Evaluating Myelodysplastic Syndrome Risks in NET Patients Planned for Peptide Radionuclide Therapy

Обзор

This is a prospective observational study which aims to identify individuals predisposed to developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) could improve patient outcomes in different ways. First, it will enable improved patient selection for PRRT where alternative treatment options are available. Second, understanding the final pathway and how it is modulated by PRRT could allow the design of strategies to halt this process. Third, while it is unknown whether the development of MDS and AML is a late effect of radiopharmaceuticals in general or it is confined to cancer populations or specific radioisotopes will need to be confirmed. Finally, understanding this devastating complication is expected to be the cornerstone towards advancing radiopharmaceuticals' role in the adjuvant setting.

Подробное описание

Radiopharmaceuticals is currently used for the treatment of metastatic cancer date. While radiopharmaceuticals are generally well tolerated, one of its most devastating long-term toxicities is the development of therapy related myeloid neoplasms (t-MN), an umbrella term for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). PRRT (Receptor Radionuclide Therapy) is a targeted radiopharmaceutical therapy (RPT) used to treat neuroendocrine tumors. RPTs use drugs to attack cancer cells while reducing harm to healthy tissue. PRRT delivers high doses of radiation to tumors in the body to destroy or slow their growth and reduce disease side effects.

While PRRT is generally well tolerated, one of its long-term side effects is the development of therapy related myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The identification of genetic changes that lead to the development of MDS and AML during PRRT is a growing area of research. It is now known that the genetic changes that lead to progression into AML typically occur through many years of pre-leukemic hematopoietic stem cell clonal evolution, before development of late mutations that lead to malignant disease. The short interval between exposure to PRRT and appearance of MDS and AML would suggest some patients are already at high risk of developing AML and are potentially detectable. The ability to identify individuals predisposed to developing MDS/AML could improve patient selection for PRRT and design strategies to mitigate the development of MDS/AML.

This research proposes to study the genetic changes that occur pre-PRRT and post-PRRT using blood samples obtained from a patient population at Princess Margaret Hospital. Cohort A will consist of 20 patients that have had PRRT within the past 4 years. Cohort B will consist of 20 patients planned for PRRT. Cohort C will consist of 1-5 patients post PRRT, diagnosed with t-MN.

Вмешательства

• Лучевая терапия Peptide receptor radionuclide therapy (PRRT)
  Specialized type of radionuclide therapy used to treat neuroendocrine tumors.
• Диагностический тест Blood collection
  Patients will have approximately 5 ml of blood drawn 6,12,24,36,48, 60 months and at the time of MDS/AML diagnosis on follow up. Genomic DNA will be extracted from serum sample using the Qiagen QIAamp DNA Mini Kit. Single-molecule molecular inversion probes (smMIPs) will be used to detect mutations. Single nucleotide variants (SNVs), short insertions and deletions (indels), and mutated myeloid genes will be captured (e.g PPM1D, DNMT3A, TET2, TP53).

Первичные конечные точки

• Identify individuals predisposed to developing MDS/AML to improve patient selection for PRRT where alternative treatment options are available. [Срок оценки: 5 years]

Вторичные конечные точки (5)

• Detection of Genetic Mutations in the Blood Post-PRRT [Срок оценки: 5 years]
• Assessment of Variant Allele Frequencies Post-PRRT [Срок оценки: 5 years]
• Incidence of Therapy-Related Myeloid Neoplasms (t-MN) Post-PRRT [Срок оценки: 5 years]
• Proportion of Patients Developing MDS/AML Post-PRRT [Срок оценки: 5 years]
• Identification of Clonal Mutations Conferring Increased Risk of MDS/AML Post-PRRT [Срок оценки: 5 years]

Критерии участия

Критерии включения

• ECOG 0-3
• Life expectancy > 6 months
• Informed consent and willingness to undergoing serial genetic panel CHIP testing.
• Cohort Specific criteria

• Cohort A: PRRT completed within 5 years of enrolment
• Cohort B: PRRT planned to commence within 4 months of enrolment
• Cohort C: diagnosis of MDS or AML following prior PRRT.

Критерии исключения

• Unwillingness to provide blood sample and follow up as per protocol

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Канада · 1 центр

• Princess Margaret Cancer Centre — Toronto

Идентификаторы

NCT: NCT06510868 · 22-5247

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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