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INTRODUCTION

Acute myeloid leukemia (AML) accounts for approximately 80% of acute leukemia diagnoses in adults and 32% of all leukemia diagnoses in the United States.^1,2 AML is diagnosed in both children and adults; however, the majority of cases occur in adults, and the incidence increases with age. The SEER Cancer Statistics Review demonstrate that the median age at diagnosis is 67 years, and one third of all patients are at least 75 years of age.³

Although age is not the sole determining factor of which therapy a patient will receive, or how aggressive the treatment will be, the prognosis of individuals 60 years or older is far worse than those of a younger age. Several factors are key in the poor prognosis of the older patient. The prevalence of unfavorable cytogenetic abnormalities, baseline myelodysplasia (e.g., AML developing from myelodysplastic syndrome [MDS]), increased comorbidities and thus intolerance to aggressive therapies, and increased incidence of multidrug resistance are all contributory in the poorer prognosis of the older patient.⁴ The diagnostic and prognostic implications of certain cytogenetic abnormalities are well described. For example, the translocation of portions of chromosome 15 and 17, t(15;17), is diagnostic for acute promyelocytic leukemia, which has a particularly favorable prognosis for most patients. AML that have core binding factor aberrations (such as inversion 16 and translocation of 8 and 21) also have a favorable prognosis.⁵

In contrast, deletions of portions of chromosome 5 or 7 demonstrate a poor prognostic outcome and are generally associated with therapy-related mutations. The presence of multiple cytogenetic abnormalities, also called complex cytogenetics, is a poor prognostic finding. Many cytogenetic abnormalities are not fully understood as to their prognostic impact and continue to be studied. See Table 1 for cytogenetic risk stratification.⁶

For younger patients and fit older patients, the classic paradigm of treatment has persisted since the 1970s.⁷ In this setting, treatment starts with induction, or induction of remission, with the goal of clearing leukemic cells from the bone marrow and general circulation. The induction regimen typically involves cytarabine plus an anthracycline (either idarubicin or daunorubicin) for 1 or 2 cycles. A common induction regimen is “7 + 3,” which is 7 days of intermediate-dose cytarabine and 3 days of an anthracycline.⁸ Published induction regimens also use fludarabine.⁶ If the AML has the specific surface marker CD33, gemtuzumab ozogamacin may also be included in the induction regimen.^6,8

Once remission is achieved, consolidation treatment ensues, with the goal of increasing the disease-free survival and rate of cure. High-dose cytarabine, or “HiDAC,” is an example of a commonly used consolidation therapy. It can consist of cytarabine 1.5 to 3 g/m² intravenously (IV) given every 12 hours for 6 doses or every 12 hours on days 1, 3, and 5 of a cycle for a total of 6 doses. Other consolidation regimens may incorporate an anthracycline also.^6,8 Allogeneic stem cell transplant is considered in specific situations as a postremission therapy.

Induction and consolidation therapy can be intense and toxic. Historically, maintenance strategies following consolidation have been attempted but have not resulted in survival advantages.^8–10 The goal of any maintenance therapy is to prolong survival and disease-free survival without negatively affecting a patient’s quality of life. Before the recent incorporation of hypomethylating agents (HMAs) and targeted therapies into AML management, maintenance therapy demonstrated survival benefit only in those with acute promyelocytic leukemia.¹¹ This review focuses on AML and its treatment outside the acute promyelocytic leukemia setting (Table 2).

Case 1

ML is a 56-year-old man who is fit and participates in marathons twice a year. He notices feeling more fatigued with his daily 10-mile runs. He also has noticed gingival bleeding when he brushes his teeth. A week ago, he had a syncopal episode and his wife brought him to the emergency department.

He is found to have AML with normal cytogenetics without mutations of FLT3, IDH1, or IDH2. This is determined to be intermediate-risk AML, and induction therapy with “7+3” cytarabine and idarubicin is initiated.

Many patients are not candidates for intensive induction therapy because of comorbidities, baseline performance status, or patient preference to not receive aggressive therapy.^8,12 Comorbid conditions such as renal dysfunction, decreased cardiac ejection fraction, or significant pulmonary disease could put the patient at increased risk for treatment-related toxicities and mortality. Chronologic age is not the sole factor in prognosis and treatment outcome, but patients older than 60 years of age have a significant decrease in complete remission following standard induction therapy with 7+3. Specifically, the complete remission rate in younger adults is 60% to 80% as compared with 40% to 60% in those older than 60 years.⁸ Maneuvers to improve complete remission rate by increasing anthracycline dose in induction therapy have been successful in patients younger than 65 years of age, but consistent benefits in those 65 years or older have not been demonstrated.⁸

Tools are available to estimate the probability of treatment response and early death with standard induction therapies in older patients, and these can help in making treatment decisions (the AML-Score tool and the AML–Composite tool). Fortunately, over the past decade, less intensive regimens have been found to induce remissions and prolong survival as compared with traditional intensive therapies in older patients or those with comorbidities.^6,13 Some of these less aggressive regimens are more frequently administered beyond the 5 to 6 months of the classic induction therapy followed by consolidation therapy, with use continuing as long as possible to maintain their clinical benefits.^14–17

Case 2

HK is a 76-year-old woman who presents to her primary care physician with shortness of breath, productive cough, and temperature of 102.2° F. A complete blood count and complete metabolic panel are checked and reveal the following: white blood cell count of 1.1 X10⁹/L, hemoglobin of 8.2 g/dL, platelet count of 68 X 10¹²/L. Differential: 22% neutrophils, 38% lymphocytes, 37% blasts, 3% basophils.

Her primary care provider tells her to go promptly to the local hospital and consults the local hematology/oncology specialists urgently.

MEDICATIONS USED FOR AML WITHOUT ACTIONABLE MUTATIONS

Hypomethylating Agents

Azacitidine and decitabine, pyrimidine nucleoside analogs of cytidine, cause cytotoxicity through hypomethylation of DNA and directly damage developing abnormal hematopoietic cells. Hypomethylation of DNA may restore normal function to genes that are critical for differentiation and proliferation.¹⁴

Unlike traditional chemotherapy, these drugs work slowly to remodel the processes of blood cell development. Both azacitidine and decitabine were first studied and used in patients with high-risk MDS that had a propensity to transform to AML. As established in the treatment schema for MDS, HMAs are administered until disease progression or until unacceptable toxicities, or “as long as patient continues to benefit” from the therapy.^14,18

The utility of treatment with a single HMA in AML has been documented in several settings.

Two phase 3 trials compared subcutaneous azacitidine with conventional care, which included low-dose cytarabine, intensive chemotherapy, or best supportive care in patients with AML.^13,19 The populations included patients who had unfavorable risk cytogenetics, with one trial focused exclusively on patients older than 65 years of age.¹³ Both trials demonstrated overall survival benefits for the azacitidine arms.

The AZA-AML-001 trial enrolled 488 patients with newly diagnosed AML who were 65 years of age or older. They were randomized 1:1 to azacitidine or a conventional care regimen (defined as standard induction chemotherapy, low-dose cytarabine, or supportive care only). Azacitidine was administered as 75 mg/m² per day subcutaneously for 7 consecutive days of a 28-day cycle for at least 6 cycles, thus serving as both induction and maintenance therapy. Although this trial did not specifically define the continuation of azacitidine as maintenance, more than half the azacitidine-treated patients received 6 or more treatment cycles, and one-third of patients received 12 or more cycles. Of the conventional-care patients, 64% received low-dose cytarabine, and 18% each received either best supportive care or induction chemotherapy. The median age was 75 years old in both groups, and 15% to 20% of participants had prior MDS, 1.2% had a secondary AML, and 35% of patients had poor-risk cytogenetics.¹³

Median overall survival was 10.4 months in the azacitidine arm and 6.5 months in the conventional care arm, with stratified hazard ratio (HR) of 0.85 (95% CI 0.69–1.03, P = 0.1009). The 1-year survival rate was also higher in the azacitidine arm, 46.5% versus 34.2% in the conventional care regimen group. Median overall survival was double that of patients receiving conventional care for patients with poor-risk cytogenetics, 6.4 months versus 3.2 months. The complete response rate (CR) and complete response with incomplete blood count recovery (CRi) were similar in the 2 groups, 27.8% with azacitidine and 25.1% the conventional care arm, highlighting that a survival advantage is observed despite low complete response rates. The 241 patients randomized to azacitidine received a median of 6 cycles, with a range of between 1 and 28 cycles, 52.5% of patients received 6 or more cycles, and 32.2% received 12 or more cycles. In reviewing safety and tolerability from this trial, a similar incidence of febrile neutropenia occurred in all 4 treatment options: 28% azacitidine, 27.5% best supportive care, 30.1% low-dose cytarabine, and 31% induction chemotherapy. An expected effect on all blood lineages occurred with azacitidine with grade 3–4 neutropenia (26.3%), thrombocytopenia (23.7%), anemia (15.7%), and leukopenia (6.8%), all higher in incidence compared with patients receiving best supportive care and similar to those receiving low-dose cytarabine. Nausea was controlled with the addition of antiemetic premedication. The authors reported that in accounting for patient-years of treatment exposure, the incidence of anemia, febrile neutropenia, neutropenia, and thrombocytopenia were lower in the azacitidine arm than either the low-dose cytarabine and induction chemotherapy arm.¹³

Decitabine, another HMA, has been studied in older patients with newly diagnosed AML. In a phase 3 trial, 485 patients were randomized 1:1 to receive decitabine or provider’s choice of either low-dose subcutaneous cytarabine or supportive care (best supportive care). Decitabine was administered as 20 mg/m² IV over 1 hour for 5 consecutive days of each 28-day cycle and continued as long as the patient was appreciating a clinical benefit and had no unacceptable toxicities. The median age of these patients was 73 years old, with 71% of patients being 70 years of age or older. Other high-risk features of this study population included secondary AML in 35.3% of participants, poor-risk cytogenetics in 36%, European Cooperative Oncology Group (ECOG) performance status of 2 in 24.3%, and a median baseline bone marrow blast percentage of 46%.²⁰

The phase 3 decitabine trial yielded an increase in median overall survival of 7.7 months versus 5.0 months in the traditional treatment arm, not a statistically significant improvement (P = 0.108) at the predefined cut-off time. Mature survival data ultimately did demonstrate a statistically significant benefit in overall survival from decitabine, but this analysis was unplanned and outside of the initial study protocol. Exploratory subgroup analyses indicated an improved benefit in patients aged 70 years of age or older and in those with de novo AML, baseline marrow blasts >30%, and ECOG performance status of 2. More participants in the decitabine group had a higher remission rate (17.8%) than those receiving standard care (7.8%, P = 0.001). The median treatment duration of decitabine was 4.4 months, but ranges were not shared in the publication. Key adverse effects of decitabine included decreased blood counts and associated toxicities: febrile neutropenia (24% of participants), pneumonia/bronchopneumonia (24%), thrombocytopenia (9%), and anemia (6%). Drug-related adverse events lead to discontinuation of decitabine in only 6% of patients. The authors concluded that decitabine achieved a higher response rate with possible survival advantage as compared with supportive care or low-dose cytarabine in this difficult-to-treat AML population.²⁰

HMAs have a favorable toxicity profile, particularly in comparison to traditional induction regimens, and thus can be tolerated for a longer duration of time. Until September 2020, the place in therapy of HMAs in AML was primarily in older individuals and/or those with significant comorbid conditions that would preclude traditional induction and consolidation treatment.⁶ However, due to these foundational studies, the groundwork was established that demonstrate HMAs as effective and tolerable for a longer duration of time in AML.

The QUAZAR AML-001 clinical trial was a phase 3, randomized, double-blind, placebo-controlled clinical trial that studied CC-486 as maintenance therapy in patients with confirmed complete remission following traditional induction and consolidation therapy for AML. CC-486 is an oral formulation of azacitidine. This trial enrolled 472 participants who were randomized 1:1 to CC-486 300 mg orally daily for 14 days of a 28-day cycle or placebo. Patients were 55 years old or older and were not eligible for a hematopoietic stem cell transplant. If the AML remained in remission, patients could continue on the study drug indefinitely. If follow-up bone marrow assessment indicated between 5% and 15% blasts, CC-486 could be extended to 21 days of administration of a 28-day cycle, and if the bone marrow assessment indicated more than 15% blasts, the treatment was stopped.²¹

The median age of patients in the QUAZAR trial was 68 years. Of the total population, approximately 90% of patients had de novo AML, 14% with poor-risk cytogenetics, and 80% had received at least 1 cycle of consolidation therapy. Minimal residual disease status at randomization was 43% in the study arm and 50% in the placebo arm. With a median follow-up of 41.2 months, the primary outcome of overall survival was 24.7 months in the study group and 14.8 months in the placebo arm, with a 9.9-month difference in survival and stratified HR of 0.69 (P = 0.0009). Relapse-free survival was also improved from 4.8 months in the placebo group to 10.2 months in the group receiving CC-486 (HR 0.65, P = 0.0001). The 1-year relapse rate was 71% in the placebo group and 53% in the study group. CC-486 was well tolerated, and patients received a median of 12 cycles, ranging from 1 to 80 cycles. Without premedication in cycles 1 and 2, mild nausea occurred in 65% and vomiting in 60% of participants receiving CC-486; both adverse effects were controlled in subsequent cycles with premedication. Among those in the active treatment arm, 50% of patients experienced diarrhea and 39% experienced constipation. Grade 3–4 hematologic toxicities occurred at expected rates (neutropenia, 41%; thrombocytopenia, 23%; anemia, 14%). The safety profile of CC-486 was consistent with that of injectable azacitidine. The authors concluded CC-486 is the first maintenance therapy to provide statistically significant and clinical meaningful improvements in overall survival and relapse-free survival following induction chemotherapy in patients with AML.²¹

Case 1, continued

ML has now completed 1 cycle of induction “7+3” therapy that was complicated by sepsis and a 17-day stay in an intensive-care unit. At day 25 following start of induction therapy, a bone marrow biopsy showed fewer than 5% blasts, and ML was considered to be in remission.

ML completed 2 cycles of consolidation HiDAC; however, he required hospital admission following cycle 2 of HiDAC due to pneumonia and was on a ventilator for 4 days.

During the induction and consolidation treatments for AML, his ECOG performance status changed from 0 to 2. He is deemed to not be a candidate for stem cell transplant at this time.

What treatment options does ML have?

Venetoclax

Venetoclax is an oral B-cell lymphoma 2 (BCL2) inhibitor that has demonstrated efficacy in a variety of malignancies. The BCL2 gene regulates apoptosis in cells, and overactivation of BCL-2 leads to increased anti-apoptotic activity in a cell.¹⁷BCL-2 facilitates the survival of leukemic cells and enables chemoresistance.²²

Venetoclax has been studied in the front-line setting of AML in several phase 1 and 2 clinical trials and has also been studied in the relapsed and refractory setting. Thus far, most published trials in the front-line setting use a combination of venetoclax with either a HMA or low-dose cytarabine. In a phase 1b dose-escalation and expansion trial, 145 patients were assigned to 1 of 3 doses of venetoclax (400, 800, or 1200 mg per day) with either azacitidine or decitabine at standard schedules and doses. All patients were hospitalized for the 3- to 5-day ramp-up dosing of venetoclax for cycle 1. Therapy with both drugs was continued until disease progression or unacceptable toxicity. Only the 400 mg and 800 mg per day venetoclax dosing were further evaluated in the expansion phase of the trial. The median age of enrolled patients was 74 years, 51% had intermediate-risk cytogenetics, the remaining 49% had high-risk cytogenetic features, and 25% had secondary AML. The complete response rate (CR + CRi) was 67% for all patients, and the median overall survival was 17.5 months; at the time of publication, the median overall survival had not been reached in the venetoclax 400 mg daily group. In comparing outcomes with dose of venetoclax, the venetoclax 400 mg group had a trend toward improved complete response rate versus the 800 mg group (73% versus 65% CR + CRi, P = 0.35). The response rates were comparable in the azacitidine and decitabine arms when given with venetoclax 400 mg daily (76% versus 71%, respectively).²²

The median number of completed cycles of venetoclax was 5, with a range of 1 to 25 cycles. The median time to best response was 2.1 months but was as long as 13.5 months after the start of treatment. As expected with newly diagnosed AML, baseline grade 3–4 cytopenias were frequent, with 71% of participants having neutropenia, 54% with thrombocytopenia, and 28% with anemia. This complicated the assessment of therapy-induced impact on blood counts. Overall, 74% of patients had some type of documented infection, with 45% reported as grade 3 to 4. Notably, febrile neutropenia occurred in 32% of patients, pneumonia in 18%, bacteremia/sepsis in 10%, and grade 3–4 fungal infections in 8%. In all, 7% of patients died of infectious complications during the study period. Gastrointestinal toxicities were the most common nonhematologic adverse events; these were primarily grades 1 and 2. All-grade nausea (61%), diarrhea (52%), constipation (48%), vomiting (30%), and decreased appetite (33%) were not severe enough to warrant therapy discontinuation. These authors concluded that the combination of venetoclax with an HMA was effective and well tolerated in older adults with newly diagnosed AML.²²

Venetoclax has also been studied with low-dose cytarabine in the front-line setting. A phase 1b/2 study used venetoclax 600 mg orally daily and cytarabine 20 mg/m² subcutaneously on days 1 though 10 of a 28-day cycle. The median age at diagnosis of enrolled individuals was 74 years, 49% had secondary AML, and 32% had poor-risk cytogenetics. Prior HMA was allowed; 29% of patients with antecedent MDS had received these agents. For all 82 patients enrolled, the median treatment duration was 4.2 months (range, 0.2 to 29 months), and the median number of cycles was 5. However, in patients who obtained a complete remission, the median number of cycles of low-dose cytarabine was 7 (range, 2 to 30). The median overall survival was 10.1 months, the CR+CRi was 54%, and the duration of response was 8.1 months. Notably, in patients without prior HMA exposure, the median overall survival was 13.5 months, CR + Cri rate was 62%, and duration of response was 14.8 months. Hematologic-related toxicities predominated: febrile neutropenia (42% of patients), thrombocytopenia (38%), neutropenia (27%), and anemia (27%). All-grade nonhematologic toxicities included nausea (70%), diarrhea (49%), hypokalemia (48%), and fatigue (43%); these were generally mild and did not impact dose intensity. Overall, 55% of patients required a dose interruption of venetoclax primarily due to delayed neutrophil and platelet recovery. The duration of venetoclax was decreased to either 14 or 21 days of the 28-day cycle in 47% of patients. No clinical tumor lysis syndrome was found in this trial, but 2 patients experienced laboratory-defined tumor lysis syndrome.²³

Glasdegib

Glasdegib is an oral Hedgehog pathway inhibitor. Chemotherapy resistance has been documented in myeloid leukemia cells that overexpress components of the Hedgehog pathway, and inhibition of this pathway enhances chemotherapy sensitivity. Specifically, glasdegib binds to Smoothened, a transmembrane protein involved in hedgehog signal transduction.²⁴

A phase 2, randomized clinical trial provides evidence of the efficacy of both single-agent, low-dose cytarabine and the combination of glasdegib with low-dose cytarabine. Patients were randomized 2:1 to either glasdegib 100 mg daily by mouth with cytarabine 20 mg (flat dose) subcutaneously twice a day for 10 consecutive days of a 28-day cycle or to cytarabine alone. Patients remained on treatment until disease progression, unacceptable toxicity, or patient refusal. The median age of patients was 77 years in the combination arm and 75 years in the low-dose cytarabine arm. Patients with both AML and high-risk MDS were enrolled, and 88.6% and 86.4% of patients had AML in the combination arm and cytarabine arm, respectively. More than 50% of patients in both arms had an ECOG performance status of 2. Baseline poor-risk cytogenetics were identified in 40.9% and 43.2% of patients randomized to the combination and cytarabine arms, respectively. Prior HMA therapy for MDS was allowed, and 17.1% in the combination group and 20.5% in the cytarabine group had received either azacytidine or decitabine before study entry.²⁴

The addition of glasdegib demonstrated an almost doubling of median overall survival, 8.8 months versus 4.9 months (HR 0.513, P = 0.0004). The 12-month survival rate for the combination group was 39.5% versus 9.5% in the low-dose cytarabine group. Complete remission rates were low with 17% and 2.3% of patients obtaining CR in the combination and cytarabine arms, respectively. Treatment durations were short primarily due to progressive disease or death. A 2.7-month median duration was reported for glasdegib and cytarabine (range, 0.1–31.9 months), as compared with 1.5 months of cytarabine (range, 0.2–7.9 months). Patients were able to maintain an 89% dose intensity of glasdegib.²⁴

Notable nonhematologic all-grade toxicities in the combination arm include: nausea (35.7% of participants), decreased appetite (33.3%), fatigue (31%), peripheral edema (26.2%), constipation (25%), dysgeusia (25%), dyspnea (25%), muscle spasms (22.6%), dizziness (21.4%), and vomiting (21.4%). Serious adverse events in the combination and cytarabine arms, respectively, included febrile neutropenia (28.6% and 17.1%) and pneumonia (22.6% and 17.1%). Acute kidney injury, serious muscle spasms, and elevated liver function tests were considered related to glasdegib in this trial. Elevations in the corrected QT interval by Fredericia (QTcF) of >480 ms and/or mean QTcF increase >60 ms from baseline occurred in 9 patients in the combination arm as compared with 5 patients in the cytarabine arm. These elevations lead to 2 permanent dose reductions and 2 temporary discontinuations of glasdegib. Overall, 44% of patients in the combination arm and 36.6% in the cytarabine-alone arm received subsequent treatment after this clinical trial treatment. The authors concluded that glasdegib with low-dose cytarabine has a favorable benefit-risk profile and may be a promising option for patients unsuitable for intensive induction therapy for AML.²⁴

Case 2, continued

HK is admitted to the hospital. Her peripheral WBC has a high percentage of blasts. A bone marrow biopsy is performed also revealing a high percentage of blasts at 52%.

A thorough medical history reveals long-standing hypertension and hypercholesterolemia. She has a history of Crohn’s disease but is currently off therapy.

Baseline ejection fraction by ECHO = 40%.

The inpatient leukemia team starts subcutaneous azacitidine based on findings from the AZA-AML-001 trial.

Case 1, Continued

Following ML’s complete remission to 7+3 induction and 2 cycles of HiDAC, the interdisciplinary team decides to start him on CC486 (oral azacitidine) maintenance therapy.

What educational and monitoring plan do you employ for ML? What resources do you want to share with him? How do you engage his caregivers?

MEDICATIONS USED BASED ON SPECIFIC MUTATIONAL FINDINGS

As new data emerge, the treatment of AML becomes more refined. Patients with AML with any of several known mutations have responded to specific medications with improved clinical outcomes. FMS-related tyrosine kinase 3 gene (FLT3) aberrations can lead to overgrowth of leukemia cells. It is known that AMLs that possess a mutation in the FLT3 gene have a poor prognosis.²⁵ Most AMLs with FLT3 mutations fall into the intermediate cytogenetic classification; thus, presence of this mutation further elucidates the prognosis of these AMLs. There are 2 main types of FLT3 mutations: internal tandem duplication mutations (ITD) and tyrosine kinase domain (TDK) subtypes.

FLT3: Midostaurin and Sorafenib

The addition of midostaurin to traditional induction therapy, consolidation, and a continued maintenance phase was assessed in the RATIFY Alliance/CALGB 10603 trial. In this large, randomized phase 3 clinical trial, 717 patients were randomized 1:1 to receive either midostaurin or placebo. Midostaurin was given as 50 mg orally twice a day on days 8 through 21 of 7+3 induction chemotherapy. This was repeated if re-induction was clinically warranted. All patients who appreciated a remission went on to receive HiDAC and midostaurin 50 mg orally twice a day on days 8 through 21 of each 28-day consolidation cycle. Patients could receive up to 4 cycles of consolidation. Midostaurin maintenance therapy of 50 mg orally twice a day for up to 12 cycles of 28 days was given to patients who were still in remission following the completion of consolidation. Important patient demographics included a median age of 47.9 years with a range of 18 to 60.9 years; only 7.1% had adverse (high-risk) cytogenetics. Regarding FLT3 mutations, TDK was observed in 22.6% of patients, ITD with low allelic ratio in 47.6%, and ITD with high allelic ratio in 29.8%. Midostaurin demonstrated an impressive improvement in overall survival of 74.7 months versus 25.6 months for placebo, P = 0.009, and an HR for death of 0.78. The 4-year overall survival was 51.4% in the midostaurin group and 44.3% in the placebo group. Focusing on toxicities that were higher in the midostaurin group, anemia grade 3 to 4 was more common (92.7% vs. 87.8%, P = 0.03), and grade 3+ rash (9.6%. vs. 5.6%, P = 0.05). Neutrophil and platelet recovery were similar between the groups in patients who did obtain a remission. The addition of midostaurin to standard treatment of FLT3-mutated AML demonstrated a practice-changing outcome and included a maintenance phase of midostaurin.²⁵

Midostaurin was similarly studied with standard induction, consolidation or allogeneic hematopoietic stem cell transplantation (HSCT), followed by a 12-month maintenance phase, in the AMLSG 16-10 trial. This was an open-label, historical control, phase 2 trial. The median age of patients was 54 years. A total of 292 patients were enrolled, 152 patients received at least one cycle of consolidation, and 134 underwent an allogeneic HSCT in first complete remission. In all, 97 patients received the planned single-agent maintenance midostaurin for 12 months following intensive induction and consolidation therapy. Also included in the outcomes are the data from 415 historical controls. The median overall survival was 26 months, and event-free survival of 13.2 months. When compared with the historical controls, addition of midostaurin resulted in an HR of 0.58 (P <0.001). Key toxicity findings included an increased incidence of cardiotoxicity at 22%, including arrythmias at a rate of 10%, and pulmonary toxicities such as pneumonia. Almost half of patients (46.6%) had to stop midostaurin due to toxicity. These toxicities are explored further below.²⁶

Sorafenib could be considered the original FLT3 inhibitor used in AML, and it was the only FLT3 inhibitor available for years.²⁷ Its use is highlighted in the SORAML trial, in which sorafenib was added to standard induction and consolidation therapy and continued for 12 months after the end of consolidation therapy. The SORAML trial was a phase 2, placebo-controlled, randomized study that enrolled 267 patients. Sorafenib was given irrespective of FLT3 mutation status. The event-free survival was 26 months in the sorafenib arm and 9 months in the placebo arm (P = 0.01). Long-term follow-up revealed a median overall survival in the placebo arm of 83 months and not reached in the sorafenib arm. Five-year overall survival was 52% in the placebo group and 61% in the sorafenib group, with an HR of 0.81 (P = 0.263), which is not statistically significant. Sorafenib is not approved by the U.S. Food and Drug Administration (FDA) for AML.²⁸

Sorafenib has been studied in the maintenance setting following allogeneic HSCT. Patients ages 18–60 years with FLT3-ITD mutation positive AML were randomized 1:1 to receive sorafenib 400 mg by mouth twice a day or placebo starting 30–60 days post-transplant. The 1-year incidence of relapse was 7.0% in the sorafenib group and 24.5% in the control group (HR 0.25, 95% CI 0.11–0.57; P = 0.0010). The most notable toxicities included infections (25% vs. 24%), acute graft-versus-host-disease (GVHD; 23% vs. 21%), chronic GVHD (18% vs. 17%), and hematologic toxicity (15% vs. 7%), in the sorafenib and placebo groups, respectively. There were no treatment-related deaths. The authors concluded that sorafenib maintenance post-transplantation can reduce relapse and is well tolerated in patients with FLT3-ITD AML undergoing allogeneic HSCT.²⁹

Additional FLT3 inhibitors are used in the relapsed and refractory AML that are outside the scope of this program.

IDH1: Ivosidenib

Isocitrate dehydrogenase (IDH) mutations lead to the overproduction of oncometabolites (2-hydroxyglutarate or 2-HG) that block cell differentiation and cause leukemogenesis.³⁰ IDH1 is located in the cytoplasm, and IDH2 is located on the mitochondria, and a third isoform, IDH3, is located in the mitochondrial matrix. IDH mutations are most commonly found in AML with normal cytogenetics and in the intermediate-risk group. IDH1 and IDH2 mutations are mutually exclusive and always accompany nucleophosmin-1, or NMP1, mutations. IDH mutations have been associated with poorer prognosis in AML.^30,31 In AML, the prevalence of mutated IDH1 is 6%–10%, and the prevalence of mutated IDH2 is 9%–13%.³²

Ivosidenib is approved by FDA for both newly diagnosed and relapsed or refractory AML that has a susceptible IDH1 mutation.¹⁵ In both settings, the drug is continued until disease progression or unacceptable toxicity. Ivosidenib has been studied in combination and as a single agent in patients with untreated AML.

Roboz and colleagues describe the outcomes of single-agent ivosidenib in newly diagnosed AML. Patients enrolled were not eligible for standard induction therapy. The drug was administered as 500 mg orally daily to 34 patients. The median age of these patients was 76.5 years, 76% had secondary AML, and 47% had prior treatment with an HMA. The complete remission (CR + CRi) rate was 42.4%, and the median overall survival was 12.6 months. One notable outcome was that 43% of patients who were transfusion-dependent before the start of the study became transfusion-independent. As is common with oral small molecule inhibitors, diarrhea was the most common toxicity (53%), followed by fatigue (47%), nausea (38%), and decreased appetite (35%). Differentiation syndrome (DS) can occur with IDH inhibitors. It was documented in 18% of patients in this trial; half of the patients had more severe cases, but none resulted in drug discontinuation.³¹

A phase 1b clinical trial combined azacitidine with either ivosidenib or enasidenib in untreated AML patients.^33,34 At the most recent update, only 11 patients had received the combination of azacitidine with ivosidenib 500 mg orally daily. The median age of these patients was 76 years. The median number of treatment cycles was 3 (range 1–13). Of the 11 patients, 8 appreciated a response, and 4 patients had a CR.³⁴ Fatigue (5), nausea (8), constipation (6), and diarrhea (4) were common toxicities. There are 2 ongoing phase 3 clinical trials looking at the combination of azacitidine and ivosidenib, which include the expansion phase of this trial and the phase 3 AGILE trial (NCT03173248).³³

IDH2: Enasidenib

Enasidenib is currently approved by FDA for relapsed and refractory AML but has not been studied in frontline settings.³⁵

Preliminary results of the enasidenib arm of the Beat AML Master trial have been described. The Leukemia & Lymphoma Society (LLS) Beat AML Master Trial is a precision medicine trial that matches eligible mutations with targeted treatments in patients 60 years of age or older with untreated AML. Patients were started on single-agent enasidenib 100 mg orally daily in 28-day cycles. If patients had not achieved a complete remission (CR or CRi) by the fifth cycle, azacitidine 75 mg/m²/day days 1–7 was added to each cycle. In all, 23 patients started therapy; the median age was 76 years, and 17% had high-risk cytogenetics. Complete remission (CR + CRi) was 43%. The median time on enasidenib monotherapy was 110 days, and on treatment (combination or monotherapy) was 138 days. Serious adverse events included DS (4), sepsis (4), grade 5 bleeding (1), elevated liver function tests (3), and respiratory failure (2). ³⁵

Reviewing the phase 1B clinical trial that combined azacitidine with either ivosidenib or enasidenib in untreated AML patients, 6 patients had received either 100 mg or 200 mg of enasidenib orally daily.^33,36 The median age of patients that received enasidenib was 68 years. The median number of enasidenib cycles was 9, range 1–13. The overall response rate reported was 66.7% with 33% CR, and notable toxicities were hyperbilirubinemia (66.7%), nausea (66.7%), and thrombocytopenia (16.7%).³⁴ Serious treatment-related adverse events included hyperbilirubinemia, febrile neutropenia, and a thromboembolic event.

The phase 2 expansion portion of the above trial enrolled 101 patients to receive enasidenib with azacitidine or azacitidine alone, randomized 2:1. Response rates were significantly higher in the combination arm, with a CR rates of 50% versus 12%, and overall response rate of 68% and 42% (P = 0.0155), in the combination group and azacitidine-alone group respectively. The median duration of response in the azacitidine arm was 10.2 months and was not yet reached in the combination arm. In the 68 participants receiving the combination, the following toxicities were reported: neutropenia (34%), thrombocytopenia (34%), anemia (21%), febrile neutropenia (12%), and DS (10%).³⁶

Case 2, Continued

HK continues in the hospital with newly diagnosed AML. She is now 6 days into her first cycle of subcutaneous azacitidine, when additional pathology results reveal that the AML is IDH-1 positive.

What treatment options does she have now? What educational points do you want to discuss with HK? What baseline and ongoing monitoring do you have planned?

CLINICAL CONSIDERATIONS AND MONITORING

Hypomethylating Agents

HMAs can be given intravenously, subcutaneously, and now orally. Compared with conventional chemotherapy, they have a milder hematologic and nonhematologic toxicity profile. This tolerable toxicity profile lends itself to chronic administration of these agents. In a key AML trial of azacitidine, only 3.4% of patients experienced treatment-emergent toxicities that required dose reductions, and 9.6% of patients required study discontinuation due to treatment-emergent adverse events.¹³ Hematologic toxicities associated with HMAs decrease with continued treatment. Patients receiving initial azacitidine therapy are also more likely and more able to receive subsequent antileukemic treatment, which extends overall survival by 5 months.¹³ Azacitidine possesses moderate emetogenic risk, and prophylactic antiemetics should be used concomitantly. Decitabine possesses minimal emetogenic risk and does not require standard prophylactic antiemetics.³⁷

Route of administration and duration of treatment per cycle are important factors to discuss with patients. Oral and injectable HMAs are generally given for 5 to 14 days out of a 28-day cycle. Subcutaneous azacitidine will require 2 to 4 separate injections per day of administration for most adult patients.¹⁴ The majority of patients have some degree of injection site reactions (92.9%), with approximately 10% experiencing grade 2 reactions (pain, edema, phlebitis, or lipodystrophy).³⁸ Some patients need to be switched from subcutaneous azacitidine due to skin reactions. For intravenous HMAs, consideration of central venous access device is warranted due to the multiple venipunctures for blood draws and therapy administration. If intravenous or subcutaneous routes are selected, patients in the clinic setting must present on multiple days of each cycle. This therapy requires careful consideration of the available resources of the patient, specifically regarding transportation to multiple appointments and time away from work for caregivers, if applicable.

CC486, or oral azacitidine, should be swallowed whole without splitting or crushing the tablets. For patients who cannot swallow and who do not have a nasogastric tube or gastric tube, no official recommendations for extemporaneous formulations are currently available. Patients should receive antiemetic prophylaxis prior to each dose for at least the first 2 cycles, but this can be discontinued if not necessary after cycle 2.¹⁶ Only 5% of patients discontinued treatment due to toxicity, demonstrating that this is a well-tolerated therapy.²¹ It is important to note that CC486 cannot be substituted for intravenous or subcutaneous azacitidine at this time.¹⁶

Venetoclax

Venetoclax is exquisitely effective at cytoreduction in patients with AML and other hematologic malignancies such as chronic lymphocytic leukemia (CLL). When leukemia cells rapidly die and break apart, known as tumor lysis, they release the intracellular contents into the circulation. This can cause increased levels of potassium, phosphorus, and uric acid and decreased levels of calcium that can lead to serious complications such as cardiac arrythmias, renal failure, and even death. This serious toxicity can occur with venetoclax. To control tumor lysis syndrome, the initial doses of venetoclax are ramped up over time. It must be noted that this ramp-up period is much quicker in AML than when venetoclax is used in CLL. In AML, a 3-day ramp-up is recommended as 100 mg on day 1, 200 mg on day 2, and 400 mg on day 3 when combined with a HMA. If venetoclax is used with low-dose cytarabine, then an additional increase to 600 mg is recommended. Hyperhydration is key during the initial days of venetoclax treatment. Use of preventive allopurinol or other antihyperuricemics is also imperative to prevent the clinical consequences of high uric acid.¹⁷ At diagnosis, many patients are already in the hospital during the start of this therapy so that electrolytes, renal function, blood counts, and fluid intake and output can be monitored at least daily. These parameters can be checked more frequently if the initial tumor burden is high, the baseline renal function is poor, or other factors warrant close monitoring.

Before obtaining a complete remission, venetoclax-containing regimens are generally given regardless of neutrophil counts; however, prophylactic anti-infective agents can be used to minimize the risk of life-threatening infections.¹⁷ Once remission is obtained, several interventions can be considered if grade 4 neutropenia or thrombocytopenia occurs: holding therapy until recovery, use of myeloid growth factors as applicable, or consideration of dose adjustment. Dose modifications are also warranted when venetoclax is used if liver disease is in the Child-Pugh C category or concomitant use of strong cytochrome P450 3A inhibitors and P-glycoprotein inhibitors cannot be avoided (Table 3). Venetoclax has low emetogenic potential and does not need antiemetic prophylaxis in most patients.³⁷ This drug should be taken with a meal and water at approximately the same time each day, swallowed whole.¹⁷

FLT3 Inhibitors

In the AML maintenance setting, midostaurin is usually given cyclically on days 8 through 21 of a 28-day cycle.³⁹ Midostaurin’s key toxicities as defined by the RATIFY trial include anemia and rash. Pulmonary toxicities including pneumonitis and interstitial lung disease occurred in fewer than 10% of patients but were sometimes fatal. Pulmonary toxicity may be increased when midostaurin is co-administered with azole antifungals and cytochrome P450 3A4 is inhibited²⁵; therefore, these combinations should be avoided. Because of the intermittent scheduling of midostaurin, extra education of patients and caregivers should occur, and use of drug calendars and reminders should be tailored to the patient’s needs. Midostaurin has moderate emetogenic potential, and antiemetic prophylaxis is recommended.³⁷ Caution in patients with congenital prolonged QT interval and those on other QT-prolonging medications. QT prolongation has occurred in up to 11% of patients.³⁹ Baseline electrocardiogram and repeat at steady state blood levels and periodically thereafter are suggested for at-risk patients. Concomitant grapefruit and grapefruit juice should be avoided while on midostaurin due to alterations in hepatic metabolism.

FLT3 is just one of many kinases that sorafenib inhibits. Sorafenib also inhibits vascular endothelial growth factor (VEGF), BRAF, cKIT, and RET, to name a few targets. With all of these interactions, off-target toxicities result. In association with VEGF inhibition, increased rates of hypertension, arterial thromboses, proteinuria, and decreased wound healing can be observed. Sorafenib is associated with multiple dermatologic toxicities such as palmar–plantar erythrodysesthesia (hand–foot skin reaction) in up to 69% of patients, rash, pruritus, and alopecia.²⁷ Careful education to patients and caregivers should include skin care, avoid exacerbating factors such as pressure and friction, and preventive removal of callouses. As with many oral kinase inhibitors, diarrhea can affect quality of life, and strategies to minimize daily low-grade loose stools should be employed. These include minimizing exacerbating foods (e.g., greasy, spicy, lactate-containing), increasing oral hydration, and using loperamide to maintain normal bowel function. Home blood pressure monitoring should be facilitated. QT interval and heart failure (decreased ejection fraction) are rare but serious toxicities.²⁷ Baseline and periodic electrocardiograms can be considered in patients at high risk for QT prolongation. Hypothyroidism is observed in more than one third of patients, and assessment should be included in the monitoring plan. Dosing for sorafenib is continuous at 400 mg orally twice a day on an empty stomach. An empty stomach is considered as at least 1 hour before or 2 hours after a meal.

IDH Inhibitors

Differentiation syndrome is not new to the AML landscape. It has been previously described in key treatments for acute promyelocytic leukemia. In this disease, both arsenic trioxide and all-trans retinoic acid have the potential to induce a DS.¹¹ DS can be identified in as many as 19% of patients receiving ivosidenib or enasidenib for IDH-mutated AML.⁴⁰ DS is a serious and sometimes fatal toxicity that occurs more commonly when the circulating or bone marrow leukemia burden is high. As the drugs stimulate maturation or proliferation of the leukemia cells to a mature form, cytokine balance is altered leading to inflammation, tissue damage, and organ dysfunction.⁴¹

Close monitoring for signs and symptoms of DS include unexplained fever, respiratory symptoms (dyspnea, hypoxia), pleural and pericardial effusions, and weight gain. Frequency of these symptoms have been documented as dyspnea (85%), unexplained fever (79%), pulmonary infiltrates (73%), hypoxia (58%), acute kidney injury grade ≥2 (42%), pleural effusion (42%), bone pain or arthralgia (27%), lymphadenopathy (24%), rash (24%), disseminated intravascular coagulopathy (21%), edema or weight gain of more than 5 kg from baseline (21%), and pericardial effusion (15%).⁴¹ Close monitoring and rapid intervention save lives.

Dexamethasone 10 mg twice a day should be started at first suspicion of DS and continued for at least 3 days and until signs and symptoms resolve. Dexamethasone can be tapered according to institutional guidelines once symptoms resole. Empiric anti-infectives are also recommended early in the treatment of DS when it is not fully known if the symptoms are from DS or an infection. Tumor lysis syndrome can occur with DS, and management with hyperhydration and hyperuricemic agents may be necessary. Lastly, use of a debulking agent, such as hydroxyurea, will decrease the total white blood cell count temporarily to curb DS. Patients should be hospitalized if they exhibit rapidly progressive symptoms such as respiratory symptoms, disseminated intravascular coagulopathy, renal failure, or rapidly rising white blood cell count. In this setting the IDH inhibitor should also be held. Published algorithms of care are helpful.⁴¹ In patients with DS, leukocytosis was identified in 79% of patients on ivosidenib and 61% of patients of enasidenib. The median range of onset is approximately 20 days after therapy begins, but the range is days 1 to 78 for ivosidenib and days 1 through 86 for enasidenib. In the FDA review of DS, toxicity was grade 3 or greater in 68% and 66% of patients receiving ivosidenib and enasidenib, respectively, and fatal in 6% and 5% of patients.⁴⁰ Lower complete remission rates are also observed in patients who experience DS.

The dosing of both ivosidenib and enasidenib is daily until disease progression or unacceptable toxicity. Ivosidenib can cause QT prolongation; therefore, baseline and periodic electrocardiograms should be performed in at-risk patients, and electrolytes maintained at optimal levels.¹⁵ If QTc interval exceeds 480 to 500 msec, holding and/or reducing the dose is warranted. If the patient experiences symptomatic QT prolongation or arrythmias, stop ivosidenib permanently. Ivosidenib has also been associated rarely with Guillain-Barre syndrome. Ivosidenib is a major substrate of cytochrome P450 3A4, and caution with concomitant 3A4 inhibitors, specifically potent azole antifungals, is recommended. Enasidenib has been associated with hyperbilirubinemia in approximately 15% of patients.⁴² Dose reduction to 50 mg daily is recommended for isolated hyperbilirubinemia greater than 3 times the upper limit of normal. Lastly, enasidenib has moderate emetogenic potential, and prophylactic antiemetics should be used initially and continued if needed.³⁷

Glasdegib

Glasdegib is approved by FDA for the treatment of newly diagnosed AML in combination with low-dose cytarabine in patients who are 75 years of age or older or who are not able to undergo intensive induction chemotherapy.⁴³ Glasdegib therapy should continue until disease progression or unacceptable toxicity occurs, with patients receiving at least 6 months of the combined therapy if possible. This drug can also cause QT prolongation, and all patients should have a baseline and periodic electrocardiograms, and continual assessment and optimization of electrolytes (potassium, sodium, magnesium, calcium). Concomitant QT-prolonging drugs should be avoided, and doses of glasdegib should be held or adjusted for a QTc interval of more than 480 to 500 msec. Glasdegib is a major substrate of cytochrome P450 3A4 and should be used with caution with strong inducers or inhibitors of CYP 3A4. Glasdegib can cause embryo-fetal death or severe birth defects and is to be avoided in pregnant women, and men should use a barrier method to avoid female pregnancy for at least 30 days after the last dose of glasdegib.

Case 2, continued

HK is now an outpatient, has been on ivosidenib for 21 days, and now has fever of 101.9° F, oxygen saturation of 86%, bilateral pulmonary infiltrates, and pericardial effusion on chest X-ray images. She complains that she feels terrible, has gained 12 pounds in the past week, and aches all over.

What do you do? What additional tests do you order? Are there any medications you want to start?

CONCLUSION

For younger and more fit older adults with AML, the classic treatment plan of induction chemotherapy, followed by consolidation therapy (either in the form of chemotherapy or stem cell transplant) remains the initial approach.^6,8 Since the median age at AML diagnosis is 67 years, only a minority of newly diagnosed patients fit into this young and fit population. Older patients with AML have a poorer prognosis based on increased cytogenetic and mutational abnormalities, inherent resistance of the AML to standard chemotherapies, and comorbid conditions that preclude the use of intensive chemotherapy.⁴

The era of successful maintenance therapy in AML has emerged primarily in the form of tolerable oral targeted and nontargeted agents.^{14,19,21,22,25,32,35,39} Additionally, the increased use of HMA-based regimens in the AML frontline setting has allowed more individuals to receive treatment for newly diagnosed AML.^13,19,20 This shift has also enabled more community-based oncology treatment centers to treat patients closer to home and outside a tertiary-care referral center. This is largely due to the decreased toxicity of the regimens and decreased incidence of emergent toxicities requiring specialty care.

CC486, or oral azacitidine, has emerged as the first agent specifically studied for maintenance therapy following successful induction with or without consolidation therapy.²¹ However, the use of other agents in a chronic, continuous fashion aims to maintain remission of the AML. Long-term use of venetoclax, IDH inhibitors, FLT3 inhibitors, injectable HMAs, and glasdegib have demonstrated success in the frontline AML arena.^{22,24–26,28,31,32}

Currently, treatment with most of these agents should continue for as long as the AML is controlled and the patient is not experiencing unacceptable toxicities. Adherence and persistence of these self-administered maintenance therapies through education and management of toxicities are major factors in treatment success. Pharmacists can provide life-sustaining support to their patients through educated care and management of these new therapies for AML.

RESOURCES

Leukemia and Lymphoma Society

Oral Therapy Education Sheets

American Cancer Society

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