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Acute myeloid leukemia

Recent drug approvals for newly diagnosed acute myeloid leukemia: gifts or a Trojan horse?

Abstract

Since 2017 the US Food and Drug Administration (FDA) has approved glasdegib, venetoclax, ivosidenib, midostaurin, CPX- 351, and gemtuzumab ozogamicin (GO) to treat persons with newly diagnosed acute myeloid leukemia. The European Medicines Agency (EMA) has done likewise for midostaurin, CPX-351, and GO. While increasing options for persons, particularly older ones, for whom current therapy is unsatisfactory, or simply not given, these approvals raise several concerns. Although the venetoclax and glasdegib approvals were for persons considered “unfit” for intensive induction, the criteria for fitness were not well defined (age ≥75 per se being insufficient) and are frequently subjective, making it likely that many subjects in the venetoclax and glasdegib registration trials were fit for intensive induction; for example, none had performance status 3–4. Fitness must be assessed together with the potential efficacy of a proposed therapy. We note the modest complete remission rates and durations in the venetoclax + hypomethylating agent trial. Although these formed the basis for FDA approval, it is unclear that better results might not have obtained with more intense induction, as several studies, with considerably longer-follow up, have suggested. Hence, we question the venetoclax (and glasdegib) approvals absent randomized comparisons with intense induction. Given the uncertain relation in older individuals between survival and complete remission (CR), much less responses less than CR, we are skeptical of the sole use of these responses in the ivosidenib and venetoclax approvals; we also question the use of survival, without event-free survival, in the glasdegib approval. Noting the midostaurin and CPX-351 approvals included populations not participating in the registration studies we suggest means to address this issue as well as those involving fitness, randomization, and endpoints.

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References

  1. Medeiros B, Satram-Hoang S, Hurst D, Hoang KQ, Momin F, Reyes C. Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. Ann Hematol. 2015;94:1127–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Walter R, Othus M, Borthakur, Ravandi F, Cortes JE, Pierce SA, et al. Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment assignment. J Clin Oncol. 2011;29:4417–23.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Klepin H. Geriatric perspective: how to assess fitness for chemotherapy in acute myeloid leukemia. Hematol Am Soc Hematol Educ Program. 2014;2014:8–13.

    Article  Google Scholar 

  4. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults:2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019;33:379–89.

    Article  CAS  PubMed  Google Scholar 

  6. DiNardo C, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133:7–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wei A, Strickland S Jr, Hou J, Fiedler W, Lin TL, Walter RB, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol. 2019;37:1277–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bories P, Lamy S, Simand C, Bertoli S, Delpierre C, Malak S, et al. Physician uncertainty aversion impacts medical decision making for older patients with acute myeloid leukemia: results of a national survey. Haematologica. 2018;103:2040–8.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Cook R, Gill J, Prasad V. Registration studies—when should patients be deemed ineligible for aggressive therapy? Nat Rev Clin Oncol. 2019;16:333–4.

    Article  CAS  PubMed  Google Scholar 

  10. Krug U, Röllig C, Koschmieder A, Heinecke A, Sauerland MC, Schaich M, et al. Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes. Lancet. 2010;376:2000–8.

    Article  CAS  PubMed  Google Scholar 

  11. Appelbaum F, Gundacker H, Head D, Slovak ML, Willman CL, Godwin JE, et al. Age and acute myeloid leukemia. Blood. 2006;107:3481–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yanada M, Garcia-Manero G, Borthakur G, Ravandi F, Kantarjian H, Estey E. Relapse and death during first remission in acute myeloid leukemia. Haematologica. 2008;93:633–4.

    Article  PubMed  Google Scholar 

  13. Othus M, Kantarjian H, Petersdorf S, Ravandi F, Godwin J, Cortes J, et al. Declining rates of treatment-related mortality in patients with newly diagnosed AML given ‘intense’ induction regimens: a report from SWOG and MD Anderson. Leukemia. 2014;28:289–92.

    Article  CAS  PubMed  Google Scholar 

  14. Del Paggio J, Tannock I. The fragility of phase 3 trials supporting FDA-approved anticancer medicines: a retrospective analysis. Lancet Oncol. 2019;20:1065–9.

    Article  PubMed  Google Scholar 

  15. Soni P, Hartman H, Dess R, Abugharib A, Allen SG, Feng FY, et al. Comparison of population-based observational studies with randomized trials in oncology. J Clin Oncol. 2019;37:1209–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gyawali B, Hey S, Kesselheim AS. Assessment of the clinical benefit of cancer drugs receiving accelerated approval. JAMA Intern Med. 2019;179:906–13.

    Article  PubMed  PubMed Central  Google Scholar 

  17. DiMagno S, Glickman A, Emanuel E. Accelerated approval of cancer drugs-righting the ship of the US food and drug administration. JAMA Intern Med. 2019;179:922–3.

    Article  PubMed  Google Scholar 

  18. Beaver J, Howie L, Pelosof L, Kim T, Liu J, Goldberg KB, et al. A 25-year experience of US food and drug administration accelerated approval of malignant hematology and oncology drugs and biologics: a review. JAMA Oncol. 2018;4:849–56.

    Article  PubMed  Google Scholar 

  19. Sigal E. Accelerated approval program: for the benefit of patients. Huntington, NY, USA: The ASCO Post; June 25, 2019.

  20. Prassek V, Rothenberg-Thurley M, Suaerlan M, Herold T, Janke H, Ksienzyk B, et al. Genetics of acute myeloid leukemia in the elderly: mutation spectrum and clinical impact in intensively treated patients aged 75 years or older. Haematologica. 2018;103:1853–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sorror M, Storer B, Elsawy M, Fathi A, Brunner AM, Gerds A, et al. Intensive versus non-intensive induction therapy for patients (Pts) with newly diagnosed acute myeloid leukemia (AML) using two different novel prognostic models. Blood. 2016;128:216.

    Article  Google Scholar 

  22. Sorror M, Storer B, Fathi A, Gerds AT, Medeiros BC, Shami P, et al. Development and validation of a novel acute myeloid leukemia-composite model to estimate risks of mortality. JAMA Oncol. 2017;3:1675–82.

    Article  PubMed  PubMed Central  Google Scholar 

  23. de Lima M, Strom S, Keating M, Kantarjian H, Pierce S, O’Brien S, et al. Implications of potential cure in acute myelogenous leukemia: development of subsequent cancer and return to work. Blood. 1997;90:4719–24.

    Article  PubMed  Google Scholar 

  24. Schuurhuis G, Heuser M, Freeman S, Béné MC, Buccisano F, Cloos J, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131:1275–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hochman M, Othus M, Shaw C, Gardner K, Percical M-E, Hendrie P, et al. Does intensity of induction chemotherapy affect the impact of measurable residual disease (MRD) on prognosis in acute myeloid leukemia? J Clin Oncol. 2019;37:7031

  26. Halpern A, Othus M, Heubner E, Scott BL, Becker PS, Percival MM, et al. Phase 1/2 trial of GCLAM with dose-escalated mitoxantrone for newly diagnosed AML or other high-grade myeloid neoplasms. Leukemia. 2018;32:2352–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Buckley S, Kirtane K, Walter R, Lee SJ, Lyman GH. Patient-reported outcomes in acute myeloid leukemia- where are we now? Blood Rev. 2018;32:81–7.

    Article  PubMed  Google Scholar 

  28. El-Jawhari A, Abel G, Traeger L, Waldman L, Markovitz N, VanDusen H, et al. Quality of life and mood of older patients with acute myeloid leukemia (AML) receiving intensive and non-intensive chemotherapy. Leukemia. 2019;33:2393–402.

    Article  CAS  Google Scholar 

  29. Roboz G, DiNardo C, Stein E, de Botton S, Mims AS, Prince GT, et al. Ivosidenib (AG-120) induced durable remissions and transfusion independence in patients with IDH1-mutant untreated AML: results from a phase 1 dose escalation and expansion study. Blood. 2018;132:561.

    Article  Google Scholar 

  30. Burnett A, Russell N, Hunter A, Milligan D, Knapper S, Wheatley K, et al. Clofarabine doubles the response rate in older patients with acute myelogenous leukemia but does not improve survival. Blood. 2013;122:1384–94.

    Article  CAS  PubMed  Google Scholar 

  31. Burnett A, Hills RK, Hunter AE, Milligan D, Kell WJ, Wheatley K, et al. The addition of gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner comparison. Leukemia. 2013;27:75–81.

    Article  CAS  PubMed  Google Scholar 

  32. Chen X, Xie H, Wood B, Walter RB, Pagel JM, Becker PS, et al. Relation of clinical response and minimal residual disease and their prognostic impact on outcome in acute myeloid leukemia. J Clin Oncol. 2015;33:1258–64.

    Article  PubMed  Google Scholar 

  33. Norsworthy K, By K, Subramaniam S, Zhuang L, Del Valle PL, Przepiorka D, et al. FDA approval summary: glasdegib for newly diagnosed acute myeloid leukemia. Clin Cancer Res. 2019;25:6021–5. Epub 7 May 2019.

    Article  PubMed  Google Scholar 

  34. Estey E, Othus M, Lee S, Walter RB, Pagel JM, Becker PS, et al. New drug approvals in acute myeloid leukemia: what’s the best end point? Leukemia. 2016;30:521–5.

    Article  CAS  PubMed  Google Scholar 

  35. Stone R, Mandrekar S, Sanford B, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N. Engl J Med. 2017;377:454–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lancet J, Uy G, Cortes J, Newell LF, Lin TL, Ritchie EK, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36:2684–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yin J, LaPlant B, Uy G, Marcucci G, Blum W, Larson RA, et al. Evaluation of event-free survival as a robust end point in untreated acute myeloid leukemia (Alliance A151614). Blood Adv. 2019;3:1714–21.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Kantarjian H, DeAngelo D, Stelljes M, Martinelli G, Liedtke M, Stock W, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N. Engl J Med. 2016;375:740–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Krauss A, Gao X, Li L, Manning ML, Patel P, Fu W, et al. FDA approval summary (daunorubicin and cytarabine) liposome for injection for the treatment of adults with high-risk acute myeloid leukemia. Clin Cancer Res. 2019;25:2685–90.

    Article  PubMed  Google Scholar 

  40. Nardi V, Winkfield K, Ok C, Niemierko A, Kluk MJ, Attar EC, et al. Acute myeloid leukemia and myelodysplastic syndromes after radiation therapy are similar to de novo disease and differ from other therapy-related myeloid neoplasms. J Clin Oncol. 2012;30:2340–7.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Gale R, Bennett J, Hoffman FO. Who has therapy-related AML? Mediterr J Hematol Infect Dis. 2017;9:e2017025.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Goasguen J, Bennett J, Bain B, Brunning R, Vallespi MT, Tomonaga M, et al. Dyserythropoiesis in the diagnosis of the myelodysplastic syndromes and other myeloid neoplasms: problem areas. Br J Haematol. 2018;182:526–33.

    Article  PubMed  Google Scholar 

  43. Goasguen J, Bennett J, Bain B, Brunning RD, Vallespí MT, Tomonaga M, et al. Quality control initiative on the evaluation of the dysmegakaryopoiesis in myeloid neoplasms: difficulties in the assessment of dysplasia. Leuk Res. 2016;45:75–81.

    Article  PubMed  Google Scholar 

  44. Schlenk RF, Weber D, Fiedler W, Salih HR, Wulf G, Salwender H, et al. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myelogenous leukemia with FLT3 ITD. Blood. 2019;133:840–51.

    Article  CAS  PubMed  Google Scholar 

  45. Röllig C, Serve H, Hüttmann A, Noppeney R, Müller-Tidow C, Krug U, et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015;16:1691–9.

    Article  CAS  PubMed  Google Scholar 

  46. Serve H, Krug U, Wagner R, Sauerland MC, Heinecke A, Brunnberg U, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013;31:3110–8.

    Article  CAS  PubMed  Google Scholar 

  47. Jin S, Pazdur R, Sridhara R. Re-evaluating eligibility criteria for oncology clinical trials: analysis of investigational new drug applications in 2015. J Clin Oncol. 2015;35:3745–52.

    Article  Google Scholar 

  48. Percival ME, Othus M, Mirahsani S, Gardner KM, Shaw CM, Halpern AB, et al. Frequency, and effect on survival, of ineligibility for clinical trials in newly diagnosed acute myeloid leukemia and high-grade myeloid neoplasms. Blood. 2019;134(Supplement_1):3824.

  49. Estey E, Gale RP. Acute myeloid leukemia therapy and the chosen people. Leukemia. 2017;31:269–71.

    Article  CAS  PubMed  Google Scholar 

  50. Joffe S, Lynch H. Federal right-to-try legislation—threatening the FDA’s public health mission. N. Engl J Med. 2018;378:695–7.

    Article  PubMed  Google Scholar 

  51. Pocock S, Stone G. The primary outcome is positive—is that good enough? N. Engl J Med. 2016;375:971–9.

    Article  PubMed  Google Scholar 

  52. Kashoki M, Hanaizi Z, Yordanova S, Veselý R, Bouygues C, Llinares J, et al. A comparison of EMA and FDA decisions for new drug marketing applications 2014–2016: concordance, discordance, and why. Clin Pharmacol Ther. 2020;107:195–202.

  53. Kantarjian H, O’Brien S, Cortes J, Giles F, Faderl S, Jabbour E, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer. 2006;106:1090–8.

    Article  PubMed  Google Scholar 

  54. Etienne A, Esterni B, Charbonnier A, Mozziconacci MJ, Arnoulet C, Coso D, et al. Comorbidity is an independent predictor of complete remission in elderly patients receiving induction chemotherapy for acute myeloid leukemia. Cancer. 2007;109:1376–83.

    Article  PubMed  Google Scholar 

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Acknowledgements

Drs Fred Appelbaum (Fred Hutchinson Cancer Research Center and University of Washington, Seattle USA) and Christoph Röllig (Medizinische Klinik und Poliklinik I, Universitätsklinikum der Technischen Universität Dresden, Germany) provided many helpful suggestions. RPG acknowledges support from the National Institute of Health Research Biomedical Research Centre funding scheme. No commercial entity participated in the concept or preparation of the typescript.

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EE conceived the idea of the paper. EE, JEK, AE, MO, and RPG contributed to the organization and content and reviewed the final typescript.

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Correspondence to Elihu Estey.

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RPG is a part-time employee of Celgene Corp. The other authors declare that they have no conflict of interest.

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Estey, E., Karp, J.E., Emadi, A. et al. Recent drug approvals for newly diagnosed acute myeloid leukemia: gifts or a Trojan horse?. Leukemia 34, 671–681 (2020). https://doi.org/10.1038/s41375-019-0704-5

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