TP53-mutated Acute Myeloid Leukemia Research Articles

The role of TP53 in acute myeloid leukemia: Challenges and opportunities.

The tumor suppressor gene TP53 is one of the most frequently mutated genes in human cancer. The central role of the TP53 protein in several fundamental processes such as cancer, aging, senescence, and DNA repair has ensured enormous attention. However, the role of TP53 in acute myeloid leukemia (AML) is enigmatic. Unlike many other human cancers, a vast majority of AMLs display no genomic TP53 alterations. There is now growing appreciation of the fact that the unaltered TP53 status of tumor cells can be exploited therapeutically. As most AMLs have an intact TP53 gene, its physiological tumor-suppressive roles could be harnessed. Therefore, the use of pharmacological activators of the TP53 pathway may provide clinical benefit in AML. Conversely, even though the frequency of TP53 mutations in AML is substantially lower than in other human cancers, TP53 mutations are associated with chemoresistance and high risk of relapse. In patients with TP53 mutations, these alterations may lead to novel, selective vulnerabilities, creating opportunities for therapeutic targeting of TP53 mutant AML. The mutational status of TP53 therefore poses challenges and opportunities in terms of advancing effective treatment strategies in AML. An increasing armamentarium of small-molecule activators of the TP53 pathway, and a growing understanding of molecular pathways triggered by mutant TP53 have accelerated efforts aimed at targeting TP53 function in AML. In combination with standard AML chemotherapy or emerging targeted therapies, pharmacological targeting of the TP53 pathway may provide therapeutic benefit in AML.

Patterns of leukemic transformation in patients with TP53-mutant myelodysplastic syndromes.

7054 Background: TP53 is the most frequently mutated gene in human cancers, including 7-13% of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. Although it is associated with transformation to AML in patients with MDS, the additional genomic events leading to transformation are poorly understood. Methods: We retrospectively evaluated 312 patients with TP53-mutated AML or MDS diagnosed between 2013-2016. Patient characteristics and bone marrow data, including cytogenetic and next generation sequencing information, were assessed at the time of diagnosis and progression to AML. Results: There were 151 TP53-mutated MDS patients and 161 TP53-mutated de novo AML patients with a median follow-up time of 34.1 months. Forty-one patients with TP53-mutated MDS transformed to AML. Sequencing data at transformation was available in 17 patients (41%). At diagnosis, median age was 67 with 2 patients with intermediate-risk, 7 patients with high-risk, and 32 patients with very high-risk MDS by IPSS-R. Complex karyotype was seen in 40 patients, and 12 patients had 1, 25 patients had 2, and 4 patients had 3 TP53 abnormalities. Predictors of transformation to AML include TP53 loss of heterozygosity (p = 0.008), 3 TP53 abnormalities (p = 0.049), complex cytogenetics (p = 0.023), and female gender (p = 0.002). Median time to transformation was 10.4 months. At transformation, an increase in TP53 variant allelic frequency was observed in 7 patients (41%), and new mutations, particularly NRAS, IDH1, TP53, MLL, KDM6A, TET2, and NOTCH1, were acquired by 10 patients (59%). Cytogenetic evaluation revealed identical clones in 5 patients, linear acquisition of cytogenetic abnormalities in 12 patients, and new clones in 8 patients. Patients with TP53-mutated AML from MDS also had worse median overall survival than patients with TP53-mutated de novo AML at 2.5 months vs. 5.7 months respectively (p < 0.001). Conclusions: TP53 mutations confer a worse prognosis, especially in the setting of AML transformed from MDS. This may be due to the acquisition of new mutations and cytogenetic abnormalities. Further exploration of the biological mechanisms leading to transformation in TP53-mutant MDS is warranted.

Activity of venetoclax-based therapy in TP53-mutated acute myeloid leukemia.

7034 Background: Mutations in TP53 are associated with low response rates to standard therapy and poor outcomes in patients (pts) with acute myeloid leukemia (AML). Combination therapy with the BCL2 inhibitor venetoclax (VEN) has emerged as an effective treatment option for pts with AML. Methods: We reviewed pts with TP53-mutated AML treated with VEN-based therapy between 2014-2018. Mutation testing was performed using a whole-exome next-generation sequencing panel. We analyzed the characteristics of these pts, responses to therapy, and outcomes. Results: Sixty nine pts with TP53-mutated AML treated with VEN were identified, 36 (52%) in frontline & 33 (48%) in the salvage (R/R) setting (Table). The median follow up was 4.5 [0.5 - 48.5] and 8 [1 - 46.5] months for frontline & R/R pts, respectively. Karyotype was complex in 32 (88%) and 29 (88%) pts in the frontline & R/R cohorts, respectively. In the R/R cohort, the number of median prior treatments was 2 [0 – 8]. VEN was given in combination with: 1) Hypomethylating agents (HMA) (87%), 2) FLAG-Ida (3%), 3) Low dose Ara-C (4%), or 4) CPX-351 (6%). The overall response rate (ORR) was 47% & 24% in frontline and R/R pts, respectively. All 6 pts with negative minimal residual disease (MRD) achieved complete cytogenetic response after taking VEN % remain in complete remission (CR) with a median of 3.4 [1.7-4.7] months. Two pts (both R/R) underwent allogeneic stem cell transplantation. Conclusions: VEN based therapy was associated with similar ORR, but higher CR rates in TP53 mutated AML compared with HMAs alone. Larger studies with longer follow up are needed to determine the role of VEN-based therapy in this difficult subset. Patient characteristics and outcome. [Table: see text]

The distribution of T‐cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia

BackgroundPhenotypic characterization of immune cells in the bone marrow (BM) of patients with acute myeloid leukemia (AML) is lacking.MethodsT‐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 1[IDH1], IDH2, Tet methylcytosine dioxygenase 2 [TET2], and Fms‐related tyrosine kinase 3 [FLT3]).ResultsOn 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.ConclusionsThe 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.

The Impact of Clonal Hematopoiesis of Indeterminate Potential on Survival in Patients with Newly Diagnosed Acute Myeloid Leukemia

The Impact of Clonal Hematopoiesis of Indeterminate Potential on Survival in Patients with Newly Diagnosed Acute Myeloid Leukemia

Five-Day Versus Ten-Day Schedules of Decitabine in Older Patients with Newly Diagnosed Acute Myeloid Leukemia: Results of a Randomized Phase II Study

Five-Day Versus Ten-Day Schedules of Decitabine in Older Patients with Newly Diagnosed Acute Myeloid Leukemia: Results of a Randomized Phase II Study

Acute Myeloid Leukemia: The Good, the Bad, and the Ugly.

Acute myeloid leukemia (AML) was initially subdivided according to morphology (the French-American-British system), which proved helpful in pathologic categorization. Subsequently, clinical and genomic factors were found to correlate with response to chemotherapy and with overall survival. These included a history of antecedent hematologic disease, a history of chemotherapy or radiation therapy, the presence of various recurrent cytogenetic abnormalities, and, more recently, the presence of specific point mutations. This article reviews the biology and responses of one AML subgroup with consistent response and good outcomes following chemotherapy (core-binding factor leukemia), and two subgroups with persistently bad, and even ugly, outcomes (secondary AML and TP53-mutated AML).

Allogeneic Tcrα/β Deficient CAR T-Cells Targeting CD123 Prolong Overall Survival of AML Patient-Derived Xenografts

Acute myeloid leukemia (AML) is a disease with a high incidence of relapse and mortality. Relapse is attributed to the inability of current chemotherapeutic agents to eliminate leukemia stem cells (LSCs). Thus, to improve leukemia therapy, it is critical to identify agents that effectively target LSCs, e.g. via unique cell surface antigens. A target of major interest is CD123, the transmembrane alpha chain of the interleukin-3 receptor, expressed on blasts, leukemic progenitor and LSCs in the majority of AML patients. We have developed an allogeneic chimeric antigen receptor (CAR) T-cell platform using T-cells from third-party healthy donors to generate engineered T-cells targeting CD123 (UCART123). UCART123 cells no longer express a TCR, having undergone a disruption of the TCRα gene using TALEN¨ gene editing technology followed by elimination of TCRα/β-positive cells, thus minimizing the potential for engineered T-cells to cause graft versus host disease (GvHD). We tested the activity of UCART123 cells in vitro using primary AML samples, normal bone marrow (nBM) and cord blood (CB) cells. Additionally, we established patient derived xenograft (PDX), nBM- or CB- humanized xenografts (HuX) and a competitive nBM/AML xenograft model to evaluate the in vivo potential of UCART123 cells to preferentially eliminate AML over normal BM cells.In vitro studies reveled that UCART123 cells eliminate AML cells and had minimum effect on normal cells at effector:target ratios as low as 0.5:1. Next, we evaluated the in vivo activity of UCART123 against PDX (AML37, TP53 mutant relapsed AML and AML20, FLT3-ITD+ and TP53 mutant AML) and normal-HuX mice (n=3). At 3 weeks post T-cell injection we found that UCART123 treatment eliminated the leukemic cells when using 10M or 3M UCART123 cells per mouse and no significant difference between PBS or TCR-deficient T-cells (TCRkoT; 10M/mouse). Toxicity to normal cells was dose dependent, doses of 2.5M UCART123 cells did not significantly affect hematopoietic cells. T-cells were detected in the BM at day 14 after treatment, without evidence of GvHD.Since we found complete elimination of human AML cells in the BM of the PDX precluding serial transplantation to evaluate LSC activity, we initiated two new sets of PDX-AML mice [AML2 (NPM1+FLT3-ITD+) and AML37 (TP53 mutant)] to evaluate long-term survival, and time to relapse. Animals were treated with PBS, UCART123 (2.5M or 1M), TCRkoT (2.5M), or Ara-C (60mg/kg 5 days). Animal weight and peripheral blood (PB) was monitored. Cytokines changes were evaluated at day 2. We found that the cytokine release and the kinetics of AML targeting by UCART123 were dose dependent. We found a significant overall survival (OS) benefit with UCART123 in both PDX tested. For example, all PDX-AML2 mice treated with UCART123 are alive to date (day 167; updates will be presented). All other cohorts were lost (PBS day124, TCRkoT day126, AraC day144) (Figure 1A).Finally, to determine selectivity of UCART123 cells for AML cells over nBM cells, we generated a competitive model bearing both nBM and AML (NPM1+FLT3-ITD+). With PB monitoring, treatment with 1M UCAR123 cells resulted in selective elimination of AML cells. Untreated and TCRkoT treated mice showed a rapid progression of AML, while treated mice showed normal hematopoiesis (Figure 1B). NPM1 transcripts were also monitored in the mice and confirmed molecular remission in mice.Taken together, our data show that UCART123, an "off-the-shelf" allogeneic engineered CAR-T product targeting CD123 potently eliminates AML cells in vivo, prevents relapse, and improves OS in PDX mice. Also, UCART123 cells preferentially targets AML cells in a competitive BM/AML model. A phase I trial of UCART123 in AML is under development. [Display omitted] DisclosuresGuzman:Cellectis: Research Funding. Sugita:Cellectis: Research Funding. Galetto:Cellectis SA: Employment. Gouble:Cellectis: Employment. Smith:Cellectis SA: Employment. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding.

Clinical Effects of Driver Somatic Mutations on the Outcomes of Patients With Myelodysplastic Syndromes Treated With Allogeneic Hematopoietic Stem-Cell Transplantation

The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various combinations of somatic mutations are associated with different clinical phenotypes and outcomes. Whether the genetic basis of MDS influences the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) is unclear. We studied 401 patients with MDS or acute myeloid leukemia (AML) evolving from MDS (MDS/AML). We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms. We then analyzed the impact of mutations on the outcome of HSCT. Overall, 87% of patients carried one or more oncogenic mutations. Somatic mutations of ASXL1, RUNX1, and TP53 were independent predictors of relapse and overall survival after HSCT in both patients with MDS and patients with MDS/AML (P values ranging from .003 to .035). In patients with MDS/AML, gene ontology (ie, secondary-type AML carrying mutations in genes of RNA splicing machinery, TP53-mutated AML, or de novo AML) was an independent predictor of posttransplantation outcome (P = .013). The impact of ASXL1, RUNX1, and TP53 mutations on posttransplantation survival was independent of the revised International Prognostic Scoring System (IPSS-R). Combining somatic mutations and IPSS-R risk improved the ability to stratify patients by capturing more prognostic information at an individual level. Accounting for various combinations of IPSS-R risk and somatic mutations, the 5-year probability of survival after HSCT ranged from 0% to 73%. Somatic mutation in ASXL1, RUNX1, or TP53 is independently associated with unfavorable outcomes and shorter survival after allogeneic HSCT for patients with MDS and MDS/AML. Accounting for these genetic lesions may improve the prognostication precision in clinical practice and in designing clinical trials.

TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes.

Mutations in the tumor protein 53 (TP53) gene predict a poor prognosis in patients with acute myeloid leukemia (AML). Peripheral blood or bone marrow samples from 293 patients with newly diagnosed AML were analyzed with targeted, amplicon-based, next-generation sequencing-based mutation analysis. TP53 mutations were identified in 53 patients (18%; 45 were missense mutations). In 13 of the 53 patients, the most common pattern of amino acid substitution was a substitution of arginine to histidine on different codons. The clinical characteristics, pattern of mutations, response to different therapies, and outcomes of patients with AML-TP53-mutated (n = 53) versus wild-type TP53 (n = 240) were compared. TP53 mutations were significantly more likely in patients who had a complex karyotype; abnormalities of chromosome 5, 7, and 17; and therapy-related AML. Patients who had TP53-mutated AML had significantly lower incidence of mutations in Fms-like tyrosine kinase 3 (FLT3), rat sarcoma (RAS), and nucleophosmin (NPM1) and higher incidence of coexisting MPL mutations compared with those who had wild type TP53. The distribution of TP53 mutations was equal for both age groups (ages <60 years vs ≥60 years). TP53-mutated AML was associated with a lower complete remission rate (41% vs 57%; P = .04), a significantly inferior complete remission duration (at 2 years: 30% vs 55%; P = .001), and overall survival (at 2 years: 9% vs 24%; P ≤ .0001) irrespective of age or the type of treatment received (high-intensity vs low-intensity chemotherapy). The type of treatment received did not improve outcomes in younger or older patients with TP53-mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with AML who have TP53 mutations. Cancer 2016;122:3484-3491. © 2016 American Cancer Society.