-
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 -
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 -
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 -
HemaSphere Oct 2020New insights have emerged from maturing long-term academic and commercial clinical trials regarding optimum management of chronic myeloid leukemia (CML). Velocity of... (Review)
Review
New insights have emerged from maturing long-term academic and commercial clinical trials regarding optimum management of chronic myeloid leukemia (CML). Velocity of response has unexpectedly proved less important than hitherto thought, does not predict survival, and is of unclear relevance for treatment-free remission (TFR). Serious and cumulative toxicity has been observed with tyrosine kinase inhibitors that had been expected to replace imatinib. Generic imatinib has become cost-effective first-line treatment in chronic phase despite chronic low-grade side-effects in many patients. Earlier recognition of end-phase by genetic assessment might improve prospects for blast crisis (BC). TFR has become an important new treatment goal of CML. To reflect this new situation ELN has recently revised and updated its recommendations for treating CML. After a brief review of 175 years of CML history this review will focus on recent developments and on current evidence for treating CML in 2020.
PubMed: 33134861
DOI: 10.1097/HS9.0000000000000468 -
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 -
Journal of Blood Medicine 2023Chronic myeloid leukemia (CML) is one of the most common leukemias occurring in the adult population. The course of CML is divided into three phases: the chronic phase,... (Review)
Review
Chronic myeloid leukemia (CML) is one of the most common leukemias occurring in the adult population. The course of CML is divided into three phases: the chronic phase, the acceleration phase, and the blast phase. Pathophysiology of CML revolves around Philadelphia chromosome that constitutively activate tyrosine kinase through BCR-ABL1 oncoprotein. In the era of tyrosine kinase inhibitors (TKIs), CML patients now have a similar life expectancy to people without CML, and it is now very rare for CML patients to progress to the blast phase. Only a small proportion of CML patients have resistance to TKI, caused by BCR-ABL1 point mutations. CML patients with TKI resistance should be treated with second or third generation TKI, depending on the BCR-ABL1 mutation. Recently, many studies have shown that it is possible for CML patients who achieve a long-term deep molecular response to stop TKIs treatment and maintain remission. This review aimed to provide an overview of CML, including its pathophysiology, clinical manifestations, the role of stem cells, CML treatments, and treatment-free remission.
PubMed: 37051025
DOI: 10.2147/JBM.S382090 -
Journal of Education & Teaching in... Apr 2020This scenario was developed to educate emergency medicine residents on the diagnosis and management of blast crisis.
AUDIENCE
This scenario was developed to educate emergency medicine residents on the diagnosis and management of blast crisis.
INTRODUCTION
Chronic myeloid leukemia (CML) makes up 15% of diagnosed adult leukemias with the median age of diagnosis being 67 years old. Chronic myeloid leukemia consists of three phases: chronic, accelerated, and blast phases. Most patients are initially diagnosed while in the chronic phase.1 Of those diagnosed in the chronic phase and being treated with a tyrosine kinase inhibitor (TKI), about 1% -1.5% of CML patients per year will subsequently transform into an advanced phase or blast crisis.2 While rare, blast crisis is considered an oncologic emergency, with increased mortality occurring primarily from subsequent infections or bleeding. Therefore, emergency physicians must be familiar with its clinical presentation and subsequent management.
EDUCATIONAL OBJECTIVES
By the end of this simulation, the participant will be able to: 1) create a thorough differential for the undifferentiated febrile, altered patient, 2) identify the signs and symptoms of blast crisis, 3) describe proper resuscitation of a patient in blast crisis, and 4) describe the indications, steps, and contraindications of performing a lumbar puncture.
EDUCATIONAL METHODS
This session was conducted using high-fidelity simulation, followed by a debriefing session and lecture on the diagnosis, differential diagnosis, and management of blast crisis. Debriefing methods may be left to the discretion of participants, but the authors have used advocacy-inquiry techniques. This scenario may also be run as an oral boards case.
RESEARCH METHODS
Our simulation center's feedback form is based on the Center of Medical Simulation's Debriefing Assessment for Simulation in Healthcare (DASH) Student Version Short Form, with the inclusion of required qualitative feedback if an element was scored less than a 6 or 7.
RESULTS
This session received all 6 or 7 scores (consistently effective/very good or extremely effective/outstanding). During the debriefing session, feedback from the residents was largely positive. They appreciated reviewing the broad differential of altered mental status and oncologic emergencies. While many groups anchored on the diagnosis of encephalitis, they also expressed that after this experience, blast crisis would be added to their differential for patients with CML.
DISCUSSION
This is a cost-effective method for reviewing blast crisis. Learners were able to identify more common causes of altered mental status in their differentials, but without further prompting, they were unable to ultimately come up with the diagnosis of blast crisis. Our main take-away is to continue reviewing oncologic emergencies as a part of our residency curriculum.
TOPICS
Medical simulation, chronic myeloid leukemia, blast crisis, leukostasis, emergency medicine, oncologic emergencies, hematologic emergencies.
PubMed: 37465412
DOI: 10.21980/J8W35K -
Nature May 2017Reprogrammed cellular metabolism is a common characteristic observed in various cancers. However, whether metabolic changes directly regulate cancer development and...
Reprogrammed cellular metabolism is a common characteristic observed in various cancers. However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukaemia (CML) in humans and in mouse models of CML. BCAT1 is upregulated during progression of CML and promotes BCAA production in leukaemia cells by aminating the branched-chain keto acids. Blocking BCAT1 gene expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML both in vitro and in vivo. Stable-isotope tracer experiments combined with nuclear magnetic resonance-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function through BCAA production in blast crisis CML cells. Importantly, BCAT1 expression not only is activated in human blast crisis CML and de novo acute myeloid leukaemia, but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for blast crisis CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukaemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2-BCAT1 axis drives cancer progression in myeloid leukaemia.
Topics: Amino Acids, Branched-Chain; Animals; Blast Crisis; Cell Differentiation; Cell Proliferation; Disease Progression; Enzyme Activation; Female; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Mice; Mice, Inbred C57BL; RNA-Binding Proteins; Transaminases
PubMed: 28514443
DOI: 10.1038/nature22314 -
Cancer Research Sep 2023Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in...
UNLABELLED
Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematologic malignancies suggests that it could also play a role in drug resistance and relapse in acute myeloid leukemia (AML). In a cohort of 1,273 AML patients, we uncovered that the multifunctional scavenger receptor CD36 was positively associated with extramedullary dissemination of leukemic blasts, increased risk of relapse after intensive chemotherapy, and reduced event-free and overall survival. CD36 was dispensable for lipid uptake but fostered blast migration through its binding with thrombospondin-1. CD36-expressing blasts, which were largely enriched after chemotherapy, exhibited a senescent-like phenotype while maintaining their migratory ability. In xenograft mouse models, CD36 inhibition reduced metastasis of blasts and prolonged survival of chemotherapy-treated mice. These results pave the way for the development of CD36 as an independent marker of poor prognosis in AML patients and a promising actionable target to improve the outcome of patients.
SIGNIFICANCE
CD36 promotes blast migration and extramedullary disease in acute myeloid leukemia and represents a critical target that can be exploited for clinical prognosis and patient treatment.
Topics: Humans; Animals; Mice; Leukemia, Myeloid, Acute; Treatment Outcome; Prognosis; Recurrence; Blast Crisis; Chronic Disease
PubMed: 37327406
DOI: 10.1158/0008-5472.CAN-22-3682 -
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