Will new drugs cure acute myeloid leukaemia?

Introduction

There are many new therapies approved to treat acute myeloid leukaemia (AML) including new conventional and targeted drugs and immune therapy. A summary of new AML drugs is displayed in Figure 1 increasing from one approval every 6 years to one approval every 150 days, a 12-fold increase.

The question I consider is whether these new therapies will cure AML. My discussion is divided into 3 categories: (1) conventional drugs; (2) targeted therapies; and (3) immune therapy.

Figure 1. Drug approvals in AML 1973-2020

New drugs

I consider 4 new drugs: (a) venetoclax [1]; (b) CPX-351 [2]; (c) CC-486 [3]; and (d) glasdegib (± low-dose cytarabine) [1-4]. Results of these, quite recent trials demonstrate that, although each new drug, alone or combined with previously-approved drugs improved outcomes, there remains a high rate of failures by 2 years.

Targeted drugs

Four targeted drugs are approved in AML including: (1) midostaurin; (2) gilteritinib; (3) enasidenib, and (4) ivosidenib. Results of recent trials of these 3 drugs are published, and the survival curves can be compared [5-8]. Except for enasidenib, these drugs improve outcomes but 2-year failure rates are high. A US trial Beat AML in persons with newly-diagnosed AML assigned subjects with druggable mutations to targeted or conventional drugs. There was no important difference in outcomes [9]. Therefore, according to recent estimates, current targeted drugs are likely to help only a limited subgroup (ca. 10 percent) of patients with acute myeloid leukemia [10].

Immune therapy

Gemtuzumab, an anti-CD33 monoclonal toxin-linked antibody, is the only approved immune therapy of AML [11]. It modestly improves outcomes and is rarely used.

Table 1. Differential effects of azacitidine and venetoclax in sub-cohorts

Table 2. Impact of azacitidine and venetoclax on reversing loss in life-expectancy

Table 3. Relative per year costs of some new drugs

Issues in new drug approvals

Several important issues confound analyses of the appropriate use of new drugs in AML including: (1) who is unfit for intensive therapy? (2) no randomized trial proves less-intensive therapy is better than conventional intensive therapy amongst persons who could receive either; (3) what is the best endpoint for new drug approvals; (4) what is the appropriate comparator for a new drug approval; (5) several recent approvals are for unstudied populations; (6) recent approvals will decrease enrollment in clinical trials; and (7) most new drugs improve survival only slightly and long-term results remain unsatisfactory [12]. Table 1 displays data indicating not everyone benefits from a new drug such as venetoclax [1].

Table 2 shows although azacitidine and venetoclax improve survival of older persons with AML there remains a major loss of potential life-expectancy. Finally, Table 3 displays the cost of several new AML drugs compared with conventional drugs.

Conclusions

Based on the data I review above I conclude: (1) many new AML therapies target specific AML sub-types; (2) none are proved better than intensive radiochemotherapy in persons who could receive either therapy; (3) there is disagreement defining who can or cannot receive intensive therapy; (4) there are important problems with several new drug approvals; (5) azacitidine and venetoclax may be the new standard-of-care in elderly persons with AML judged unable to receive intensive therapy; and (6) new drugs are welcome but have not had a big impact on long-term survival of most people with AML.

Acknowledgement

Presented in part at the Raisa Gorbacheva Symposium in St. Petersburg on 17 September 2021. RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme.

Conflict of interest

RPG is a consultant to: BeiGene Ltd., Fusion Pharma LLC, LaJolla NanoMedical Inc., Mingsight Pharmaceuticals Inc. and CStone Pharmaceuticals. Medical Director of FFF Enterprises Inc, on the Board of Directors: RakFond Foundation for Cancer Research Support. Scientific Advisory Board: Antegene Biotech LLC , StemRad Ltd. Author Contribution: I conceived, wrote and submitted the typescript for publication. Ethics Approval: None required.

References

1. DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and Venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi: 10.1056/NEJMoa2012971
2. Lancet JE, Uy GL, Newell LF, Lin TL, Ritchie EK, Stuart RK, et al. CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2021;8(7):e481-e491. doi: 10.1016/S2352-3026(21)00134-4. PMID: 34171279
3. Wei AH, Döhner H, Pocock C, Montesinos P, Afanasyev B, Dombret H, et al.; QUAZAR AML-001 Trial Investigators. Oral Azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Engl J Med. 2020; 383(26):2526-2537.
   doi: 10.1056/NEJMoa2004444
4. 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(2):379-389. doi: 10.1038/s41375-018-0312-9
5. 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):454-464. doi: 10.1056/NEJMoa1614359
6. Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019; 381(18):1728-1740. doi: 10.1056/NEJMoa1902688
7. DiNardo CD, Schuh AC, Stein EM, Montesinos P, Wei AH, de Botton S. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 2021; 22(11):1597-1608. doi: 10.1016/S1470-2045(21)00494-0
8. Roboz GJ, DiNardo CD, Stein EM, de Botton S, Mims AS, Prince GT, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020 Feb 13;135(7):463-471. doi: 10.1182/blood.2019002140
9. Burd A, Levine RL, Ruppert AS, Mims AS, Borate U, Stein EM, et al. Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial. Nat Med. 2020; 26(12):1852-1858. doi: 10.1038/s41591-020-1089-8
10. Prasad V, Gale RP. Precision medicine in acute myeloid leukemia: Hope, hype or both? Leuk Res. 2016; 48:73-77.
    doi: 10.1016/j.leukres.2016.07.011
11. Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, et al. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019; 104(1):113-119.
    doi: 10.3324/haematol.2018.188888
12. Estey E, Karp JE, Emadi A, Othus M, Gale RP. Recent drug approvals for newly diagnosed acute myeloid leukemia: gifts or a Trojan horse? Leukemia. 2020;34(3):671-681. doi: 10.1038/s41375-019-0704-5