Real-World Data Reveal Risk Factors for Myeloid Neoplasm After Lutetium Lu 177 Dotatate

Older age, chronic kidney disease, and prior irradiation independently predicted therapy-related myeloid neoplasms (t-MNs) in patients with neuroendocrine tumors (NETs) treated with lutetium Lu 177 dotatate (Lutathera), according to a multicenter, real-world analysis presented by Charles W. Shi, MD, an internal medicine resident at Winship Cancer Institute of Emory University, at the 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium.¹

Among 1819 patients with NETs who received lutetium Lu 177 dotatate, 52 developed a t-MN, either myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), for a cumulative incidence of 2.88%. The investigators noted that this rate is consistent with the 2% to 4% risk reported previously in clinical trials, cohort studies, and systematic reviews.

On multivariable Cox proportional hazards analysis, 3 factors were independently associated with t-MN development. Each additional year of age at the start of peptide receptor radionuclide therapy (PRRT) was associated with an approximately 3.4% increase in risk (HR, 1.034; 95% CI, 1.000-1.069; P = .048). Chronic kidney disease was associated with a nearly threefold increase in risk (HR, 2.692; 95% CI, 1.320-5.490; P = .006), and prior irradiation was associated with a similarly elevated risk (HR, 2.942; 95% CI, 1.347-6.424; P = .007).

Other variables examined, including sex, race, nicotine dependence, primary tumor site, and the presence of liver or bone metastases, were not significantly associated with t-MN risk.

Patients who did and did not develop t-MNs had similar baseline characteristics. Overall, 70.7% of patients were aged 65 years or older, 53.8% were male, and 82.4% were White.

“There was no significant difference between the cohorts that did and did not develop t-MNs,” Shi said.

Retreatment and Temozolomide Did Not Raise Risk

Two treatment exposures examined by the investigators were not associated with higher t-MN risk in this analysis. Temozolomide exposure was not a significant predictor on multivariable analysis, and prolonged temozolomide exposure of 6 months or longer occurred at similar rates among patients who did and did not develop t-MNs (18.6% vs 16.4%; P = .78).

Repeat PRRT administered 12 months or more after initial therapy also did not differ between groups, occurring in 2.3% of patients who developed t-MNs and 2.8% of those who did not (P = 1.0).

“Of note, PRRT retreatment greater than 12 months after initial therapy did not have a significant impact on t-MN development,” Shi said.

Because t-MNs can take years to emerge, the investigators performed a subgroup analysis restricted to 683 patients with at least 2 years of follow-up after NET diagnosis. In this group, 20 patients (2.9%) developed t-MNs, and neither prolonged temozolomide exposure nor repeat PRRT differed significantly between those who did and did not develop t-MNs.

Study Limitations

The investigators acknowledged several limitations. The study was retrospective and relied on administrative coding, which carries a risk of misclassification. Detailed treatment data, including cumulative PRRT dose, number of cycles, dosimetry, and precise chemotherapy exposure, were not available, limiting assessment of dose-response relationships and treatment sequencing. Outcome adjudication, such as confirmation by bone marrow biopsy, was also not available.

Follow-up may also have been too short to capture late-onset t-MNs, as prior studies have shown median latency periods exceeding 2 to 4 years. In addition, biologic variables with emerging relevance to PRRT-related toxicity, including clonal hematopoiesis, cytogenetics, and germline predisposition, were not captured, and residual confounding and selection bias inherent to real-world database analyses could not be excluded.

Study Design and Rationale

PRRT has transformed the treatment of NETs, improving disease control and progression-free survival. However, as patients live longer after treatment, delayed hematologic toxicities, including t-MNs, have come into focus. In the phase 3 NETTER-1 trial (NCT01578239), the t-MN risk with lutetium Lu 177 dotatate was approximately 1.8% to 2.3%,² and a systematic review of patients treated with PRRT for NETs reported a mean t-MN incidence of 2.61%.³ PRRT-associated t-MNs carry a poor prognosis, but large-scale, real-world data on their incidence and risk factors in North American patients have been limited.

The study had 2 aims: to characterize the real-world incidence and timing of t-MNs following lutetium Lu 177 dotatate in a large, multicenter cohort, and to identify clinical predictors of t-MN development, including demographic factors, comorbidities, and prior treatment exposures, to inform risk stratification and long-term surveillance.

The investigators conducted a retrospective cohort study using the TriNetX network, which aggregates electronic health records from 111 health care organizations. The analysis included adults aged 18 to 90 years with NETs who received lutetium Lu 177 dotatate between 2010 and 2026. The index date was the first administration of lutetium Lu 177 dotatate, and patients with preexisting MDS or AML were excluded. Incident t-MNs were assessed beginning 30 days after the index date, and the median follow-up was 650 days.

Prior and subsequent systemic therapies were evaluated using the TriNetX Treatment Pathways tool. Cumulative event probability was estimated using Kaplan-Meier methods, multivariable Cox proportional hazards regression identified factors associated with t-MN development, and Fisher’s exact test assessed subgroup differences.

The investigators concluded that the findings underscore the importance of individualized risk assessment and risk-adapted, long-term hematologic surveillance after PRRT. They added that prospective studies incorporating molecular biomarkers, clonal hematopoiesis assessment, and personalized dosimetry are needed to refine risk prediction and optimize patient selection for PRRT.

References

1. Parekh D, Shi CW, Pustake M, et al. Therapy-related myeloid neoplasms after radioligand therapy in neuroendocrine tumors: a multi-center real world analysis. Presented at: 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium; November 5-7, 2026; Las Vegas, NV.

2. Strosberg JR, Caplin ME, Kunz PL, et al. ¹⁷⁷Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22(12):1752-1763. doi:10.1016/S1470-2045(21)00572-6

3. Sonbol MB, Halfdanarson TR, Hilal T. Assessment of therapy-related myeloid neoplasms in patients with neuroendocrine tumors after peptide receptor radionuclide therapy: a systematic review. JAMA Oncol. 2020;6(7):1086-1092. doi:10.1001/jamaoncol.2020.0078