Disease Analysis: Acute Myeloid Leukemia (AML)

Definition

Acute myeloid leukemia (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 2021, there were 162,200 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. Out of the three contenders for Rydapt’s position in the first-line setting, quizartinib has taken the lead, with a priority review granted by the FDA in October 2022, a Marketing Authorization Application validated by the EMA in August 2022, and a label expansion to include use in newly diagnosed (ND) FLT3-ITD-positive AML patients filed in Japan in August 2022.
• 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 in combination with azacitidine 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. 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 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. In September 2022, the UK’s NICE recommended use of Onureg.
• 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 patients with intermediate or unfavorable cytogenetic risks, with the aim of improving the rate of durable response. The DASH AML Phase III trial was initially aiming to enroll 570 patients but stopped recruiting when only nine patients were enrolled. With an estimated primary completion date (PCD) brought forward from May 2024 to December 2022, the trial is unlikely to provide enough data to support a regulatory submission.
• 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, third, or fourth 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. In August 2022, the EMA accepted Otsuka’s Marketing Authorization Application (MAA) for Inqovi. 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 playload. Iomab-B is the subject of one Phase III trial (SIERRA), which is assessing the agent as a conditioning treatment for enabling relapsed/refractory AML patients to access a bone marrow transplant, and is 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, the FDA 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. The hold was lifted in April 2022 after an FDA review of the safety data from each affected trial.
• 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. Meanwhile, Zeltherva (galinpepimut-S) is a therapeutic vaccine targeting the WT1 antigen being 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 in the AML space include topline results from Phase III and/or pivotal trials for Zeltherva and uproleselan.