Disease overview
The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute ...myelogenous leukemia (AML). MDS occurs more frequently in older males and in individuals with prior exposure to cytotoxic therapy.
Diagnosis
Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry, and molecular genetics is usually complementary and may help refine diagnosis. A new WHO classification of MDS was proposed in 2022. Under this classification, MDS is now termed myelodysplastic neoplasms.
Risk‐stratification
Prognosis of patients with MDS can be calculated using a number of scoring systems. All these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow, and cytogenetic characteristics. The most commonly accepted system is the Revised International Prognostic Scoring System (IPSS‐R). Recently, genomic data has been incorporated resulting in the new IPSS‐M classification.
Risk‐adapted therapy
Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts, cytogenetic and mutational profiles, comorbidities, potential for allogeneic stem cell transplantation (alloSCT), and prior exposure to hypomethylating agents (HMA). Goals of therapy are different in lower risk patients than in higher risk and in those with HMA failure. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or AML, as well as to improve survival. In higher risk, the goal is to prolong survival. In 2020, two agents were approved in the US for patients with MDS: luspatercept and oral decitabine/cedazuridine. In addition, currently other available therapies include growth factors, lenalidomide, HMAs, intensive chemotherapy, and alloSCT. A number of phase 3 combinations studies have been completed or are ongoing at the time of this report. At the present time there are no approved interventions for patients with progressive or refractory disease particularly after HMA based therapy. In 2021, several reports indicated improved outcomes with alloSCT in MDS as well as early results from clinical trials using targeted intervention.
Disease overview
The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute ...myelogenous leukemia (AML). MDS occurs more frequently in older males and in individuals with prior exposure to cytotoxic therapy.
Diagnosis
Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry or molecular genetics is usually complementary and may help refine diagnosis.
Risk‐stratification
Prognosis of patients with MDS can be calculated using a number of scoring systems. In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow and cytogenetic characteristics. The most commonly used system is probably the International Prognostic Scoring System (IPSS). IPSS is now replaced by the revised IPSS‐R score. Although not systematically incorporated into new validated prognostic systems, somatic mutations can help define prognosis and should be considered as new prognostic factors.
Risk‐adapted therapy
Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts and cytogenetic and mutational profiles. Goals of therapy are different in lower risk patients than in higher risk. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or AML, as well as to improve survival. In higher risk, the goal is to prolong survival. Current available therapies include growth factor support, lenalidomide, hypomethylating agents, intensive chemotherapy and allogeneic stem cell transplantation. The use of lenalidomide has significant clinical activity in patients with lower risk disease, anemia and a chromosome 5 alteration. 5‐azacitidine and decitabine have activity in both lower and higher‐risk MDS. 5‐azacitidine has been shown to improve survival in higher risk MDS. A number of new molecular lesions have been described in MDS that may serve as new therapeutic targets or aid in the selection of currently available agents. Additional supportive care measures may include the use of prophylactic antibiotics and iron chelation.
Management of progressive or refractory disease
At the present time there are no approved interventions for patients with progressive or refractory disease particularly after hypomethylating based therapy. Options include participation in a clinical trial or cytarabine based therapy and stem cell transplantation.
Disease overview
The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute ...myelogenous leukemia (AML). Myelodysplastic syndromes occur more frequently in older males and in individuals with prior exposure to cytotoxic therapy.
Diagnosis
Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry and molecular genetics is usually complementary and may help refine diagnosis.
Risk‐stratification
Prognosis of patients with MDS can be calculated using a number of scoring systems. In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow and cytogenetic characteristics. The most commonly accepted system is the Revised International Prognostic Scoring System (IPSS‐R). Somatic mutations can help define prognosis and therapy.
Risk‐adapted therapy
Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts, cytogenetic and mutational profiles, comorbidities, potential for allogeneic stem cell transplantation (alloSCT) and prior exposure to hypomethylating agents (HMA). Goals of therapy are different in lower‐risk patients than in higher‐risk individuals and in those with HMA failure. In lower‐risk MDS, the goal is to decrease transfusion needs and transformation to higher risk disease or AML, as well as to improve survival. In higher‐risk disease, the goal is to prolong survival. In 2020, we witnessed an explosion of new agents and investigational approaches. Current available therapies include growth factor support, lenalidomide, HMAs, intensive chemotherapy and alloSCT. Novel therapeutics approved in 2020 are luspatercept and the oral HMA ASTX727. At the present time, there are no approved interventions for patients with progressive or refractory disease particularly after HMA‐based therapy. Options include participation in a clinical trial, cytarabine‐based therapy or alloSCT.
Background
The impact of the allelic burden of ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations on survival remains unclear in patients with newly diagnosed acute myeloid leukemia (AML).
Methods
The ...authors assessed bone marrow aspirates from 421 patients with newly diagnosed AML using next‐generation sequencing for ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations, defined as the presence of mutations in ASXL1, DNMT3A, JAK2, TET2, or TP53 with a minimum variant allele frequency (VAF) of 5%.
Results
A total of 71 patients (17%) had ASXL1 mutations, 104 patients (25%) had DNMT3A mutations, 16 patients (4%) had JAK2 mutations, 82 patients (20%) had TET2 mutations, and 86 patients (20%) had TP53 mutations. Among patients with each mutation, the median VAF of ASXL1 was 34.31% (range, 1.17%‐58.62%), the median VAF of DNMT3A was 41.76% (range, 1.02%‐91.66%), the median VAF of JAK2 was 46.70% (range, 10.4%‐71.7%), the median VAF of TET2 was 42.78% (range, 2.26%‐95.32%), and the median VAF of TP53 was 45.47% (range, 1.15%‐93.74%). The composite complete response rate was 60%, and was 77% in patients with AML with and without ASXL1, DNMT3A, JAK2, TET2, or TP53 mutations, respectively (P = .006); the median overall survival was 11 months and 27 months, respectively (P < .001). Multivariate analysis identified age; an antecedent history of dysplasia; white blood cell count; adverse cytogenetic risk; previous treatment with an FLT3 inhibitor; and the VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations by next‐generation sequencing as prognostic factors for overall survival.
Conclusions
The VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations is associated with worse prognosis in patients with newly diagnosed AML.
Prognostic factors for the overall survival of patients with newly diagnosed acute myeloid leukemia (AML) include age; an antecedent history of dysplasia; white blood cell count; adverse cytogenetic risk; previous treatment with an FLT3 inhibitor; and the variant allele frequencies (VAFs) of genetic mutations in ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1. Incorporation of mutation VAFs from these genes may improve risk stratification for patients with AML.
Background
Phenotypic characterization of immune cells in the bone marrow (BM) of patients with acute myeloid leukemia (AML) is lacking.
Methods
T‐cell infiltration was quantified on BM biopsies from ...13 patients with AML, and flow cytometry was performed on BM aspirates (BMAs) from 107 patients with AML who received treatment at The University of Texas MD Anderson Cancer Center. The authors evaluated the expression of inhibitory receptors (programmed cell death protein 1 PD1, cytotoxic T‐lymphocyte antigen 4 CTLA4, lymphocyte‐activation gene 3 LAG3, T‐cell immunoglobulin and mucin‐domain containing‐3 TIM3) and stimulatory receptors (glucocorticoid‐induced tumor necrosis factor receptor‐related protein GITR, OX40, 41BB a type 2 transmembrane glycoprotein receptor, inducible T‐cell costimulatory ICOS) on T‐cell subsets and the expression of their ligands (41BBL, B7‐1, B7‐2, ICOSL, PD‐L1, PD‐L2, and OX40L) on AML blasts. Expression of these markers was correlated with patient age, karyotype, baseline next‐generation sequencing for 28 myeloid‐associated genes (including P53), and DNA methylation proteins (DNA methyltransferase 3α, isocitrate dehydrogenase 1IDH1, IDH2, Tet methylcytosine dioxygenase 2 TET2, and Fms‐related tyrosine kinase 3 FLT3).
Results
On histochemistry evaluation, the T‐cell population in BM appeared to be preserved in patients who had AML compared with healthy donors. The proportion of T‐regulatory cells (Tregs) in BMAs was higher in patients with AML than in healthy donors. PD1‐positive/OX40‐positive T cells were more frequent in AML BMAs, and a higher frequency of PD1‐positive/cluster of differentiation 8 (CD8)‐positive T cells coexpressed TIM3 or LAG3. PD1‐positive/CD8‐positive T cells were more frequent in BMAs from patients who had multiply relapsed AML than in BMAs from those who had first relapsed or newly diagnosed AML. Blasts in BMAs from patients who had TP53‐mutated AML were more frequently positive for PD‐L1.
Conclusions
The preserved T‐cell population, the increased frequency of regulatory T cells, and the expression of targetable immune receptors in AML BMAs suggest a role for T‐cell–harnessing therapies in AML.
T‐cell subsets are preserved in the bone marrow of patients with acute myeloid leukemia. The expression of targetable immune checkpoints by T cells suggests that therapies harnessing T cells may benefit these patients.
Time to blur the blast boundaries DiNardo, Courtney D.; Garcia‐Manero, Guillermo; Kantarjian, Hagop M.
Cancer,
April 15, 2022, Letnik:
128, Številka:
8
Journal Article
Recenzirano
A fixed 20% blast percentage to discriminate myelodysplastic neoplasms from acute myeloid leukemia is arbitrary and overly simplistic. Key factors for identifying the optimal therapy for a patient ...with a myeloid malignancy should rely most on the patient's characteristics (particularly age and fitness/frailty) and disease cytogenetic and mutational profile, with less reliance on the bone marrow blast percentage.
Despite evidence of chronic inflammation in myelodysplastic syndrome (MDS) and cell-intrinsic dysregulation of Toll-like receptor (TLR) signaling in MDS hematopoietic stem and progenitor cells ...(HSPCs), the mechanisms responsible for the competitive advantage of MDS HSPCs in an inflammatory milieu over normal HSPCs remain poorly defined. Here, we found that chronic inflammation was a determinant for the competitive advantage of MDS HSPCs and for disease progression. The cell-intrinsic response of MDS HSPCs, which involves signaling through the noncanonical NF-κB pathway, protected these cells from chronic inflammation as compared to normal HSPCs. In response to inflammation, MDS HSPCs switched from canonical to noncanonical NF-κB signaling, a process that was dependent on TLR-TRAF6-mediated activation of A20. The competitive advantage of TLR-TRAF6-primed HSPCs could be restored by deletion of A20 or inhibition of the noncanonical NF-κB pathway. These findings uncover the mechanistic basis for the clonal dominance of MDS HSPCs and indicate that interfering with noncanonical NF-κB signaling could prevent MDS progression.