Definition
AML is a type of heterogeneous hematological malignancy that originates from immature white blood cells (blasts) in the bone marrow, which may be derived from either a hematopoietic stem cell or a lineage-specific progenitor cell. “Acute” means that the leukemia may progress rapidly – AML generally spreads quickly to the bloodstream and can then spread to other parts of the body including the lymph nodes, spleen, central nervous system, and testicles.
Latest key takeaways
- Datamonitor Healthcare estimates that in 2018, there were 158,400 incident cases of acute myeloid leukemia (AML) worldwide, and expects that number to increase to 169,000 incident cases by 2027. Approximately 60% of newly diagnosed patients are eligible for intensive chemotherapy, such as the 7+3 regimen of cytarabine and daunorubicin.
- Since 2017, there have been nine new drugs approved for AML in the US, dramatically changing the treatment landscape. Gone is the era where all front-line patients received either 7+3 chemotherapy or a hypomethylating agent (decitabine or azacitidine). Many of the new therapies target specific segments of AML or patients with specific mutations. As such, there is currently little competition between the new therapies, but that will change as therapies receive label expansions and new competitors are approved.
- Two FLT3 inhibitors have been approved by the FDA for FLT3-mutated AML: Rydapt for front-line patients eligible for intensive chemotherapy, and Xospata for relapsed/refractory patients. Rydapt may soon face competition in the front-line FLT3 setting, as quizartinib, crenolanib, and Xospata are being evaluated in combination with standard chemotherapy and as single-agent maintenance therapies following either chemotherapy consolidation or hematopoietic stem cell transplant (HSCT). Approval in the lucrative maintenance setting would give these drugs a favorable long-term commercial outlook, as approximately 25–30% of AML patients have an FLT3 mutation.
- Tibsovo and Idhifa are approved in the US as oral, single-agent therapies for relapsed/refractory AML patients with IDH1 and IDH2 mutations, respectively. Tibsovo is also approved as a monotherapy for front-line patients over the age of 75 years. Potential approvals of Tibsovo and Idhifa in the EU will depend on the results of ongoing Phase III trials which are evaluating these drugs in combination with intensive induction (7+3) and consolidation chemotherapy and as maintenance therapy in front-line AML. The Phase III AGILE trial evaluating Tibsovo combined with azacitidine in front-line patients not suited for intensive therapy reported positive results in December 2021. Tibsovo may face competition from olutasidenib, an IDH1 inhibitor being evaluated in the relapsed/refractory setting in a pivotal single-arm Phase II trial. IDH1 mutations are present in 6–9% of AML patients, while IDH2 mutations are present in approximately 12% of cases.
- Mylotarg, an antibody-drug conjugate targeting CD33, is the only monoclonal antibody therapy approved for AML. Mylotarg combined with intensive chemotherapy is recommended for newly diagnosed (ND) patients with favorable cytogenetic risk (approximately 10% of patients eligible for intensive chemotherapy), and is approved in the US, EU, and Japan. Over 90% of AML patients are positive for CD33 expression.
- Vyxeos, a liposomal formulation of the 7+3 chemotherapy regimen, was approved in the US and EU for the treatment of ND patients with secondary AML after showing an improvement in overall survival compared to the 7+3 regimen in patients ≥60 years of age. Secondary AML accounts for approximately one third of new AML diagnoses, but most of these patients will be too frail for Vyxeos. Market access for Vyxeos is strengthened by positive recommendations from the US Centers for Medicare and Medicaid Services and from NICE in England and Wales.
- Venclexta combined with a hypomethylating agent is the new standard of care for ND AML patients not suited for intensive chemotherapy (approximately 40% of ND patients). A confirmatory Phase III trial evaluating Venclexta + azacitidine demonstrated a survival advantage (15 months vs 10 months) and supported regulatory approvals in the EU (May 2021) and Japan (March 2021). Venclexta is currently being evaluated in combination with novel agents in several trials, and a Phase III study (VIALE-M) is evaluating Onureg with and without Venclexta as maintenance therapy for AML patients in first remission after conventional chemotherapy.
- Daurismo is the first and only Hedgehog pathway inhibitor approved for AML. Daurismo is approved in combination with low-dose cytarabine (LDAC) for ND AML patients not suited for intensive chemotherapy, and will compete with Venclexta in this difficult-to-treat setting. However, in the US, hypomethylating agents are preferred over LDAC, so Venclexta may be preferred over Daurismo.
- Onureg, an oral formulation of azacitidine, increased overall survival and relapse-free survival in a Phase III trial and has been approved in the US (September 2020) and EU (June 2021) as a maintenance therapy following intensive chemotherapy for patients not suited for an HSCT.
- Dociparstat sodium (DSTAT), a glycosaminoglycan analog of heparin designed to have reduced anticoagulant effects, targets the CXCR4 pathway, which is involved in the homing and adhesion of AML cells to the bone marrow and is associated with resistance to systemic drugs. DSTAT is being developed in combination with intensive 7+3 chemotherapy for ND AML, with the aim of improving the rate of durable response. The DASH AML Phase III trial is enrolling patients with intermediate or unfavorable cytogenetic risk. The estimated primary completion date (PCD) for DASH AML is May 2024.
- Radgocitabine (DFP-10917) is a novel deoxycytidine analog that inactivates DNA polymerase and blocks DNA synthesis, in a similar fashion to cytarabine. The drug is delivered at low dose by continuous IV infusion for 14 days of each 28-day cycle. Radgocitabine is being evaluated in a Phase III trial against non-intensive therapy (low-dose cytarabine, hypomethylating agents, or Venclexta combination) or intensive therapy (high- or intermediate-dose cytarabine regimens) in AML patients in second or third relapse. The trial’s PCD is December 2022. Early data from relapsed/refractory AML patients are encouraging, but they come from a single-center, single-arm Phase I/II trial.
- Kronos Bio and Gilead’s entospletinib is a first-in-class spleen tyrosine kinase (SYK) inhibitor being developed for NPM1-mutated ND AML patients. NPM1 mutations are detected in ~30% of AML patients. A pivotal Phase III trial is evaluating entospletinib in combination with standard induction and consolidation chemotherapy in ND AML patients who are positive for the NPM1 mutation and are eligible for intensive chemotherapy. The primary endpoint is the rate of MRD-negative complete response (CR) following two cycles of induction, and the estimated PCD is December 2023.
- Otsuka’s Inqovi, an oral formulation of decitabine combined with cedazuridine, is being developed for patients with AML unsuited for intensive induction chemotherapy. In ASCERTAIN, a Phase III trial enrolling patients with myelodysplastic syndrome, Inqovi met the trial’s primary endpoint of demonstrating pharmacokinetic (PK) equivalence to intravenous decitabine. ASCERTAIN has now been extended to include patients with AML, but only in the EU. Otsuka is also developing ASTX030, an oral combination of azacitidine and cedazuridine. The ASTX030 trial has an estimated PCD of April 2024.
- Actinium Pharmaceuticals’ Iomab-B is an immunoconjugate of monoclonal antibody BC8 that targets CD45, a widely expressed antigen on leukemic cells, stem cells, and B cells, and radioisotope iodine-131 (I-131). The agent attaches to its target and destroys cancer cells and ablates the bone marrow through its radioactive payload. Iomab-B is the subject of one Phase III trial (SIERRA), assessing the agent as a conditioning treatment for enabling relapsed/refractory AML patients to access a bone marrow transplant, the only Phase III trial intended to offer a transplant to this patient population.
- Gilead’s magrolimab is a monoclonal antibody specific for CD47 and blocks the “don’t eat me” signal used by cancer cells to avoid being ingested by macrophages. Two Phase III trials are assessing magrolimab in AML: ENHANCE-2, evaluating magrolimab + azacitidine in ND TP53-mutant AML patients; and ENHANCE-3, evaluating magrolimab + Venclexta + azacitidine in ND AML patients who are ineligible for intensive therapy. TP53 mutations are seen in 5–10% of AML patients. In January 2022, Gilead announced that the FDA had placed a partial clinical hold on studies evaluating magrolimab in combination with azacitidine due to an apparent imbalance in investigator-reported suspected unexpected serious adverse events.
- Forma Therapeutics’ olutasidenib is aiming to become the second inhibitor of IDH1 to enter the AML market, after Tibsovo. Preliminary data from a Phase I/II trial show similar CR/CR with partial hematologic recovery (CRh) rates to those of Tibsovo in the relapsed/refractory setting, and its developers plan to submit an NDA for the drug.
- Uproleselan is a first-in-class inhibitor of E-selectin that is being evaluated in a pivotal Phase III trial in combination with chemotherapy for relapsed/refractory AML. The trial has an estimated PCD of April 2022. Zeltherva (galinpepimut-S) is a therapeutic vaccine targeting the WT1 antigen, developed as maintenance therapy for patients who have achieved CRh and who are ineligible for HSCT. Zeltherva’s outlook in the specialized setting of second complete remission (CR2) will depend on results from its Phase III REGAL trial.
- Key upcoming catalysts through 2022 include topline results from Phase III and/or pivotal trials for uproleselan (April 2022), Zeltherva (H1 2022), Iomab-B (mid-2022), crenolanib (November 2022), and radgocitabine (December 2022).
CONTENTS
8 OVERVIEW
8 Latest key takeaways
11 DISEASE BACKGROUND
11 Definition
11 Patient segmentation
15 Other risk factors
15 Symptoms
16 Diagnosis
17 TREATMENT
17 First-line treatment of AML consists of induction and consolidation
20 EPIDEMIOLOGY
20 Incidence methodology
23 MARKETED DRUGS
26 PIPELINE DRUGS
48 KEY REGULATORY EVENTS
48 NICE Reverses Venclyxto Refusal
48 EMA Says Yes To Eight New Medicines, Holds Fire On Others
49 PROBABILITY OF SUCCESS
50 LICENSING AND ASSET ACQUISITION DEALS
50 Molecular Partners Announces Research Collaboration With University Of Bern
50 Bristol Partners With Century On Cancer Cell Therapies
50 Actinium And EpicentRx Announce Research Collaboration
50 PDS Ties Up With NCI
51 Oncoheroes Grants Volasertib Global Rights To Notable Labs
51 Pleco Partners With Hyloris To Develop Novel Plecoid Agent
51 Aptose Partners With Hanmi To Target Myeloid Cancer
51 Takeda Buys Out Partner GammaDelta In Cell Therapy Push
52 Ipsen, Accent Team On Preclinical METTL3 Candidate
52 Pfizer To Buy Trillium For $2.26bn In A Hematology Pipeline Play
53 Ipsen Buys Into BAX Inhibitor, Targeting Certain Cancers
53 Advaxis And BioSight Agree To Merge
53 Janssen Biotech Unveils Collaboration With Vor Biopharma
53 Innovent Buys Into Ascentage, Opening New China Biopharma Chapter
54 Dismay For Argenx As J&J Pulls Out Of Lucrative Blood Cancer Pact
54 Catching Up With Fate: Deal With CRISPR Brings Nkarta Up In NK Cell Race
55 CytoImmune Acquires City Of Hope Cell Therapy IP
55 Sorrento Acquires Abivertinib Partner ACEA
55 Nippon Shinyaku Licenses Menarini’s Tagraxofusp For Japan
55 XOMA Gets Two Potential Revenue Streams From Viracta
56 Wugen Aligns With Alpha Biopharma For Asia Markets
56 CASI Obtains Greater China Rights To Cleave Cancer Candidate
56 Wugen To Use HCW Proteins In Cancer Cell Therapy Products
57 CLINICAL TRIAL LANDSCAPE
58 Sponsors by status
59 Sponsors by phase
60 Recent events
63 DRUG ASSESSMENT MODEL
70 MARKET DYNAMICS
71 FUTURE TRENDS
71 Venclexta is set to become a blockbuster in AML
71 Immunomodulators are being developed for AML
72 New drug launches, including therapies for relapsed/refractory disease, will drive growth in the AML market over the forecast period
72 FLT3 inhibitors are expected to move into the first-line maintenance setting
72 IDH inhibitor combinations are expected to move into earlier stages of AML
72 Oral hypomethylating agents are under development in AML
74 CONSENSUS FORECASTS
76 RECENT EVENTS AND ANALYST OPINION
76 CA-4948 for AML (April 4, 2022)
76 Tibsovo for AML (December 13, 2021)
78 Iomab-B for AML (December 11, 2021)
79 Quizartinib for AML (November 18, 2021)
80 CPI-613 for AML (October 28, 2021)
82 Pevonedistat for AML (September 1, 2021)
83 Tibsovo for AML (August 2, 2021)
84 Eprenetapopt for AML (July 21, 2021)
86 Eprenetapopt for AML (June 16, 2021)
88 Aspacytarabine for AML (June 4, 2021)
89 FF-10101 for AML (June 4, 2021)
90 FT-2102 for AML (May 20, 2021)
92 Xospata for AML (December 21, 2020)
94 Magrolimab for AML (December 6, 2020)
96 Venclexta for AML (December 6, 2020)
98 Actimab-A for AML (December 5, 2020)
99 KO-539 for AML (December 5, 2020)
101 SY-1425 for AML (December 5, 2020)
103 Motixafortide for AML (November 23, 2020)
105 Guadecitabine for AML (October 14, 2020)
108 KEY UPCOMING EVENTS
109 KEY OPINION LEADER INSIGHTS
110 BIBLIOGRAPHY
111 APPENDIX
LIST OF FIGURES
17 Figure 1: NCCN recommended induction regimens for patients <60 years old
18 Figure 2: NCCN recommended consolidation regimens for patients <60 years old
18 Figure 3: NCCN recommended induction regimens for patients ≥60 years old
19 Figure 4: NCCN recommended consolidation regimens for patients ≥60 years old
19 Figure 5: Relapse treatment regimens
22 Figure 6: Trends in incident cases of AML, 2018–27
26 Figure 7: Overview of pipeline drugs for AML in the US
26 Figure 8: Pipeline drugs for AML, by company
27 Figure 9: Pipeline drugs for AML, by drug type
27 Figure 10: Pipeline drugs for AML, by classification
49 Figure 11: Probability of success in the AML pipeline
57 Figure 12: Clinical trials in AML
57 Figure 13: Top 10 drugs for clinical trials in AML
58 Figure 14: Top 10 companies for clinical trials in AML
58 Figure 15: Trial locations in AML
59 Figure 16: AML trials status
60 Figure 17: AML trials sponsors, by phase
63 Figure 18: Datamonitor Healthcare’s drug assessment summary for AML
70 Figure 19: Market dynamics in AML
71 Figure 20: Future trends in AML
78 Figure 21: Tibsovo for AML (December 13, 2021): Phase III – AGILE (w/Azacitidine, IDH1)
84 Figure 22: Tibsovo for AML (August 2, 2021): Phase III – AGILE (w/Azacitidine, IDH1)
86 Figure 23: Eprenetapopt for AML (July 21, 2021): Phase II – Post-Transplant
88 Figure 24: Eprenetapopt for AML (June 16, 2021): Phase I/II – w/Venetoclax
89 Figure 25: Aspacytarabine for AML (June 4, 2021): Phase IIb – ELPIS (Newly Diagnosed)
92 Figure 26: FT-2102 for AML (May 20, 2021): Phase I/II – w/Azacitidine or Cytarabine
94 Figure 27: Xospata for AML (December 21, 2020): Phase II/III – LACEWING (w/Azacitidine)
96 Figure 28: Magrolimab for AML (December 6, 2020): Phase Ib – w/Azacitidine (AML/MDS)
98 Figure 29: Venclexta for AML (December 6, 2020): Phase Ib/II – w/FLAG-IDA (MD Anderson)
99 Figure 30: Actimab-A for AML (December 5, 2020): Phase I – w/CLAG-M
103 Figure 31: SY-1425 for AML (December 5, 2020): Phase II – AML/MDS
105 Figure 32: Motixafortide for AML (November 23, 2020): Phase IIb – BLAST (Consolidation)
107 Figure 33: Guadecitabine for AML (October 14, 2020): Phase III – ASTRAL-2
108 Figure 34: Key upcoming events in AML
LIST OF TABLES
12 Table 1: 2017 revision of the World Health Organization classification of AML
14 Table 2: AML risk status based on cytogenetics or molecular abnormalities
21 Table 3: Incident cases of AML, 2018–27
24 Table 4: Marketed drugs for AML
28 Table 5: Pipeline drugs for AML in the US
74 Table 6: Historical global sales, by drug ($m), 2016–20
75 Table 7: Forecasted global sales, by drug ($m), 2022–26
76 Table 8: CA-4948 for AML (April 4, 2022)
77 Table 9: Tibsovo for AML (December 13, 2021)
78 Table 10: Iomab-B for AML (December 11, 2021)
80 Table 11: Quizartinib for AML (November 18, 2021)
81 Table 12: CPI-613 for AML (October 28, 2021)
82 Table 13: Pevonedistat for AML (September 1, 2021)
83 Table 14: Tibsovo for AML (August 2, 2021)
85 Table 15: Eprenetapopt for AML (July 21, 2021)
87 Table 16: Eprenetapopt for AML (June 16, 2021)
88 Table 17: Aspacytarabine for AML (June 4, 2021)
90 Table 18: FF-10101 for AML (June 4, 2021)
91 Table 19: FT-2102 for AML (May 20, 2021)
93 Table 20: Xospata for AML (December 21, 2020)
94 Table 21: Magrolimab for AML (December 6, 2020)
97 Table 22: Venclexta for AML (December 6, 2020)
98 Table 23: Actimab-A for AML (December 5, 2020)
100 Table 24: KO-539 for AML (December 5, 2020)
101 Table 25: SY-1425 for AML (December 5, 2020)
104 Table 26: Motixafortide for AML (November 23, 2020)
106 Table 27: Guadecitabine for AML (October 14, 2020)