Prognostic factors influencing survival after allogeneic transplantation for AML/MDS patients with TP53 mutations

Ciurea, Stefan O.; Chilkulwar, Abhishek; Saliba, Rima M.; Chen, Julianne; Rondón, Gabriela; Patel, Keyur P.; Khogeer, Haitham; Shah, Abdul Rashid; Randolph, Brion; Pérez, Julie; Popat, Uday; Hosing, Chitra; Bashir, Qaiser; Mehta, Rohtesh S.; Alatrash, Gheath; Im, Jin; Khouri, Issa F.; Kebriaei, Partow; Champlin, Richard E.

doi:10.1182/blood-2018-02-832360

Cited by 75 publications

(68 citation statements)

References 15 publications

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“…Third, we demonstrated the modest effects of HSCT on LFS and OS of typical CK/MK AML patients, suggesting their resistance to myeloablative chemotherapy and graft‐versus‐leukemia (GVL) effects even when HSCT was performed at morphologic remission. Similar outcome after allogeneic HSCT has also been reported previously . Measurable residual disease (MRD) positivity pre‐HSCT has recently been shown to predict subsequent relapse and clinical trials incorporating MRD monitoring post‐HSCT and strategies to act on positive MRD are urgently needed to address if GVL could be more effectively harnessed for this AML subtype.…”

Section: Discussionsupporting

confidence: 65%

Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations

Leung

Zhang

et al. 2019

American J Hematol

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The present study aimed to define a subtype of complex/monosomal karyotype (CK/MK) acute myeloid leukemia (AML) by its distinct clinical features, p53 signaling and responses to p53 targeting agents. Ninety‐eight young adults (range: 21‐60 years; median: 49 years) with CK/MK AML were studied. They received standard induction, consolidation and allogeneic hematopoietic stem cell transplantation from siblings or matched unrelated donors if available. Chromosomal abnormalities most commonly affected chromosome 5 (30%), 7 (22%) and 17 (21%). Next generation sequencing of a 54‐myeloid gene panel were available in 76 patients. Tumor protein 53 (TP53) mutations were most common (49%) and associated with the presence of −5/5q‐ (P < .001) and −17/17p‐ (P < .001), but not −7/7q‐ (P = .370). This “typical” CK/MK AML subtype was associated with significantly lower presenting white cell counts, higher number of karyotypic abnormalities, and inferior leukemia‐free and overall survivals, compared with CK/MK AML without the typical features. Blood or bone marrow samples from typical CK/MK AML patients showed defective p53 signaling upon induction by etoposide. In vitro drug sensitivity analysis showed that they were sensitive to APR‐246 that targeted mutant p53, but resistant to MDM2 antagonist MI‐77301. Novel therapeutic strategies targeting TP53 mutations in CK/MK AML should be developed and tested in clinical trials.

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Section: Discussionsupporting

confidence: 65%

Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations

Leung

Zhang

et al. 2019

American J Hematol

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“…Facing different therapeutic options, it is, therefore, of importance to develop tools supporting proper therapeutic decision-making in this cohort of patients. In a recently published article, clinical parameters-preferably performance status and achievement of a complete remission following induction therapy-have been shown to be of prognostic relevance in patients with TP53-mutated AML [55]. Analyzing a large cohort of patients treated with intensive chemotherapy and HSCT here, we were able to show that the AML-specific RFS enables discrimination of a low-risk group with a median OS of 12.9 months and a high-risk group with a median OS of only 5.5 months.…”

Section: Discussionmentioning

confidence: 99%

Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Dutta

Pregartner

Rücker

et al. 2020

Cancers

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Mutations of the TP53 gene occur in a subset of patients with acute myeloid leukemia (AML) and confer an exceedingly adverse prognosis. However, whether different types of TP53 mutations exert a uniformly poor outcome has not been investigated yet. Here, we addressed this issue by analyzing data of 1537 patients intensively treated within protocols of the German-Austrian AML study group. We classified TP53 mutations depending on their impact on protein structure and according to the evolutionary action (EAp53) score and the relative fitness score (RFS). In 98/1537 (6.4%) patients, 108 TP53 mutations were detected. While the discrimination depending on the protein structure and the EAp53 score did not show a survival difference, patients with low-risk and high-risk AML-specific RFS showed a different overall survival (OS; median, 12.9 versus 5.5 months, p = 0.017) and event-free survival (EFS; median, 7.3 versus 5.2 months, p = 0.054). In multivariable analyses adjusting for age, gender, white blood cell count, cytogenetic risk, type of AML, and TP53 variant allele frequency, these differences were statistically significant for both OS (HR, 2.14; 95% CI, 1.15–4.0; p = 0.017) and EFS (HR, 1.97; 95% CI, 1.06–3.69; p = 0.033). We conclude that the AML-specific RFS is of prognostic value in patients with TP53-mutated AML and a useful tool for therapeutic decision-making.

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“…Over the last decade, information regarding molecular data has been shown to be strongly associated with outcomes of patients with AML, particularly for those with diploid karyotype [15,[29][30][31]. These data have led to the development of a risk stratification model incorporating genetic abnormalities from cytogenetic and molecular mutational analyses proposed by the ELN group [32].…”

Section: Discussionmentioning

confidence: 99%

Novel Disease Risk Model for Patients with Acute Myeloid Leukemia Receiving Allogeneic Hematopoietic Cell Transplantation

Kongtim

Hasan

Pérez

et al. 2020

Biology of Blood and Marrow Transplantation

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Molecular data and minimal residual disease (MRD) have been shown to influence outcomes in acute myeloid leukemia (AML) patients undergoing allogeneic hematopoietic cell transplantation (AHCT). Here we developed and validated a novel AML-specific disease risk group (AML-DRG) and revised our previously developed hematopoietic cell transplant-composite risk (HCT-CR) model by incorporating molecular data and MRD status to predict outcomes of patients with AML. The study included 1414 consecutively treated adult AML patients who received a first AHCT. Patients were randomly assigned into training (n = 944) and validation (n = 470) sets. To develop the AML-DRG model, the coefficient of all significant AML-related variables in multivariable Cox regression analysis in a training dataset was converted into scores, whereas the AML-HCT-CR was the sum of disease-related factors assessed by the AML-DRG model with the addition of weighted scores from patient-related factors. The AML-DRG was developed by assigning the following scores: 1 point to secondary AML, 1 point to the European Leukaemia-Net adverse genetic risk, 2 points to complete remission with MRD positive/unknown, and 4 points to active disease. These scores were used to generate 3 risk groups of the AML-DRG with significantly different overall survivals. By adding the score for significant patient-related factors (HCT-specific comorbidity index/age), we created 4 risk groups of AML-HCT-CR with distinct survival outcomes. Both the AML-DRG and AML-HCT-CR provided significantly better discriminative capacity compared with the disease risk index, European LeukaemiaNet genetic risk model, and cytogenetic risk model. Prognostic models incorporating molecular data and MRD status allow better stratification and improved survival estimates of AML patients post-transplant.

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Prognostic factors influencing survival after allogeneic transplantation for AML/MDS patients with TP53 mutations

Cited by 75 publications

References 15 publications

Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations

Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations

Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Novel Disease Risk Model for Patients with Acute Myeloid Leukemia Receiving Allogeneic Hematopoietic Cell Transplantation

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