Targeting the Untargetable: Novel Agents in Acute Myeloid Leukemia

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Directions in Pharmacy, December 2021, Volume 3, Issue 6
Pages: 20

Pharmacists have an important role in the optimization of AML therapies.

Acute myeloid leukemia (AML) is the most common acute adult leukemia with an estimated 20,000 new cases annually in the United States and a median age at diagnosis of 68 to 71 years.1 With a complex pathophysiology, AML’s genetic mutations can cause accelerated growth and impaired differentiation in hematopoietic stem cells, leading to accumulation of immature myeloid cells. Over time, immature myeloid cells make up a progressively greater portion of the marrow, leading to impaired hematopoiesis and development of AML’s hallmark symptoms.2

Diagnosis of AML can be made based on detection of certain chromosomal abnormalities or by presence of 20% or greater immature myeloid cells in the peripheral blood or bone marrow.2 Upon diagnosis of AML, prognostic factors such as physiologic age, functional status, and cytogenetics guide the selection of initial treatment.

Younger individuals with few comorbidities typically receive anthracycline and cytarabine containing chemotherapeutic regimens aimed at producing a deep and durable remission. Older patients unfit for intensive induction will alternatively be offered lower intensity induction therapy, most commonly a hypomethylating agent with or without venetoclax.1,2

Despite significant advances over the past decades, overall prognosis remains poor because of a high rate of disease relapse. The 5-year overall survival (OS) in patients with favorable-risk disease is 34% to 65% and drops to 2% to 14% in those with poor risk.2,3 To more effectively combat such an aggressive disease, the AML treatment landscape has drastically changed in recent years with the introduction of targeted agents; however, many genetic and molecular abnormalities detected in AML remain without any targeted pharmacotherapy options.

Molecular Targets

Innovative research in AML has been focused on developing pharmaceutical agents to target specific molecular abnormalities, also known as driver mutations.3 Current FDA-approved targeted agents include midostaurin and gilteritinib for FLT3 mutations and gemtuzumab ozogamicin for CD33-positive leukemic blasts.

Around 30% of newly diagnosed AML expresses a mutated form of FLT3, a transmembrane ligand-activated receptor tyrosine kinase. FLT3 is normally present on hematopoietic stem cells and promotes cell survival, differentiation, and proliferation.4 Midostaurin is a multitargeted FLT3 kinase inhibitor and has been shown to improve OS when added to standard AML induction chemotherapy in patients with FLT3 mutations.5 Gilteritinib is another multitargeted FLT3 kinase inhibitor; however, its approval is for relapsed or refractory (R/R) AML.6

Additionally, over 80% of patients with AML express CD33 on their leukemic cells.7 A CD33-targeted monoclonal antibody conjugate, gemtuzumab ozogamicin works by binding to leukemic cells expressing CD33, which is internalized by the cell, and then releases cytotoxic calicheamicin, leading to apoptosis.

However, initial studies with a single high dose of gemtuzumab ozogamicin demonstrated an unacceptable risk of sinusoidal obstruction syndrome,8 leading to its momentary removal from the market. A more recent study with lower, fractionated dosing has since demonstrated benefit in adding it to intensive induction chemotherapy in patients with favorable risk disease without excessive hepatotoxicity, leading to the incorporation of this agent as a first-line therapeutic in clinical guidelines.1,9

Although these therapies have improved treatment outcomes for patients with AML, there are numerous molecular abnormalities that confer a poor prognosis with no available targeted therapies (Table 1).10

The treatment of R/R AML also remains a substantial challenge as current treatment options are limited in their ability to produce durable response without excessive toxicity. Encouragingly, there are numerous novel targeted agents currently under investigation that may further change the treatment landscape of AML.10

Pipeline Drugs: Existing Molecular Targets

In the pipeline currently, quizartinib is a once-daily oral multitargeted tyrosine kinase inhibitor with activity against mutant FLT3. In a phase 3 study among patients with R/R AML, quizartinib was compared against salvage chemotherapy and was found to be associated with significantly improved OS, with median OS of 6.2 months, compared with 4.7 months with salvage chemotherapy.

In an exploratory analysis, composite complete response (CRc) was observed in 48% of patients receiving quizartinib, compared with 27% of patients receiving traditional chemotherapy. In the quizartinib arm, the response was more durable with a CRc median duration of 12.1 weeks vs 5 weeks for traditional chemotherapy. Consequently, a greater percentage of patients in the quizartinib arm were able to proceed
to hematopoietic stem cell transplant (32% vs 11%). Toxicities of quizartinib include QT interval prolongation, nausea, hepatotoxicity, and myelosuppression.11

Currently, quizartinib is currently being studied in newly diagnosed AML as an addition to induction and consolidation therapy.12 Quizartinib could be an alternative to midostaurin and gilteritinib in the newly diagnosed and R/R settings, respectively.

Another therapy in the pipeline is AMG330, which is a bispecific T-cell engager (BiTE) which redirects T lymphocytes expressing CD3 to target and attack CD33-expressing cells. AMG330 is currently undergoing a phase 1 study investigation in patients with R/R AML. Preliminary results have demonstrated response in 8 of 42 evaluable patients, with 3 exhibiting a complete response (CR).

It is important to take into account that this is a dose-finding study and a substantial number of non-responding patients may have been treated with doses lower than what will be recommended in the phase 2 study. Overall, it is too early to speculate the role AMG330 may play in AML therapy, but the observation of complete responses in the phase 1 study is encouraging. If eventually approved, AMG330 would be the first BiTE indicated for treatment of AML.13

Pipeline Drugs: Novel Molecular Targets

In the pipeline currently, devimistat (CPI-613) is an intravenously administered inhibitor of the ketoglutarate dehydrogenase (KGDH) and pyruvate dehydrogenase (PDH) complexes in the mitochondrial tricarboxylic acid cycle of leukemic cells, which results in decreased oxygen consumption and sensitization of leukemic cells to chemotherapy.14 In a phase 1 trial, devimistat was combined with high-dose cytarabine and mitoxantrone for treatment of patients with R/R AML. CR or CR with incomplete hematologic recovery was observed in 50% of patients and efficacy was similar in a subgroup of patients aged greater than 60 years.

Notable nonhematologic toxicities of grade 3 or greater included hyperglycemia, hypokalemia, hypophosphatemia, transaminase elevation, QT interval prolongation, and diarrhea. Devimistat is currently being evaluated to improve response rates in older patients with R/R AML, which is a historically challenging population to treat.15

Also in the pipeline, magrolimab is a CD47-targeted monoclonal antibody that blocks CD47 cell interactions with its ligand on macrophages, leading to phagocytic elimination of cancer cells. CD47 expression is upregulated in leukemic cells and functions as a macrophage checkpoint, providing an inhibitory signal that allows for tumor cell evasion of immune destruction by macrophages.16

Additionally, a phase 1b trial of magrolimab in combination with azacitidine in patients with newly diagnosed AML unfit for intensive chemotherapy with predominantly poor risk cytogenetics (65% with TP53 mutations) showed promising results. During the trial, overall response was achieved in 65% of patients, with 44% achieving CR. The objective response (OR) in patients with TP53 mutations was 71%, with 48% achieving a CR. Since TP53 mutations are associated with inferior response and survival, magrolimab may be an attractive therapeutic option for this patient population.16

Also in the pipeline, APR-246 (Eprenetapopt) is an intravenous agent that restores transcriptional activity of mutant TP53, a tumor suppressor gene, leading to apoptosis of leukemic cells with mutant TP53. TP53 mutations are detected in 10% to 20% of patients with AML and are associated with a poor prognosis, with median OS ranging from 6 to 8 months.17

APR-246 was evaluated in combination with azacitidine in a phase 1b/2 study in 55 adult patients (median age, 66 years) with newly diagnosed AML, myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia with TP53 mutation. Median OS was 10.8 months in the AML population with CR in 36%.

During the study, APR-246 was well tolerated with most grade 3 or greater toxicities being hematologic in nature.17 APR-246 is being further evaluated in an ongoing randomized, phase 3 study in patients with MDS.18 Should this trial yield positive results, future randomized controlled studies in patients with AML may be warranted to investigate its role in patients with a TP53 mutation.

Also in the pipeline, onvansertib is an oral serine-threonine kinase inhibitor that inhibits PLK-1. PLK-1 is highly expressed in leukemic cells and plays a role in centrosome maturation, spindle formation, and cytokinesis during mitosis. Inhibition of this process results in mitotic arrest and leukemic cell death.19

Onvansertib is currently being investigated in combination with low-dose cytarabine or decitabine in a phase 1b/2 study of patients with R/R AML. Of the 30 evaluable patients at the interim assessment, only 4 achieved OR. However, response was significantly associated with translationally controlled tumor protein biomarker positivity, indicating leukemic cell reliance on PLK-1–mediated pathways of survival.

Nonhematologic AEs of grade 3 or greater thus far include stomatitis and elevated bilirubin. Results have yet to be reported, but onvansertib could be a compelling option for AML with high PLK-1 expression.19

Targeted therapies continue to play a vital role in changing the landscape of AML treatment. Numerous investigational therapies in the pipeline for AML with novel mechanisms of action have so far demonstrated encouraging results in various populations of patients with AML. As these novel agents enter the market and further complicate treatment decisions, pharmacists will play an important role in optimizing therapies for patients with AML.

Jordan Tabish, PharmD, is a resident pharmacist - PGY2 oncology in the Department of Pharmacy at the University of Washington Medicine, and in the Department of Pharmacy at the Seattle Cancer Care Alliance in Seattle, Washington.

Ashley Chen, PharmD, is a hematology/oncology pharmacy resident in the Department of Pharmacy at Seattle Cancer Care Alliance, and in the Department of Pharmacy at the University of Washington Medicine in Seattle, Washington.

Ivan Huang, PharmD, BCOP, is a clinical pharmacy specialist
in the Department of Pharmacy at Seattle Cancer Care Alliance, and Department of Pharmacy, University of Washington Medicine in Seattle, Washington.

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