Palliative and End-of-Life Care for Patients With Hematologic Malignancies

Abstract

Hematologic malignancies are a heterogeneous group of diseases with unique illness trajectories, treatment paradigms, and potential for curability, which affect patients’ palliative and end-of-life care needs. Patients with hematologic malignancies endure immense physical and psychological symptoms because of both their illness and often intensive treatments that result in significant toxicities and adverse effects. Compared with patients with solid tumors, those with hematologic malignancies also experience high rates of hospitalizations, intensive care unit admissions, and in-hospital deaths and low rates of referral to hospice as well as shorter hospice length of stay. In addition, patients with hematologic malignancies harbor substantial misperceptions about treatment risks and benefits and frequently overestimate their prognosis. Even survivors of hematologic malignancies struggle with late effects, post-treatment complications, and post-traumatic stress symptoms that can significantly diminish their quality of life. Despite these substantial unmet needs, specialty palliative care services are infrequently consulted for the care of patients with hematologic malignancies. Several illness-specific, cultural, and system-based barriers to palliative care integration and optimal end-of-life care exist in this population. However, recent evidence has demonstrated the feasibility, acceptability, and efficacy of integrating palliative care to improve the quality of life and care of patients with hematologic malignancies and their caregivers. More research is needed to develop and test population-specific palliative and supportive care interventions to ensure generalizability and to define a sustainable clinical delivery model. Future work also should focus on identifying moderators and mediators of the effect of integrated palliative care models on patient-reported outcomes and on developing less resource-intensive integrated care models to address the diverse needs of this population.

INTRODUCTION

Hematologic malignancies are a heterogeneous group of diseases characterized by marked variation in their illness trajectories, treatment paradigms, and potential for curability.^1,2 Compared with patients with solid tumors, patients with hematologic malignancies experience unique illness trajectories that affect their palliative and end-of-life (EOL) care needs.^1,2 Specifically, these patients often experience an unpredictable illness course, with the possibility of cure persisting even in relapsed and refractory settings, contrary to most advanced solid tumors.^1-3 Many hematologic malignancies require treatment with intensive therapies, including hematopoietic stem-cell transplantation (HCT) and, more recently, chimeric antigen receptor (CAR) T-cell therapy, both of which are associated with significant toxicities and risks of mortality.^4-8 Even among patients with more indolent and chronic hematologic malignancies, intermittent or continuous therapies may be required indefinitely, which can contribute to morbidity and long-term quality-of-life (QOL) impairments.

Early integration of specialty palliative care has been shown to improve a wide range of outcomes for patients with advanced solid tumors, including QOL, mood, symptom burden, illness understanding, coping, and quality of EOL care.^9-14 Although palliative care clinicians are increasingly asked to care for patients with solid tumors, they are rarely consulted for patients with hematologic malignancies.^1,3,15 Given palliative care clinicians’ expertise in managing complex symptoms, facilitating adaptive coping and illness understanding, and addressing the EOL care of patients with cancer, they could play an important role in addressing the palliative and EOL care needs of patients with hematologic malignancies.

In this article, we first describe the unmet palliative care needs of patients with hematologic malignancies and then examine the barriers to palliative care integration and optimal EOL care for this population. We also review the literature on palliative care integration strategies and discuss future directions to enhance the QOL and care of patients with hematologic malignancies through collaborative care.

UNMET PALLIATIVE CARE NEEDS IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES

Table 1 lists the palliative care needs of patients with hematologic malignancies during key phases of their illness, including during treatment, during survivorship, and at the EOL.

TABLE 1.

Palliative Care Needs in Patients With Hematologic Malignancies

Palliative Care Needs During Treatment

Studies have shown that patients with hematologic malignancies experience a symptom burden that is comparable to or exceeds that of patients with metastatic solid tumors.^1,16 In a cross-sectional study of 180 patients with hematologic malignancies who received their care at a tertiary hospital, patients experienced a mean of 8.8 symptoms.¹⁷ The most prevalent symptoms were lack of energy, difficulty with sleep, pain, and dry mouth, which affected 40% to 70% of study participants.¹⁷ Of note, the mean number of symptoms and level of distress were comparable to patients with metastatic solid tumors in previously published symptom prevalence studies.¹⁷ In another cross-sectional analysis of patients with cancer who received palliative care across 17 sites within the Global Palliative Care Quality Alliance, rates of pain, dyspnea, nausea, and anorexia were similar among those with hematologic and solid malignancies.¹⁸ However, patients with hematologic malignancies reported higher rates of clinically significant fatigue and drowsiness.¹⁸ Other studies in patients with hematologic malignancies also have demonstrated that the prevalence of fatigue is high, affecting 80% to 90% of patients with acute leukemia, myelodysplastic syndrome, and multiple myeloma.^19-22 Thus, patients with hematologic malignancies experience substantial physical symptom burden during their illness that is comparable to patients with metastatic solid tumors.

Many patients with hematologic malignancies receive intensive treatments that require prolonged hospitalization, such as HCT.^7,23-25 Studies have shown that patients who receive autologous or allogeneic HCT experience a dramatic decline in their QOL, which is associated with an increase in symptoms such as nausea, vomiting, mucositis, fatigue, and diarrhea during their transplantation course.^23,26-30 Patients with acute leukemia also struggle with toxicities that result from intensive chemotherapy, which often requires a prolonged hospitalization.^31-34 In one study, patients with relapsed acute myeloid leukemia (AML) who received intensive chemotherapy reported a mean of 14.1 moderate to severe symptoms that led to substantial QOL impairment across multiple domains.³⁵ Although the symptoms experienced during intensive treatments are often temporary, they may contribute to long-term psychological distress, including post-traumatic stress symptoms and depression.^36,37

Psychological distress, including symptoms of depression and anxiety, are also prevalent in patients with hematologic malignancies and affect 30% to 60% of the population during treatment.^17,23,38 In a study of 104 patients with hematologic cancers who received chemotherapy, 50% reported clinically significant distress.³⁹ Of note, patients with acute leukemia and those who undergo HCT also struggle with acute stress reactions and post-traumatic stress symptoms as they endure the shock of a life-threatening diagnosis and the need for prolonged and socially isolating hospitalizations.^31,40-42 A recent population-level analysis suggested that patients with leukemia are among the most distressed of all those with cancer.⁴³ Thus, scalable interventions are critically needed to address the immense emotional and psychological burden that patients with hematologic malignancies experience during their illness course.

Patients with hematologic malignancies also have identified lack of information, difficulty with treatment decision making, and prognostic uncertainty as important challenges in dealing with their illness.^1,42,44 In addition, studies have shown that these patients have significant misperceptions about their treatment risks and benefits, and they often overestimate their prognosis.^21,45,46 In one study of older patients with AML, 90% reported that they were somewhat or very likely to be cured of their disease, whereas their oncologists estimated this chance of cure for only 31%.⁴⁶ These gaps in illness and prognostic understanding may have important clinical implications for patients’ medical decision making. In fact, patients’ understanding of the likelihood of cure is associated with their willingness to accept chemotherapy,^47-49 and those who overestimate their survival are more likely to prefer intensive medical care at the EOL.^50,51 Thus, enhancing patients’ illness and prognostic understanding is essential for patients with hematologic malignancies to make informed decisions about their cancer care.

Palliative Care Needs During Survivorship

Survivors of hematologic malignancies often deal with QOL impairments and long-term sequalae of their illness and associated treatments.^{5-7,26-29,52-57} Fatigue, pain, neuropathy, infertility, cardiomyopathy, neurocognitive deficits, psychological distress, fear of recurrence, and post-traumatic stress symptoms may result in diminished QOL compared with the normal population.^{26-29,52-56,58-60} Among allogeneic HCT recipients, chronic graft-versus-host disease (GVHD) is the major cause of morbidity, physical and functional impairments, symptom burden, and poor QOL.^6,54,61-66 The severity of chronic GVHD is associated with the extent of QOL decline in this population.⁶⁷ In a recent survey of transplantation physicians, 52% perceived GVHD symptoms as an important unmet palliative care need for allogeneic HCT recipients.⁶⁸ Even among patients with highly curable hematologic malignancies, such as Hodgkin’s lymphoma, 30% of patients struggle with clinically meaningful distress years after completing their therapy.⁶⁹ Similarly, patients with chronic lymphocytic leukemia, an often indolent disease that patients may live with for more than a decade, have been shown to have worse emotional well-being than patients with more serious solid tumors.⁷⁰ More research is needed to better understand the needs of survivors of hematologic malignancies, especially in the era of new treatments such as CAR T-cell therapy, to inform the development of palliative and supportive care interventions.

Palliative Care Needs at the EOL

In addition to substantial physical and psychological symptom burden at the EOL,^38,71-73 patients with hematologic malignancies often receive intensive EOL care, including high rates of hospitalizations,^72,74,75 emergency department visits,⁷⁵ intensive care unit (ICU) admissions,^72,74,76,77 and chemotherapy administration near the EOL.^74,75,77,78 One study quantified the amount of contact with the health care system among older patients with AML from the time of diagnosis until death.⁷⁴ Patients experienced on average 4.2 hospital admissions.⁷⁴ Those who died spent on average 28.3% of their lives postdiagnosis in the hospital and 13.8% of their time in the clinic.⁷⁴ Furthermore, patients with hematologic malignancies have a high likelihood of dying in the hospital, low rates of hospice referral, and a short length of stay in hospice.^72,75,78-80 In a systematic review and meta-analysis, patients with hematologic malignancies were more than twice as likely to die in the inpatient setting compared with those with other cancers.⁸¹ Although recent studies suggest an increase in hospice use in some patients with hematologic malignancies, hospice length of stay remains very short, with a median time of 6 to 9 days.^82,83 Despite the intensity of care at the EOL, advance directives and code status documentation are rarely addressed or documented in the medical record.^1,78,84 These data underscore the need for interventions to optimize the quality of EOL care for patients with hematologic malignancies.

BARRIERS TO PALLIATIVE CARE INTEGRATION

Despite the numerous unmet palliative care needs in patients with hematologic malignancies, specialty palliative care is rarely used in this population.^{2,74,77,78,85,86} Figure 1 summarizes the illness-specific, cultural, and system-based barriers that contribute to low rates of palliative care use.

FIG 1.

Barriers to palliative care use in patients with hematologic malignancies. EOL, end of life.

Illness-Specific Barriers

Many patients with hematologic malignancies require treatment with intensive therapies such as HCT, CAR T-cell therapy, or high-dose chemotherapy regimens given in hospital settings. Although these treatments carry a significant risk of morbidity and mortality, they are also potentially curative.^4-8 Given that specialty palliative care has been traditionally offered to patients with advanced cancer who receive noncurative therapy, patients who pursue curative treatments generally have been excluded from referral to palliative care.^{9-11,14,87,88} Furthermore, a clear transition is absent between the curative and palliative phase of treatment because many patients with relapsed and refractory hematologic malignancies can still achieve a cure, which also contributes to the lack of early palliative care use.^1,2 The extent of prognostic uncertainty in patients with hematologic malignancies makes the identification of triggers for palliative care use rather challenging if only patients with incurable disease are referred for these services.

Cultural Barriers

Oncologists who care for patients with hematologic malignancies have significant misperceptions that equate palliative care with just EOL care.^68,84,89 In a recent survey of transplantation physicians, 52% reported that palliative care is synonymous with EOL care, and 66% stated that the service name can decrease hope in patients and families.⁶⁸ Studies show that oncologists who care for patients with hematologic malignancies also have a strong sense of ownership over addressing the palliative care needs of their patients, which may also result in low palliative care referral rates.^68,84 In fact, 84% of transplantation physicians in a recent survey stated that the oncologist should coordinate the care of patients across all stages of disease, including the EOL.⁶⁸ Finally, oncologists’ limited knowledge about the potential benefits of palliative care for improving the experience of patients and families also represents an important cultural barrier to palliative care use.^68,90

System-Based Barriers

Most studies that have evaluated the efficacy of early integrated palliative and oncology care focused on patients with advanced solid tumors and excluded those with hematologic malignancies, which reflects these early biases.^9,10,14 Thus, the lack of data that support the role of palliative care for patients with hematologic malignancies, rather than evidence to the contrary, has served as an important barrier to palliative care integration in the past decade. Recent studies that demonstrated the potential benefit of integrated palliative care for patients with hematologic malignancies may overcome this barrier in the coming years.^91,92 Increasing demand for integrated palliative care may exacerbate the shortage of palliative care clinicians and an adequate outpatient specialty palliative care infrastructure, which will limit access to palliative care for many patients with hematologic malignancies, especially those treated in community centers and rural areas.^93,94

BARRIERS TO OPTIMAL EOL CARE

Figure 2 summarizes the illness, cultural, and system-based barriers to optimal EOL care for patients with hematologic malignancies

FIG 2.

Barriers to optimal end-of-life (EOL) care for patients with hematologic malignancies.

Illness-Specific Barriers

Patients with hematologic malignancies often experience a rapid and unpredictable trajectory of decline at the EOL.^95,96 The rapid decline and absence of a clear transition between the curative and palliative phases of treatment of many patients with hematologic malignancies often result in the receipt of intensive medical care at the EOL, including hospitalization and ICU admission. Even in patients with hematologic malignancies admitted to the ICU, there is substantial prognostic uncertainty because 50% of these patients may survive and recover after an ICU admission.⁹⁷ Moreover, patients with hematologic malignancies have unique needs at the EOL, including the need for blood product support and intravenous antibiotics, which additionally complicates the delivery of EOL care.^1-3 Of note, the routine assumption that most patients wish to die at home may not apply as uniformly to those with hematologic malignancies and their caregivers.⁹⁸ After spending months receiving intensive treatments in the hospital setting, some patients and their caregivers feel more comfortable in the inpatient setting and less equipped to address their EOL care needs at home.⁹⁸ Studies are needed to enhance our understanding of the EOL care needs of patients with hematologic malignancies and the optimal EOL care delivery models for this population.

Cultural Barriers

Oncologists who care for patients with hematologic malignancies have identified unrealistic expectations from both patients and oncologists as important barriers to optimizing EOL care.⁹⁹ In a survey of 182 oncology clinicians who care for patients with solid tumors and hematologic malignancies, hematologic specialists also reported feeling less comfortable with discussing death and dying (72% v 88%) and hospice referral (81% v 93%) and were more likely to feel a sense of failure with disease progression (46% v 31%).¹⁰⁰ In a qualitative study of 10 oncologists who care for patients with hematologic malignancies, the oncologists expressed concerns that EOL discussions may undermine their relationship with their patients.¹⁰¹ Consequently, EOL care discussions occur late in the illness course for patients with hematologic malignancies, which results in poor-quality EOL care.^95,102 In addition, oncologists who care for patients with hematologic malignancies are more likely to prescribe cancer therapy at the EOL than solid tumor oncologists, which also contributes to the intensity of EOL care in this population.¹⁰⁰

System-Based Barriers

Our current EOL care delivery models are inadequate for addressing the needs of patients with hematologic malignancies. Many of these patients require transfusion support to palliate symptoms, reduce the risk of serious complications like bleeding, or promote longevity. Unfortunately, many hospice agencies do not allow any transfusion support because of the logistics and costs involved. Several analyses point to transfusions as a barrier to hospice referral and high-quality EOL care in the United States.^76,82,83 In a recent large SEER Medicare analysis of US adults age 65 years and older with myelodysplastic syndrome, transfusion dependence was associated with a lower rate of hospice enrollment.⁷⁶ Similarly, in another SEER Medicare analysis of patients with leukemia, those who were transfusion dependent had a markedly shorter hospice length of stay, which suggests that transfusion dependence precludes timely hospice referral.⁸² In one study, 46% of oncologists who care for patients with hematologic malignancies reported that home hospice care is inadequate to address their patients’ EOL needs, and more than half of respondents stated that they would refer more patients to hospice care if blood transfusions were permitted.¹⁰³

PALLIATIVE CARE INTEGRATION STRATEGIES

Despite the significant barriers to palliative care integration for patients with hematologic malignancies, recent studies have demonstrated the feasibility, acceptability, and benefits of integrating palliative care with oncologic care in this population (Table 2). Several studies have reported on the feasibility of integrating palliative care as a consultative or embedded service in the care of patients with multiple myeloma and those undergoing HCT.^{104,105,108,109} In a recent study, Loggers et al¹⁰⁶ reported that early palliative care consultation before transplantation is feasible and acceptable for patients with high-risk hematologic malignancies who undergo allogeneic HCT. The overall participation rate was 63%, and 82% of participants reported feeling very comfortable with the intervention.

TABLE 2.

Summary of Studies of Palliative Care Integration for Patients With Hematologic Malignancies

In addition to descriptive reports, published literature now includes a prospective randomized clinical trial that demonstrated the efficacy of palliative care for improving patient and caregiver QOL and psychosocial outcomes. In a single-center randomized trial of 160 patients with hematologic malignancies who underwent autologous or allogeneic HCT, patients were randomly assigned to receive integrated palliative and transplantation care versus standard transplantation care.⁹¹ Patients randomly assigned to the intervention were seen by palliative care clinicians twice per week throughout their HCT hospitalization. Patients who received the intervention reported clinically significant improvements in their QOL, symptom burden, depression, and anxiety symptoms. In addition, caregivers of patients randomly assigned to the intervention also reported significant improvement in their coping and depression symptoms compared with caregivers of those who received transplantation care alone.⁹¹ Of note, the effects of the intervention were sustained at 3 and 6 months after HCT, with patients randomly assigned to the intervention reporting improvement in their depression and post-traumatic stress symptoms compared with those who received transplantation care alone.⁹² These findings highlight the potential benefits of integrated palliative care for improving the QOL and care of patients with hematologic malignancies and their caregivers. However, it is important to note that palliative care integration research in hematologic malignancies remains in its early stages, with a lot of the literature focused on feasibility and acceptability testing and the needs of the HCT population. A critical need exists to expand the evidence base to demonstrate the benefits of palliative care in patients with various hematologic malignancies and across care settings. Several promising randomized clinical trials are currently under way to test the efficacy of palliative care additionally for addressing the palliative and EOL care needs of this population (ClinicalTrials.gov identifiers: NCT02975869, NCT03310918, and NCT03641378).

In recognition of the challenges posed by the palliative care workforce shortage, Foxwell et al¹⁰⁷ developed a novel program that consisted of palliative care nurse practitioner office hours to provide support for clinicians who care for patients with hematologic malignancies in the inpatient setting. The program entailed having a palliative care nurse practitioner visit the inpatient hematology-oncology advanced practice offices daily at a consistent time to discuss patients and answer questions. Discussions typically included medication recommendation, resources for patients with hematologic malignancies and their families, and informal education. A mean of 11 patients were discussed per week during office hours. Of the 299 patients discussed, 14.7% subsequently required a full palliative care consultation. Overall, the program resulted in a decrease in palliative care consultation rate from 19.6% to 10.2% with an increase in consults focused on addressing goals of care.¹⁰⁷ Although these data are encouraging, future studies that investigate the impact of such programs on patient outcomes are needed.

FUTURE DIRECTIONS

In summary, patients with hematologic malignancies have substantial unmet palliative care needs that span their illness course from diagnosis to the EOL as well as during the survivorship period. Significant illness, cultural, and system-based barriers to integrating palliative care and optimizing EOL care for this population exist. However, recent evidence has demonstrated that integrated palliative and oncology care models are feasible and acceptable and have promising potential to improve the QOL and care of patients with hematologic malignancies and their caregivers.

Given the heterogeneous nature of hematologic malignancies, the emerging models of palliative care integration must appropriately fit patients’ needs and their disease trajectories. Figure 3 depicts a potential approach for identifying the appropriate palliative care integration strategy in patients with various illness trajectories. For example, patients who live with a more indolent disease and low symptom burden, such as indolent lymphomas, may benefit from a palliative care consultation when their prognosis becomes poor. In contrast, patients with high symptom burden and risk of mortality, such as those with acute leukemias, may benefit from early integrated longitudinal palliative care involvement. Population-specific palliative care interventions can more effectively address the unique needs of patients with various hematologic malignancies while appropriately allocating palliative care resources. Of note, models of palliative care integration must be tested rigorously in randomized clinical trials and implementation and dissemination studies to ensure their efficacy, generalizability, and effectiveness for improving the care of patients with hematologic malignancies. Future work also should focus on identifying mediators and moderators of the effect of palliative care interventions on patient-reported outcomes because this information can help us to develop a sophisticated understanding of how these interventions work and for whom they are most effective. The development of less resource-intensive integrated care models, such as stepped care models, and primary palliative care interventions to address the growing needs of patients with hematologic malignancies amid growing workforce challenges is also an important priority for the field.

FIG 3.

Potential strategies for palliative care (PC) integration in patients with hematologic malignancies. Note that the diseases included here are only examples and do not represent a comprehensive list of hematologic malignancies.

AUTHOR CONTRIBUTIONS

Conception and design: Areej El-Jawahri, Thomas W. LeBlanc

Collection and assembly of data: Areej El-Jawahri, Ashley M. Nelson

Data analysis and interpretation: Areej El-Jawahri, Tamryn F. Gray, Stephanie J. Lee

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Palliative and End-of-Life Care for Patients With Hematologic Malignancies

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/journal/jco/site/ifc.

Stephanie J. Lee

Honoraria: Mallinckrodt

Consulting or Advisory Role: Incyte, Pfizer, EMD Serono (I), Pfizer (I), Kadmon, MSD Oncology (I), Sanofi (I), Genzyme (I), Regeneron Pharmaceuticals (I)

Research Funding: Kadmon, Takeda Pharmaceuticals, Amgen, Bristol-Myers Squibb (I), EMD Serono (I), Merck Sharp & Dohme (I)

Patents, Royalties, Other Intellectual Property: Patent pending for high-affinity T-cell receptors that target the Merkel polyomavirus (I)

Travel, Accommodations, Expenses: Mallinckrodt, Incyte

Thomas W. LeBlanc

Honoraria: Celgene, Helsinn Therapeutics, Quintiles

Consulting or Advisory Role: Flatiron Health, Helsinn Therapeutics, Otsuka, Heron, Amgen, Seattle Genetics, Pfizer, Agios, AbbVie, Genentech, Medtronic, AstraZeneca

Research Funding: Seattle Genetics (Inst), AstraZeneca (Inst)

Travel, Accommodations, Expenses: Celgene, Otsuka, Heron, Amgen, Agios, AbbVie, Genentech

No other potential conflicts of interest were reported.