ORIGINAL ARTICLE

Nonhematologic Toxicity of Imatinib Mesylate in Pediatric Patients With Chronic Myelogenous Leukemia: A Predominance of Musculoskeletal Pain Kenneth M. Heym, MD,* Sarah M. Gressett Ussery, PharmD,w Heidi Trinkman, PharmD,* and Lindsey M. Philpot, PhDz

Summary: Therapy with the tyrosine kinase inhibitor imatinib mesylate has become standard initial treatment for adult and pediatric patients with chronic myelogenous leukemia. Long-term follow-up data are now available in the adult population, and the toxicity profile of imatinib mesylate among adults has been extensively studied and reported. Despite its increasing use in the pediatric population, there are limited data regarding adverse event profiles of imatinib mesylate in children, and few reports exist in the literature focusing on nonhematologic toxicity in this population. We reviewed our institutional experience with imatinib therapy for chronic myelogenous leukemia over an 8-year period of time. Nine pediatric patients began therapy with imatinib mesylate and were included in this review. We reviewed the occurrence of nonhematologic toxicity in this cohort and the impact of that toxicity on continuation of therapy. Eight patients experienced nonhematologic toxicity, including nausea/vomiting (44.4%) and musculoskeletal pain (88.9%). Three patients (33.3%) required discontinuation of imatinib therapy due to grade 3/4 musculoskeletal pain, a rate that is significantly higher than that seen in the adult population. As imatinib therapy becomes increasingly widespread in the treatment of pediatric malignancies, there may be different patterns of clinically significant nonhematologic toxicity, including higher grade musculoskeletal pain. Key Words: CML, imatinib mesylate, pain, nonhematologic toxicity, toxicity

(J Pediatr Hematol Oncol 2015;37:e111–e113)

C

hronic myelogenous leukemia (CML) accounts for 2% to 3% of all childhood leukemias.1 Ninety percent of cases are characterized by a balanced translocation between the long arms of chromosomes 9 and 22, which results in the translation of the oncogenic bcr/abl protein tyrosine kinase. Imatinib mesylate is a small molecule that selectively inhibits proliferating myeloid cell lines expressing the bcr/abl kinase2,3 and its development has paved the way for the next generation of anticancer therapies: small molecule inhibitors selective for specific molecular targets which are essential for the malignant phenotype of the disease.4 Imatinib is generally well tolerated due to its specificity. Myelosuppression may occur, although significant Received for publication April 30, 2014; accepted September 22, 2014. From the *Department of Hematology/Oncology, Cook Children’s Medical Center, Fort Worth; wMedical Science Liaison-Hematology, Celgene Corporation; and zOffice of the Chief Quality Officer, Baylor Scott & White Health, Dallas TX. The authors declare no conflict of interest. Reprints: Kenneth M. Heym, MD, Department of Hematology/ Oncology, Cook Children’s Medical Center, 1500 Cooper Street, Fifth Floor, Fort Worth, TX 76104 (e-mail: kenneth.heym@ cookchildrens.org). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.

J Pediatr Hematol Oncol



nonhematologic toxicities, including musculoskeletal complaints, are less frequent.4 Although side-effect profiles have been extensively studied in the adult population,5–7 there is little published literature on imatinib toxicity in pediatric patients and no reported study focusing on the occurrence of musculoskeletal pain in children. Here we review our institutional experience of imatinib use in the treatment of CML in pediatric patients and analyze the observed toxicity profiles, incidence and severity of musculoskeletal pain, and the implications of toxicity on continuation of imatinib therapy.

MATERIALS AND METHODS Nine patients diagnosed with CML in chronic phase began treatment with imatinib at Cook Children’s Medical Center between January 2001 and December 2008. Patients were eligible for inclusion in this retrospective chart review if they were between the ages of 0 and 18 years at diagnosis of histopathologically confirmed adult-type CML. Before patient identification, approval was obtained from the Cook Children’s Institutional Review Board. Primary exposure variables included imatinib dose and duration of therapy. The primary outcome variables included occurrence and management of nonhematologic toxicities, reason for imatinib discontinuation (if applicable), and subsequent management of disease if imatinib was discontinued. Musculoskeletal pain was graded using the National Cancer Institute Common Toxicity Criteria version 2.0.8

RESULTS All 9 patients treated with imatinib for CML were included in the study population for evaluation of imatinibinduced toxicity. Their characteristics are presented in Table 1. The median age at diagnosis and initiation of imatinib therapy was 11.6 years (range, 2.8 to 17.5 y). The median total daily dose of imatinib was 400 mg (340 mg/m2) once daily (range, 300 to 600 mg and 230 to 440 mg/m2) and the median duration of therapy was 90 days (range, 34 to 2430 d). The incidences of nonhematologic toxicities attributed to imatinib are outlined in Figure 1. Musculoskeletal pain was seen in 8 patients (88.9%), nausea and vomiting in 4 patients (44.4%), constipation in 2 patients (22.2%), rash in 1 patient (11.1%), joint swelling in 1 patient (11.1%), and dyspepsia in 1 patient (11.1%). For the patients with musculoskeletal pain, the pain was grade 1 or 2 in 5 patients (62.5%) and grade 3 or 4 in 3 patients (37.5%). The pain was managed with nonsteroidal anti-inflammatory drugs in 4 patients (50%), acetaminophen in 2 patients (25%), and tramadol in 1 patient (12.5%). Opioids were used in 4 patients (50%). Eight patients (88.9%) discontinued therapy with imatinib for the following reasons: 3 patients (37.5%)

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TABLE 1. Characteristics of 9 Chronic Myelogenous Leukemia Patients Treated With Imatinib Mesylate at Cook Children’s Medical Center, January 2001 to December 2008

Sex

Age (y) at Initiation of Imatinib

Initial Dose (mg/m2)

Duration of Therapy (d)

MS Pain Grade

Reason for Discontinuation

Female Female Female Male Male Male Male Male Male

11.6 17.5 14.7 9.4 11.0 15.3 15.9 10.5 2.8

440 340 340 340 340 340 230 340 400

4083 66.9 1284 981 90 67 34 93 56

2 3/4 1/2 1/2 3/4 3/4 1 None 1/2

— MS pain Imatinib failure Imatinib failure MS pain MS pain SCT SCT Imatinib failure

Patients 1 2 3 4 5 6 7 8 9

MS indicates musculoskeletal pain; SCT, stem cell transplant.

experienced grade 3 or 4 musculoskeletal pain, 2 patients (25%) went on to matched-related donor hematopoietic stem cell transplantation, and 3 patients (37.5%) failed imatinib therapy and developed breakthrough disease. All 3 patients who discontinued imatinib due to grade 3 or 4 musculoskeletal pain experienced the onset of their pain within 1 week of starting imatinib. All patients reported multiple sites of pain, including the arms, legs, and feet, and only 1 patient experienced concomitant joint swelling, located in bilateral ankles and knees. Two of the patients required withdrawal from high school and institution of homebound schooling, and 1 reported such an inability to maintain normal activity that she was placed on disability. All 3 patients were started on dasatinib as the next line of therapy. Two of the patients had prompt, complete resolution of their pain, whereas 1 had significant improvement, although still complained of chronic pain. At the time of this study, all 3 patients were alive and in CR on dasatinib.

DISCUSSION Imatinib has become first-line therapy for CML as multiple studies have shown its superiority over previous therapies, including interferon and cytarabine, in inducing complete cytogenetic remission.6,9 Patients taking imatinib also report improved quality of life and a more tolerable side-effect profile.6,10 Few patients experience grade 3 or 4 toxicities and rates of discontinuation of imatinib due to toxicity are reported as low as 2% to 5% in adult studies.10 Musculoskeletal pain

88.9%

Nausea and vomiting

44.4%

Constipation

22.2%

Dyspepsia

11.1%

Joint Pain

11.1%

Rash

11.1%

FIGURE 1. Incidence of nonhematologic toxicities attributed to imatinib therapy among chronic myelogenous leukemia patients, Cook Children’s Medical Center, January 2001 to December 2008 (n = 9).

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Significant musculoskeletal toxicity of imatinib is fairly uncommon. Published results from the IRIS study report the incidence of muscle cramps at 49%, musculoskeletal pain at 47%, and joint pain at 31%. Grade 3 or 4 musculoskeletal toxicity was not common and the pain diminished over time.6 Another adult study reported bone pain and muscle cramps in 14% and 25% of patients, respectively, with grade 3 or 4 pain in

Nonhematologic toxicity of imatinib mesylate in pediatric patients with chronic myelogenous leukemia: a predominance of musculoskeletal pain.

Therapy with the tyrosine kinase inhibitor imatinib mesylate has become standard initial treatment for adult and pediatric patients with chronic myelo...
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