Oncology 2014;87:133–147 DOI: 10.1159/000362816 Received: August 2, 2013 Accepted after revision: April 8, 2014 Published online: July 8, 2014
© 2014 S. Karger AG, Basel 0030–2414/14/0873–0133$39.50/0 www.karger.com/ocl
Review
The Impact of Symptom Burden on Patient Quality of Life in Chronic Myeloid Leukemia David Cella
Cindy J. Nowinski
Olga Frankfurt
Northwestern University Feinberg School of Medicine, Chicago, Ill., USA
Key Words Adherence · Chronic myeloid leukemia · Health-related quality of life · Symptom burden · Tyrosine kinase inhibitors Abstract Patients with chronic myeloid leukemia (CML) in chronic phase are living longer on BCR-ABL1 tyrosine kinase inhibitor (TKI) therapy, placing emphasis on issues related to symptom burden and quality of life (QoL). Furthermore, the potential for adverse events with longer-term therapy may result in dose adjustments, treatment discontinuation, or nonadherence, all of which may negatively affect treatment efficacy and QoL. However, instruments to specifically measure the impact of symptom burden and treatment on health-related QoL in patients with CML have not been widely available until recently. The FACT-Leu is a validated tool that measures leukemia-specific and more general QoL concerns. Other tools specific to CML, including the MDASI-CML and the EORTC QLQ-CML24, are undergoing validation. Here, we describe TKI therapy-related symptom burden and its effect on adherence and treatment response, outline instruments to measure symptom burden and QoL in CML, and summarize the available clinical data on QoL of patients on TKI therapy. QoL is an aspect of CML disease management that will continue to gain prominence in the coming years. We believe that the instruments developed now will have a role in informing treatment decisions in routine practice and allowing clinicians to proactively address issues related to symptom burden and QoL. © 2014 S. Karger AG, Basel
Introduction
David Cella, PhD Department of Medical Social Sciences Northwestern University Feinberg School of Medicine 633 North St. Clair Street, 19th Floor, Chicago, IL 60611 (USA) E-Mail d-cella @ northwestern.edu
Downloaded by: Selçuk Universitesi 193.255.248.150 - 1/28/2015 3:03:50 AM
Chronic myeloid leukemia (CML) is a malignancy of the pluripotent hematopoietic stem cells leading to the uncontrolled proliferation and accumulation of myeloid cells in bone marrow and peripheral blood. The constitutive activity of an aberrant tyrosine kinase,
134
Oncology 2014;87:133–147 DOI: 10.1159/000362816
© 2014 S. Karger AG, Basel www.karger.com/ocl
Cella et al.: The Impact of Symptom Burden on Patient Quality of Life in Chronic Myeloid Leukemia
BCR-ABL1, has been identified as the molecular defect responsible for the pathogenesis of CML [1, 2], and this has led to the development of tyrosine kinase inhibitors (TKIs) that directly suppress BCR-ABL1 function. Currently, there are 5 TKIs approved for the treatment of CML: imatinib, nilotinib, and dasatinib for both first- and second-line therapy, bosutinib for second- or third-line therapy, and ponatinib for patients with the T315I mutation or for whom no other TKI is indicated. In 2001, imatinib was the first BCR-ABL1 TKI to be approved by the US Food and Drug Administration (FDA) for CML treatment. Since then, the overall survival of patients newly diagnosed with CML has improved considerably [3, 4], in large part because imatinib significantly delays disease progression compared with previous standard therapies. In the phase 3 IRIS [International Randomized Study of Interferon and STI571 (imatinib)] study, imatinib was superior to the combination of interferon-α and low-dose cytarabine in maintaining patients free from disease progression from chronic phase (CP) to accelerated phase or blast crisis (AP/BC) [5]. Patient-reported symptoms and functioning were also better in the imatinib arm, resulting in a safety label claim in the FDA approval of imatinib [6]. Similarly, phase 3 randomized controlled studies of second-generation TKIs have demonstrated favorable or comparable reductions in the rates of disease progression compared with imatinib in patients newly diagnosed with CML-CP. The 3-year follow-up of the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients) study has shown significantly lower rates of disease progression with nilotinib 300 mg twice daily than with imatinib 400 mg once daily [7]. The 2-year follow-up of the DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML Patients) study and the 1-year follow-up of the BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) study have found similar rates of disease progression with dasatinib 100 mg once daily and bosutinib 500 mg once daily, respectively, versus imatinib 400 mg once daily [8, 9]. Because patients with CML diagnosed in the current ‘TKI era’ are living longer than ever before and CML requires long-term, potentially lifelong, TKI therapy, a shift in the focus of care to minimizing symptoms of CML and side effects of its treatment has been evident in recent years. Moreover, greater attention has been placed on understanding the impact of symptom burden on patient quality of life (QoL). At the moment, however, validated instruments to measure QoL in CML are not widely known or regularly used in clinical research or routine practice. This review describes the symptoms associated with CML and its treatment with TKIs; symptom burden, adherence, and response to TKI therapy in CML; approaches to measurement of health-related QoL; assessment of symptom burden in CML, and the effect of TKI therapy on patient QoL.
An estimated 5,430 new cases of CML were diagnosed in the US in 2012 [10]. Most patients are diagnosed in CML-CP, an early, indolent stage of the disease in which many patients are asymptomatic or may experience only mild CML-related symptoms [11]. Thus, many patients diagnosed in CML-CP may feel physically ‘well’ for extended periods [12]. Even in the absence of overt disease symptoms, however, negative emotional consequences can manifest. For example, patients younger than 59 years of age and women with CML both report more severe role limitations due to emotional problems than matched healthy controls [13], suggesting that having CML can diminish overall QoL by affecting emotional health. As CML advances to CML-AP and CML-BC, the final stage of the disease, clinical symptoms become progressively worse (table 1). Patients with advanced forms of CML frequently report symptoms reflective of progressive bone marrow failure and splenomegaly, including
Downloaded by: Selçuk Universitesi 193.255.248.150 - 1/28/2015 3:03:50 AM
Symptoms Associated with CML and Its Treatment with TKIs
135
Oncology 2014;87:133–147 DOI: 10.1159/000362816
© 2014 S. Karger AG, Basel www.karger.com/ocl
Table 1. Common clinical symptoms of CML
Stage of disease
Clinical symptoms
Chronic phase (CP) [50, 51]
Fatigue Weight loss/loss of appetite Abdominal fullness Splenomegaly Anemia Sweats
Advanced phases (AP and BC) [12, 50]
Worsening/persistent fatigue, weight loss/ loss of appetite, abdominal fullness Bleeding Progressive splenomegaly Worsening anemia (hematocrit
© 2014 S. Karger AG, Basel 0030–2414/14/0873–0133$39.50/0 www.karger.com/ocl
Review
The Impact of Symptom Burden on Patient Quality of Life in Chronic Myeloid Leukemia David Cella
Cindy J. Nowinski
Olga Frankfurt
Northwestern University Feinberg School of Medicine, Chicago, Ill., USA
Key Words Adherence · Chronic myeloid leukemia · Health-related quality of life · Symptom burden · Tyrosine kinase inhibitors Abstract Patients with chronic myeloid leukemia (CML) in chronic phase are living longer on BCR-ABL1 tyrosine kinase inhibitor (TKI) therapy, placing emphasis on issues related to symptom burden and quality of life (QoL). Furthermore, the potential for adverse events with longer-term therapy may result in dose adjustments, treatment discontinuation, or nonadherence, all of which may negatively affect treatment efficacy and QoL. However, instruments to specifically measure the impact of symptom burden and treatment on health-related QoL in patients with CML have not been widely available until recently. The FACT-Leu is a validated tool that measures leukemia-specific and more general QoL concerns. Other tools specific to CML, including the MDASI-CML and the EORTC QLQ-CML24, are undergoing validation. Here, we describe TKI therapy-related symptom burden and its effect on adherence and treatment response, outline instruments to measure symptom burden and QoL in CML, and summarize the available clinical data on QoL of patients on TKI therapy. QoL is an aspect of CML disease management that will continue to gain prominence in the coming years. We believe that the instruments developed now will have a role in informing treatment decisions in routine practice and allowing clinicians to proactively address issues related to symptom burden and QoL. © 2014 S. Karger AG, Basel
Introduction
David Cella, PhD Department of Medical Social Sciences Northwestern University Feinberg School of Medicine 633 North St. Clair Street, 19th Floor, Chicago, IL 60611 (USA) E-Mail d-cella @ northwestern.edu
Downloaded by: Selçuk Universitesi 193.255.248.150 - 1/28/2015 3:03:50 AM
Chronic myeloid leukemia (CML) is a malignancy of the pluripotent hematopoietic stem cells leading to the uncontrolled proliferation and accumulation of myeloid cells in bone marrow and peripheral blood. The constitutive activity of an aberrant tyrosine kinase,
134
Oncology 2014;87:133–147 DOI: 10.1159/000362816
© 2014 S. Karger AG, Basel www.karger.com/ocl
Cella et al.: The Impact of Symptom Burden on Patient Quality of Life in Chronic Myeloid Leukemia
BCR-ABL1, has been identified as the molecular defect responsible for the pathogenesis of CML [1, 2], and this has led to the development of tyrosine kinase inhibitors (TKIs) that directly suppress BCR-ABL1 function. Currently, there are 5 TKIs approved for the treatment of CML: imatinib, nilotinib, and dasatinib for both first- and second-line therapy, bosutinib for second- or third-line therapy, and ponatinib for patients with the T315I mutation or for whom no other TKI is indicated. In 2001, imatinib was the first BCR-ABL1 TKI to be approved by the US Food and Drug Administration (FDA) for CML treatment. Since then, the overall survival of patients newly diagnosed with CML has improved considerably [3, 4], in large part because imatinib significantly delays disease progression compared with previous standard therapies. In the phase 3 IRIS [International Randomized Study of Interferon and STI571 (imatinib)] study, imatinib was superior to the combination of interferon-α and low-dose cytarabine in maintaining patients free from disease progression from chronic phase (CP) to accelerated phase or blast crisis (AP/BC) [5]. Patient-reported symptoms and functioning were also better in the imatinib arm, resulting in a safety label claim in the FDA approval of imatinib [6]. Similarly, phase 3 randomized controlled studies of second-generation TKIs have demonstrated favorable or comparable reductions in the rates of disease progression compared with imatinib in patients newly diagnosed with CML-CP. The 3-year follow-up of the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients) study has shown significantly lower rates of disease progression with nilotinib 300 mg twice daily than with imatinib 400 mg once daily [7]. The 2-year follow-up of the DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML Patients) study and the 1-year follow-up of the BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) study have found similar rates of disease progression with dasatinib 100 mg once daily and bosutinib 500 mg once daily, respectively, versus imatinib 400 mg once daily [8, 9]. Because patients with CML diagnosed in the current ‘TKI era’ are living longer than ever before and CML requires long-term, potentially lifelong, TKI therapy, a shift in the focus of care to minimizing symptoms of CML and side effects of its treatment has been evident in recent years. Moreover, greater attention has been placed on understanding the impact of symptom burden on patient quality of life (QoL). At the moment, however, validated instruments to measure QoL in CML are not widely known or regularly used in clinical research or routine practice. This review describes the symptoms associated with CML and its treatment with TKIs; symptom burden, adherence, and response to TKI therapy in CML; approaches to measurement of health-related QoL; assessment of symptom burden in CML, and the effect of TKI therapy on patient QoL.
An estimated 5,430 new cases of CML were diagnosed in the US in 2012 [10]. Most patients are diagnosed in CML-CP, an early, indolent stage of the disease in which many patients are asymptomatic or may experience only mild CML-related symptoms [11]. Thus, many patients diagnosed in CML-CP may feel physically ‘well’ for extended periods [12]. Even in the absence of overt disease symptoms, however, negative emotional consequences can manifest. For example, patients younger than 59 years of age and women with CML both report more severe role limitations due to emotional problems than matched healthy controls [13], suggesting that having CML can diminish overall QoL by affecting emotional health. As CML advances to CML-AP and CML-BC, the final stage of the disease, clinical symptoms become progressively worse (table 1). Patients with advanced forms of CML frequently report symptoms reflective of progressive bone marrow failure and splenomegaly, including
Downloaded by: Selçuk Universitesi 193.255.248.150 - 1/28/2015 3:03:50 AM
Symptoms Associated with CML and Its Treatment with TKIs
135
Oncology 2014;87:133–147 DOI: 10.1159/000362816
© 2014 S. Karger AG, Basel www.karger.com/ocl
Table 1. Common clinical symptoms of CML
Stage of disease
Clinical symptoms
Chronic phase (CP) [50, 51]
Fatigue Weight loss/loss of appetite Abdominal fullness Splenomegaly Anemia Sweats
Advanced phases (AP and BC) [12, 50]
Worsening/persistent fatigue, weight loss/ loss of appetite, abdominal fullness Bleeding Progressive splenomegaly Worsening anemia (hematocrit
