Advertisement

Characteristics and outcomes of therapy-related myeloid neoplasms after peptide receptor radionuclide/chemoradionuclide therapy (PRRT/PRCRT) for metastatic neuroendocrine neoplasia: a single-institution series

  • Isaac GoncalvesEmail author
  • Kate Burbury
  • Michael Michael
  • Amir Iravani
  • Aravind S. Ravi Kumar
  • Tim Akhurst
  • Ing S. Tiong
  • Piers Blombery
  • Michael S. Hofman
  • David Westerman
  • Rodney J. Hicks
  • Grace Kong
Original Article
Part of the following topical collections:
  1. Oncology – Digestive tract

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

177Lu-DOTATATE Pepetide receptor radionuclide therapy Neuroendocrine neoplasm Therapy-related myeloid neoplasm Myelodysplasia Acute myeloid leukaemia 

Notes

Acknowledgements

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.

Funding

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.

Ethical approval

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.

References

  1. 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.CrossRefGoogle Scholar
  2. 2.
    Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of (177)Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376:125–35.  https://doi.org/10.1056/NEJMoa1607427.CrossRefGoogle Scholar
  3. 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.CrossRefGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 5.
    Kesavan M, Turner JH. Myelotoxicity of peptide receptor radionuclide therapy of neuroendocrine tumors: a decade of experience. Cancer Biother Radiopharm. 2016;31:189–98.  https://doi.org/10.1089/cbr.2016.2035.CrossRefGoogle Scholar
  6. 6.
    Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.  https://doi.org/10.1182/blood-2016-03-643544.CrossRefGoogle Scholar
  7. 7.
    Kayser S, Dohner K, Krauter J, Kohne CH, Horst HA, Held G, et al. The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML. Blood. 2011;117:2137–45.  https://doi.org/10.1182/blood-2010-08-301713.CrossRefGoogle Scholar
  8. 8.
    Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477–87.  https://doi.org/10.1056/NEJMoa1409405.CrossRefGoogle Scholar
  9. 9.
    Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488–98.  https://doi.org/10.1056/NEJMoa1408617.CrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.CrossRefGoogle Scholar
  12. 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.CrossRefGoogle Scholar
  13. 13.
    Claringbold PG, Price RA, Turner JH. Phase I-II study of radiopeptide 177Lu-octreotate in combination with capecitabine and temozolomide in advanced low-grade neuroendocrine tumors. Cancer Biother Radiopharm. 2012;27:561–9.  https://doi.org/10.1089/cbr.2012.1276.CrossRefGoogle Scholar
  14. 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. 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.
  16. 16.
    Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000;96:3671–4.Google Scholar
  17. 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.CrossRefGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 19.
    Bodei L, Modlin IM, Luster M, Forrer F, Cremonesi M, Hicks RJ, et al. Myeloid neoplasms after chemotherapy and PRRT: myth and reality. Endocr Relat Cancer. 2016;23:C1–7.  https://doi.org/10.1530/ERC-16-0258.CrossRefGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 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.CrossRefGoogle Scholar
  22. 22.
    Scarpa A, Chang DK, Nones K, Corbo V, Patch AM, Bailey P, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543:65–71.  https://doi.org/10.1038/nature21063.CrossRefGoogle Scholar
  23. 23.
    Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–88.Google Scholar
  24. 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.Google Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Isaac Goncalves
    • 1
    Email author
  • Kate Burbury
    • 1
  • Michael Michael
    • 2
    • 3
    • 4
  • Amir Iravani
    • 2
    • 5
  • Aravind S. Ravi Kumar
    • 2
    • 3
    • 5
  • Tim Akhurst
    • 2
    • 3
    • 5
  • Ing S. Tiong
    • 1
  • Piers Blombery
    • 1
  • Michael S. Hofman
    • 2
    • 3
    • 5
  • David Westerman
    • 1
  • Rodney J. Hicks
    • 2
    • 3
    • 5
  • Grace Kong
    • 2
    • 3
    • 5
  1. 1.Department of HaematologyPeter MacCallum Cancer CentreMelbourneAustralia
  2. 2.Nuclear Medicine DepartmentPeter MacCallum Cancer CentreMelbourneAustralia
  3. 3.Sir Peter MacCallum Department of OncologyThe University of MelbourneMelbourneAustralia
  4. 4.Department of Medical OncologyPeter MacCallum Cancer CentreMelbourneAustralia
  5. 5.Neuroendocrine Tumour ServicePeter MacCallum Cancer CentreMelbourneAustralia

Personalised recommendations