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. Author manuscript; available in PMC: 2014 Oct 29.
Published in final edited form as: Clin Adv Hematol Oncol. 2013;11(9):571–577.

Outpatient Management Following Intensive Induction or Salvage Chemotherapy for Acute Myeloid Leukemia

Roland B Walter 1,2,3, Lenise R Taylor 4, Kelda M Gardner 4, Kathleen Shannon Dorcy 1, Jennifer E Vaughn 1, Elihu H Estey 1,2
PMCID: PMC4212516  NIHMSID: NIHMS634218  PMID: 24518520

Abstract

Adults with newly diagnosed or relapsed acute myeloid leukemia (AML) commonly receive intensive chemotherapy to achieve disease remission. In the United States and many other countries, it is standard practice that these patients remain hospitalized “preemptively” until blood count recovery due to the risk for overwhelming infections and bleeding during pancytopenia. This care policy requires hospitalization for an average of 3–4 weeks after completion of chemotherapy. However, highly effective oral prophylactic antimicrobials are now available, and transfusion support of outpatients has become routine in recent years. As a result, the care of patients with hematologic malignancies treated with other intensive modalities is increasingly shifting from inpatient to outpatient settings. Benefits of this shift could include reduced need for medical resources such as transfusions or intravenous antimicrobial therapy, improved quality of life (QOL), decreased rates of nosocomial infections, and lower cost. Increasing evidence indicates that selected AML patients undergoing intensive remission induction or salvage chemotherapy can be discharged early after completion of chemotherapy and followed closely in a well-equipped and –staffed outpatient facility safely and less costly. Further demonstration that the current approach of “preemptive” hospitalization is medically unjustified, economically more burdensome, and adversely affects health-related QOL would very likely change the management of these patients throughout this country and elsewhere and establish a new standard practice that improves cancer care.

Keywords: Acute myeloid leukemia (AML), early hospital discharge, health care cost, intensive chemotherapy, outpatient management, quality of life

INTRODUCTION

In 2013, an estimated 14,590 individuals in the United States will be confronted with a new diagnosis of acute myeloid leukemia (AML),1 a cancer of immature hematopoietic cells that leads to proliferation and accumulation of abnormal myeloid cells that do not differentiate normally.2,3 Despite aggressive therapies, most patients will eventually die from their disease either as a consequence of impaired normal hematopoiesis, organ infiltration by tumor cells, or treatment-related toxicities.4–7

Typically, patients with AML receive intensive chemotherapy to induce complete remission (CR) as first step towards cure of the disease.4–7 A CR, conventionally defined as the presence of <5% blasts in the bone marrow together with the recovery of peripheral blood counts and absence of extramedullary disease,5 can be achieved in up to 60–80% of adults with newly diagnosed AML who are younger than 60 years of age but only 50% or less of adults > 60 years of age. However, disease relapse affects the majority of patients who initially achieve a CR. While different therapeutic options are currently available for relapsed/refractory AML, high-intensity salvage chemotherapy remains a mainstay of therapy aimed to re-induce remission.4–7 Thus, patients are frequently treated with high-dose chemotherapy regimens throughout the course of their disease.

IMPROVEMENTS IN ADMINISTERING INTENSIVE CHEMOTHERAPY FOR AML PATIENTS

It is well known that the risk of serious complications or early death as a complication of treatment-related toxicities varies considerably between individual patients. For example, among patients treated on SWOG trials between 1991 and 2003, the day-30 mortality was less than 5% in some patient subsets but 50% or higher in others.8 However, despite that fact that curative-intent induction and salvage treatment regimens for AML have remained relatively unchanged for several decades,4–7 Othus et al. very recently demonstrated a decline of treatment-related mortality following intensive induction chemotherapy over the last 20 years, with rates for patients treated between 2006–2009 being significantly lower than those of patients treated in earlier years.9 Although various selection biases cannot be fully excluded, this observation strongly suggests that significant improvements have been made in the supportive care of AML patients undergoing curative-intent chemotherapy. Chief among these is likely the introduction of more potent antibiotics, particularly antifungals. Many of these can be administered by mouth and are well tolerated.10 Below we discuss how the availability of these drugs may render superfluous the need for inpatient management of AML during remission induction therapy.

Numerous factors have been identified that are associated with adverse treatment outcome, including age and covariates that may serve as surrogates for the biological (rather than chronological) age, such as performance status, organ function parameters (e.g. bilirubin, fibrinogen, albumin, creatinine), degree of cytopenias, and disease characteristics. Such factors formed the basis for several scoring systems aimed initially at recognizing patients at high risk for treatment-related mortality with intensive induction chemotherapy,11–14 and may need to be critically re-assessed in the light of improved supportive care measures. Nonetheless, they offer an empiric approach in identifying subsets of AML patients that will very likely do well following intensive chemotherapy.

INPATIENT CARE AS STANDARD FOR PATIENTS UNDERGOING INTENSIVE CHEMOTHERAPY FOR NEWLY DIAGNOSED OR RECURRENT AML

AML patients are routinely hospitalized for intensive chemotherapies as they usually entail continuous infusions that are easier to deliver in hospital. Moreover, as these patients often present with fever and/or infections or bleeding at initial diagnosis or disease relapse, they may require hospital admission independent of their intensive treatment. Despite improvements in supportive care, however, it is standard practice even in 2013 at most academic institutions in the United States and many other parts of the world to keep patients “pre-emptively” in the hospital for the additional 3–4 weeks required for recovery of normal blood counts to allow close monitoring for treatment-related toxicities and complications of cytopenias such as bleeding and infection, with the latter being the principal cause of death in this disease.15 An informal poll of physicians in private practice in Washington State and of physicians at the VA Puget Sound Health Care System in Seattle, WA, suggests that a similar policy is in place in the community setting as well. This is the case even in patients not requiring intensive supportive therapy when chemotherapy is completed; such patients constitute the majority of those under age 75. In contrast, AML patients receiving consolidation therapy are routinely discharged from the hospital after completion of chemotherapy, although it is often as intense or more intense than induction therapy and produces a similar degree and duration of cytopenia. Subsequent outpatient care is not only feasible but also well accepted by patients and is cost effective.16–19 This contrasting approach may reflect the observation that infection at any given neutrophil count is less common in patients in remission than in those with active disease.20–22 Nevertheless, it is arguable whether the difference in infection rates is sufficient to justify such a dramatic difference in practice standards and warrant pre-emptive hospitalization in many cases, in particular those predicted to be at very low risk of experiencing serious side effects of treatment-related mortality.

QUALITY OF LIFE OF AML PATIENTS UNDERGOING INTENSIVE CHEMOTHERAPY

Along with life expectancy, quality of life (QOL) is among the most important considerations for patients with AML/MDS. Its significance is highlighted by the fact that improvement in QOL can serve as primary end point in the regular drug approval process in the U. S.23 The need to include QOL has motivated efforts to formally include patients’ perspectives of QOL. To date the lack of validated measures of QOL for AML and methodological limitations have hampered use of this end point, and only very few randomized studies have so far utilized QOL end-points in AML.24 The measure most frequently used has been the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30).24 Not surprisingly, the available evidence suggests that QOL is greatly impaired in AML patients, particularly immediately after diagnosis and during therapy.25 Affected domains include physical, psychological and emotional, as well as sexual function.25 Factors such as fatigue, number of blood transfusions, hemorrhages, days with fever, days on antibiotics, and days spent in hospital can adversely affect a patient’s QOL.24

ECONOMIC BURDEN OF AML THERAPY

Several studies have addressed the economics of AML.25–34 For example, in a study reviewing Medicare claims for 2,657 patients with AML, the largest cost driver was hospital reimbursement (84% of costs) followed by physician payments (7% of costs), outpatient hospital/clinic payments (4% of costs), and home health care payments (2% of costs).25,30 Similarly, a longitudinal study on 275 older adults with AML treated at 28 U.S. hospitals from 2000–2003 showed that these patients incurred substantial hospital charges ($113,118 [~$145,000 in 2012 $US] for a mean length of stay of 23 days).31 Although comparable data are not readily available for younger patients in the U.S., experience suggests that hospitalization accounts for a disproportionate share of their costs as well. Several European studies from France, Germany, Sweden, and the Netherlands likewise highlighted the high cost of AML therapy: consistent with the U.S. data, these studies have demonstrated that the vast majority of costs are associated with induction and re-induction/relapse treatment, with inpatient costs driven by length of hospital stay as the single largest cost component during therapy.25,28,29,32–34 Thus, it is evident that the resource-intense nature of AML therapy renders these diseases disproportionately expensive, and such treatments are a significant economic burden for patients, insurance companies, and society.

POTENTIAL BENEFITS OF OUTPATIENT MANAGEMENT AFTER INTENSIVE CHEMOTHERAPY FOR ACTIVE AML

The established practice of prolonged hospitalization after induction chemotherapy for AML may potentially be harmful. For example, it is well known that hospital-acquired (“nosocomial”) infections are more difficult to treat than infections acquired outside a hospital. Moreover, the recent refusal of Medicare to recompense hospitals for “iatrogenic” errors has drawn attention to the fact that hospitals may not be as safe as previously believed.35 Furthermore, it is conceivable that early discharge of patients following completion of chemotherapy is associated with improved QOL. Obviously, an improvement in QOL measures is most compelling if the intervention (early discharge) does not affect response rates and survival.

Together with increasing attention to costs, these considerations have boosted the desire to change management of AML from the inpatient to the outpatient setting during much of induction/re-induction therapy. Awareness of the potential benefits of outpatient management has coincided with improvements in supportive care to accomplish this goal. Perhaps foremost among these are an increased ability to deliver transfusions in the outpatient setting and new, oral, broad-spectrum antimicrobials with high activity against organisms such as Pseudomonas sp and Aspergillus sp, commonly responsible for fatal infections during neutropenia in AML. When given prophylactically, they reduce morbidity and mortality from infection in AML.36 Employing prophylactic oral antibiotics, Halim et al. reported a decrease in the incidence of septicemia from 22% to 13% associated with a shift from inpatient to outpatient management.37 In fact, very limited data suggest that early hospital discharge may reduce the number of days on intravenous antibiotics relative to inpatients.18 Nevertheless, effective inpatient antibiotics are available for outpatients who develop infections or neutropenic fever while on prophylactic therapy.

There may be additional benefits to early discharge after remission induction chemotherapy, as prolonged hospitalizations are associated with a decreased ability to resume independent functioning after discharge, leading to significant productivity losses and costs due to morbidity.25,38 Early discharge may thus facilitate resumption of independent functioning and re-integration into family and professional life after completion of AML treatment and provide another potential opportunity for societal cost savings.

EXPLORATION OF OUTPATIENT MANAGEMENT STRATEGIES AFTER INDUCTION OR SALVAGE CHEMOTHERAPY FOR AML

Unlike consolidation chemotherapy, only a few retrospective and non-controlled prospective studies have investigated whether selected patients could be safely discharged after completion of induction chemotherapy for AML/MDS.18,37,39–42 In 1995, Ruiz-Argüelles et al. reported on selected 24 adult patients that received standard induction chemotherapy with cytarabine and Adriamycin (“7+3”) and were discharged from 3 institutions in Mexico after completion of chemotherapy to remain at home or in a nearby hotel provided they had no fevers or obvious infections and a very good performance status.39 While re-hospitalizations for infections were necessary in seven patients, no fatalities occurred, and it was estimated that outpatient management saved $1,700 (~$2,600 in 2012 $US) per patient. One year later, Gillis et al. reported in a prospective study on 29 adult AML patients that received a total of 86 induction or consolidation courses at Hadassah University Medical Center in Jerusalem, Israel.40 After 50 of these treatment cycles, patients could be discharged early and followed as outpatients. However, outpatient management was feasible after only 4 of the 33 induction or salvage therapy cycles but in 46 of the 53 consolidation cycles, indicating that, in unselected patients, an early discharge policy might be difficult to implement. More encouraging was a retrospective analysis on 19 consecutive adult AML patients that received induction chemotherapy with 7+3 between 1996 and 1998 in Toronto, Canada.18 Ten of these 19 patients were able to be discharged with 10 days of initiating induction chemotherapy. All but one required readmission (on average 1.5 re-admissions per patient, principally for episodes of neutropenic fever). Nevertheless, no fatalities occurred, and patients discharged early had 30% fewer in-hospital days than inpatient controls and 57% fewer days of inpatient antibiotic therapy, while transfusion requirements were comparable. In another Canadian study, 70 adult patients were prospectively evaluated after receipt of various types of induction chemotherapy for newly diagnosed AML (n=61), relapsed/refractory AML (n=8), or both (n=1), between 2001 and 2002 at the Vancouver General Hospital and B.C. Cancer Agency.41 Determining eligibility based on a set of medical criteria (absence of fever, use of prophylactic antimicrobials, hemodynamic stability, resolution of coagulopathy, absence of serious comorbidities) as well as logistic criteria (availability of accommodation with 60 min of treatment center, availability of suitable caregiver), patients were discharged after 25 of these 71 induction therapy courses; only nine patients required readmissions for neutropenic fever, and no fatalities occurred. Finally, in a study conducted at the National University Hospital in Copenhagen, Denmark, 60 patients with acute leukemia (50 of which with AML) were enrolled between 2004 and 2007 as candidates for outpatient treatment if they lived within a 120 km radius from the hospital and had a caregiver at night available; patients with severe infections and/or refractoriness to platelet transfusions could not be treated in the outpatient setting.42 After 48 of the total 73 induction or re-induction courses, patients were discharged after completion of chemotherapy and followed as outpatients, with no readmission after 19 of these. A median of 8 and 6 days were spent at home with an absolute neutrophil count of 0.5×109/L and a platelet count < 20×109/L. Similar to the other studies, readmissions were primarily for neutropenic fevers, and no fatalities were observed..

At our institution, we conducted a pilot study (NCT00844441) to explore discharge of adult AML patients (excluding acute promyelocytic leukemia) once induction chemotherapy was completed.43 In our study, we also included patients with high-grade myelodysplastic syndromes (MDS; i.e. >10% blasts in the bone marrow), as these diseases clinically and biologically resemble AML, and patients that undergo intensive AML-like induction therapies have similar outcomes to AML patients.44,45 Patients aged 18–60 years were eligible if, within the preceding 3 days, they had begun intensive chemotherapy for untreated or relapsed disease. After completion of chemotherapy, patients were re-evaluated and considered eligible for hospital discharge if they fulfilled medical criteria including: ECOG performance status of 0–1; adequate liver, kidney, and cardiac function; no intravenous antimicrobial therapy, no active bleeding, and no refractoriness to platelet transfusions. Once eligibility for medical discharge was determined, patients were screened for logistic criteria: agreeable to close outpatient follow-up, and having a reliable caregiver and residency within 30 minutes of the Study Center. Patients meeting both medical and logistic criteria were discharged. If readmitted, subsequent early hospital discharge was possible if all medical/logistic criteria were again met. Patients who met the medical but not the logistic criteria served as inpatient controls and remained hospitalized until peripheral blood count recovery. Patients were discharged on antimicrobial prophylaxis that was continued until the absolute neutrophil count (ANC) was ≥0.5×109/L. Patients were seen by an outpatient oncology nurse three times per week and by a physician once weekly. Transfusion thresholds in asymptomatic patients were: hematocrit <26% and platelet count <10×109/L. Patients with febrile neutropenia were hospitalized for intravenous antimicrobials. Patients continued on study until recovery of peripheral blood counts (i.e. ANC > 0.5 × 109/L and self-sustained platelet count >20 × 109/L), they required additional chemotherapy, or 45 days had elapsed from day of re-evaluation. To determine resource utilization and estimate cost, pertinent information was collected from medical records and electronic billing information (to capture professional and facility charges). Since previous data from our center suggested an induction mortality rate of 5% in preemptively hospitalized patients receiving induction chemotherapy, the study was monitored to ensure that the rate of death on study did not exceed 5%.

Between April 2009 and April 2010, we enrolled 39 patients. Nineteen of the 39 patients did not meet medical early discharge criteria after completion of chemotherapy and were taken off study. Five of the 20 medically eligible patients did not meet logistic discharge criteria and remained hospitalized (controls; all 5 patients did not have permanent or temporary local housing), while 15 met both medical and logistic criteria and were discharged after completion of chemotherapy. Thirteen of the 15 patients who were discharged early required readmission prior to peripheral blood count recovery, with 6 patients being readmitted twice while on protocol. Causes for readmission were neutropenic fever (n=16), bleeding (n=2) and nausea/vomiting (n=1). The patients who were discharged early spent a median of 8 days (range, 3–36 days) as outpatients over a median of 2 outpatient periods (range, 1–3). The median total number of days spent in the hospital was 6 (range 0–28); in other words, patients who were discharged early spent a median of 53.8% (range, 28.6–100%) of the time from discharge until removal from study as outpatients. In contrast, the 5 inpatient controls patients were hospitalized for a median of 21 days (range, 10–21; p < 0.01 compared to patients discharged early) after completion of chemotherapy before removal from protocol. No patient required intensive care unit (ICU)-level care, and no deaths occurred in either group. Despite the small sample size of our pilot study, the median daily total professional and facility charges were significantly lower for patients discharged early compared to inpatient controls over the study period ($3,270 vs. $5,467, p=0.01). In contrast, the daily charges per inpatient day were relatively similar between these 2 groups (p=0.40), suggesting that charges are not substantially higher if readmission is necessary. Thus, although we analyzed charges and not costs, our data suggest that outpatient management of selected patients is safe and may significantly reduce financial burden.43

NURSING IMPLICATIONS OF OUTPATIENT MANAGEMENT FOLLOWING INTENSIVE AML CHEMOTHERAPY

Historically, when the AML patient remained hospitalized for several weeks following induction remission chemotherapy, the nursing focus was on ensuring patient safety. This was accomplished by routine vital signs and physical assessments, monitoring for subtle signs of infection and bleeding, and providing supportive care measures, e.g. administering medications to control nausea and pain. During this time, the nurse would spend time each shift educating the patient about not only the side effects of chemotherapy, but also how to prevent infection and care for the central venous catheter, and when to seek emergency care. In addition, social work resources were available for emotional and financial support.

Discharging a patient at the conclusion of induction chemotherapy significantly shortens the time available for initial and reinforced education and places increased responsibility on the patient and caregiver for the monitoring of side effects and the timely recognition (or prevention) of infections so that emergency care is appropriately sought. At our institution, the inpatient nursing staff who traditionally cared for AML patients during their most vulnerable phase of therapy were concerned that the patient would not have sufficient time to understand the nature of their disease and importance of preventive care measures and need for immediate medical attention at minimal signs or symptoms of a cytopenia-associated complication. On the other hand, the outpatient nursing staff who would be following these patients did not have a clinic schedule or structure available to care for these patients in the early phase after completion of induction or salvage chemotherapy as they traditionally had only assumed care responsibilities after peripheral blood count recovery in such cases. These concerns, along with the need for the patient to acquire the skills necessary to care for central venous catheters and have sufficient time to grasp the implications of the disease in their entire breadth, including the psychosocial and financial aspects, led the Clinical Nurse Specialist to form workgroups to design a program for implementation of an early discharge practice. Questions that need to be addressed included: how often will patients be seen while neutropenic and/or thrombocytopenic and who would see them? How would the laboratory monitoring need to be? Where will patients be seen when presenting with fevers? If they present to the emergency department, how do we ensure they are triaged quickly to receive antibiotics? How will social workers know to initiate central venous catheter referrals earlier than what has so far been the standard? As soon as these issues were identified, subgroups were formed to work on each of these questions and concerns. Inpatient nursing staff worked to identify key items necessary in patient education for safe patient discharge and easy reference for the patient. Outpatient nursing and social work identified triage routes for patients with fevers and the myriad of possibilities for central venous catheter care. The Principal Investigator and study nurse leading the initial pilot study exploring an early discharge policy identified the need to educate the emergency department staff about the neutropenic AML patient. The Clinical Nurse Specialist served as a resource to each group. The outcomes are summarized in Table 1.

TABLE 1.

Logistic Implications of Outpatient Management Following Intensive Induction or Salvage Chemotherapy for AML

Implementation Issue Resolution
Outpatient Management
   After hours care

  • Establishment of call procedures and with specific identification of steps for patient referral and flow during after hours
   Emergency care

  • ED alerted of potential increased number of pancytopenic patients at risk for sepsis and bleeding

  • Generation of patient wallet card with relevant study information to present on arrival to ED to expedite triage and time to intervention

  • Identification of a “sepsis pack” (antimicrobial cocktails) for rapid delivery in OPD prior to transport to hospital
   Clinical management in outpatient clinic

  • Assessed by RN and/or primary provider 3 times per week

  • Assessed by attending physician once weekly

  • Lab monitoring 3 times weekly or more frequently if needed

  • Symptomatic patient – triage in infusion area with direct admission to inpatient leukemia ward if appropriate, or referral to the ED for further work-up
   Education

  • Continuing of patient and family education by outpatient clinic nursing to reinforce patient education

  • Creation and provision of quick reference guide (“who to call and when to call”)
   Psychosocial support

  • Social worker referral for all patients with newly diagnosed disease
Inpatient Management
   Outpatient CVC care

  • Referral to social worker at time of CVC placement to identify home infusion resources

  • Emphasis on formal CVC care education and reinforcement
   Education

  • Establishment of education roadmap and checklist

  • Establishment of written discharge instructions
   Handoffs

  • Identification of OPD attending physician

  • Inpatient resident physician tasked with setting up OPD appointments
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Abbreviations: CVC, central venous catheter; ED, emergency department; OPD, outpatient department

Once the pilot study of early discharge following completion of induction chemotherapy was launched, further issues were identified that required just-in-time adjustments. For example, as outpatients required review of laboratory results 7 days a week but individual clinic schedules were only available 5 days a week, the infusion room, which was open 7 days a week, became available for lab reviews and symptom management triage. Moreover, as these patients required frequent transfusions of packed red blood cells and/or platelets, support with fluids, and replacement with electrolytes, it was quickly recognized that available slots in the infusion room became a limiting factor – in large part because of our institution’s large transplant patient population – and required cooperation and prioritization of scheduling of transfusions/supportive care between programs.

CONCLUSION

While the curative-intent induction and salvage treatment regimens for AML have changed little over the last several decades, the supportive care has significantly improved in this time frame and now enables a more flexible management of AML patients. For example, highly effective oral prophylactic antimicrobials are now available, and transfusion support of outpatients has become routine in recent years. As increasing evidence indicates, such advancements may allow selected AML patients to be discharged early after completion of intensive remission induction or salvage chemotherapy and to be managed as outpatients with close follow-up in well-equipped and –staffed outpatient facilities, although specific outpatient support and readmission procedures will need to be put in place in individual institutions to ensure maximal patient safety.

It is noteworthy that published data on this care strategy is still relatively sparse, and additional studies on larger cohorts of patients are warranted to investigate whether early outpatient management can be implemented safely; such studies are currently ongoing (e.g. NCT01235572). In addition, defining the elements necessary for optimal outpatient management remains an area for active research. Further demonstration that the current approach of “preemptive” hospitalization is medically unjustified, economically more burdensome, and adversely affects health-related QOL would very likely change the management of these patients throughout this country and elsewhere and establish a new standard practice that improves cancer care.

Acknowledgments

Supported by a grant from the National Cancer Institute/National Institutes of Health (NCI/NIH; P30-CA015704-35S6 to R.B.W.).

Footnotes

Conflict of interest: the authors declare no competing financial interests.

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