international panel of pediatric CML experts to develop recommendations for consistent therapy in children and adolescents with this high-risk disease based on the current literature and national standards. Recommendations include detailed information on initial diagnosis and treatment monitoring, differentiation from Philadelphia-positive acute leukemia, subtype-specific selection of induction therapy, and combination with tyrosine kinase inhibitors. Given that allogeneic hematopoietic stem cell transplantation currently remains the primary curative intervention for CML-BP, we also provide recommendations for the timing of transplantation, donor and graft selection, selection of a conditioning regimen and prophylaxis for graft-versus-host disease, post-transplant TKI therapy, and management of molecular relapse. Management according to the treatment recommendations presented here is intended to provide the basis for the design of future prospective clinical trials to improve outcomes for this challenging disease.
Topics: Adult; Humans; Child; Adolescent; Blast Crisis; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Hematopoietic Stem Cell Transplantation; Prognosis; Graft vs Host Disease; Leukemia, Myeloid, Acute
PubMed: 36707619
DOI: 10.1038/s41375-023-01822-2 -
Blood Mar 2021Plasmacytoid dendritic cells (pDCs) are the principal natural type I interferon-producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to...
Plasmacytoid dendritic cells (pDCs) are the principal natural type I interferon-producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN), and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia. The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here, we characterize patients with AML with pDC expansion (pDC-AML), which we observe in ∼5% of AML cases. pDC-AMLs often possess cross-lineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without pDC expansion and BPDCN. We demonstrate that pDCs are clonally related to, as well as originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells toward pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML.
Topics: Adult; Aged; Blast Crisis; Core Binding Factor Alpha 2 Subunit; Dendritic Cells; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation
PubMed: 32871587
DOI: 10.1182/blood.2020007897 -
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 -
Nature Medicine Jun 2017Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations...
Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations to molecularly targeted cancer therapies. However, current single-cell RNA-sequencing approaches lack the sensitivity required to reliably detect somatic mutations. We developed a method that combines high-sensitivity mutation detection with whole-transcriptome analysis of the same single cell. We applied this technique to analyze more than 2,000 SCs from patients with chronic myeloid leukemia (CML) throughout the disease course, revealing heterogeneity of CML-SCs, including the identification of a subgroup of CML-SCs with a distinct molecular signature that selectively persisted during prolonged therapy. Analysis of nonleukemic SCs from patients with CML also provided new insights into cell-extrinsic disruption of hematopoiesis in CML associated with clinical outcome. Furthermore, we used this single-cell approach to identify a blast-crisis-specific SC population, which was also present in a subclone of CML-SCs during the chronic phase in a patient who subsequently developed blast crisis. This approach, which might be broadly applied to any malignancy, illustrates how single-cell analysis can identify subpopulations of therapy-resistant SCs that are not apparent through cell-population analysis.
Topics: Adult; Aged; Blast Crisis; Chromatin Immunoprecipitation; Core Binding Factor Alpha 2 Subunit; Female; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Library; Genes, abl; Humans; In Situ Hybridization, Fluorescence; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Neoplastic Stem Cells; Reverse Transcriptase Polymerase Chain Reaction; Sequence Analysis, DNA; Sequence Analysis, RNA; Single-Cell Analysis; Transcriptome; Young Adult
PubMed: 28504724
DOI: 10.1038/nm.4336 -
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 -
International Journal of Molecular... Oct 2022Blast crisis (BC) is one of the most dreaded complications of chronic myeloid leukemia (CML). Fortunately, the incidence of BC has diminished markedly in the tyrosine... (Review)
Review
Blast crisis (BC) is one of the most dreaded complications of chronic myeloid leukemia (CML). Fortunately, the incidence of BC has diminished markedly in the tyrosine kinase inhibitor (TKI) era. The primary objective of initial treatment in BC is to achieve a second chronic phase (CP) and to proceed to an allogeneic stem cell transplantation (SCT) in eligible patients. The clinical outcome of patients with CML BC remains unsatisfactory, even with highly potent TKIs, as remissions are short lived and there is an unmet need for novel therapies. We provide a comprehensive summary reviewing the current management of Lymphoid BC.
Topics: Blast Crisis; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors
PubMed: 36233138
DOI: 10.3390/ijms231911836