Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative overlap neoplasm characterized by sustained peripheral blood monocytosis and an inherent risk for ...transformation to acute myeloid leukemia (AML; 15-30% over 3-5 years). While CMML is morphologically classified in CMML-0,1 and 2 based on peripheral blood and bone marrow promonocyte/blast counts, a more clinically relevant classification into dysplastic (dCMML) and proliferative (pCMML) subtypes, based on the presenting white blood cell count is helpful in prognostication and therapeutics. CMML is a neoplasm associated with aging, occurring on the background of clonal hematopoiesis, with TET2 and SRSF2 mutations being early initiating events. The subsequent acquisitions of ASXL1, RUNX1, SF3B1 and DNMT3A mutations usually give rise to dCMML, while ASXL1, JAK2V617F and RAS pathway mutations give rise to pCMML. Patients with pCMML have a more aggressive course with higher rates of AML transformation. Allogeneic stem cell transplant remains the only potential cure for CMML, however, given the advanced median age at presentation (73 years) and comorbidities, is an option to only a few affected patients (10%). While DNA methyltransferase inhibitors are approved for the management of CMML, the overall response rates are 40-50%, with true complete remission rates of.
Disease overview
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an ...inherent risk for leukemic transformation (~15% over 3‐5 years).
Diagnosis
Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 109/L; monocytes ≥10%), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ~ 30% of patients, while >90% have gene mutations. Mutations involving TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%) and the oncogenic RAS pathway (~30%) are frequent; while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact over‐all survival.
Risk stratification
Molecularly integrated prognostic models include; the Groupe Français des Myélodysplasies (GFM), Mayo Molecular Model (MMM) and the CMML specific prognostic model (CPSS‐Mol). Risk factors incorporated into the MMM include presence of nonsense or frameshift ASXL1 mutations, absolute monocyte count>10 × 109/L, hemoglobin <10 g/dL, platelet count <100 × 109/L and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into four groups; high (≥3 risk factors), intermediate‐2 (2 risk factors), intermediate‐1 (1 risk factor) and low (no risk factors), with median survivals of 16, 31, 59 and 97 months, respectively.
Risk‐adapted therapy
Hypomethylating agents such as 5‐azacitidine and decitabine are commonly used, with overall response rates of ~40%‐50% and complete remission rates of ~7%‐17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option, but is associated with significant morbidity and mortality.
Activating mutations in FMS-like tyrosine kinase 3 (FLT3), including internal tandem duplications (ITDs) and tyrosine kinase domain (TKD) mutations, are common in patients with acute myeloid leukemia ...(AML). FLT3-ITD is a negative prognostic factor that remains prognostically relevant even after intensive chemotherapy and/or stem cell transplant. FLT3 testing was historically viewed as being purely prognostic; however, with the advent of FLT3 inhibitors, it will likely be seen as both prognostic and predictive. The multikinase inhibitor midostaurin, in combination with chemotherapy, is the first targeted agent to significantly prolong survival in patients with newly diagnosed FLT3-mutated AML and was recently approved by health authorities. Recently, the European LeukemiaNet recommended FLT3 testing (both TKD and ITD) for all patients with AML, with results required within 3 days. The need for optimized, multigene platform testing incorporating FLT3 mutations will increase as knowledge of interactions between FLT3 and other myeloid-relevant mutations grows.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Disease overview
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an ...inherent risk for leukemic transformation (∼15%‐20% over 3‐5 years).
Diagnosis
Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 109/L; monocytes ≥10%), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ∼ 30% of patients, while >90% have gene mutations. Mutations involving TET2 (∼60%), SRSF2 (∼50%), ASXL1 (∼40%) and the oncogenic RAS pathway (∼30%) are frequent; while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact over‐all survival.
Risk stratification
Molecularly integrated prognostic models include; the Groupe Français des Myélodysplasies (GFM), Mayo Molecular Model (MMM), and the CMML specific prognostic model (CPSS‐Mol). Risk factors incorporated into the MMM include presence of nonsense or frameshift ASXL1 mutations, absolute monocyte count > 10 × 109/L, hemoglobin <10 gm/dL, platelet count <100 × 109/L and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into 4 groups; high (≥3 risk factors), intermediate‐2 (2 risk factors), intermediate‐1 (1 risk factor), and low (no risk factors), with median survivals of 16, 31, 59, and 97 months, respectively.
Risk‐adapted therapy
Hypomethylating agents such as 5‐azacitidine and decitabine are commonly used, with overall response rates of ∼30%‐40% and complete remission rates of ∼7%‐17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option, but is associated with significant morbidity and mortality.
Telomeres shorten by approximately 50–200 base pairs with each division and when they reach a critically short length, termed as the Hayflick limit, a telomeric crisis occurs in the cell, triggering ...senescence and apoptosis.1 A key regulator of telomere length is the telomerase holoenzyme, a ribonucleoprotein complex consisting of an enzymatic core (TERT–TERC) and the H/ACA domain (evolutionarily conserved family of non-coding RNA that serve as guides for site-specific pseudouridylation of ribosomal and spliceosomal RNA).2 Neoplastic cells circumvent replicative senescence and apoptosis by increasing their telomerase activity, or by lengthening telomere length with alternative mechanisms.3,4 The fact that hTERT is silenced in most somatic cells and is expressed transiently in haematopoietic stem and progenitor cells (HSPC) and activated lymphocytes makes hTERT an attractive oncological target5. Pre-clinical work had shown that in myelodysplastic syndromes, leukocytes had shorter telomere length and higher telomerase activity compared with controls.9 Given the previous signal for responses in patients with splicing gene mutations, the phase 1 myelodysplastic syndrome study was carried out at a lower dose (7·5 mg/kg every 4 weeks) in eight patients with myelodysplastic syndromes with ring sideroblasts (high concordance with SF3B1 mutations), with three (38%) of eight patients who were red blood cell transfusion dependent (RBC-TD) sustaining transfusion independence for a median of 28 weeks (range 9–37).10 All three responding patients were SF3B1 mutant, with no effect of therapy on mutant clones.10 The phase 2 study was conducted in patients with RBC-TD myelodysplastic syndromes graded as lower risk on the International Prognostic Scoring System (IPSS) who were erythropoiesis stimulating agent (ESA) refractory or ineligible, with responses being seen in 16 (42%) of the 38 patients with non-del(5q) myelodysplastic syndromes.11 For adverse events of grade 3 or higher in the total cohort of 57 patients, neutropenia occurred in 34 (60%) patients, anaemia occurred in 11 (19%) patients, and thrombocytopenia occurred in 31 (54%) patients. The IMerge study offers little information on the safety and efficacy of the drug in people of diverse ethnic origins globally and has no data on patients with telomere biology disorders who often develop myelodysplastic syndromes, for whom theoretically this drug could cause severe cytopenias.13 Reliable and practical biomarkers and patient selection criteria are much needed and, depending on the cost of the drug, one questions whether it would be feasible for patients to avoid getting hypomethylating agents or lenalidomide (not globally approved for use in myelodysplastic syndromes without del5q) in the real world before they access imetelstat.
Disease Overview
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an ...inherent risk for leukemic transformation (~15% over 3–5 years).
Diagnosis
Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 109/L; monocytes ≥10%), usually with accompanying bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ~30% of patients, while >90% have somatic gene mutations. Mutations involving TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%), and the oncogenic RAS pathway (~30%) are frequent, while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact overall survival.
Risk‐Stratification
Molecularly integrated prognostic models include the Groupe Français des Myélodysplasies, Mayo Molecular Model (MMM), and the CMML specific prognostic model. Risk factors incorporated into the MMM include presence of truncating ASXL1 mutations, absolute monocyte count >10 × 109/L, hemoglobin <10 g/dL, platelet count <100 × 109/L, and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into four groups: high (≥3 risk factors), intermediate‐2 (2 risk factors), intermediate‐1 (1 risk factor), and low (no risk factors), with median survivals of 16, 31, 59, and 97 months, respectively.
Risk‐adapted therapy
Hypomethylating agents such as 5‐azacitidine and decitabine are commonly used, with overall response rates of ~40%–50% and complete remission rates of ~7%–17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option but is associated with significant morbidity and mortality.
Disease Overview
Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include ...myelodysplastic syndromes with RS (MDS‐RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN‐RS‐T).
Diagnosis
MDS‐RS is a lower risk MDS, with single or multilineage dysplasia (MDS‐RS‐SLD/MLD), <5% bone marrow (BM) blasts, <1% peripheral blood blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN‐RS‐T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS‐RS‐SLD, along with a platelet count ≥450 × 109/L and large atypical megakaryocytes.
Mutations and Karyotype
Mutations in SF3B1 are seen in ≥80% of patients with MDS‐RS‐SLD and MDS/MPN‐RS‐T, and strongly correlate with the presence of BM RS; MDS/MPN‐RS‐T patients also demonstrate JAK2V617F (50%), DNMT3A, TET2 and ASXL1 mutations. Cytogenetic abnormalities are uncommon in both.
Risk Stratification
Most patients with MDS‐RS‐SLD are stratified into lower risk groups by the revised‐IPSS. Disease outcome in MDS/MPN‐RS‐T is better than that of MDS‐RS‐SLD, but worse than that of essential thrombocythemia (MPN). Both diseases are associated with a low risk of leukemic transformation.
Treatment
Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Luspatercept, a first‐in‐class erythroid maturation agent is now approved for the management of anemia in patients with MDS‐RS and MDS/MPN‐RS‐T. Aspirin therapy is reasonable in MDS/MPN‐RS‐T, especially in the presence of JAK2V617F, but the value of platelet‐lowering drugs remains to be defined.
Imatinib mesylate was the first tyrosine kinase inhibitor (TKI) approved for the management of chronic myeloid leukemia. Imatinib produces acceptable responses in approximately 60% of patients, with ...approximately 20% discontinuing therapy because of intolerance and approximately 20% developing drug resistance. The advent of newer TKIs, such as nilotinib, dasatinib, bosutinib, and ponatinib, has provided multiple options for patients. These agents are more potent, have unique adverse effect profiles, and are more likely to achieve relevant milestones, such as early molecular responses (3-6 months) and optimal molecular responses (12 months). The acquisition of BCR-ABL kinase domain mutations is also reportedly lower with these drugs. Thus far, none of the randomized phase III clinical trials have shown a clinically significant survival difference between frontline imatinib versus newer TKIs. Cost and safety issues with the newer TKIs, such as vascular disease with nilotinib and ponatinib and pulmonary hypertension with dasatinib, have dampened the enthusiasm of using these drugs as frontline options. While the utility of new TKIs in the setting of imatinib failure or intolerance is clear, their use as frontline agents should factor in the age of the patient, additional comorbidities, risk stratification (Sokal score), and cost. Combination therapies and newer agents with potential to eradicate quiescent chronic myeloid leukemia stem cells offers future hope.
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