Clonal Hematopoiesis and Risk of Thrombocytopenia in Neuroendocrine Tumor Patients Undergoing 177Lu Therapy: A Prospective Study

Background and Research Motivation

The incidence of Neuroendocrine Tumors (NETs) has gradually increased in recent years. Prognosis depends on various factors such as the location of the primary tumor, disease grading, staging, differentiation, and proliferation rates. Since most NETs highly express somatostatin receptors (SSTR), somatostatin analogs (SSAs) are often used as the first-line treatment. Due to the high expression of somatostatin receptors (SSTR) in most NETs, somatostatin analogs (SSAs) are commonly used as the first-line treatment. Second-line therapy includes Peptide Receptor Radionuclide Therapy (PRRT). In PRRT, by combining SSAs with specific radioactive isotopes such as 177Lu, the radiopharmaceutical can be directly delivered to tumor cells.

During this treatment, hematotoxicity, particularly thrombocytopenia, is a relatively common dose-limiting toxicity. This not only limits the patient’s ability to undergo complete treatment courses but may also lead to some patients developing persistent cytopenia, eventually resulting in therapy-related myeloid neoplasms (t-MN), which have a very poor prognosis. As PRRT indications continue to expand, it is particularly important to research and predict factors associated with cytopenia during and after PRRT.

Source and Author Introduction

This study was conducted by doctors and researchers Yael Kusne, Terra Lasho, Christy Finke, Zaid Elsabbagh, and Shaylene McCue, among others, affiliated with Mayo Clinic and other collaborative institutions. The paper was published in the journal “JCO Precision Oncology” on July 8, 2024.

Study Design and Methods

Study Process and Specific Steps

This study is a prospective study, approved by the Mayo Clinic Institutional Review Board (IRB), with written informed consent obtained from patients. Study objectives include:

• Including eligible patients: metastatic NET patients aged 18 and above scheduled to receive PRRT treatment between September 2020 and May 2022.
• Study drug: 177Lu was administered intravenously every 8 weeks, for a total of four times, each dose being 200 mCi.
• Data collection: Complete blood counts were performed before each treatment and every 3 months after treatment to record toxic reactions.
• Clonal Hematopoiesis (CH) analysis: CH was analyzed before treatment using a targeted capture deep sequencing method with a 220-gene panel.

With this setup, the primary endpoint was set to thrombocytopenia (≥ grade 1) during and after treatment. Secondary endpoints included the prevalence of baseline CH and cytopenia, the incidence of t-MN, and overall survival (OS).

Data Analysis

The Wilcoxon rank-sum test was used to compare continuous variables between patients with and without CH, and the chi-square test was used to compare categorical variables. OS was estimated using the Kaplan-Meier method and compared using the log-rank test. A multistate model was applied to study the longitudinal changes in blood counts, and a disease-death model was used to analyze the dynamic changes in thrombocytopenia.

Study Results

Patient Characteristics and Clonal Hematopoiesis (CH)

Among the 37 patients included, the median age was 68 years, and 51.4% were males. Thirty percent had previously received alkylating agents, 8% had received platinum-based chemotherapy, and 13% had undergone external radiation therapy. CH was detected in 35.1% of cases with Variant Allele Frequency (VAF) ≥ 2%, while it was 45.9% for VAF ≥ 1%.

Using the 220-gene targeted capture deep sequencing technology, 28 pathogenic variants were detected, with the most common variants being in DNMT3A and TET2 genes.

Baseline and Post-treatment Cytopenia

During PRRT treatment and follow-up, no significant differences were observed between groups for hemoglobin, red blood cell distribution width, mean corpuscular volume, white blood cells, neutrophils, or lymphocytes. However, CH patients had a lower mean baseline platelet count (185 × 10^9/L) compared to non-CH patients (231 × 10^9/L).

During PRRT, the transitions from normal platelet counts to thrombocytopenia showed that CH patients were more likely to be in a thrombocytopenic state post-treatment and had a lower probability of recovering to normal platelet levels. Over long-term observation of state transitions, CH patients were in a thrombocytopenic state for an average of 200 days after treatment, compared to 99 days for non-CH patients.

Bone Marrow Examination and Long-term Impact

Five patients (13.5%) underwent bone marrow biopsy due to persistent cytopenia post-treatment. Among them, three were confirmed to have clonal cytopenia of undetermined significance (CCUS), and two had idiopathic cytopenia of undetermined significance (ICUS). Interestingly, some patients had low-frequency variants (e.g., PPM1D gene) before treatment, which significantly increased in frequency post-treatment.

Conclusion and Research Value

This study indicates that 35.1% of NET patients treated with PRRT show CH and have a higher risk of thrombocytopenia during and post-PRRT. Further follow-up studies to clarify whether CH could potentially be a predictive factor for t-MN risk are of great importance.

Research Highlights

• Key Finding: The study reveals that clonal hematopoiesis may be a risk factor for thrombocytopenia during and after PRRT.
• Innovative Method: Using targeted deep sequencing analysis of CH, the study detected key gene variants and determined their correlation with treatment outcomes.
• Clinical Application: This approach can be used to screen NET patients planned for PRRT, thereby enhancing the monitoring and prevention of hematotoxicity.

Outlook and Recommendations

Further long-term follow-up studies will uncover the relationship between CH and the risk of therapy-related myeloid neoplasms, aiding in the formulation of more precise treatment plans and improving patient prognosis.

Through this study, we have utilized prospective analysis to uncover the impact of CH on PRRT treatment and its potential mechanisms, providing valuable data support for the prediction of toxicity in neuroendocrine tumor treatment.