Pain in patients with newly diagnosed or relapsed acute leukemia

Acute leukemia (AL) is a malignant disorder of hematopoietic stem cells that is usually treated with aggressive chemotherapy [1]. AL includes two distinct disease entities, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), which differ in cell of origin, clinical course, and treatment. AML is primarily a disease of the bone marrow that is treated with induction chemotherapy—classically the “7+3” protocol (7 days of continuous cytarabine with 3 days of anthracycline)—and then consolidation with either chemotherapy or allogeneic bone marrow transplantation [1]. Acute promyelocytic leukemia (APL) is a subtype of AML, characterized by the presence of the PML-RARA gene translocation, life-threatening disseminated intravascular coagulopathy at onset, and good overall prognosis [2]. ALL is a disease of the bone marrow and the lymphatic system, with a higher degree of organ invasion and central nervous system involvement. Treatment involves continuous courses of induction, consolidation, and maintenance chemotherapy (systemic and intrathecal) for a prolonged period of up to 2 years [3]. Both the disease process and the intense treatment regimens provided for AL can result in substantial morbidity and mortality, but there is limited literature on the prevalence and correlates of pain in this population.

Data from small prospective studies in end-of-life settings suggest that pain is a prominent symptom in patients with AL late in the disease course [4‐7]. However, there is limited research on pain in newly diagnosed patients receiving induction chemotherapy [8]. Our group has previously reported a high physical and psychological symptom burden in newly diagnosed and relapsed patients with AL [9‐11]. We now report data on pain prevalence and characteristics in a large cohort of patients receiving induction chemotherapy for AL and report on predictors and sites of pain in this population.

Three hundred eighteen patients with AL were recruited (Table 1); 289 (90.9%) had new onset disease, while 29 (9.1%) had relapsed disease. A total of 213 (67.0%) patients had AML, 32 (10.0%) had APL, and 73 (23.0%) had ALL. All patients with ALL were treated with the Dana Farber protocol [19]; 209 (85.3%) of AML patients received the “7+3” regimen, while 36 (14.7%) received other induction chemotherapy. Study questionnaires were completed during the first week after chemotherapy by 46 participants (14.5%), during the second week by 79 (24.9%), during the third week by 101 (31.9%), during the fourth week by 63 (19.9%), and from 28 to 46 days after treatment by 28 (8.8%). Within 46 days of treatment initiation, 7/318 (2.2%) patients died, and 3 were referred to palliative care.

A total of 156 (49.2%) patients reported having pain, and 55 (35.3%) of these reported their pain to be severe to very severe (MSAS severity ≥ 3/4) (Table 2). Pain prevalence was associated with all measured psychological symptoms, including difficulty sleeping, worrying, difficulty concentrating, and feeling sad, nervous, or irritable, with a consistent trend for more severe pain to be associated with increased psychological symptoms. For example, the prevalence of difficulty sleeping was 41% in patients with no pain, 60% in those with pain that was not severe (MSAS severity ≤ 2), and 71% in those with severe pain (≥ 3/4). Some physical symptoms were also correlated with pain, including lack of energy, hair loss, sweats, mouth sores, bloating, numbness/tingling in hands and/or feet, and difficulty swallowing (Table 3).

On univariable analysis (Table 4), severe pain was associated with younger age (OR 0.98, 95% CI 0.96–0.99, severe pain vs not severe or no pain, p = 0.01), worse KPS performance status (OR 0.96, 95% CI 0.93–0.99, p = 0.01), ALL (OR 2.46, 95% CI 1.32–4.59, p = 0.005), ALL chemotherapy protocol (OR 2.47, 95% CI 1.30–4.68, p = 0.02), and longer time from chemotherapy initiation to study assessment (OR 1.25, 95% CI 1.01–1.54, p = 0.04). On multivariable analysis (Table 4), severe pain was associated with younger age (OR 0.98, 95% CI 0.96–0.996, p = 0.02), worse performance status (OR 0.96, 95% CI, 0.93–0.998, p = 0.04), ALL (OR 2.05, 95% CI 1.05–4.00, p = 0.04), and longer time from chemotherapy start to assessment (OR 1.28, 95% CI 1.02–1.61, p = 0.03). In both AML and ALL, average pain increased sharply from two to 4–5 weeks after initiation of chemotherapy, and then subsided (Fig. 1).

For patients with severe pain (n = 55), pain was localized to the following areas: oropharynx in 22 (40%), head in 12 (21.8%), abdomen in 11 (20%), musculoskeletal in 9 (16.4%), rectal in 5 (9.1%), chest in 2 (3.6%), and other sites in 7 (12.7%) (Fig. 2). Ten (18%) patients reported severe pain in more than one site. In two cases, the site of pain could not be identified from the chart review. There was no significant association between the site of pain and disease type or time from chemotherapy; however, there was a trend for headache and oropharyngeal pain to be more common in patients with ALL and rectal pain to be more common in patients with AML.

In this cohort of patients with AL undergoing induction chemotherapy, pain was a frequent symptom, reported by 49.2% overall; of these, 35.3% reported their pain as severe to very severe. Pain was associated with several other physical symptoms and with all psychological symptoms assessed, including difficulty sleeping, worrying, difficulty concentrating, and feeling sad, nervous, or irritable. Severe pain was associated with younger age, poorer performance status, a diagnosis of ALL, and time from onset of chemotherapy, with pain increasing sharply from 2 to 4–5 weeks after initiation of chemotherapy. The most common sites of severe pain were oropharynx, head, and abdomen.

Pain was prevalent in our cohort despite maximal inpatient treatment by the leukemia team. The prevalence of pain in approximately half of the sample was higher than that reported by patients with stage 1–3 solid tumors, though not as high as that of hospitalized patients with advanced cancer [20]. The association between pain and time from chemotherapy onset suggests that, in contrast with other malignancies, pain in patients with AL results mainly from the treatment and its complications, rather than from the disease process itself. Indeed, the prevalence of severe pain over time in our cohort mirrors the decrease in blood counts, which reach their nadir during the second and third weeks from initiation of chemotherapy. Chemotherapy-induced cytopenias may result in bleeding and localized infections, which in addition to chemotherapy-induced mucositis, may be the primary cause of pain during leukemia induction therapy. Indeed, all of the physical symptoms associated with severe pain in our study may be complications of chemotherapy treatment, including lack of energy, hair loss, sweats, mouth sores, bloating, numbness/tingling in the hands or feet, and difficulty swallowing. The rapid appearance of severe pain in opioid-naïve patients with AL is challenging, as medications such as opioid medications and neuropathic agents require titration in order to avoid adverse side effects, particularly in this population of fragile patients [21].

ALL was associated with a higher prevalence of severe pain, which was particularly prominent in the head and oropharynx; the abdomen was also a frequent site for severe pain in both AML and ALL. Oropharyngeal and abdominal pain are most likely the result of mucositis and typhlitis, while headaches may be secondary to lumbar puncture, brain and leptomeningeal spread of disease, anemia, or cranial hemorrhage secondary to thrombocytopenia. ALL induction chemotherapy includes multiple intrathecal treatments which may cause chemical meningitis and post-lumbar puncture headache, which may account for the trend for increased headache in ALL in comparison with AML. As well, ALL may be associated with more pain as a result of central nervous system involvement or mass effect secondary to lymphadenopathy or hepatosplenomegaly, which are more prominent in ALL.

The tendency for severe pain to be more common in younger patients has also been observed in other studies of patients with cancer [22‐25]. This may in part be due to an age-related “response shift” in the perception of pain, whereby the pain experience in older patients is reconceptualized based on the previous experience of pain associated with chronic medical conditions [26]. In addition, lower doses of chemotherapy are commonly utilized in older patients [27, 28], which may result in decreased toxicity to mucosa [29, 30], fewer infections [28, 30], and therefore less pain. Correspondingly, chemotherapy-induced mucositis pain has previously been reported as more prevalent in younger patients with cancer [31].

In our cohort of patients with AL receiving aggressive induction chemotherapy, less than 1% of patients were referred to palliative care, despite a high pain burden and a median survival of 30.9 months. Despite the high prevalence of pain and other distressing symptoms in patients with AL, they are less likely to be referred to palliative care and are referred later in their disease trajectory relative to patients with other malignancies [32‐34]. In comparison with solid tumor oncologists, hemato-oncologists are more likely to favor aggressive therapy even when the chance of survival is low [35] and generally equate palliative care with end of life care [36]. In patients undergoing hematopoietic stem cell transplantation, early palliative care intervention has been shown to improve pain and other symptoms [37]. Given the predictable appearance of pain following chemotherapy in patients with AL, early palliative care may be able to attenuate pain, resulting in improved long-term effects, regardless of prognosis [38, 39].

Our study has several limitations. Although we collected patient-reported information on prevalence, severity, and distress associated with pain, we did not collect information on the site of pain, which was gathered from chart review. The assessment of differences in sites of pain in AML and ALL is limited in this regard as well as due to the small sample size for this comparison. Symptoms in AL may change rapidly, and our cross-sectional results do not allow for an evaluation of the pain trajectory over the period of induction chemotherapy. Results from our longitudinal study of pain and other symptoms over time will add to knowledge in this regard.

Although treatment protocols for AL have changed little over the past 30 years, patient survival has improved substantially as a result of improvements in treatment of severely neutropenic patients with new antibacterial and antifungal agents and because of new imaging modalities [40]. However, it is unclear whether there has been concomitant improvement in quality of life in these patients. The high prevalence and predictable trajectory of pain in our study highlight the need for further research into the trajectory of symptoms and interventions to alleviate them. This may entail approaches for early diagnosis of pain syndromes specific to AL as well as rapid and aggressive pain control. Early palliative care interventions may play a role in this regard and should be tested in this patient population.