Tumor protein p53 (TP53) is the most frequently mutated gene in cancer
. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease
, rapid transformation ...to acute myeloid leukemia (AML)
, resistance to conventional therapies
and dismal outcomes
. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations
. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R)
. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.
Decitabine produced responses in patients with acute myeloid leukemia or myelodysplastic syndromes who had cytogenetic abnormalities associated with a poor prognosis, including 21 of 21 patients with ...tumors that contained
TP53
mutations.
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are clonal disorders of myeloid hematopoiesis.
1
Adult patients with AML who have karyotypes that are associated with unfavorable risk and older patients with AML (≥60 years of age) have poor outcomes, with a median survival of approximately 1 year.
2
,
3
Patients with AML and
TP53
mutations tend to be older (median age, 61 to 67 years), and almost all have karyotypes that are associated with unfavorable risk; if they receive standard cytotoxic chemotherapy, these patients have especially poor outcomes (median survival, 4 to 6 months).
3
–
6
Decitabine (5-aza-2′-deoxycytidine) is commonly used as . . .
Myelodysplastic syndromes (MDS) arise in older adults through stepwise acquisitions of multiple somatic mutations. Here, analyzing 1809 MDS patients, we infer clonal architecture by using a ...stringent, the single-cell sequencing validated PyClone bioanalytic pipeline, and assess the position of the mutations within the clonal architecture. All 3,971 mutations are grouped based on their rank in the deduced clonal hierarchy (dominant and secondary). We evaluated how they affect the resultant morphology, progression, survival and response to therapies. Mutations of SF3B1, U2AF1, and TP53 are more likely to be dominant, those of ASXL1, CBL, and KRAS are secondary. Among distinct combinations of dominant/secondary mutations we identified 37 significant relationships, of which 12 affect clinical phenotypes, 5 cooperatively associate with poor prognosis. They also predict response to hypomethylating therapies. The clonal hierarchy has distinct ranking and the resultant invariant combinations of dominant/secondary mutations yield novel insights into the specific clinical phenotype of MDS.
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.
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.
Acute myeloid leukemia with myelodysplasia‐related changes (AML‐MRC) is a heterogeneous disorder defined by multilineage dysplasia, myelodysplastic syndrome (MDS)‐related karyotype, or history of ...prior MDS. We evaluated 415 patients with AML‐MRC treated from 2013 to 2018 and analyzed their clinical outcomes based on the diagnostic criteria of AML‐MRC, therapy type and mutation profile. Criteria for AML‐MRC included: cytogenetic abnormalities (AML‐MRC‐C) in 243 (59%), prior history of MDS in 75 (18%) including 47 (11%) with previously untreated MDS (AML‐MRC‐H) and 28 (7%) with previously treated MDS (AML‐MRC‐TS), and 97 (23%) with multilineage dysplasia (AML‐MRC‐M). Median age was 70 years (range 18‐94). Among 95 evaluable patients, a total of 37 (39%) had secondary‐type (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) mutations. Mutations in ASXL1, BCOR, SF3B1, SRSF2, and U2AF1 tended to appear in dominant clones. By multivariate analysis, AML‐MRC subtype, age and serum LDH levels were independent predictors of outcome, with patients with AML‐MRC‐M (HR 0.56, CI 0.38‐0.84, P = .004) and AML‐MRC‐H having better OS. Compared to a cohort of 468 patients with AML without MRC, patients with AML‐MRC‐M/AML‐MRC‐H had similar outcomes to those with intermediate risk AML by European LeukemiaNet criteria. Intensive therapy was associated with improved OS in patients with AML‐MRC‐M (HR 0.42, CI 0.19‐0.94, P = .036) and with improved EFS in AML‐MRC‐M and AML‐MRC‐H (HR 0.26, CI 0.10‐0.63, P = .003). This data suggests that not all diagnostic criteria for AML‐MRC define high‐risk patients and that specific subgroups may benefit from different therapeutic interventions.
Prognostic systems for myelodysplasia rely on clinical factors, but particular genetic lesions can influence relapse rate, overall survival, and nonrelapse-related mortality as well as the choice of ...conditioning regimen for hematopoietic stem-cell transplantation.
The myelodysplastic syndrome (MDS) is clinically and biologically heterogeneous. In children and young adults, MDS can arise in the context of congenital mutations that cause bone marrow failure syndromes or inherited predisposition to myeloid cancers.
1
Therapy-related MDS develops as a late complication in patients with previous exposure to chemotherapy, radiation therapy, or both.
2
In most patients, however, primary MDS arises in the absence of an identified exposure, prodromal bone marrow failure syndrome, or inherited predisposition.
Although allogeneic hematopoietic stem-cell transplantation is the only curative therapy for MDS, mortality after transplantation is high, with deaths attributable to relapsed disease and to . . .
Established prognostic tools in patients with myelodysplastic syndromes (MDS) were largely derived from untreated patient cohorts. Although azanucleosides are standard therapies for higher-risk ...(HR)-MDS, the relative prognostic performance of existing prognostic tools among patients with HR-MDS receiving azanucleoside therapy is unknown. In the MDS Clinical Research Consortium database, we compared the prognostic utility of the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), MD Anderson Prognostic Scoring System (MDAPSS), World Health Organization-based Prognostic Scoring System (WPSS) and the French Prognostic Scoring System (FPSS) among 632 patients who presented with HR-MDS and were treated with azanucleosides as the first-line therapy. Median follow-up from diagnosis was 15.7 months. No prognostic tool predicted the probability of achieving an objective response. Nonetheless, all five tools were associated with overall survival (OS, P=0.025 for the IPSS, P=0.011 for WPSS and P<0.001 for the other three tools). The corrected Akaike Information Criteria, which were used to compare OS with the different prognostic scoring systems as covariates (lower is better) were 4138 (MDAPSS), 4156 (FPSS), 4196 (IPSS-R), 4186 (WPSS) and 4196 (IPSS). Patients in the highest-risk groups of the prognostic tools had a median OS from diagnosis of 11-16 months and should be considered for up-front transplantation or experimental approaches.
HighlightsActivation of NF-κB signaling in mesenchymal cells is common in LR-MDS.Activation of NF-κB in mesenchymal cells leads to transcriptional overexpression of inflammatory factors including ...negative regulators of hematopoiesis.Activation of NF-κB attenuates HSPC numbers and function ex vivo.
Myelodysplastic syndromes (MDS) encompass a heterogeneous set of acquired bone marrow neoplastic disorders characterized by ineffective hematopoiesis within one or more bone marrow lineages. Nearly ...half of MDS patients carry cytogenetic alterations, with del(5q) being the most prevalent. Since its first description, del(5q) was consistently correlated with a typical clinical phenotype marked by anemia, thrombocytosis, and a low risk of evolving into acute leukemia. Presently, the World Health Organization (WHO) classification of myeloid neoplasms recognizes a specific subtype of MDS known as “myelodysplastic neoplasm with low blast and isolated del(5q)” identified by the sole presence of 5q deletion or in combination with one other abnormality excluding −7/del(7q). Several studies have sought to unravel the biological processes triggered by del(5q) in the development of MDS, revealing the involvement of various genes localized in specific regions of chromosome 5 referred to as common deleted regions (CDR). This intricate biological landscape makes the MDS cells with del(5q) exceptionally sensitive to lenalidomide. Several studies have confirmed the efficacy of lenalidomide in this context. Regrettably, the response to lenalidomide is not conclusive, prompting ongoing research into biological mechanisms that drive patients toward leukemia and strategies to circumvent lenalidomide resistance and disease progression.
PDF
