scholarly journals How I treat atypical chronic myeloid leukemia

Blood ◽  
2017 ◽  
Vol 129 (7) ◽  
pp. 838-845 ◽  
Author(s):  
Jason Gotlib
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasm ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
High Rate ◽  
Current Standard ◽  
Hematopoietic Stem ◽  
Genetic Features ◽  
Atypical Chronic Myeloid Leukemia

Abstract Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) for which no current standard of care exists. The challenges of aCML relate to its heterogeneous clinical and genetic features, high rate of transformation to acute myeloid leukemia, and historically poor survival. Therefore, allogeneic hematopoietic stem cell transplantation should always be an initial consideration for eligible patients with a suitable donor. Nontransplant approaches for treating aCML have otherwise largely relied on adopting treatment strategies used for MDS and MPN. However, such therapies, including hypomethylating agents, are based on a paucity of data. With an eye toward making a more meaningful impact on response rates and modification of the natural history of the disease, progress will rely on enrollment of patients into clinical trials and molecular profiling of individuals so that opportunities for targeted therapy can be exploited.

scholarly journals Atypical Chronic Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5455-5455
Author(s):  
Chandralekha Ashangari ◽  
Praveen K. Tumula
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Neoplasm ◽  
Peripheral Blood Flow ◽  
Current Standard ◽  
Atypical Chronic Myeloid Leukemia ◽  
Wbc Count

Abstract Introduction: Atypical chronic myeloid leukemia (aCML), BCR-ABL1 negative is a rare myelodysplastic syndromes (MDS)/myeloproliferative neoplasm (MPN) for which no current standard of care exists. We present one of the rare presentations of aCML in an elderly patient. Case: A 76 year old male presented to the Hematology clinic for consultation after discharge from local hospital for elevated WBC count. Past medical history was significant for COPD, acid reflux, peripheral arterial disease and hypertension. Physical exam was unremarkable. Initial labs were significant for leukocytosis of 30 k/cu mm, anemia with Hb 10 gm/dl, thrombocytosis 695,000 with neutrophilia of ANC 25,200. Peripheral blood was negative for JAK2 V617F and BCR-ABL. Peripheral blood flow cytometry showed granulocytic left shift with 1.5% myeloblasts. Bone marrow biopsy suggestive of hypercellular marrow (100%) with myeloid predominance, atypical megakaryocytes, increased ring sideroblasts (49% of NRBC), increased blasts (5%) and dysgranulopoeisis over all suggestive of Myelodyplastic Syndrome/Chronic Myeloproliferative Disorder (MDS/MPD). Cytogenetics were positive for U2AF1 positive, CSF3R T6181, CSF3R Q776 pathognomonicof atypical CML and negative for BCR-ABL, FLT3. He was considered transplant ineligible. He was started on Azacitadine and is currently receiving 2nd cycle therapy. He is also receiving darbepoeitin periodically to avoid frequent transfusions. He is currently transfusion independent. Discussion: Increased WBC count (e.g., cutoffs of >40×109/L or 50×109/L), increased percentage of peripheral blood myeloid precursors, female sex, and older age are adverse prognostic factors for overall survival or leukemia-free survival in aCML. aCML cases lack in Philadelphia chromosome. Overall 50-65% of patients show cytogenetic abnormalities. The most frequent is +8 (25%). Other changes such as -7 and del(12p) have also been recurrently observed. Patients with aCML have an estimated median survival between 14 and 30 months. aCML tends to exhibit a more aggressive clinical course than other MDS/MPN subtypes. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Atypical Chronic Myeloid Leukemia: Where Are We Now?

2020 ◽  
Vol 21 (18) ◽  
pp. 6862
Author(s):  
Elena Crisà ◽  
Maura Nicolosi ◽  
Valentina Ferri ◽  
Chiara Favini ◽  
Gianluca Gaidano ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Treatment Options ◽  
Myeloproliferative Neoplasm ◽  
High Rate ◽  
Molecular Profile ◽  
Poor Survival ◽  
Myeloid Neoplasms ◽  
Atypical Chronic Myeloid Leukemia ◽  
Generation Sequencing

Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia, and poor survival. Until now, the diagnosis has been based on morphological grounds only, possibly making the real frequency of the disease underestimated. Only recently, new insights in the molecular biology of MDS/MPN syndromes have deepened our knowledge of aCML, enabling us to have a better molecular profile of the disease. The knowledge gleaned from next generation sequencing has complemented morphologic and laboratory WHO criteria for myeloid neoplasms and can provide greater specificity in distinguishing aCML from alternative MDS/MPN or MPNs. The most commonly mutated genes (>20%) in aCML are SETBP1, ASXL1, N/K-RAS, SRSF2, and TET2, and less frequently (< 10%) CBL, CSFR3, JAK2, EZH2, and ETNK1. Several of these mutations affect the JAK-STAT, MAPK, and ROCK signaling pathways, which are targetable by inhibitors that are already in clinical use and may lead to a personalized treatment of aCML patients unfit for allogeneic transplant, which is currently the only curative option for fit patients. In this review, we present two emblematic clinical cases and address the new molecular findings in aCML and the available treatment options.

scholarly journals ENOX2 NADH Oxidase: A BCR-ABL1-dependent cell surface and secreted redox protein in chronic myeloid leukemia (CML)

2021 ◽  
Author(s):  
Seda Baykal-Köse ◽  
Maud Voldoire ◽  
Christophe Desterke ◽  
Nathalie Sorel ◽  
Emilie Cayssials ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Mrna Expression ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasm ◽  
Chronic Phase ◽  
Dependent Manner ◽  
Western Blots ◽  
Hematopoietic Stem ◽  
Redox Protein

AbstractChronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the acquisition of BCR-ABL1 fusion in a hematopoietic stem cell. We identified the ENOX2 gene as up-regulated in BCR-ABL1-expressing UT-7 cell lines through a transcriptome assay. The oncofoetal ENOX2 protein (Ecto-Nicotinamide Adenine Dinucleotide Oxidase Disulfide Thiol Exchanger 2) is expressed on the external plasma membrane surface of cancer cells and can be released in cancer patients’ serum. Considering these data, we studied ENOX2 expression in CML cell lines and patients using quantitative RT-PCR, western-blots, the ELISA method, and transcriptomic dataset reanalysis. We confirmed increased ENOX2 mRNA expression in the BCR-ABL1-expressing UT-7 cell line. Comparable results were obtained in CML patients at diagnosis. Western-blot analyses on UT-7 and TET-inducible Ba/F3 cell lines established the up-regulation of ENOX2 protein. BCR-ABL1 has been found to induce ENOX2 overexpression in a kinase-dependent manner. In a series of 41 patients with CML, ELISA assays showed a highly significant increase of ENOX2 protein levels in the plasma of patients with CML (p < 0.0001) as compared to controls (n=28). Transcriptomic dataset (GSE4170) reanalyzes have shown specific ENOX2 mRNA overexpression in the chronic phase of the disease. Bioinformatic analyses identified several genes whose mRNA expression was positively correlated to ENOX2. Some of them encode proteins involved in cellular functions compatible with the growth deregulation observed in CML. All in all, our results demonstrate for the first time the upregulation of a secreted Redox protein in a BCR-ABL1-dependent manner in CML. Our data suggest that ENOX2 (through its transcriptional program) plays a significant role in the BCR-ABL1 leukemogenesis. Further studies are required to clarify the relationship between BCR-ABL1 and ENOX2.

Current Therapies for Chronic Myeloid Leukemia

2008 ◽  
Vol 21 (2) ◽  
pp. 116-125
Author(s):  
Laureen K. Kenealy ◽  
Courtney B. Christenson ◽  
Casey B. Williams
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Management Strategies ◽  
Treatment Strategies ◽  
Chronic Phase ◽  
Initial Therapy ◽  
Molecular Monitoring ◽  
Hematopoietic Stem ◽  
Current Therapies

Management strategies for patients with chronic-phase chronic myeloid leukemia (CML) have changed dramatically since the introduction of imatinib into clinical trials in 1998. Imatinib is generally accepted, at present, to be the most appropriate initial therapy for newly diagnosed chronic-phase CML; however, a proportion of patients will not respond adequately. Many of these patients may benefit from alternative treatment strategies, including second- and third-generation BCR-ABL kinase inhibitors and allogeneic hematopoietic stem cell transplantation (HSCT). Additionally, with continued improvements in molecular monitoring, it is much more clinically routine to measure ongoing treatment efficacy or characterize pending disease relapse via molecular analysis. The challenge is to now combine molecular monitoring information with timely treatment decisions to achieve the best possible outcomes. Additionally, unanswered questions about HSCT remain, and include (1) What is the role of allogeneic HSCT in CML? (2) What type of transplant, reduced-intensity or myeloablative, should be performed? The goal of this article is to provide an overview of where we stand in the treatment of CML in 2008.

scholarly journals Therapeutic targeting of FLT3 and associated drug resistance in acute myeloid leukemia

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Melat T. Gebru ◽  
Hong-Gang Wang
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Gene Mutations ◽  
Standard Of Care ◽  
Cell Transplant ◽  
Current Standard ◽  
Hematopoietic Stem ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is a heterogeneous disease caused by several gene mutations and cytogenetic abnormalities affecting differentiation and proliferation of myeloid lineage cells. FLT3 is a receptor tyrosine kinase commonly overexpressed or mutated, and its mutations are associated with poor prognosis in AML. Although aggressive chemotherapy often followed by hematopoietic stem cell transplant is the current standard of care, the recent approval of FLT3-targeted drugs is revolutionizing AML treatment that had remained unchanged since the 1970s. However, despite the dramatic clinical response to targeted agents, such as FLT3 inhibitors, remission is almost invariably short-lived and ensued by relapse and drug resistance. Hence, there is an urgent need to understand the molecular mechanisms driving drug resistance in order to prevent relapse. In this review, we discuss FLT3 as a target and highlight current understanding of FLT3 inhibitor resistance.

A Rare Case of Chronic Myeloid Leukemia with t(3;9;22) 3-way Translocation

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S147-S147
Author(s):  
S Elzamly ◽  
O Padilla ◽  
M McAlice ◽  
M Gohar ◽  
S Gaur ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Myeloproliferative Neoplasm ◽  
Molecular Response ◽  
Hematopoietic Stem

Abstract Introduction/Objective Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm originating from malignant clonal proliferation of a pluripotent hematopoietic stem cell. CML is characterized by a reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11), that gives rise to an abnormal chromosome 22 called the Philadelphia (Ph) chromosome. The translocation results in the formation of a chimeric BCR-ABL1 fusion gene, which is the molecular hallmark of the disease. However, 5-10% of CML patients present with additional chromosomal abnormalities which is often considered a sign of clonal evolution, genetic instability, and is generally thought to portend a poor prognosis. Methods We present a case of CML with a rare 3- way translocation, t(3;9;22)(q21;q34;q11.2), who achieved a major molecular response on imatinib for 18 months. A review of the literature and Mitelman database search is presented focusing on the prognostic implications of this 3 way translocation in the era of tyrosine kinase inhibitors starting in 2001 till now. Results Twenty seven cases were reported, but the patient therapeutic response to imatinib and clinical outcome were only reported in 11 cases. Nine cases achieved a cytogenetic remission while the remaining two cases had an adverse outcome. Conclusion Taken in conjunction with the favorable outcome in our patient, we suggest that t(3;9;22) is not an adverse prognostic factor in the era of tyrosine kinase inhibitors.

scholarly journals Atypical Chronic Myeloid Leukemia: New Developments from Molecular Diagnosis to Treatment

Medicina ◽  
2021 ◽  
Vol 57 (10) ◽  
pp. 1104
Author(s):  
Alessia Castellino ◽  
Elisa Santambrogio ◽  
Davide Rapezzi ◽  
Massimo Massaia
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Presentation ◽  
Disease Incidence ◽  
High Rate ◽  
Small Samples ◽  
New Developments ◽  
Atypical Chronic Myeloid Leukemia ◽  
Few Data ◽  
Generation Sequencing

Atypical Chronic Myeloid Leukemia, BCR-ABL1 negative (aCML) is a rare hematological entity, included in the group of myelodysplastic (MDS)/myeloproliferative (MPN) overlap syndromes. It is characterized by an aggressive course, a high rate of acute myeloid leukemia (AML) transformation, and a dismal outcome. The clinical presentation includes splenomegaly and leukocytosis with neutrophilia and left-shifted granulocytosis accompanied by granulocytic dysplasia and sometimes multilineage dysplasia. In past years, the disease incidence was likely underestimated, as diagnosis was only based on morphological features. Recently, the improving knowledge in the molecular biology of MDS/MPN neoplasms has made it possible to distinguish aCML from other overlapping syndromes, basing on next generation sequencing. Among the most commonly mutated genes, several involve the Jak-STAT, MAPK, and ROCK signaling pathways, which could be actionable with targeted therapies that are already used in clinical practice, opening the way to tailored treatment in aCML. However, currently, there are few data available for small samples, and allogeneic transplant remains the only curative option for eligible patients.

Nilotinib Therapy in Patients with Chronic Myeloid Leukemia Who Have Failed Imatinib

2009 ◽  
Vol 02 ◽  
pp. 30
Author(s):  
Ronan Swords ◽  
Kevin Kelly ◽  
Francis J Giles ◽  
◽  
◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Point Mutations ◽  
Standard Of Care ◽  
Kinase Domain ◽  
Current Standard ◽  
Imatinib Resistance ◽  
Prior Therapy ◽  
Advanced Phase ◽  
Failure Point

Chronic myeloid leukemia (CML) results from a single translocation that produces the BCR–ABL fusion oncogene, which is detectable in virtually all patients. Imatinib mesylate has radically changed the outlook for newly diagnosed patients and represents the current standard of care for this disorder. While most patients do well well with imatinib upfront, a minority of patients do not. In addition, this therapy offers little benefit for patients with advanced-phase disease. Several mechanisms underlie imatinib failure, point mutations within the Abelson tyrosine (ABL) kinase domain being the most significant of these. The development of novel agents designed to overcome imatinib resistance led to the creation of the high-affinity BCR-ABL inhibitor nilotinib. The purpose of this article is to summarize the pre-clinical and clinical data on nilotinib in patients with CML who have failed prior therapy with imatinib or dasatinib.

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