Will new drugs cure acute myeloid leukaemia?
Robert Peter Gale MD
Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK
Robert Peter Gale MD, PhD, DSc (hc), FACP, FRCPI (hon), FRSM, Centre for Haematology Research, Department of Immunology and Inflammation, Imperial College London, London, UK SW7 2AZ
Phone: +1 908 656 0484
Fax: +1 310 388 1320
Citation: Gale RP. Will new drugs cure acute myeloid leukaemia? Cell Ther Transplant 2021; 10(3-4): 4-7.
There are many new therapies approved to treat acute myeloid leukaemia (AML) including conventional and targeted drugs, and immune therapy. Most improve diverse outcomes including event- and relapse-free survivals and survival. However, most effect sizes are small and failure rates by 2 years are high. Based on the data reviewed 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.
Acute myeloid leukemia, targeted therapy, efficiency.
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
I consider 4 new drugs: (a) venetoclax ; (b) CPX-351 ; (c) CC-486 ; 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.
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 . 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 .
Gemtuzumab, an anti-CD33 monoclonal toxin-linked antibody, is the only approved immune therapy of AML . 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 . Table 1 displays data indicating not everyone benefits from a new drug such as venetoclax .
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.
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.
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.
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