Skip to main content

Advertisement

SpringerLink
Log in

Trends in Clinical Benefits and Costs of Novel Therapeutics in AML: at What Price Does Progress Come?

  • Health Economics (N Khera, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Since 2017, eight novel agents have been approved for the treatment of acute myeloid leukemia (AML) in the USA. Here, we review the clinical benefits and costs associated with these drugs.

Recent Findings

For some of the newly-approved drugs, clinical benefit has been documented in randomized trials. Others received accelerated approval based on surrogate endpoints in early phase trials. All, however, carry significant costs and toxicities. Cost-effectiveness analyses are so far only available for midostaurin, CPX-351, and gemtuzumab ozogamicin.

Summary

Recently approved drugs for AML have varying levels of evidence for clinical effectiveness and because of associated high costs may further increase the overall economic burden of AML care. This issue is complex and whether novel AML drugs will cost-effective will depend on multiple factors, including their ability to improve survival and quality of life while simultaneously reducing the costs of healthcare resource utilization.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136–52. https://doi.org/10.1056/NEJMra1406184.

  2. Deschler B, de Witte T, Mertelsmann R, Lübbert M. Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica. 2006;91(11):1513–22.

  3. O’Donnell MR, Tallman MS, Abboud CN, Altman JK, Appelbaum FR, Arber DA, et al. Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2017;15(7):926–57. https://doi.org/10.6004/jnccn.2017.0116.

    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(4):424–47. https://doi.org/10.1182/blood-2016-08-733196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Krok-Schoen JL, Fisher JL, Stephens JA, Mims A, Ayyappan S, Woyach JA, et al. Incidence and survival of hematological cancers among adults ages >/=75 years. Cancer Med. 2018;7:3425–33. https://doi.org/10.1002/cam4.1461.

    Article  PubMed Central  Google Scholar 

  6. Bailey C, Richardson LC, Allemani C, Bonaventure A, Harewood R, Moore AR, et al. Adult leukemia survival trends in the United States by subtype: a population-based registry study of 370,994 patients diagnosed during 1995-2009. Cancer. 2018;124(19):3856–67. https://doi.org/10.1002/cncr.31674.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lichtman MA. A historical perspective on the development of the cytarabine (7days) and daunorubicin (3days) treatment regimen for acute myelogenous leukemia: 2013 the 40th anniversary of 7+3. Blood Cells Mol Dis. 2013;50(2):119–30. https://doi.org/10.1016/j.bcmd.2012.10.005.

    Article  CAS  PubMed  Google Scholar 

  8. Allen PB, Flowers CR. Balancing patient value and payer cost in hematologic malignancies: can it be done? Expert Rev Pharmacoecon Outcomes Res. 2018;18(2):123–6. https://doi.org/10.1080/14737167.2018.1444478.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Saret CJ, Winn AN, Shah G, Parsons SK, Lin PJ, Cohen JT, et al. Value of innovation in hematologic malignancies: a systematic review of published cost-effectiveness analyses. Blood. 2015;125(12):1866–9. https://doi.org/10.1182/blood-2014-07-592832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mahmoud D, Skikne BS, Kucmin-Bemelmans I, Alleman C, Hensen M. Overall economic burden of total treatment costs in acute myeloid leukemia throughout the course of the disease. Blood [Internet]. 2012 [cited 2019 Apr 23];120(21):3614. Available from: http://www.bloodjournal.org/content/120/21/3614?ssochecked=true.

  11. •• Stone RM, Mandrekar SJ, Sanford BL, 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(5):454–64. https://doi.org/10.1056/NEJMoa1614359 Phase 3 trial that demonstrated surival benefit when midostaurin added to 7+3 in FLT3-mutated AML. Led to approval of midostaurin in frontline treatment of FLT3-mutated AML.

  12. U.S. Food & Drug Administration. FDA approves gilteritinib for relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation. 2018. [cited 2019 Apr 23]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm627045.htm.

  13. Patel KP, Ravandi F, Ma D, Paladugu A, Barkoh BA, Medeiros LJ, et al. Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features. Am J Clin Pathol. 2011;135(1):35–45. https://doi.org/10.1309/AJCPD7NR2RMNQDVF.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. • Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722–31. https://doi.org/10.1182/blood-2017-04-779405 Phase 1/2 study demonstrating efficacy of venetoclax in combination with low-dose cytarabine among AML patients ineligible for intensive chemotherapy .

  15. • DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386–98. https://doi.org/10.1056/NEJMoa1716984 Phase 1b dose escalation and expansion study suggesting safety and efficacy of venetoclax in combination with hypomethylating agents in treatment-naïve AML among patients ineligible for intensive chemotherapy.

  16. • Wei AH, Strickland SA, Roboz GJ, Hou JZ, Fiedler W, Lin TL, et al. Safety and efficacy of venetoclax (VEN) plus low-dose cytarabine (LDAC) in treatment-naive patients (PTS) aged >= 65 years with acute myeloid leukemia (AML). Ann Hematol. 2017;96:S85-S Phase 1/2 study demonstrating efficacy of venetoclax in combination with low-dose cytarabine among AML patients ineligible for intensive chemotherapy.

  17. • DiNardo CD, 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(1):7–17. https://doi.org/10.1182/blood-2018-08-868752 Phase 1b dose escalation and expansion study suggesting safety and efficacy of venetoclax in combination with hypomethylating agents in treatment- naïve AML among patients ineligible for intensive chemotherapy .

  18. •• 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. 2018. 9;33(2):379–1389. https://doi.org/10.1038/s41375-018-0312-9. Randomized trial demonstrating a 4-month survival benefit among elderly patients treated with glasdegib in combination with low-dose cytarabine vs. low-dose cytarabine .

  19. Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126(3):291–9. https://doi.org/10.1182/blood-2015-01-621664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Feldman EJ, Lancet JE, Kolitz JE, Ritchie EK, Roboz GJ, List AF, et al. First-in-man study of CPX-351: a liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia. J Clin Oncol. 2011;29(8):979–85. https://doi.org/10.1200/JCO.2010.30.5961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wei AH, Tiong IS. Midostaurin, enasidenib, CPX-351, gemtuzumab ozogamicin, and venetoclax bring new hope to AML. Blood. 2017;130(23):2469–74. https://doi.org/10.1182/blood-2017-08-784066.

    Article  CAS  PubMed  Google Scholar 

  22. •• Lancet JE, Uy GL, Cortes JE, 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(26):2684–92. https://doi.org/10.1200/JCO.2017.77.6112 Randomized study of CPX-351 vs. 7 + 3 among patients with newly diagnosed secondary acute myeloid leukemia demonstrating survival benefit .

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. •• Hills RK, Castaigne S, Appelbaum FR, Delaunay J, Petersdorf S, Othus M, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15(9):986–96. https://doi.org/10.1016/S1470-2045(14)70281-5 Meta-analysis demonstrating reduced risk of relapse and improved survival among patients with newly diagnosed AML treated with GO in addition to induction chemotherapy .

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Network NCC. Acute Myeloid Leukemia 1.2019. 2018. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed January 21, 2019.

  25. Taksin AL, Legrand O, Raffoux E, de Revel T, Thomas X, Contentin N, et al. High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group. Leukemia. 2007;21(1):66–71. https://doi.org/10.1038/sj.leu.2404434.

    Article  CAS  PubMed  Google Scholar 

  26. Rydapt (midostaurin) [prescribing information]. East Hanover: NJ: Novartis Pharmaceuticals Corporation. 2018.

  27. ™ L. LexiDrugs Walters Kluwer Health, Inc, uptodate.com. Accessed January 30 2019.

  28. • Stein E, Xie J, Duchesneau E, Bhattacharyya S, Vudumula U, Ndife B, et al. Cost effectiveness of midostaurin in the treatment of newly diagnosed flt3-mutated acute myeloid leukemia in the United States. Pharmacoeconomics. 2019;37(2):239–53. https://doi.org/10.1007/s40273-018-0732-4 Cost-effectivness evaluation of midostaurin in the treatment of newly diagnosed FLT3-mutated AML.

    Article  PubMed  Google Scholar 

  29. Xospata (gilteritinib) [prescribing information]. Northbrook: Astellas Pharma US, Inc. 2018.

  30. Idhifa (enasidenib) [prescribing information]. Summit: Celgene Corporation. 2017.

  31. Tibsovo (ivosidenib) [prescribing information]. Cambridge: Agios Pharmaceuticals, Inc. 2018.

  32. Savage P. Approvals in 2016: cost-benefit challenges of new anticancer agents. Nat Rev Clin Oncol. 2017;14(3):133–4. https://doi.org/10.1038/nrclinonc.2017.12.

    Article  PubMed  Google Scholar 

  33. Vyxeos (daunorubicinand cytarabine [liposomal]) [prescribing information]. Jazz Pharmaceuticals Inc. 2017.

  34. Mylotarg (gemtuzumab ozogamicin) [prescribing information]. Philadelphia: Wyeth Pharmaceuticals. 2018.

  35. Bosshard R, O'Reilly K, Ralston S, Chadda S, Cork D. Systematic reviews of economic burden and health-related quality of life in patients with acute myeloid leukemia. Cancer Treat Rev. 2018;69:224–32. https://doi.org/10.1016/j.ctrv.2018.07.005.

    Article  PubMed  Google Scholar 

  36. Menzin J, Lang K, Earle CC, Kerney D, Mallick R. The outcomes and costs of acute myeloid leukemia among the elderly. Arch Intern Med. 2002;162(14):1597–603.

    Article  PubMed  Google Scholar 

  37. Redaelli A, Botteman MF, Stephens JM, Brandt S, Pashos CL. Economic burden of acute myeloid leukemia: a literature review. Cancer Treat Rev. 2004;30(3):237–47. https://doi.org/10.1016/j.ctrv.2003.11.002.

    Article  PubMed  Google Scholar 

  38. Nerich V, Lioure B, Rave M, Recher C, Pigneux A, Witz B, et al. Induction-related cost of patients with acute myeloid leukaemia in France. Int J Clin Pharm. 2011;33(2):191–9. https://doi.org/10.1007/s11096-010-9462-1.

    Article  PubMed  Google Scholar 

  39. Leunis A, Blommestein HM, Huijgens PC, Blijlevens NM, Jongen-Lavrencic M, Uyl-de Groot CA. The costs of initial treatment for patients with acute myeloid leukemia in the Netherlands. Leuk Res. 2013;37(3):245–50. https://doi.org/10.1016/j.leukres.2012.09.018.

    Article  PubMed  Google Scholar 

  40. Fedele PL, Avery S, Patil S, Spencer A, Haas M, Wei A. Health economic impact of high-dose versus standard-dose cytarabine induction chemotherapy for acute myeloid leukaemia. Intern Med J. 2014;44(8):757–63. https://doi.org/10.1111/imj.12478.

    Article  CAS  PubMed  Google Scholar 

  41. Walter RB, Taylor LR, Gardner KM, Dorcy KS, Vaughn JE, Estey EH. Outpatient management following intensive induction or salvage chemotherapy for acute myeloid leukemia. Clin Adv Hematol Oncol. 2013;11(9):571–7.

    PubMed  PubMed Central  Google Scholar 

  42. Vaughn JE, Othus M, Powell MA, Gardner KM, Rizzuto DL, Hendrie PC, et al. Resource utilization and safety of outpatient management following intensive induction or salvage chemotherapy for acute myeloid leukemia or myelodysplastic syndrome: a nonrandomized clinical comparative analysis. JAMA Oncol. 2015;1(8):1120–7. https://doi.org/10.1001/jamaoncol.2015.2969.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Preussler JM, Meyer CL, Mau LW, Majhail NS, Denzen EM, Edsall KC, et al. Healthcare costs and utilization for patients age 50 to 64 years with acute myeloid leukemia treated with chemotherapy or with chemotherapy and allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2017;23(6):1021–8. https://doi.org/10.1016/j.bbmt.2017.02.017.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Bell JA, Galaznik A, Farrelly E, Blazer M, Murty S, Ogbonnaya A, et al. Economic burden of elderly patients with acute myeloid leukemia treated in routine clinical care in the United States. Leuk Res. 2018;71:27–33. https://doi.org/10.1016/j.leukres.2018.06.010.

    Article  PubMed  Google Scholar 

  45. Knight TGRM, Bohannon L, Blackwell E, Ai J, Ragon B, Davis R, et al. Patient reported financial toxicity in acute leukemia. Blood. 2018;132(Suppl 1):4796. https://doi.org/10.1182/blood-2018-99-119163.

  46. • Tremblay G, Dolph M, Patel S, Brandt P, Forsythe A. Cost-effectiveness analysis for midostaurin versus standard of care in acute myeloid leukemia in the United Kingdom. Cost Eff Resour Alloc. 2018;16:33. https://doi.org/10.1186/s12962-018-0153-4 Cost-effectiveness analysis evaluating addition of midostaurin to 7 + 3 in treatment of newly diagnosed FLT3-mutated AML.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Shen C, Zhao B, Liu L, Shih YT. Adherence to tyrosine kinase inhibitors among Medicare Part D beneficiaries with chronic myeloid leukemia. Cancer. 2018;124(2):364-73. https://doi.org/10.1002/cncr.31050.

  48. Jiang Q, Wang H, Yu L, Gale RP. Higher out-of-pocket expenses for tyrosine kinase-inhibitor therapy is associated with worse health-related quality-of-life in persons with chronic myeloid leukemia. J Cancer Res Clin Oncol. 2017;143(12):2619-30. https://doi.org/10.1007/s00432-017-2517-0.

  49. Shen C, Zhao B, Liu L, Shih YT. Financial Burden for Patients With Chronic Myeloid Leukemia Enrolled in Medicare Part D Taking Targeted Or al Anticancer Medications. J Oncol Pract. 2017;13(2):e152-e62. https://doi.org/10.1200/JOP.2016.014639.

  50. Dusetzina SB, Winn AN, Abel GA, Huskamp HA, Keating NL. Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia. J Clin Oncol. 2014;32(4):306-11. https://doi.org/10.1200/JCO.2013.52.9123.

  51. Jensen IS, Wu E, Sacks NC, Cyr PL, Chung KC. Budget impact analysis of using daunorubicin-cytarabine liposome in patients with newly diagnosed therapy-related AML or AML and myelodysplasia-related changes. Am Health Drug Benefits. 2018;11(7):380–6.

    PubMed  PubMed Central  Google Scholar 

  52. Kansal A, Du M, Herrera-Restrepo O, Leipold R, Ryan RJ, Louie AC, et al. Cost-effectiveness of CPX-351 versus 7+3 regimen in the treatment of treatment-related acute myeloid leukemia (tAML) or AML with myelodysplasia-related changes (MRC). Blood [Internet]. 2017 [cited 2019 Apr 23];130(Suppl 1):4674. https://www.bloodjournal.org/content/130/Suppl_1/4674.

  53. Walter RB, Mamolo C, Welch V, Brockbank J, Cawson M, Knight C, Wilson M. Budget impact analysis for gemtuzumab ozogamicin in CD 33+ acute myeloid leukemia. World Congress of the International Society of Hematology 2. Presented at the XXXVII World Congress of the International Society of Hematology (ISH), September 13–16, 2018; Vancouver, Canada.

  54. Chen Q, Jain N, Ayer T, Wierda WG, Flowers CR, O’Brien SM, et al. Economic burden of chronic lymphocytic leukemia in the era of oral targeted therapies in the United States. J Clin Oncol. 2017;35(2):166–74. https://doi.org/10.1200/JCO.2016.68.2856.

    Article  CAS  PubMed  Google Scholar 

  55. • Schnipper LE, Davidson NE, Wollins DS, Blayney DW, Dicker AP, Ganz PA, et al. Updating the American Society of Clinical Oncology Value Framework: revisions and reflections in response to comments received. J Clin Oncol. 2016;34(24):2925–34. https://doi.org/10.1200/jco.2016.68.2518 Budget impact analysis evaluating addition of CPX 351 in treatment of adults with newly diagnosed secondary AML.

    Article  PubMed  Google Scholar 

  56. Carlson RW, Jonasch E. NCCN Evid Blocks. 2016;14(5S):616–9. https://doi.org/10.6004/jnccn.2016.0177.

    Article  Google Scholar 

Download references

Acknowledgments

R.B.W. is a Leukemia & Lymphoma Society Scholar in Clinical Research.

Author information

Authors and Affiliations

  1. Department of Medicine, Virginia Tech Carilion School of Medicine, 2 Riverside Dr., Roanoke, VA, 24016, USA

    Jennifer E. Vaughn

  2. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Veena Shankaran & Roland B. Walter

  3. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Veena Shankaran

  4. Division of Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA

    Veena Shankaran

  5. Department of Pharmacy, University of Washington School of Medicine, Seattle, WA, USA

    Veena Shankaran

  6. Department of Pharmacy, Seattle Cancer Care Alliance, Seattle, WA, USA

    Veena Shankaran

  7. Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA

    Roland B. Walter

  8. Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA

    Roland B. Walter

  9. Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA

    Roland B. Walter

Authors
  1. Jennifer E. Vaughn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Veena Shankaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roland B. Walter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jennifer E. Vaughn.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Health Economics

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vaughn, J.E., Shankaran, V. & Walter, R.B. Trends in Clinical Benefits and Costs of Novel Therapeutics in AML: at What Price Does Progress Come?. Curr Hematol Malig Rep 14, 171–178 (2019). https://doi.org/10.1007/s11899-019-00510-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-019-00510-2

Keywords

Search

Navigation