Top Ten Tips Palliative Care Clinicians Should Know About Caring for Patients with Hematologic Malignancies

Abstract

Hematologic malignancies differ in several important ways from solid organ cancers, and warrant a unique approach to palliative care (PC) integration. As PC has moved upstream from end-of-life care, PC clinicians are increasingly asked to see patients with hematologic malignancies. Unfortunately, many PC specialists have limited knowledge of these diseases, and have had few prior opportunities to participate in their care. This article, written by hematologic oncologists and PC specialists, seeks to educate PC teams about the unique features of hematologic malignancies, to inform effective integration of PC into the care of these patients, their caregivers, and treating hematologists.

Introduction

Specialty palliative care (PC) clinicians are infrequently asked to see patients with hematologic malignancies. There are several reasons PC specialists should approach patients with hematologic malignancies differently than those with solid tumors. For example, hematologic malignancies often have more variable or uncertain prognoses than do solid tumors, such that a patient with a very aggressive or relapsed blood cancer might still have a chance at cure with intensive treatment, including hematopoietic stem cell transplantation (HSCT). Yet, outcomes data also show that patients with hematologic malignancies, on average, experience worse end-of-life care compared to patients with solid tumors, with a higher likelihood of dying in the hospital, spending time in an intensive care unit at the end of life, receiving chemotherapy in the last two weeks of life, and not utilizing hospice care services.¹ In this article, we present 10 useful tips for PC clinicians to consider when caring for patients with hematologic malignancies, along with their caregivers and cancer care teams.

Tip 1: Blood Cancers are Often More Responsive to Chemotherapy than Solid Tumors, So Standard Prognostic Assessments Such As Functional Status Do Not Apply Well to Many Scenarios in Malignant Hematology

PC specialists often measure performance status with Eastern Cooperative Oncology Group (ECOG) or Karnofsky/Palliative Performance Status scales, to estimate the likelihood that a patient will tolerate chemotherapy and live long enough to benefit from it.² In 2012, an American Society of Clinical Oncology (ASCO) expert panel recommended against the use of chemotherapy in solid tumor patients who have an ECOG performance status score of 3 or 4, asserting that once patients become so debilitated from cancer that they are unable to function at a basic level, chemotherapy will not work quickly enough or well enough to reverse those cancer-related changes before death. Since many hematologic malignancies are marked by impressive chemotherapy response, the prognostic utility of performance status assessment is less certain in hematology.

For example, patients with acute myelogenous leukemia (AML), which is frequently a disease of older patients (median age at onset of 68), generally have better outcomes with aggressive treatment even with an ECOG >2.³ Other evidence demonstrates that patients with hematologic malignancies fare better than those with solid tumors when treated with chemotherapy, even if they have relapsed or otherwise advanced disease.⁴ In a focus group, hematologists noted that patients with hematologic malignancies with borderline to poor performance status are often initially treated with chemotherapy, due to the potential for cure and/or meaningful response to treatment.⁵ In AML, for example, intensive induction chemotherapy yields a complete remission in 60–70% of adults, with a sizeable subset surviving more than three years, wherein many are cured.⁶ As such, prognostication is one of the most significant challenges clinicians face in caring for patients with hematologic malignancies.

Tip 2: Staging Is Different in Hematology and Is Based Heavily on Molecular/Genetic Features; “Advanced Disease” Does Not Always Mean Incurable

Hematologic malignancies differ from solid tumors because the underlying cell of origin, rather than stage, correlates most closely with prognosis. Genetic features significantly predict outcomes as well. For example, a p53 mutation is often a poor prognostic sign, such as in chronic lymphocytic leukemia (CLL), multiple myeloma, or AML. There are three major categories of hematologic malignancies—leukemias, lymphomas, and myeloma—each of which is defined by uncontrolled cell growth within these particular cell lineages in the marrow and/or lymph system. While a detailed discussion of prognostication schemas across all of hematologic malignancies is beyond the scope of this article; we briefly highlight salient aspects of prognostication below.

In leukemia, immature white blood cells proliferate in the bloodstream. Chronic leukemias (e.g., chronic myeloid leukemia [CML] and CLL) generally have favorable prognoses (years) and are treated as chronic illnesses. In fact, expected survival of patients with CML is similar to that of age-matched population controls.⁷ Acute leukemias, however, are often medical emergencies that warrant urgent hospital admission and timely initiation of chemotherapy. Acute leukemia prognoses vary widely. Prognosis is predicted mostly by the subtype, mutations present, and the patient's ability to tolerate intensive treatments, rather than any traditional staging.^8,9 Prognosis varies from an overwhelmingly high remission and cure rate in acute promyelocytic leukemia (a special subtype of AML), to a high risk of mortality in older AML patients harboring certain gene mutations, such as those in the FMS-like tyrosine kinase domain (FLT-3 mutations), and poor outcomes among those with a complex chromosomal karyotype (usually defined as those having at least three chromosomal abnormalities, without one conveying favorable features), or a p53 mutation.¹⁰

Lymphomas come in two main subtypes, non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL, sometimes called Hodgkin disease). However, there are over 60 subtypes of lymphomas, making it very difficult for PC specialists to know what to expect for a particular patient. Most lymphomas are B cell lymphomas, while about 10% of lymphomas are of T cell origin; T cell lymphomas generally confer a worse prognosis. Some lymphomas are entirely curable with chemotherapy alone, while others are thought to be incurable from diagnosis. The five-year survival rate is 86% for classical HL, and 71% for NHL.¹¹ Prognosis is generally favorable for HL if it develops in early adulthood and can be treated aggressively (usually with chemotherapy, and sometimes radiation). NHL prognoses vary widely, given the wide range of subtypes, but poorer outcomes tend to occur in those older than the age of 65 years and those with multiply relapsed disease.¹¹ We often group NHL into aggressive and indolent variants, which can be helpful prognostically. The prototypical aggressive NHL is diffuse large B cell lymphoma (DLBCL, sometimes called large cell lymphoma), while the most common indolent NHL is follicular lymphoma. DLBCL is associated with a 60% cure rate with chemotherapy alone, even when presenting as stage IV disease, while follicular lymphoma is generally thought of as incurable, yet associated with a median overall survival of a decade or more.

Finally, multiple myeloma is cancer of plasma cells, a type of mature B cell that creates antibodies. Although multiple myeloma is incurable, some patients with multiple myeloma can live a decade or more, receiving intermittent multiagent chemoimmunotherapy, with some undergoing one or more HSCTs; others have refractory or relapsed multiple myeloma and a more aggressive course. The development of novel nonchemotherapeutic treatments for multiple myeloma has dramatically changed the course of this disease, such that the median overall survival for multiple myeloma is over seven years, and it is not unusual for standard-risk patients to live a decade or more.¹² Consequently, the problem of chronic, cumulative toxicity is a growing challenge, and an opportunity for integrated PC to make a difference.

Tip 3: HSCT Can Vary Significantly in Both Intensity and Expected Outcomes; PC Approaches to His Population Must Be Tailored Accordingly

During a HSCT, sometimes called bone marrow transplantation or stem cell transplantation, patients receive healthy blood-forming cells either from a matched donor (allogeneic HSCT) or their own cells (autologous HSCT). The different types of transplants have different goals, and are associated with varying toxicities and risks.

Autologous HSCT is generally used either for multiple myeloma or for relapsed lymphomas. In myeloma, autologous HSCT allows for the administration of higher chemotherapy doses than could safely be given without the subsequent hematopoietic stem cell “rescue.” This results in a deeper remission, improved overall survival, and prolonged time to next relapse (median time to relapse is about two-and-a-half years).¹³ While autologous HSCT is associated with some risks and acute toxicities, it is generally well tolerated, with an associated mortality of just a few percent, even in patients older than the age of 65 years.¹⁴ When used in lymphoma, autologous HSCT can be curative, such as for patients with relapsed HL or DLBCL. The benefit of autologous HSCT is conferred by the higher doses of chemotherapy that it permits.

Allogeneic HSCT, on the contrary, provides an immunological effect from the donor. As such, it is the usual curative-intent treatment for patients with acute leukemias such as AML, in cases where more chemotherapy alone is unlikely to yield a cure (such as relapsed AML). Allogeneic HSCT is sometimes also used in difficult cases of CLL, CML, lymphomas, myelodysplastic syndromes, and other hematologic malignancies wherein the patient is young and healthy enough to tolerate and benefit from this aggressive treatment, and where standard treatment options are unlikely to change the outcome. These transplants come in different levels of intensity: myeloablative and nonmyeloablative. The former uses more aggressive preparative regimens to entirely eliminate the native marrow, which confers greater toxicity but also reduced relapse rates. The goal of allogeneic HSCT is to allow donor cells to repopulate the marrow and replace the recipient's immune system, to thereby kill any remaining cancer cells, potentially curing the disease (the so-called graft vs. leukemia effect). Mortality rates in allogeneic HSCT are between 15% and 25% overall (10–15% mortality rate in nonmyeloablative transplants, and 20–25% in fully myeloablative transplants).^15–18 An unfortunate side effect of bringing a foreign immune system into the body is that the donor stem cells can also attack the patient's other organs, resulting in graft versus host disease (GVHD).^19–21 GVHD mostly commonly affects the gut, skin, lung, eye, and liver and can lead to significant morbidity.²¹ GHVD for each organ has both acute and chronic stages and can even occur when a person's cancer is in complete remission, sometimes years later.¹⁹

HSCT is associated with many unmet PC needs. These patients suffer marked symptom burden, particularly during the active transplant process, with significant insomnia, nausea, diarrhea, pain, and other bothersome symptoms.²² This results in impaired quality of life, significant anxiety and depression, and even posttraumatic stress posttransplant.²² HSCT patients may spend significant amounts of time in the hospital and/or in isolation during and after the transplant procedure, and their caregivers may need significant support. Evidence suggests that early integration of specialist PC significantly improves patient-centered outcomes in the transplant population, as discussed in tip #6.^23,24 By focusing on aggressive symptom management and psychological support, PC specialists can improve the transplant experience.

Tip 4: High Intensity or Novel Therapies Are More Common in Hematologic Malignancies and Warrant Unique Approaches to Integrated PC that Are Independent of Prognosis

Hematologic malignancies care is at the forefront of personalized cancer care given its longstanding use of genetic testing and widespread application of novel targeted treatments. Caring for these patients as a PC specialist requires humility, lest one make the mistake of misapplying rules and expectations of solid tumor care to this unique population, with its sometimes markedly different outcomes than one might intuitively expect. The most recent example of practice-changing innovation comes in the form of chimeric antigen receptor T cell therapies (CAR-T). There are two FDA-approved CAR-T cell products, now in use for relapsed acute lymphoblastic leukemia (ALL), and also for multiply-relapsed NHL. These treatments are remarkably effective in situations that historically were hopeless, with complete remission rates of 80% in multiply-relapsed/refractory ALL, and 40–50% in cases of DLBCL relapsed after at least two prior treatments.^25,26 When exciting, novel therapies are available, patients in desperate situations will often seek them out and may sometimes achieve remarkable results.

Tip 5: Assessment and Management of Psychological Distress Is an Area of Unmet Need in Hematologic Malignancies Care and Presents an Opportunity for PC Integration

A diagnosis of a life-threatening condition can cause significant psychological distress. For example, the treatment of AML or receipt of HSCT can cause acute traumatic stress, depression, and posttraumatic stress disorder.²⁷ Depression affects nearly 18% of patients within the first month of a diagnosis of acute leukemia, and is associated with a greater burden of physical symptoms.²⁸

Screening for distress is best achieved using structured tools. The best evidence for distress screening in ambulatory settings for patients with advanced cancer includes the Distress Thermometer and the Hospital Anxiety and Depression Scale (HADS).^29,30 ASCO recommends screening for depression and anxiety for all patients with cancer at diagnosis, or at points of treatment change or disease progression, using the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7).³¹

Management of distress, overt depression, or anxiety should occur early in the course of cancer treatment. Patients who screen positive for mild to moderate major depressive disorder (PHQ-9: mild >8–14, moderate 15–19) should be offered supportive counseling, psychotherapy, and medication management when appropriate. Patients who meet diagnostic criteria for severe depression (PHQ-9 > 20) should be referred to mental health specialists (e.g., psychiatrist, psychologist) and managed concomitantly with psychotherapy and medication management.³¹ Current guidelines recommend pharmacotherapy for depression and anxiety with selective serotonin reuptake inhibitors (SSRIs) having low CYP2D6 inhibition (e.g., citalopram/escitalopram, venlafaxine, or sertraline), based on first-line efficacy and tolerability.³² Care must be taken to consider the potential antiplatelet effects of SSRIs, and drug interactions with life-saving antifungal medications such as posaconazole. The interdisciplinary PC team is uniquely equipped to support hematology patients experiencing psychological distress.

Tip 6: Integrated PC at the Time of Hospital Admission for HSCT Improves Patient-Centered and Caregiver Outcomes

A recent randomized clinical trial demonstrated the efficacy of specialty PC for improving patient and caregiver quality of life and psychosocial outcomes during HSCT.^23,24 In a single-center, randomized trial of 160 patients with hematologic malignancies undergoing autologous or allogeneic HSCT, patients were randomly assigned to receive integrated PC and transplant care, versus transplant care alone. The intervention required inpatient visits by a PC clinician at least twice weekly during the transplant hospitalization. Patients receiving the intervention reported improvements in quality of life, symptom burden, and in symptoms of depression and anxiety.^23,24 Notably, caregivers of patients randomized to the intervention also reported significant improvements in their coping and depression. Despite the focus of the PC intervention on the transplant hospital stay, intervention effects were sustained at three and six months posttransplant, including improvements in patient-reported depression and posttraumatic stress symptoms.^23,24 These findings underscore the benefits of integrated PC for improving the quality of life and care of patients with hematologic malignancies undergoing HSCT and their caregivers. Studies of integrated PC in other hematologic malignancy settings are ongoing.

Tip 7: Hematologists May Be More Aggressive with Their Treatments Compared to Solid Tumor Oncologists and Are More Likely to Misunderstand PC as a Euphemism for Hospice or End-of-Life Care

Oncologists caring for patients with hematologic malignancies harbor significant misperceptions equating PC with just “end-of-life” care.^33–35 In a survey of HSCT physicians, 52% reported that PC is synonymous with end-of-life care, and 66% stated that the term “palliative care” can decrease hope in patients and families.³³ These misperceptions are more prevalent among oncologists caring for patients with hematologic malignancies compared to those caring for patients with solid tumors.

Oncologists caring for hematologic malignancy patients also differ from those caring for patients with solid tumors in their perspectives on end-of-life care. In a survey of 182 oncologists, hematologic malignancy specialists reported less comfort discussing death and dying (72% vs. 88%), hospice referral (81% vs. 93%), and were more likely to feel a sense of failure upon disease progression (46% vs. 31%) compared to solid tumor oncologists.³⁶ Oncologists caring for hematologic malignancy patients also tend to be more aggressive, reporting a higher likelihood of prescribing systemic therapy at the end of life compared to solid tumor oncologists, further contributing to intensity of end-of-life care in this population.³⁶

Tip 8: Hematologists Often Continue to Treat Their Patients Aggressively Near the End-of-Life Because They Can Achieve Good Outcomes in These Settings, and They Struggle to Predict Who Will Benefit

Patients with hematologic malignancies often experience a vastly different disease trajectory than patients with solid tumors. In particular, patients with hematologic malignancies are more likely to receive aggressive care at the end of life.^37,38 This probably happens for two main reasons: (1) there remains a possibility of a good outcome, including the potential for cure, and (2) statistical outcomes are difficult to apply to individual patients. Treatments can offer the possibility of cure even for relapsed disease, making it difficult to predict when the end of life will occur. For those hematologic malignancies that are incurable at diagnosis, there is still usually the potential for prolonged survival and treatment response despite multiple relapses.⁵ This understandably leads many clinicians and patients to continue aggressive treatments, even in the face of advanced, relapsed, and/or refractory disease.

Accordingly, data show that in their last 30 days of life, patients with hematologic malignancy are more likely to have emergency room visits, hospital admissions, and intensive care unit stays compared to patients with solid tumors.^1,39 Unfortunately, even with poor outcomes and high health care utilization near the end of life, these patients remain less likely to receive PC services.¹ A meta-analysis shows that hematologic malignancy patients are more likely to die in the hospital, even when their preference is to die at home.⁴⁰ The use of acute and aggressive care at the end of life is partially related to the complications unique to hematologic malignancies. Anemia and thrombocytopenia improve with transfusions, neutropenic infections improve with antibiotics, and bleeding and thromboembolic events may improve with acute interventions. Due to the greater likelihood of achieving a good outcome in critically ill patients with hematologic malignancies, they are also more likely to receive chemotherapy and targeted therapy in the last weeks and days of life.¹

Tip 9: Transfusion Support Can Have Significant Palliative Benefits for Many Patients with Terminal Hematologic Malignancies, But May Complicate End-of-Life Care

Anemia and thrombocytopenia are common in hematologic malignancy patients and can manifest with acute/chronic dyspnea, fatigue, weakness, and dizziness, and can severely limit quality of life and function.⁴¹ The management of anemia using red blood cell transfusions can aide in palliating these symptoms. No major randomized controlled trials have assessed the effectiveness of blood transfusions in patients with cancer. However, a meta-analysis and systematic review of studies published to date suggest that between 31% and 70% of patients with advanced cancer have some symptomatic improvement after transfusion, with the greatest benefits for fatigue and breathlessness, although a significant proportion of patients (23–35%) with advanced cancer die within two weeks of requiring transfusion dependence.⁴²

Despite the symptom benefits of transfusions, many patients with advanced cancer who become transfusion dependent may have their end-of-life care complicated by transfusion needs. Hospice provides the highest quality care at the end-of-life, yet, many hematology patients enroll in hospice late, or not at all.⁴³ The current hospice Medicare benefit does not preclude transfusions, however, the cost of regular transfusions generally exceeds the “per diem” payment that hospice agencies receive to pay for all costs of care.⁴⁴ Medicare data for patients with acute and chronic leukemias unfortunately show markedly shorter time in hospice for transfusion dependent patients (6 days vs. 11 days for nontransfusion-dependent patients, p < 0.001), suggesting that the need for transfusion support may significantly delay hospice enrollment.⁴⁵ However, patients with leukemia who elect hospice care receive markedly better quality care at the end of life, per standard quality measures, at a significantly lower cost.⁴⁵

Tip 10: Quality Measures Point to Worse End-of-Life Outcomes in Patients with Hematologic Malignancies, Highlighting a Great Need for PC and Hospice Integration in this Population

Unfortunately, end-of-life care for patients with hematologic malignancies varies greatly, and sometimes does not meet high-quality standards as defined in the solid tumor setting. Patients with hematologic malignancies often receive chemotherapy at end of life,⁴⁶ and are frequently hospitalized, with death as likely to occur in intensive care units as under hospice care.⁴⁷ As PC programs expand nationally, partnerships with hematology clinicians are a natural fit.⁴⁸ Multiple randomized studies are underway to explore when and how PC can offer value to hematologists and their patients.

Patients with hematologic malignancies face significant symptom burden throughout treatment. Pain, dyspnea, nausea, and anorexia are experienced as commonly in hematologic malignancies as in solid malignancies, and tiredness is more prevalent.⁴⁹ PC is less established in the hematologic malignancies population and is often viewed differently by hematologic malignancies clinicians, with the vast majority of treatment-related and end-of-life symptom management provided by the cancer care team.³⁵ Yet, if integrated PC interventions improve outcomes by addressing symptoms, coping, mood, and caregiver well-being, there is much need in the hematology population.

Conclusion

While hematologic malignancies are less common than solid tumors, they account for a significant proportion of deaths from cancer each year. Patients with hematologic malignancies are more likely to have poor end-of-life care outcomes, with a greater chance of spending time in an emergency department, hospital, or intensive care unit at the end of life, and also more use of chemotherapy in the last two weeks of life. Early, integrated PC interventions have focused mostly on patients with advanced solid tumors, yielding great benefits for patients and caregivers. Emerging evidence suggests that these benefits may translate to hematology patients too, but much more work is needed to test novel interventions that meet the unique needs of the diverse hematologic malignancies population and hematologists. As PC clinicians are increasingly called to see hematology patients, it is crucial to understand the fundamental clinical differences of hematologic malignancies and their treatments, as detailed here.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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