Updates and Evolving Treatment Strategies in Acute Myeloid Leukemia

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Introduction

Acute myeloid leukemia (AML) is a malignant disease of the hematopoietic system caused by clonal proliferation of a myeloid progenitor cell. Although AML is the most common type of leukemia in adults, AML is a relatively rare disease, accounting for just 1% of new cancer diagnoses in the United States.¹ The median age at diagnosis is 68 years, with patients 55 years or older comprising over 75% of newly diagnosed cases.¹

Irrespective of treatment modality, outcomes in older adults with AML are worse than young adults due to both disease-related and patient-specific factors. Patients older than 64 years have a 5-year relative survival rate of just 9.4%.¹ Antecedent hematologic disorders (myelodysplastic syndrome [MDS] and myeloproliferative neoplasms) or secondary AML occur in 24% to 40% of older patients diagnosed with AML, portending difficult-to-treat disease.² In addition, older patients with AML typically have higher numbers of chromosomal aberrations, including mutations in genes that confer resistance to many treatments.³ In particular, TP53-mutated AML is less likely to respond to conventional chemotherapy treatments; the overall survival (OS) at 2 years is less than 10%.⁴ Molecular abnormalities not only inform prognostic discussions, but also can be the basis for targeted therapies. See Table 1^5,6 for common genetic mutations in AML.

For older patients considered fit for intensive therapy, the standard-of-care treatment for newly diagnosed AML is a cytotoxic chemotherapy induction, 7 plus 3, comprising myeloablative doses of an anthracycline, daunorubicin or idarubicin, and continuous infusion cytarabine, or a liposomal formation of cytarabine and daunorubicin. Although successful in inducing remission in 40% to 60% of patients, induction chemotherapy carries a high risk of morbidity and mortality due to infection, bleeding, and other complications from pancytopenia.^7-9 Anthracycline-containing induction chemotherapy also carries a risk of cardiotoxicity.¹⁰ Post-remission therapy, or consolidation, is recommended for patients who have achieved complete remission (CR) to prevent disease recurrence, as relapse risk is greater than 50% for adults with high-risk AML.¹¹ Based on risk stratification, many patients will need to proceed to hematopoietic stem cell transplant (HSCT) for a definitive cure.⁸

Due to the high level of morbidity and mortality associated with intensive treatment, older patients were historically not considered candidates for cytotoxic induction chemotherapy. Outpatient treatments such as the hypomethylating agents azacitidine and decitabine have been used over the past 20 years based on data demonstrating survival advantages over best supportive care alone.^12,13 Despite this evidence, registry studies indicate that as many as 50% of older patients diagnosed with AML do not receive any anti-leukemia therapy.¹⁴ In 2020, the American Society of Hematology published a consensus guideline to address the treatment of older adults (≥55 years) with newly diagnosed AML. The consensus panel’s meta-analysis demonstrated that anti-leukemia treatment has an OS advantage over best supportive care, with potential harms and burdens considered to be small (strong recommendation based on moderate certainty in the evidence of effects).³ As a larger percentage of elderly patients may be considered for therapy and/or HSCT, there is increased rationale for alternative therapies and incorporation of targeted agents, specifically designing regimens that are not as intensive as conventional induction chemotherapy.

Clinical Data for Alternative Induction Regimens

Treatment options for patients with newly diagnosed AML have grown exponentially in the past 5 years due to the approval of novel agents. The FDA has approved 5 lower-intensity regimens for patients who are treatment naïve and ineligible for intensive chemotherapy (Table 2⁶). The National Comprehensive Cancer Network (NCCN) guidelines provide a framework for approaching patients 60 years or older who are not candidates for intensive therapy, including the use of FDA-approved therapies as well as agents and combinations with clinical benefit. Categories of therapy recommendations are stratified based on mutation status: AML without actionable mutation, isocitrate dehydrogenase (IDH) 1 or 2 mutation, or fms-like tyrosine kinase 3 (FLT3) mutation.¹⁵

Venetoclax Combinations

Across all 3 groups, the NCCN category 1 recommendation for preferred therapy is venetoclax plus azacitidine, based on the landmark trial VIALE-A that was published in 2020. VIALE-A was a multicenter, double-blind, placebo-controlled, randomized, phase 3 trial in patients with newly diagnosed AML who were ineligible for standard induction therapy per Ferrari criteria. Of note, patients were ineligible if they had previously received a hypomethylating agent. The study group received intravenous (IV) azacitidine days 1 to 7 and oral venetoclax days 1 to 28 of a 28-day cycle; the control group received IV azacitidine days 1 to 7 and oral placebo days 1 to 28 of a 28-day cycle. The primary end point was median OS; secondary end points included rates of CR, red cell and platelet transfusion independence, measurable residual disease (MRD), as well as OS in molecular and cytogenetic subgroups. Median OS was 14.7 months in patients treated with venetoclax plus azacitidine versus 9.6 months for patients treated with azacitidine alone (HR, 0.66; P <.001). CR was achieved in 36.7% and 17.9% of patients, respectively (P <.001); transfusion independence was higher in the venetoclax plus azacitidine cohort. When assessing response in patients with genetic mutations, high response rates occurred for those with FLT3, IDH1, and IDH2 mutations. Rates of myelosuppressive adverse effects (AEs) differed between the groups. The venetoclax plus azacitidine group experienced higher rates of myelosuppression, including neutropenia (42% vs 28%), febrile neutropenia (42% vs 19%), and thrombocytopenia (45% vs 38%), all of which were reported at grade 3 or higher.¹⁶

Dose interruptions, including reductions in treatment duration and delays between cycles, occurred in 53% of patients receiving venetoclax plus azacitidine versus 28% of patients receiving azacitidine alone, highlighting potential complexities of managing treatment outside of a clinical trial. Nearly half of the patients randomized had at least 2 reasons for ineligibility for intensive treatment, yet treatment discontinuation was similar between the 2 groups (24% vs 20%) despite higher rates of myelosuppression and dose delay in the venetoclax plus azacitidine group, suggesting this regimen is tolerable for this patient population if recommended dosing parameters are followed.¹⁶

Management of venetoclax in combination with chemotherapy can be challenging for several reasons. As described previously, many patients will require dose reductions, interruptions, and cycle delays that can lead to confusion both for the patient and the healthcare team; multidisciplinary care including a pharmacist is vital to ensure patients are receiving appropriate prescriptions, instructions, and follow-up assessments. Venetoclax combination therapy frequently warrants antimicrobial prophylaxis due to high rates of neutropenia; however, many anti-mold medications (voriconazole, posaconazole, isavuconazonium sulfate) interact with venetoclax via the CYP3A4 pathway, requiring venetoclax dose adjustment. Although the venetoclax prescribing information provides comprehensive dose adjustment recommendations, very little data exist reporting outcomes for patients who received dose adjustments due to drug-drug interactions, raising concerns that these dose reductions may theoretically decrease the efficacy of treatment.^17,18

An alternative to the VIALE-A regimen is venetoclax plus decitabine, another hypomethylating agent. This combination was studied in the phase 1b/2 dose escalation and expansion phases of VIALE-A and showed similar safety signals as venetoclax plus azacitidine. Patients received venetoclax daily days 1 to 28 and IV decitabine days 1 to 5 of each 28-day cycle. Doses of venetoclax ranged from 400 mg to 1200 mg daily. In the phase 1b study, median OS for venetoclax plus decitabine was 16.2 months, and the CR/CR with incomplete blood count recovery (CR/CRi) rate was 74%, with a median duration of CR/CRi of 15 months. Although not studied in a randomized controlled trial, venetoclax plus decitabine was FDA approved based on the rate of CR and CR duration in these phase 1/2 studies.^19,20

Venetoclax plus low-dose cytarabine (LDAC) is a recommended option for this patient population, regardless of targetable mutation status, based on the results of VIALE-C, a randomized, double-blind, placebo-controlled, phase 3 study. Eligible patients included those with previously untreated AML who were 75 years or older or were ineligible for intensive chemotherapy due to reduced performance status, organ dysfunction, and/or any comorbidity judged to be incompatible with intensive chemotherapy. Patients with secondary AML from MDS were included and could have received previous therapy with a hypomethylating agent. The study group received subcutaneous cytarabine once daily on days 1 to 10 and oral venetoclax days 1 to 28 of a 28-day cycle; the control group received the same cytarabine therapy and oral placebo days 1 to 28 of a 28-day cycle. The primary objective was OS; secondary end points included rates of CR, CR with partial hematologic recovery (CRh), and rates of transfusion independence. Median OS was 7.2 months in patients receiving venetoclax plus LDAC versus 4.1 months in the control group (HR, 0.75; P = .11); thus, the study group failed to meet the specified primary end point. After an additional 6 months, the median OS was 8.4 months versus 4.1 months, respectively (HR, 0.70; P = .04). Rates of CR were 27% in the venetoclax plus LDAC group compared with 7% in the placebo group (P <.001); CR plus CRh was 47% versus 15%, respectively (P <.001). Transfusion independence rates were higher for patients treated with venetoclax plus LDAC (37% vs 16%; P = .002). Rates of myelosuppressive AEs differed between the groups. The venetoclax plus LDAC group experienced higher rates of neutropenia (46% vs 16%), febrile neutropenia (32% vs 29%), and thrombocytopenia (45% vs 37%), all of which were reported at grade 3 or higher. Nonhematologic events included nausea (42% vs 31%), hypokalemia (28% vs 22%), diarrhea (28% vs 16%), and constipation (18% vs 31%), but few were high grade.²¹ Although the trial did not meet the primary end point of OS improvement, venetoclax plus LDAC is a reasonable alternative to venetoclax plus azacitidine; LDAC is usually administered via subcutaneous injection in a patient’s home while hypomethylating agents must be administered in a healthcare facility, so this regimen may provide an alternative for patients who have difficulty traveling to healthcare visits or wish to spend more time at home for potential improved quality of life (QOL). Unfortunately, logistical barriers occur commonly with LDAC, including lack of insurance approval for the medication and/or home health services, and patients may have hesitations about self-administration of chemotherapy.

Hypomethylating Agents

Single-agent decitabine or azacitidine was a commonly used treatment before the publication of VIALE-A, as several noncomparative trials showed benefit in patients with AML unfit for induction chemotherapy. Two phase 3 studies followed up, and the subgroup analysis demonstrated better outcomes versus best supportive care in patients with 20% to 30% AML blasts.²² AZA-AML-001 compared azacitidine with 3 conventional care regimens (LDAC, intensive chemotherapy, and supportive care alone), and azacitidine demonstrated longer median OS (10.4 vs 6.5 months).¹³ Decitabine compared with the investigator’s choice (most commonly LDAC) was associated with a survival advantage in a post hoc analysis.¹²

Hypomethylating agents have poor bioavailability due to inactivation via gastrointestinal cytidine deaminase. Cedazuridine, a cytidine deaminase inhibitor, is combined with decitabine; this combination oral formulation is FDA approved for treatment of MDS.23 Recently, the ASCERTAIN-AML randomized, phase 3 trial compared patients with AML receiving oral decitabine/cedazuridine with IV decitabine to determine area-under-the-curve equivalence. The primary end point was achieved, demonstrating exposure bioequivalence, so decitabine/cedazuridine will likely receive an approval for use in patients with AML in the near future.24

Isocitrate Dehydrogenase Mutation Inhibitors

For patients with an IDH mutation, the NCCN guidelines preferred treatments include venetoclax plus a hypomethylating agent (category 1 with azacitidine) or treatment with an agent targeting the IDH mutation. In 2019, ivosidenib was the first IDH-targeted agent FDA approved for elderly patients with newly diagnosed AML based on the phase 1 study AG120-C-001. The study was an open-label, single-arm, dose-escalation and dose-expansion trial that enrolled patients 75 years or older or with comorbidities preventing the use of intensive induction chemotherapy. All patients had a documented IDH1-mutated hematologic cancer. Patients received single-agent ivosidenib daily until progression, toxicity, or HSCT. The primary objectives were to assess safety, maximum tolerated dose, and clinical activity in a cohort of patients with relapsed or refractory AML.25 A subset of patients with newly diagnosed AML achieved a CR rate of 30.3% (95% CI, 15.6-48.7), with an additional 42.4% achieving CR or CRh (95% CI, 25.5-60.8). Median OS was 12.6 months (95% CI, 4.5-25.7 months). Of note, 47% of patients had prior exposure to a hypomethylating agent; the CR plus CRh rate of that pretreated group was 26.7% (95% CI, 7.8-55.1). The most common treatment-related AEs were diarrhea (26%), fatigue (21%), nausea (18%), and decreased appetite (18%). AEs of special interest included treatment-related leukocytosis (6%), QT prolongation (18%) requiring dose interruption in 4 patients (12%), and treatment-related differentiation syndrome (18%) leading to dose interruption in 3 patients (9%).²⁶

Although not included as a recommended regimen in NCCN guidelines as of June 2022, a newly FDA-approved combination regimen of ivosidenib plus azacitidine may be added to guidelines soon due to results of the phase 3 AGILE trial. This double-blind, randomized, placebo-controlled trial evaluated the safety and efficacy of ivosidenib and azacitidine versus placebo and azacitidine in patients with newly diagnosed, IDH1-mutated AML who were 75 years or older or considered ineligible for intensive induction chemotherapy. Median OS was 24.0 months in the ivosidenib plus azacitidine group and 7.9 months in the placebo plus azacitidine arm (HR, 0.44; 95% CI, 0.27-0.73; P = .0010). CR occurred in 47% of patients in the study arm versus 15% of patients in the placebo arm (P <.001). Overall rates of hematologic AEs were higher in the ivosidenib plus azacitidine group versus the placebo group (77% vs 66%); however, the percentage of patients with infections was lower in the study arm (25% vs 49%). The rate of differentiation syndrome was 14% with ivosidenib plus azacitidine and 8% with placebo plus azacitidine; median time to onset was 19.5 days. AEs led to higher rates of therapy interruption in the study arm (52%) versus the placebo arm (38%), most of which were driven by neutropenia or febrile neutropenia events.²⁷

Enasidenib is an oral agent targeting the IDH2 mutation; although not FDA approved for newly diagnosed AML, NCCN guidelines recommend enasidenib as a preferred agent for older patients with IDH2-mutated AML who are not candidates for intensive therapy. A phase 1/2, open-label, dose-escalation and expansion trial enrolled patients with IDH2-mutated advanced myeloid malignancies; cohorts included older patients with relapsed/refractory AML, those with newly diagnosed AML ineligible for induction chemotherapy, younger patients with relapsed/refractory AML without HSCT, and any patient relapsed after HSCT.²⁸ A subset of 39 patients with newly diagnosed AML achieved an overall response rate of 30.8%, including 7 patients with a CR (18%). Estimated median OS at data cutoff was 11.3 months (95% CI, 5.7-15.1). The most common treatment-related AEs were nausea (23%), fatigue (18%), decreased appetite (18%), rash (18%), and anemia (15%). AEs of special interest included treatment-related differentiation syndrome (DS) (13%) leading to dose interruption in 4 patients (10%) and indirect hyperbilirubinemia (31%).²⁹ As enasidenib inhibits the UGT1A1 enzyme that glucuronidates bilirubin, isolated indirect hyperbilirubinemia does not indicate liver toxicity but is similar to the effects seen by congenital UGT1A1 deficiency (eg, Gilbert syndrome).³⁰

As IDH inhibitors are associated with myeloid maturation and differentiation of leukemia cells, DS may occur, causing pulmonary infiltrates, dyspnea, weight gain, fever, acute renal failure, and/or hypotension; DS can be life-threatening or fatal, especially if not treated urgently with high-dose dexamethasone 10 mg IV every 12 hours (or an equivalent dose of alternative corticosteroid) and hemodynamic monitoring.^31,32 Patients most commonly experience DS symptoms within the first 3 weeks of therapy; however, isolated cases have occurred months after starting treatment with an IDH inhibitor. Pharmacists are especially well poised to help educate patients on the signs and symptoms of DS, as most patients will receive the agents solely in the outpatient setting and may not have as close follow-up as patients routinely visiting infusion centers to receive IV therapies.³³

Hedgehog Inhibitors

The BRIGHT AML 1003 trial evaluated a first-in-class oral small-molecule inhibitor of the Hedgehog signaling pathway, glasdegib, combined with LDAC. The trial was a phase 2, randomized open-label, multicenter study evaluating safety and efficacy in patients with AML or high-risk MDS who were previously untreated and not eligible for intensive chemotherapy. Although the trial demonstrated improved OS of the study arm compared with LDAC alone (8.8 months vs 4.9 months; HR, 0.51; 80% CI, 0.39-0.67; P = .0004), the AE profile for glasdegib plus LDAC was significant, causing 47 patients (56%) to temporarily discontinue glasdegib and/or LDAC and 22 (26%) to require a dose reduction due to AEs. Known AEs of the Hedgehog pathway inhibitors occurred in this trial, including muscle spasms (17.9%, grade ≥3: 4.8%), dysgeusia (25%), decreased appetite (29.8%), and alopecia (6%). Because these AEs affect patient QOL, glasdegib plus LDAC is not used as frequently in practice given other alternatives.³⁴

The approval of ivosidenib plus azacitidine hints at the future of treatment of older patients with AML; many combination therapies are currently being studied, including combinations of targeted agents, hypomethylating agents, and venetoclax to determine both safety and efficacy. What remains to be known is how these agents would fit together sequentially into therapy if patients had multiple targetable mutations. Novel agents on the horizon include the anti-CD47 macrophage checkpoint molecule magrolimab, menin inhibitors, and immunotherapies such as antibody-drug conjugates (vadastuximab talirine and IMGN632), bispecific antibodies (vibecotamab and flotetuzumab), and chimeric antigen receptor T cells.⁶

Maintenance Therapy

Relapse after remission occurs in more than 50% of adults with high-risk AML, so it is vital to develop therapies that can maintain remission and improve survival. The most effective modality to maintain remission is allogeneic HSCT; however, many older patients may not be candidates due to comorbidities, frailty, or caregiver issues.¹¹ The 2020 American Society of Hematology guidelines for treating older adults with newly diagnosed AML recommend consideration of post-remission therapy over no additional therapy in patients who achieve remission after at least a single cycle of intensive anti-leukemic therapy and who are not candidates for allogeneic HSCT.³ In addition to improving OS, maintenance therapy should aim to eradicate MRD, which has been shown to be the source of most relapses after remission.¹¹ MRD is quantified by several different methods; however, the lack of standardization in assays and reporting make the results difficult to compare between trials. MRD can be used as a prognostic tool, a monitoring tool to predict relapse, and a surrogate end point for OS in future clinical trials. Per the European LeukemiaNet MRD Working Party consensus document, MRD should be assessed at diagnosis to enable comparison of biomarkers after patients have received treatment. Depending on the baseline genomic profile, MRD assessments are done at specific timepoints throughout therapy, and potential follow-up is conducted to determine response to therapy and predict impending relapse.³⁵

Approaches to maintenance therapy for AML after remission have included cytotoxic chemotherapy, hypomethylating agents, immunotherapy, and targeted therapy. Evidence in favor of maintenance therapies is limited, as, regardless of agent or schedule, multiple trials have shown no OS benefit or decrease in relapse rate, including EORTC-HOVON, LAME Group, HOVON97, ECOG-ACRIN E2906, UK NCRI AML16, CALGB 9720, and UK MRC AML11.¹¹

Hypomethylating Agents

IV azacitidine and decitabine have been studied as maintenance therapies after achievement of CR in patients who are not eligible for HSCT. The HOVAN97 phase 3 trial randomized patients to azacitidine 50 mg/m2 on days 1 to 5 every 4 weeks for 12 cycles versus placebo. Patients were 60 years or older with AML or MDS in CR/CRi after at least 2 cycles of intensive chemotherapy. Median disease-free survival (DFS) was higher in the study arm at 12 months (64% vs 42%; P = .04) but statistically significant improvement in OS was not seen.³⁶ Decitabine was studied in the randomized, phase 2 trial ECOG-ACRIN E2906. Patients were 60 years or older with AML in CR/CRi after induction and consolidation therapy. Patients in the study arm received decitabine days 1 to 3 every 28 days for 1 year versus a control arm solely on observation. Median DFS and OS were higher in the decitabine arm, but the study was closed below targeted accrual and neither end point reached statistical significance.³⁷

Oral alternatives or oral equivalents of hypomethylating agents are of interest to decrease time and cost spent on healthcare visits to administer IV chemotherapy. QUAZAR-AML-001 was a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine. Oral azacitidine or placebo was given once daily for 14 days each 28-day cycle to patients with AML who were 55 years or older and in CR after intensive chemotherapy. The primary end point was median OS, and secondary end points included DFS and health-related QOL. Median OS was 24.7 months with oral azacitidine versus 14.8 months with placebo (P <.001). Median relapse-free survival was higher in the study arm (10.15 vs 4.83 months; P <.001), and azacitidine was noninferior to placebo for health-related QOL. However, a higher rate of vomiting occurred in patients on oral azacitidine (60% vs 10%) especially during cycles 1 and 2. Patients should take a serotonin (5-HT3) receptor antagonist such as ondansetron approximately 30 minutes before each dose of oral azacitidine to mitigate risk of nausea and vomiting. Clinicians may consider observation versus initiation of maintenance therapy in patients with history of intractable nausea and vomiting.³⁸ Based on the results of this trial, oral azacitidine was FDA approved for maintenance therapy after achievement of first remission following intensive induction chemotherapy in patients who are not able to complete intensive curative therapy.³⁹

Targeted Agents

Targeted agents for AML are promising options for maintenance therapy, as these medications cause minimal myelosuppression when compared with other anti-leukemia therapies. The efficacy of targeted agents in maintenance is largely unclear, as many studies include the drug in induction, consolidation, and maintenance therapy. If patients are unfit for induction and consolidation therapy, the role of targeted therapy as maintenance is less defined.¹¹

FLT3 inhibitors have been studied most frequently for maintenance indications. Sorafenib was added to intensive standard-of-care chemotherapy in older patients with FLT3-positive AML; patients continued on sorafenib for up to 1 year following induction. The study arm failed to reach its primary end point, as no difference was shown between groups for median event-free survival. Study authors indicated that excess toxicity in the sorafenib arm led to high rates of infectious mortality and lower protocol adherence for maintenance therapy.⁴⁰ Midostaurin maintenance was analyzed in the RATIFY trial after patients in the study arm received midostaurin for 2-week courses with each cycle of induction and consolidation, followed by continuous therapy for 12 months. The trial showed significant improvement in OS and event-free survival, leading to FDA approval of midostaurin in combination with induction and consolidation chemotherapy for FLT3-mutated AML.⁴¹ However, a post hoc analysis of the trial failed to show definitive benefit of maintenance midostaurin due to no difference in DFS or OS from time of starting maintenance, thus midostaurin is not FDA approved for maintenance.⁴²

Managed Care Considerations

Decision making regarding treatment modality and choice of therapy is complex in older patients with AML. Patient-specific challenges due to age-related medical, social, and functional factors may reduce patients’ ability to tolerate conventional cytotoxic induction chemotherapy. Disease in older adults differs from younger patients with AML, typically bearing higher rates of cytogenic aberrations and unfavorable genetic mutations that may cause resistance to traditional treatments.³ Finally, physicians and patients may be hesitant to initiate treatment for AML due to perceived risk versus benefit. Many older adults value QOL over length of life, so treatment decisions should be personalized for each patient, weighing consensus guidelines, benefits and toxicities of treatments, patient-specific factors, and, most importantly, patient goals of care.^3,43

Treatment in Older Patients With Acute Myeloid Leukemia

Patient-specific medical factors include age-related decline in organ function, potential for serious preexisting comorbidities, and performance status that might not correspond with physiologic age.³ In a population-based study performed in Sweden, higher mortality rates were observed in patients with history of cerebrovascular, rheumatologic, renal, liver, and psychiatric disease. Renal dysfunction and disorders were associated with the highest increase in all-cause and AML-specific death. In addition, dementia was associated with AML-specific mortality.⁴⁴

Assessing fitness for treatment is an extremely important aspect of clinical decision making in the elderly population. Recent trials in elderly or unfit patients have used consensus criteria established by Ferrari, et al, deeming a patient unfit for intensive chemotherapy if they fulfilled 1 or more of the following criteria: severe cardiac comorbidity, severe pulmonary comorbidity, severe renal comorbidity, severe hepatic comorbidity, active infection resistant to anti-infective therapy, cognitive impairment, low performance status, or any other comorbidity that the physician judges to be incompatible with chemotherapy.⁴⁵ A comprehensive geriatric assessment evaluates multiple areas to determine fitness or frailty, including physical function, comorbid disease, cognitive function, psychological state, social support, polypharmacy, and nutritional status.⁴⁶ Geriatric assessments are recommended by NCCN and American Society of Clinical Oncology (ASCO) guidelines, and these types of assessments can provide guidance for nonintensive therapy decisions.⁴⁷ In an observational study of patients receiving treatment or best supportive care for MDS or AML, 3 variables were independently associated with worse survival: requiring assistance with activities of daily living, high fatigue score, and impaired performance status.⁴⁸ Regardless of the specific tool used, evaluating fitness for treatment is necessary to tailor the therapy plan.

AML in older patients can be difficult to treat due to inherent differences in the disease biology compared with younger patients. Older patients have increased expression of multidrug resistance (MDR1 genes), higher prevalence of secondary AML, higher prevalence of unfavorable molecular and cytogenetic abnormalities, and decreased sensitivity to anthracyclines.^7,49-51 Older patients show a decreased response to traditional chemotherapy due to these factors, leading to lower rates of remission, higher rates of complications, and inferior DFS and OS.³

Economic Burden

The treatment and supportive care of AML is associated with high healthcare costs and extensive healthcare utilization. Patients require frequent outpatient visits, numerous hospitalizations, and large amounts of blood products, including red blood cell and platelet transfusions, in addition to other supportive care services.⁵² Over a quarter of patients with AML require intensive care unit-level care, which can add significant cost to an already large economic burden.⁵³ A retrospective claims database study examining healthcare utilization and costs associated with AML in patients older than 60 years demonstrated substantial costs in the first year of treatment. Total mean per-patient per-month (PPPM) costs were $27,756 (standard deviation: $22,121), with the majority of costs associated with medical treatments. Inpatient hospitalization was the largest cost driver, accounting for 45% of total medical costs in the first year at $7739 PPPM (Figure⁵²). Ninety-two percent of patients in this analysis were hospitalized at least 1 time during the study period. Pharmacy costs, including chemotherapy, supportive care, and non-AML−related costs, totaled only $780 PPPM, likely due to the lack of chemotherapeutic and targeted options during the study time period (2007-2015).⁵² Pharmacy-related costs, specifically for outpatient prescription therapy to both treat disease and prevent infectious complications, have increased dramatically in the past 5 years due to recent approvals of oral agents. Patients with private insurance may face substantial costs for co-payments, and those on Medicare may experience challenges in access.⁵⁴

Another retrospective cohort study evaluated claims data to determine healthcare resource utilization and direct healthcare costs, as well as the relationship with clinical outcomes for patients with AML. The study defined episodes by treatments, including high-intensity chemotherapy regimens, low-intensity chemotherapy (LIC), and HSCT. LIC was defined as LDAC, anthracycline, azacitidine, decitabine, clofarabine, or gemtuzumab ozogamicin administered in the outpatient setting. Of note, none of these data included the current NCCN-preferred regimens for patients 60 years or older determined unfit for intensive chemotherapy due to the date of analysis (2008-2016). Mean total costs for LIC were $53,081, and 35.8% of patients had at least 1 inpatient hospitalization during the study period, costing a mean of $49,580.55 As both studies demonstrated the primary driver of medical costs to be inpatient hospitalization, optimization of new outpatient-based regimens to prevent unplanned inpatient hospitalizations may be key to minimizing healthcare costs.

Oncology Clinical Pathways

Clinical pathways are structured, multidisciplinary care plans that detail steps in the care of patients with a specific clinical problem. Currently, more than 170 million patients, many of whom may be receiving treatment for cancer, are potentially being treated under insurance plan-sponsored pathways.⁵⁶ Oncology clinical pathways (OCPs) are detailed protocols for delivering cancer care to ensure consistency of evidence-based care, manage medication use, decrease payer appeals and drug prices, and promote accrual to clinical trials. OCP protocols may include drug regimens for specific patient populations depending on type, stage, and molecular subtype of disease. To improve the development of OCPs by provider- and payer-marketed pathway vendors as well as decision support tool vendors, the ASCO Policy Statement on OCP recommends a collaborative, national approach to remove the unsustainable administrative burdens associated with multiple, disparate OCPs. In addition, the policy statement recommends that all OCPs⁵⁷:

• Should be developed through a process that is consistent and transparent
• Should address the full spectrum of cancer care, from diagnosis to survivorship and end-of-life care
• Should promote the best possible evidence-based care that is updated continuously
• Should recognize patient variability and autonomy
• Should be implemented in ways that promote administrative efficiencies for both oncology providers and payers
• Should promote education, research, and clinical trial access

For OCPs to realize reduction in costs while improving the overall quality of care, exacting questions should be answered to evaluate clinical pathways. ASCO has developed a guide for evaluating OCPs to determine if current or potential future pathways are of high quality. Three areas of evaluation are development, implementation and use, and analytics. Development criteria include the following: OCP created by oncology experts reflecting stakeholder input; clear process and transparency of OCP creation; OCP is evidence based, patient focused, clinically driven, timely, and comprehensive in scope; and OCP promotes participation in clinical trials. OCP implementation and use criteria revolve around the information provided to as well as support and communication offered to participant practices; OCPs should have clear, achievable expected outcomes, integrated cost-effective technology and decision support, and efficient processes for communication adjudications. The final criteria are analytics; establishing OCPs should provide efficient and public reporting of performance metrics, should have outcomes-driven results, and should promote research and continuous quality improvement.⁵⁸

As AML treatment options expand and more targeted agents are FDA approved, an OCP to manage older patients with AML will be useful to providing high-efficacy, lower-toxicity treatments.⁵⁹ Several studies in solid tumor populations indicate that use of pathways can reduce costs while either maintaining or improving the quality of care, demonstrating up to 30% to 35% cost savings with equivalent outcomes.⁵⁸ A large, independent, oncologist-led practice collaborated with Aetna to conduct a payer-sponsored program using evidence-based pathways in 746 Medicare Advantage patients diagnosed with cancer. Over 3 years, cumulative cost savings were over $3 million; drug cost savings per-patient per-treatment per-month were $1874. Interestingly, drug cost savings were largely driven by solid tumor indications. Few savings were realized in patients with hematologic malignancies.⁶⁰ Developing pathways for AML will likely involve differentiating AML into subsets based on mutational profile and patient-specific factors, then selecting the most effective therapy for that indication based on high-quality, updated evidence. If options are equivalent in efficacy, choosing the option with less toxicity should be prioritized. If risk of toxicity is equivalent among options, the treatment with the lowest cost and/or more economic value should be chosen.⁶¹

The Pharmacist’s Role

Pharmacists are uniquely poised to address the unique needs of older patients with AML. Preferred treatment regimens may be complex for many older patients to navigate. Many regimens involve both IV and oral agents that have different dosing schedules and may be frequently modified based on patients’ laboratory values or AEs. IV products are administered in a healthcare setting, whereas oral agents typically must be procured via specialty pharmacies.⁶² Prior authorization, high co-pays, and shipment of medications add an extra layer of complexity for older patients in receiving care in a timely and appropriate manner.⁶³ Pharmacists can help by alleviating barriers to access of medication, optimizing use of medications based on patient-specific factors and goals of care, improving adherence, and helping manage AEs.⁶⁴ Venetoclax-based regimens are especially complex due to frequent need to modify cycle length and start dates, as well as scheduling oral and IV chemotherapy in concert. Clinical pharmacists and specialty pharmacy support are essential to optimize care and reduce hospitalizations.⁶⁵ In addition, many oral therapies for AML have extensive drug-drug interactions that may warrant dose adjustment as well as more frequent monitoring or closer follow-up. If patients are on other medications for comorbid conditions, pharmacists can address drug interactions and ensure patients are receiving the most optimal regimen for their entire medication and disease state history.⁶² Managed care pharmacists can improve patient care by optimizing best practices, including management of utilization, drug cost, medication therapy, formulary decisions, and medical-to-pharmacy benefit channels. Managed care pharmacists can also add value by helping to develop and analyze outcomes from OCPs.⁶⁶

Conclusions

The treatment of AML in older adults is a rapidly changing landscape due to the introduction of novel agents and combinations that show a promise of long-term remission for a population that has historically not been offered, did not tolerate, or did not respond to conventional cytotoxic chemotherapy. Managed care organizations and pharmacists can help bridge the gap by recognizing the expanding indications of current drugs while staying up-to-date on new therapies, including targeted agents. As AML moves from a disease with a definitive induction, consolidation, and remission to one that may involve long-term treatments and maintenance therapies, managed care professionals must realize the nuances of these therapies to determine the value of these medications balanced with realistic outcomes, patients’ wishes, and goals of care.^6,67

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