Comparison of the Hematotoxicity of PRRT with Lutathera® and Locally Manufactured 177Lu-HA-DOTATATE in Patients with Neuroendocrine Tumors and the Impact of Different Application Intervals.

BACKGROUND/OBJECTIVES: Peptide Receptor Radionuclide Therapy (PRRT) is approved for patients with inoperable, progressive and/or metastatic well-differentiated NETs. Before the approval of Lutathera®, locally manufactured 177Lu-HA-DOTATATE was used on a regular basis in clinical routine. The aim of this study was (1) to compare the hematotoxicity of locally manufactured 177Lu-HA-DOTATATE with Lutathera® in GEP-NET patients and (2) to compare the recommended treatment interval of 8 weeks between each cycle to a prolonged scheme of up to 11 weeks for both 177Lu-HA-DOTATATE and Lutathera®.

METHODS: The included patients with GEP NETs (n = 46) received four cycles of PRRT, either 177Lu-HA-DOTATATE or Lutathera®, and were divided into four subgroups. The subgroups were treated with either locally manufactured 177Lu-HA-DOTATATE or Lutathera® and were stratified into a mean application interval of 8 (HA8weeks, n = 10/Lutathera8weeks, n = 16) or 11 weeks (HAadapted, n = 10/Lutatheraadapted, n = 10). To evaluate therapy associated hemato- and nephrotoxicity, patients underwent two laboratory follow-up examinations (follow-up 1-between 2./3. therapy cycle; follow-up 2-after the termination of the 4. therapy cycle) and were then compared to pre-PRRT laboratory results. To assess hematological and renal recovery trends, blood values and parameters of kidney function were collected up to 58.9 weeks after PRRT completion. Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) were used for grading hematological parameters.

RESULTS: The occurrence of high-grade adverse events (CTCAE grade 3/4) after PRRT was moderate, with 1/10 (10%) grade 4 lymphocytopenia in the Lutatheraadapted group, while overall, 20/46 (43.5%) patients had grade 3 lymphocytopenia. Grade 3 thrombocytopenia occurred in 1/10 (10%) patients of the HAadapted group. Absolute and percentage changes in the kidney function (creatinine, TER) remained constant during PRRT in all subgroups. All four subgroups showed a significant decrease in absolute blood value changes for PLT counts, WBC counts, neutrophil granulocytes and lymphocytes between, prior to and after PRRT (p < 0.05, each). Regarding percentage changes in laboratory parameters, only the HAadapted and the HA8weeks groups had significant decreases in WBC (p < 0.03, each) and PLT counts (p < 0.04, each) while there was no significant degradation of any other hematological parameter in any of the subgroups. Only patients with longer treatment intervals under 177Lu-HA-DOTATATE therapy showed a statistically significant correlation in the long-term recovery analysis concerning the PLT counts (r = 0.6, p < 0.0001). Other blood and kidney values showed no significant correlation in the long-term analysis in the other subgroups.

CONCLUSION: Comparing the hematotoxicity in patients that were treated with locally manufactured 177Lu-HA-DOTATATE with patients that were treated with Lutathera® and assessing different treatment intervals in both groups (8 vs. 11 weeks), revealed that there is overall a low to moderate incidence of significant changes in hematological and renal parameters directly after PRRT. Recovery trends of hematological and renal parameters after 1 year suggest that patients treated with locally manufactured 177Lu-HA-DOTATATE might benefit from a longer treatment interval of 11 weeks regarding their PLT counts. Given the risk of developing hematological diseases such as therapy-related myeloid neoplasms years after PRRT, longer observational periods after PRRT will be crucial.