Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct ...molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated. In this study, we characterized the immunological features of the malignant clone and alterations in the immune microenvironment in patients with TP53-mutant and wild-type MDS or sAML. Notably, PDL1 expression is significantly increased in hematopoietic stem cells of patients with TP53 mutations, which is associated with MYC upregulation and marked downregulation of MYC's negative regulator miR-34a, a p53 transcription target. Notably, patients with TP53 mutations display significantly reduced numbers of bone marrow-infiltrating OX40+ cytotoxic T cells and helper T cells, as well as decreased ICOS+ and 4-1BB+ natural killer cells. Further, highly immunosuppressive regulatory T cells (Tregs) (ie, ICOShigh/PD-1-) and myeloid-derived suppressor cells (PD-1low) are expanded in cases with TP53 mutations. Finally, a higher proportion of bone marrow-infiltrating ICOShigh/PD-1- Treg cells is a highly significant independent predictor of overall survival. We conclude that the microenvironment of TP53 mutant MDS and sAML has an immune-privileged, evasive phenotype that may be a primary driver of poor outcomes and submit that immunomodulatory therapeutic strategies may offer a benefit for this molecularly defined subpopulation.
Approximately 20% of patients with
-mutant myelodysplastic syndromes (MDS) achieve complete remission (CR) with hypomethylating agents. Eprenetapopt (APR-246) is a novel, first-in-class, small ...molecule that restores wild-type p53 functions in
-mutant cells.
This was a phase Ib/II study to determine the safety, recommended phase II dose, and efficacy of eprenetapopt administered in combination with azacitidine in patients with
-mutant MDS or acute myeloid leukemia (AML) with 20%-30% marrow blasts (ClinicalTrials.gov identifier: NCT03072043).
Fifty-five patients (40 MDS, 11 AML, and four MDS/myeloproliferative neoplasms) with at least one
mutation were treated. The overall response rate was 71% with 44% achieving CR. Of patients with MDS, 73% (n = 29) responded with 50% (n = 20) achieving CR and 58% (23/40) a cytogenetic response. The overall response rate and CR rate for patients with AML was 64% (n = 7) and 36% (n = 4), respectively. Patients with only
mutations by next-generation sequencing had higher rates of CR (69%
25%;
= .006). Responding patients had significant reductions in
variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission (variant allele frequency < 5%). Median overall survival was 10.8 months with significant improvement in responding versus nonresponding patients by landmark analysis (14.6
7.5 months;
= .0005). Overall, 19/55 (35%) patients underwent allogeneic hematopoietic stem-cell transplant, with a median overall survival of 14.7 months. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%).
Combination treatment with eprenetapopt and azacitidine is well-tolerated yielding high rates of clinical response and molecular remissions in patients with
-mutant MDS and oligoblastic AML.
The implementation of next-generation sequencing (NGS) has influenced diagnostic, prognostic, and therapeutic decisions in myeloid malignancies. However, the clinical relevance of serial molecular ...annotation in patients with myelodysplastic syndrome (MDS) undergoing active treatment is unknown. MDS or secondary acute myeloid leukemia (sAML) patients who had at least two NGS assessments were identified. Outcomes according to mutation clearance (NGS-) on serial assessment were investigated. Univariate and multivariate Cox regression models were used to evaluate the prognostic impact of NGS trajectory on overall survival (OS). A total of 157 patients (MDS n = 95; sAML n = 52; CMML n = 10) were identified, with 93% of patients receiving treatment between NGS assessments. Magnitude of VAF delta from baseline was significantly associated with quality of response to treatment. Patients achieving NGS- had significantly improved OS compared to patients with mutation persistence (median OS not reached vs. 18.5 months; P = 0.002), which was confirmed in multivariate analysis (HR,0.14; 95%CI = 0.03-0.56; P = 0.0064). Serial TP53 VAF evaluation predicts outcomes with TP53 clearance representing an independent covariate for superior OS (HR,0.22; 95%CI = 0.05-0.99; P = 0.048). Collectively, our study highlights the clinical value of serial NGS during treatment and warrants prospective validation of NGS negativity as a biomarker for treatment outcome.
In older patients with acute myeloid leukemia, the more frequent presence of biologically inherent therapy-resistant disease and increased comorbidities translate to poor overall survival and ...therapeutic challenges. Optimal front-line therapies for older patients with acute myeloid leukemia remain controversial. We retrospectively evaluated survival outcomes in 980 elderly (≥70 years) acute myeloid leukemia patients from a single institution between 1995 and 2016. Four treatment categories were compared: high-intensity (daunorubicin/cytarabine or equivalent), hypomethylating agent, low-intensity (low-dose cytarabine or similar without hypomethylating agents), and supportive care therapy (including hydroxyurea). At a median follow up of 20.5 months, the median overall survival for the entire cohort was 7.1 months. Multivariate analysis identified secondary acute myeloid leukemia, poor-risk cytogenetics, performance status, front-line therapy, age, white blood cell count, platelet count, and hemoglobin level at diagnosis as having an impact on survival. High-intensity therapy was used in 360 patients (36.7%), hypomethylating agent in 255 (26.0%), low-intensity therapy in 91 (9.3%), and supportive care in 274 (28.0%). Pairwise comparisons between hypomethylating agent therapy and the three other treatment groups demonstrated statistically significant superior median overall survival with hypomethylating agent 14.4 months)
high-intensity therapy 10.8 months, hazard ratio 1.35, 95% confidence interval (CI): 1.10-1.65;
=0.004, low-intensity therapy (5.9 months, hazard ratio 2.01, 95%CI: 1.53-2.62;
<0.0001), and supportive care (2.1 months, hazard ratio 2.94, 95%CI: 2.39-3.61;
<0.0001). Our results indicate a significant survival benefit with hypomethylating agents compared to high-intensity, low-intensity, or supportive care. Additionally, high-intensity chemotherapy resulted in superior overall outcomes compared to low-intensity therapy and supportive care. Results from this study highlight the need for novel therapeutic approaches besides utilization of intensive chemotherapy in this specific aged population.
Background
Thrombocytopenia in patients with myelofibrosis (MF) is prognostically detrimental and poses a therapeutic challenge. MF patients with thrombocytopenia are considered high‐risk by most ...prognostic models and their distinct phenotype has given rise to the emerging concept of cytopenic MF. Yet, the mechanisms underlying thrombocytopenia in MF are poorly understood.
Methods
This study aimed to highlight the genetic mechanisms driving low platelet counts in treatment‐naive MF patients, establish their phenotypic correlates, and assess prognostic factors specific to this group of patients.
Results
The authors found that most patients presenting with low platelets had a clear thrombocytopenia‐specific genetic abnormality involving a U2AF1 Q157 mutation, deletion 20q, molecular complexity (three or more mutations), or high‐risk karyotype. Etiologic clustering did not correlate with prognosis; however, thrombocytopenic patients were found to have unique prognostic variables including low serum albumin and mutations of SRSF2 and TP53. This led to the proposal of a prognostic model (SRSF2, albumin, TP53 score) that stratifies thrombocytopenic patients as low, intermediate, or high‐risk with corresponding median survivals of 93.5, 29.5, and 7.2 months, respectively.
Conclusions
This study demonstrates that thrombocytopenia in MF is driven by different genetic mechanisms and is not uniformly high‐risk. As novel agents with improved hematologic safety profiles enter the treatment landscape, thoughtful, risk‐adapted therapeutic decisions will be required for MF patients with thrombocytopenia.
Lay Summary
A significant minority of patients with myelofibrosis (MF) present with low platelets.
Historically, these patients have been viewed as having “high‐risk” disease, but this may not be uniformly true.
Our study shows that there are various different causes for low platelets in MF, some of which represent high‐risk disease whereas others do not.
Additionally, our study shows that genetic mutations affecting the genes SRSF2 and TP53 are uniquely problematic in this group, as is a low serum albumin level.
This study helps to risk‐stratify MF patients with thrombocytopenia, thereby providing more information to guide informed and individualized treatment decisions.
Cytopenic myelofibrosis (MF) is emerging as a distinct phenotypic entity that poses unique therapeutic challenges; however, little is known about the various causes of thrombocytopenia in MF and factors that influences prognosis in this subgroup. With the recent and upcoming approval of new, less myelosuppressive treatment options, it will be vital to understand how to risk stratify thrombocytopenic MF patients in an effort to individualize therapy.
Summary
Among 210 patients with myelodysplastic syndromes (MDSs) with del(5q), molecular information was available at diagnosis or at least 3 months before leukaemic transformation in 146 cases. ...Multivariate analysis identified therapy‐related setting (p = 0.02; HR 2.3) and TP53 variant allele frequency (VAF) ≥22% (p < 0.01; HR 2.8), but not SF3B1 mutation (p = 0.65), as independent risk factors for survival. Median survival was 11.7 versus 4 years (5/10‐year survival 73%/52% vs. 42%/14%) in the absence (N = 112) versus presence (N = 34) of ≥1 risk factors; leukaemia‐free survival was affected by TP53 VAF ≥22% (p < 0.01). Such information might inform treatment decision‐making in MDS‐del(5q) regarding allogeneic stem cell transplant.
•Treatment-naive and relapsed/refractory MDS patients receiving venetoclax and HMAs have an ORR of 59% with 63% of responders proceeding to transplant.•Allogeneic stem cell transplantation after ...treatment with venetoclax in combination with HMA is associated with prolonged survival.
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