888MO - Emergence of clonal hematopoiesis after peptide receptor radionuclide therapy for neuroendocrine tumors

Background

In the advanced/metastatic Neuroendocrine tumors (NETs), PRRT (Peptide Receptor Radionuclide Therapy), has shown efficacy but with significant hematologic toxicity, including therapy-related myeloid neoplasms (t-MN). Here, we assessed the effect of PRRT on the development of t-MN and clonal hematopoiesis (CH) known to be a risk factor for t-MN development.

Methods

Firstly, we retrospectively identified t-MNs occurring after PRRT at Gustave Roussy Cancer Center for the last 20 years and described their characteristics. Secondly, we performed a targeted 77 genes mutational analysis using Next Generation Sequencing (NGS) in blood samples of 58 patients with TNE, exposed or not to PRRT, without any hematological malignancies.

Results

Out of 190 NETs treated with PRRT, we described 6 cases of t-MNs comprising 2 AML and 4 MDS (3.16%). Median age at t-MN was 70 years; median time between PRRT and t-MNs was 2.8 years. Two had unfavorable karyotype, NGS was available for 3 patients including 1 with a TP53 mutation. Median OS from t-MN diagnosis was 9.1 months. Between August and December 2021, 58 patients with TNE were explored by NGS including 27 (46.5%) treated with PRRT and 27 with anthracyclines. 27 (46.5%) patients had CH, including 10 patients (37%) with DNMT3A mutation, 9 TET2 (33%), 4 PPM1D (15%) and 3 (11%) TP53. 12/27 (44%) had more than one mutation. Patient with CH were older compared to others with a median age of 66 years vs 55 (p >0.001), received more PRRT treatment (17/27, 63%) vs (10/31, 32%) (p=0.03) but no differences were seen in term of history of treatment with anthracyclines (14/27, 52% vs 13/31, 32%, p=0.6) and time between NGS and TNE diagnosis (7.7 years vs 6.4 years, p=0.7). Out of the 27 patients with PRRT, 17 had CH, median time between first PRRT cycle and NGS was 2 years. Incidence of TP53 and/or PPM1D mutations were more common in patients with PRRT exposure compared to others (6/27 [22%] vs 1/30 [3%], p=0.04), and had more clonal complexity (9/27 [33%] vs 3/31 [9.6%], p=0.05).

Conclusions

T-MNs after PRRT are not so rare and had an unfavorable outcome. Patients with NET have a very high incidence of CH. Patients exposed to PRRT seems to have more CH, especially PPM1D and TP53 mutations, suggesting a potential clonal selection of this treatment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

J. Baptiste Micol.

Funding

GTE-AAA Grant.

Disclosure

J. Hadoux: Financial Interests, Personal, Advisory Board: Ipsen, Lilly, PharmaMar; Financial Interests, Institutional, Invited Speaker: AAA, Pfizer. L. Lamartina: Financial Interests, Personal, Advisory Board: Eisai, Bayer; Financial Interests, Institutional, Invited Speaker: Exelixis, Eisai, Sanofi, Bayer. M.P. Ducreux: Financial Interests, Personal, Invited Speaker: Roche, Amgen, Pierre Fabre, Merck Kga, Pfizer, Bayer, Lilly; Financial Interests, Personal, Advisory Board: Roche, Basilea, Sotio, Pierre Fabre, Bohringer, Rafael, Servier, Zymeworks, Ipsen, Bayer, HalioDX, Lilly, GlaxoSmithKline; Financial Interests, Institutional, Funding, Partial funding of a trial evaluating the role of bevacizumab in NET: Roche; Financial Interests, Institutional, Funding, Partial funding of a trial evaluating the role of steptozotocin in NET: Keocyt; Financial Interests, Institutional, Invited Speaker: Rafael, Amgen; Financial Interests, Institutional, Funding: Bayer; My wife is Head of the Oncology Business Unit in the French Affiliate of Sandoz: Sandoz France. E. Baudin: Financial Interests, Institutional, Advisory Board, Advisory board and principal investigator: Novartis; Financial Interests, Institutional, Advisory Board: HRA, Hutchinson Pharma; Financial Interests, Personal, Other, Project lead and principal investigator: Ipsen; Financial Interests, Institutional, Other: Pfizer; Financial Interests, Personal, Advisory Board: Novartis-AAA; Financial Interests, Institutional, Research Grant: Novartis, HRA, Pfizer; Non-Financial Interests, Principal Investigator: Enterome; Non-Financial Interests, Advisory Role: Hutchinson Pharma; Non-Financial Interests, Leadership Role: Endocan Network. C. Marzac: Financial Interests, Personal, Invited Speaker: Astellas. J. Baptiste Micol: Financial Interests, Personal, Invited Speaker: Jazz Pharmaceuticals, Astellas; Financial Interests, Personal, Advisory Board: AbbVie. All other authors have declared no conflicts of interest.