Clonal Hematopoiesis as a Determinant for Bone Marrow Toxicities for Targeted Radiation Therapies in Prostate Cancer
Abstract
Radiation is a cornerstone in the treatment of patients with prostate cancer (PC), with many patients getting various forms of radiation therapy during their treatment course including radiation to the prostate for early-stage PC and for palliation of pain in metastatic PC (mPC). Targeted radionuclide therapy (TRT) is an emerging therapy that has recently showed improved response and survival for mPC with expected FDA approval in 2022. TRT attaches a radioactive particle to a carrier that binds only to a cancer-related tag, which in the case of PC is most commonly prostate-specific membrane antigen (PSMA). Thus, PSMA-targeted TRT can deliver a small particle of radiation to PC cells anywhere in the body, including the bone. While this is an advantage in terms of bypassing other organs, since mPC commonly involves bone, there is considerable radiation exposure to bone marrow. As a result, low blood counts after treatment to varying degrees is one of the common side effects, and there is a risk of long-term bone marrow damage due to radiation. This long-term bone marrow damage can manifest itself as either low blood counts or risk of blood cancers such as acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). To date, there is no risk prediction marker for bone marrow toxicities after TRT and ways to identify short term and long-term toxicities from TRT is of major clinical interest. Large-scale gene sequencing studies in normal healthy populations have shown that people above 60 years have a high chance (30%) of having an age related acquired mutation in peripheral blood. This condition has been termed as Clonal Hematopoiesis (CH). CH occurs as blood cells make mistakes dividing in an aging bone marrow. It is known that CH prevalence is increased with advanced age, smoking and pervious exposure to radiation/chemotherapy. We have identified that a high risk CH gene signature increases the future risk of AML by using samples collected a decade before diagnosis of AML in a population cohort. Moreover, CH has also been seen in many patients who have low blood counts of unknown reason and such individuals have a 95% lifetime risk of MDS/AML. Patients with PC are likely to have a higher chance of CH than normal individuals due to older age and previous exposure to either chemotherapy or external radiation. We believe that the presence of CH can impact the occurrence of low blood counts during TRT and that the mutations may in turn expand after TRT increasing risk of MDS/AML even further. We have a dataset from men treated with PSMA-TRT since 2003 with long-term follow-up; most have available tumor and blood specimens. We are also collecting specimens in our current PSMA-TRT studies, with all data contributing to a comprehensive database. Blood was collected at baseline before TRT, after TRT, as well as long-term follow up (>1 year) for some patients. We will perform a custom CH gene sequencing developed at Weill Cornell Medicine to determine the presence of CH in blood collected before TRT and use this to see whether CH predicts the development of low blood counts after TRT. We will also compare CH mutations before and after TRT to see whether mutation size increases and whether new high-risk mutations develop after TRT. In addition, we will compare the post-TRT treatment mutational behavior to patients treated with other PC therapies, including hormonal therapy and chemotherapy to see whether TRT has more, less, or the same risk of mutation expansion as other therapies. Our preliminary data supports our hypothesis with 84.6% of patients with significant low blood counts post-TRT demonstrating pre-existing CH mutations. We also saw emergence of new mutations and expansion of pre-existing mutations post TRT. TRT is likely to find expanded use in earlier stages of PC. As therapy choices expand and survival increases in patients with PC, the risk of short-term bone marrow toxicity and long-term
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210375
Entities
People
- Pinkal Desai
Organizations
- United States Army
- Weill Cornell Medicine