Moving the Treatment of Acute Myeloid Leukemia to the Outpatient Setting: Current Expert Perspectives and Consensus Findings

Abstract

Intensive treatments for acute myeloid leukemia (AML) have traditionally been administered on an inpatient basis due in part to chemotherapy regimen infusion requirements, transfusion support, and the need for close monitoring for infectious complications and adverse events. However, hospitalization is a major component of burgeoning healthcare costs and may contribute to impaired quality of life in patients with AML. To help inform the ongoing discussion regarding the merits and challenges of outpatient administration of AML therapy, a multidisciplinary panel of experts were engaged to identify areas of consensus, explore ongoing uncertainties, and develop an algorithm that may help inform discussions on outpatient treatment between healthcare providers and patients. Based on available evidence and clinical experience, inpatient treatment remains appropriate for majority of patients with AML undergoing conventional intensive induction chemotherapy. The more recently introduced liposomal formulation of cytarabine and daunorubicin (CPX-351) has an infusion schedule that is more amenable to outpatient administration. Outpatient administration of CPX-351 for select patients with close daily monitoring has been implemented via a multidisciplinary team-based model. The feasibility of safely managing AML patients receiving outpatient CPX-351 is being prospectively evaluated in an ongoing phase 4 study. Panelists generally agreed that lower-intensity regimens including venetoclax combined with hypomethylating agents or lowdose cytarabine (LDAC), glasdegib plus LDAC, enasidenib, ivosidenib, and gilteritinib can be administered safely in the outpatient setting for most newly diagnosed AML patients. Venetoclax-based combinations are also promising for outpatient administration but may require risk stratification due to the potential for tumor lysis syndrome (TLS). The proposed algorithm developed to inform consideration of outpatient treatment is focused on consideration of patient fitness, the treatment regimen selected, infrastructure in place to support outpatient administration, and patient/caregiver agreement with the outpatient approach. Educational needs for clinicians and recommendations to overcome knowledge gaps regarding outpatient therapy were also formulated. Outpatient administration of AML therapy is feasible in the appropriate clinical setting and patient. However, further research is needed regarding feasibility, logistics, safety, and patient outcomes including quality of life. Abbreviations: AML: Acute Myeloid Leukemia; CIVI: Continuous Intravenous Infusion; CLL: Chronic Lymphocytic Leukemia; COVID-19: Coronavirus Disease 2019; HCT: Hematopoietic Cell Transplantation; HDAC: High-Dose Cytarabine; HMA: Hypomethylating Agent; IPOP: Inpatient/Outpatient; LDAC: Low-Dose Cytarabine; MDS: Myelodysplastic Syndrome; NCCN: National Comprehensive Cancer Network; QoL: Quality of Life; TLS: Tumor Lysis Syndrome; WBC: White Blood Cell Talati C, Sweet KL, Pollyea DA, Kurtin SE, Klaus J, Eatrides J, et al. Moving the Treatment of Acute Myeloid Leukemia to the Outpatient Setting: Current Expert Perspectives and Consensus Findings. J Clin Haematol. 2021; 2(3): 86-94. J Clin Haematol. 2021 Volume 2, Issue 3 87 Introduction In patients with newly diagnosed acute myeloid leukemia (AML), the initial treatment decision is often predicated on the individual’s candidacy for intensive chemotherapy. For those patients considered eligible for intensive treatment, the standard approach historically has been induction with a combination chemotherapy regimen such as cytarabine for 7 days and an anthracycline for 3 days (“7+3” therapy) [1]. Those patients who achieve remission will typically go on to receive consolidation chemotherapy and/or allogeneic hematopoietic cell transplantation (HCT) [2,3]. Intensive AML treatments have traditionally been administered on an inpatient basis due in part to chemotherapy regimen infusion requirements, transfusion support, and to allow for close monitoring for infectious and other complications. However, prolonged hospitalization is a major contributor to burgeoning healthcare costs and may contribute to the severely impaired quality of life (QoL) observed among patients with AML [4]. Interest in moving toward outpatient management has increased as healthcare providers have become more comfortable with the prevention and treatment of complications associated with the intensive treatment of AML [5]. The trend toward outpatient management is driven not only by the potential to reduce the substantial financial costs of inpatient treatment, but also the desire to improve quality of life and family/caregiver support for patients, some of whom may find prolonged inpatient stay inconvenient or extremely challenging [5,6]. The AML treatment landscape has changed considerably since the advent of 7+3 therapy decades ago (Figure 1). Outpatient administration is a standard practice for lower intensity approaches to treatment of newly diagnosed AML. This is true not only for traditional treatment options such as low-dose cytarabine (LDAC) or hypomethylating agents (HMAs) including azacitidine or decitabine, but also for more recently introduced regimens including the combination of glasdegib and LDAC, and for the targeted agents enasidenib, ivosidenib, and gilteritinib, which are indicated for the treatment of mutation-defined patient subgroups. The introduction of a liposomal formulation of cytarabine and daunorubicin (CPX-351) and venetoclax-based combination therapy has further increased interest in outpatient administration of AML therapy. The published manuscript cited the 2019 US prescribing information for the liposomal combination of daunorubicin and cytarabine. The US prescribing information updated and released in March 2021 indicates that the liposomal daunorubicin and cytarabine is indicated for the treatment of newlydiagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older [7]. In contrast to 7+3, the induction regimen is administered via intravenous infusion over 90 minutes on days 1, 3, and 5 of induction and days 1 and 3 of consolidation, and thus is more amenable to administration in an outpatient setting with careful monitoring [8]. In addition, venetoclax combined with azacitidine has demonstrated substantially improved outcomes in older, unfit AML patients, leading to rapid and widespread uptake of venetoclax-based combinations in both academic and community-based settings [9]. The risk of tumor lysis syndrome (TLS) is associated with venetoclax, prompting the need for risk assessment and prophylaxis, with more intensive measures (including hospitalization) recommended as risk increases. An initial venetoclax ramp-up dosing schedule designed to decrease TLS risk is indicated, during which hospitalization has been recommended [10,11]. Despite ongoing interest and exploration of outpatient approaches to AML treatment and monitoring, gaps in evidence and a lack of clear consensus or guidelines represent key challenges to implementation. Relatively few studies have prospectively evaluated the feasibility of outpatient approaches, though available evidence suggests that outpatient management can be feasible, well tolerated and potentially cost effective [4]. Likewise, there remains relatively little guidance from experts and persistent uncertainties regarding best practices. The recent American Society of Hematology guidelines for treating newly diagnosed AML in older adults acknowledge that in-hospital administration of intensive antileukemic therapy is “a burden to the patients and the system” when compared to less intensive approaches [12]. To better inform the ongoing discussion regarding the Figure 1: The changing AML treatment landscape. Talati C, Sweet KL, Pollyea DA, Kurtin SE, Klaus J, Eatrides J, et al. Moving the Treatment of Acute Myeloid Leukemia to the Outpatient Setting: Current Expert Perspectives and Consensus Findings. J Clin Haematol. 2021; 2(3): 86-94. J Clin Haematol. 2021 Volume 2, Issue 3 88 merits and challenges of outpatient administration of AML therapy, a panel of experts were engaged to identify areas of consensus, explore ongoing uncertainties, and develop an algorithm that may help inform discussions of inpatient versus outpatient treatment between community healthcare providers and patients. This article provides a discussion of current evidence regarding outpatient AML therapy, expert perspectives, and a summary of needs for patient communication and education for clinicians who provide care for patients with newly diagnosed AML. Determining AML Patient Fitness Assessment of patient fitness is important to determine the optimal treatment regimen as well as feasibility for treatment in an outpatient setting. Historically, the treatment choice for newly diagnosed AML patient has been dichotomous between intensive induction chemotherapy and non-intensive approaches and hinged on overall fitness of patient to be able to tolerate such therapy. Clinical metrics to assess the fitness have been developed and have focused on chronological age, performance status, and comorbidities. However, with newer approved therapies that include HMA and venetoclax as well as other targeted approaches, the traditional model of fitness has been questioned. Moreover, emphasis on disease-specific features such as genomic profile as well as cytogenetics is becoming increasingly imperative. For example, patients with mutations in TP53 gene have significantly inferior outcomes with traditional intensive chemotherapy regimens used in AML compared to the patients with wildtype TP53 gene. Newer data is also questioning the benefit of adding venetoclax to HMA therapy for such patients [13]. Therefore, careful evaluation of the disease biology and expected outcomes need to be considered in addi