Characteristics and outcomes of therapy-related myeloid neoplasms after peptide receptor radionuclide/chemoradionuclide therapy (PRRT/PRCRT) for metastatic neuroendocrine neoplasia: a single-institution series
- 326 Downloads
Peptide receptor radionuclide/chemoradionuclide therapy (PRRT/PRCRT) is an effective therapy for metastatic neuroendocrine neoplasia (NEN), but therapy-related myeloid neoplasms (t-MN) remain of concern. The study reviewed the clinicopathological features and outcomes of patients who developed t-MN.
Retrospective analysis of all patients diagnosed with t-MN by 2016 WHO classification, from a cohort of 521 patients who received PRRT/PRCRT over a 12-year period. Molecular next-generation sequencing using an in-house 26-gene panel was performed.
Twenty-five of 521 (4.8%) patients were diagnosed with t-MN, including six acute myeloid leukaemia (AML) and 19 myelodysplastic syndrome (MDS). The median time from first cycle PRRT/PRCRT to diagnosis of t-MN was 26 months (range 4–91). Twenty-two of 25 (88%) patients had grade 1–2 pancreatic or small bowel NEN with moderate metastatic liver burden. Six patients (24%) had prior chemotherapy. Median number of PRRT cycles = 5 (22/25 (88%) with concomitant radiosensitising chemotherapy). All 25 patients achieved disease stabilisation (68%) or partial response (32%) on RECIST 1.1 at 3 months post-PRRT. At t-MN diagnosis, all patients presented with thrombocytopenia (median nadir 33 × 109/L, range 3–75) and 17 (68%) remained NEN progression-free. Marrow genetic analysis revealed unfavourable karyotype in 16/25 (66%) patients with tumour protein 53 (TP53) mutation in nine (36%). Azacitidine therapy was utilised in ten eligible patients, while four received induction chemotherapy for AML. The median overall survival from first PRRT was 62 months (19–94), but from t-MN diagnosis was only 13 months (1–56), with death due primarily to haematological disease progression.
The diagnosis of t-MN after PRRT/PRCRT is an infrequent but serious complication with poor overall survival. Most patients present with thrombocytopenia; unfavourable genetic mutations have a poor response to t-MN treatment. Prospective data are needed to explore potential pre-existing genetic factors and predictive biomarkers to minimise the risk of t-MN.
Keywords177Lu-DOTATATE Pepetide receptor radionuclide therapy Neuroendocrine neoplasm Therapy-related myeloid neoplasm Myelodysplasia Acute myeloid leukaemia
IG, KB, MM, RJH, and GK designed the study and wrote the manuscript. IG, KB, MM, IST, AI, ARK, TA, and GK identified cases and collected data. IG, PB, IST, AI, ARK, TA, MSH, GK performed data analysis. All authors contributed to and approved the final manuscript.
No funding source involved.
Compliance with ethical standards
Conflict of interest
RJH holds shares in Telix Pharmaceuticals on behalf of the Peter MacCallum Cancer Centre. MSH reports personal fees and non-financial support from Ipsen and Sanofi Genzyme, personal fees and other from Endocyte, outside the submitted work. All remaining authors declare no competing interests.
The study was approved by the Peter MacCallum Cancer Centre ethics committee as a retrospective audit with approval of waiver for patient consent (HREC Project number 18/61R). All patients had previously provided written, informed consent for PRRT/PRCRT under existing compassionate use guidelines. This article does not contain any studies with human participants or animals performed by any of the authors.
- 1.Hicks RJ, Kwekkeboom DJ, Krenning E, Bodei L, Grozinsky-Glasberg S, Arnold R, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasia: peptide receptor radionuclide therapy with radiolabeled somatostatin analogues. Neuroendocrinology. 2017;105:295–309. https://doi.org/10.1159/000475526.CrossRefPubMedGoogle Scholar
- 3.Bergsma H, Konijnenberg MW, Kam BL, Teunissen JJ, Kooij PP, de Herder WW, et al. Subacute haematotoxicity after PRRT with (177)Lu-DOTA-octreotate: prognostic factors, incidence and course. Eur J Nucl Med Mol Imaging. 2016;43:453–63. https://doi.org/10.1007/s00259-015-3193-4.CrossRefPubMedGoogle Scholar
- 4.Bodei L, Kidd M, Paganelli G, Grana CM, Drozdov I, Cremonesi M, et al. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. Eur J Nucl Med Mol Imaging. 2015;42:5–19. https://doi.org/10.1007/s00259-014-2893-5.CrossRefPubMedGoogle Scholar
- 10.Kong G, Johnston V, Ramdave S, Lau E, Rischin D, Hicks RJ. High-administered activity In-111 octreotide therapy with concomitant radiosensitizing 5FU chemotherapy for treatment of neuroendocrine tumors: preliminary experience. Cancer Biother Radiopharm. 2009;24:527–33. https://doi.org/10.1089/cbr.2009.0644.CrossRefPubMedGoogle Scholar
- 11.Hubble D, Kong G, Michael M, Johnson V, Ramdave S, Hicks RJ. 177Lu-octreotate, alone or with radiosensitising chemotherapy, is safe in neuroendocrine tumour patients previously treated with high-activity 111In-octreotide. Eur J Nucl Med Mol Imaging. 2010;37:1869–75. https://doi.org/10.1007/s00259-010-1483-4.CrossRefPubMedGoogle Scholar
- 12.Kong G, Thompson M, Collins M, Herschtal A, Hofman MS, Johnston V, et al. Assessment of predictors of response and long-term survival of patients with neuroendocrine tumour treated with peptide receptor chemoradionuclide therapy (PRCRT). Eur J Nucl Med Mol Imaging. 2014;41:1831–44. https://doi.org/10.1007/s00259-014-2788-5.CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Program CTE. Common Terminology Criteria for Adverse Events v4.0 (CTCAE). https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40. 2010.
- 15.Kenealy M, Hertzberg M, Benson W, Taylor K, Cunningham I, Stevenson W, et al. Azacitidine with or without lenalidomide in higher risk myelodysplastic syndrome & low blast acute myeloid leukemia. Haematologica. 2018. https://doi.org/10.3324/haematol.2018.201152.
- 17.Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21:4642–9. https://doi.org/10.1200/JCO.2003.04.036.CrossRefPubMedGoogle Scholar
- 18.Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–25. https://doi.org/10.1182/blood-2005-10-4149.CrossRefPubMedGoogle Scholar
- 20.Bergsma H, van Lom K, Raaijmakers M, Konijnenberg M, Kam B, Teunissen JJM, et al. Persistent hematologic dysfunction after peptide receptor radionuclide therapy with (177)Lu-DOTATATE: incidence, course, and predicting factors in patients with gastroenteropancreatic neuroendocrine tumors. J Nucl Med. 2018;59:452–8. https://doi.org/10.2967/jnumed.117.189712.CrossRefPubMedGoogle Scholar
- 21.Thang SP, Lung MS, Kong G, Hofman MS, Callahan J, Michael M, et al. Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN)—a single-institution retrospective analysis. Eur J Nucl Med Mol Imaging. 2018;45:262–77. https://doi.org/10.1007/s00259-017-3821-2.CrossRefPubMedGoogle Scholar
- 24.Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood. 1998;92:2322–33.PubMedGoogle Scholar
- 25.Montalban-Bravo G, Huang X, Naqvi K, Jabbour E, Borthakur G, DiNardo CD, et al. A clinical trial for patients with acute myeloid leukemia or myelodysplastic syndromes not eligible for standard clinical trials. Leukemia. 2017;31:318–24. https://doi.org/10.1038/leu.2016.303.CrossRefPubMedGoogle Scholar
- 26.Pollyea DA, Zehnder J, Coutre S, Gotlib JR, Gallegos L, Abdel-Wahab O, et al. Sequential azacitidine plus lenalidomide combination for elderly patients with untreated acute myeloid leukemia. Haematologica. 2013;98:591–6. https://doi.org/10.3324/haematol.2012.076414.CrossRefPubMedPubMedCentralGoogle Scholar
- 27.DiNardo C, Pollyea D, Pratz K, Thirman MJ, Letai A, Frattini M, et al. A phase 1b study of venetoclax (ABT-199/GDC-0199) in combination with decitabine or azacitidine in treatment-naive patients with acute myelogenous leukemia who are >= to 65 years and not eligible for standard induction therapy. Blood. 2015;126:327.CrossRefGoogle Scholar