Cancer Nexus Blog

Myelodysplastic syndrome (MDS) is a form of blood cancer in which the bone marrow fails to produce enough normal, healthy blood cells. For approximately 1 in 3 patients with MDS, their disease may progress to an aggressive blood cancer called acute myeloid leukemia (AML). Recurrent mutations in several genes have been found in AML, including FLT3, IDH1/2, and the well-known tumor suppressor gene TP53. Patients with MDS and AML harboring mutations in TP53 have an especially poor response to chemotherapy and exceptionally poor outcomes.

A new study from a team of researchers at UMass Cancer Center, in collaboration with researchers at Beth Israel Deaconess Medical Center and Stanford University, aimed to better understand the disease process and mechanisms of TP53-mutant MDS and AML in the hopes of ultimately identifying and delivering precision therapies for this group of patients. The study was led by Shyam A. Patel, MD, PhD, assistant professor of medicine in the Division of Hematology/Oncology, and was performed under the mentorship of Jonathan M. Gerber, MD, the Eleanor Eustis Farrington Chair in Cancer Research, chief of the Division of Hematology/Oncology, medical director of the Cancer Center, and professor of medicine and molecular, cell & cancer biology. The findings were recently published online in the journal Leukemia & Lymphoma.

Currently there are nine therapies for AML that have been approved by the US Food and Drug Administration (FDA), including several molecular inhibitors targeting FLT3 or IDH1/2, but no FDA-approved precision therapies exist for TP53-mutant AML. “TP53-mutant myeloid neoplasms are arguably the largest black box in the field of hematologic malignancies,” says Dr. Patel. “There are no unique therapies for the TP53 mutation, and no universal standard approach for management exists for this high-risk group of patients.” He adds, “There’s clearly a high need for precision medicine-based approaches for this subset of patients.” 

Dr. Patel notes that a deep biological understanding of this mutational subset of MDS and AML is necessary to open up this black box and to make strides forward.

In their study, Dr. Patel and colleagues surveyed the UMass Leukemia Registry and identified 40 patients with MDS and AML who harbored TP53 mutations and had been treated at UMass between 2011 and 2021. A subset of these patients (11 of the 40) had received allogeneic hematopoietic cell transplant (allo-HCT), a procedure in which a patient receives healthy blood-forming cells (stem cells) from a matched donor to replace their own stem cells and reconstitute the entire blood system. Dr. Patel says they had observed improved overall survival in these patients and sought to understand the basis for this improvement.

Central to unlocking this question was the availability of genomic DNA from biological samples (in particular stem cell-containing bone marrow aspirates) that had been collected from the patients at various timepoints during their treatment, such as at diagnosis, remission, relapse and post-allo-HCT. These samples served as a powerful research tool, allowing the research team to carry out comprehensive analysis of the clinico-genomic landscape and therapeutic outcomes of these patients.

To do this, they analyzed the patient samples using genetic and cytogenetic methods, and then performed bioinformatic analyses to model clonal dynamics of TP53—the changes in TP53 occurring in the stem cell population at various timepoints during the disease. They found that the TP53 mutation persisted during remission and fueled disease relapse, suggesting that the TP53 mutation is the primary pathogenic driver mutation for disease recurrence. Furthermore, they found that a higher dosage of the mutant TP53 gene predicted a lower chance of achieving durable remission, the diagnosis achieved when there are no measurable signs of cancer for a length of time.

Their findings indicate that the improved overall survival of patients with TP53-mutant MDS and AML following allo-HCT is because the treatment wipes out the patient’s cancerous stem cell population that harbors the TP53 mutation. This stem cell concept might explain why certain cytotoxic chemotherapies alone do not lead to durable remissions. “Stem cell transplant eliminates the cancer cells containing the driver TP53 mutations,” Dr. Patel says, adding “no other therapy or medication can effectively do this”.

What’s on the horizon for treatments for patients with TP53-mutant MDS and AML? Dr. Patel says what is needed is a formal assessment of the value of allo-HCT in a larger cohort of patients, as well as longitudinal studies to follow patients over time. He also looks forward to the results of clinical trials for several new therapeutic approaches, including immunotherapies and small molecule TP53 activators that are currently in the pharmacological pipeline for TP53-mutant MDS and AML.

To hear more about this exciting research study, check out the video below.

Disclosure Statement: Dr. Patel serves on the AML Advisory Board for Bristol Myers Squibb and the Multiple Myeloma Advisory Board for Pfizer. He is a consultant for the Dedman Group, SIS International and Adivo Associates.