- Email: [email protected]
Managing Chronic Myeloid Leukemia: A Coordinated Team Care Perspective
Review
Managing Chronic Myeloid Leukemia: A Coordinated Team Care Perspective Stacie Holloway,1 Katharine Lord,1 Beverly Bethelmie-Bryan,2 Marian W. Shepard,2 Jessica Neely,2 Morgan McLemore,2 Satyanarayan K. Reddy,3 Aldemar Montero,4 William S. Jonas,5 Sara Pierson Gladney,5 Shyam L. Khanwani,6 Silpa C. Reddy,7 Anup K. Lahiry,8 Leonard T. Heffner,2 Elliott Winton,2 Martha Arellano,2 Hanna Jean Khoury2 Abstract Treatment of chronic myeloid leukemia (CML) has seen dramatic progress in recent years with the development of tyrosine kinase inhibitors (TKIs). To take maximum advantage of therapy with TKIs, compliance and good understanding of monitoring response to therapy are essential. We established a team that included a hematologist, a physician assistant (PA), and a nurse who work closely with a social worker, a pharmacist, and a research coordinator to assist patients throughout their journey with CML. The patient and the referring community oncologist were incorporated into this team. This coordinated team care approach takes advantage of each member’s specific skills to provide patients with education about CML, encourage patients’ strong involvement in tracking/monitoring results/response to therapy, and support patients with issues that arise throughout the long course of the disease. A low rate of noncompliance with clinic visits (3%) was an indirect measure of the impact of this approach. The inclusion of the referring oncologist in the team extended the tracking of monitoring results to the community practice. We conclude that a coordinated team care approach is feasible in the management of patients with CML. This approach provided patients with education and a good understanding of response to therapy and improved relations with the health care team. Clinical Lymphoma, Myeloma & Leukemia, Vol. 12, No. 2, 88-93 © 2012 Elsevier Inc. All rights reserved. Keywords: Adherence, BCR-ABL, Multidisciplinary team, Patient education, Tyrosine kinase inhibitor
Introduction Targeting BCR-ABL with tyrosine kinase inhibitors (TKIs) has revolutionized outcomes in patients with chronic myeloid leukemia (CML),1– 4 practically replacing allogeneic hematopoietic stem cell transplantation (HSCT) as first-line therapy.5–7 Three TKIs are commercially available in the United States for the treatment of CML: imatinib, dasatinib, and nilotinib. These agents have remarkable activity when given as first-line therapy,1–3 and dasatinib or nilotinib produce 1
Emory Healthcare, Atlanta, GA Winship Cancer Institute of Emory University, Atlanta, GA 3 South Atlanta Hematology Oncology, Riverdale, GA 4 Suburban Hematology Oncology Associates, Lawrenceville, GA 5 Atlanta Hematology and Oncology Associates, Atlanta, GA 6 Georgia Cancer Specialists, Fayetteville, GA 7 Atlanta Cancer Care, Atlanta, GA 8 Longstreet Cancer Center, Gainesville, GA 2
Submitted: Sept 2, 2011; Revised: Oct 24, 2011; Accepted: Oct 27, 2011 Address for correspondence: H. Jean Khoury, MD, 1365 Clifton Road, C1152, Atlanta, GA 30322 Fax: 404-778-4755; e-mail contact: [email protected]
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impressive responses when administered after imatinib failure or intolerance.8 –10 Monitoring of response and timely implementation of second-line therapy are essential to maximize the benefit of these highly effective agents.11 Multidisciplinary care is an integrated team approach to health care in which medical and allied health care professionals from various specialties collaborate to develop an individualized treatment plan for each patient, after considering all relevant options. This well-recognized approach relies on the unique talents and specific skills of each team member to optimize care in chronic and complex illnesses.12 In this article, we describe, within the specialty of hematology at a tertiary center, the functionality of a coordinated team care approach for patients with CML.
Background CML is a clonal myeloproliferative hematopoietic stem cell disorder characterized by the presence of the Philadelphia (Ph) chromosome, or t(9;22).5,13 The Ph chromosome is the result of a reciprocal translocation of the breakpoint cluster region (BCR) on chromosome 22 and the
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Table 1 Definitions of Treatment Response and Recommended Monitoring Intervals ELN7,25,a Definition
NCCN6,b Monitoring
Definition
Monitoring
Hematologic
Complete (CHR)
Complete normalization of blood Platelet count ⬍ 450 ⫻ 109/L, At diagnosis, then every 15 days counts, leukocytes ⬍ 10 ⫻ no immature granulocytes, until response achieved, then every 109/L, platelets ⬍ 450 ⫻ 109/ basophils ⬍ 5%, nonpalpable 3 months as needed L, no immature cells, spleen nonpalpable spleen
–
Cytogenetic No Ph⫹ metaphases
Complete (CCyR)
No Ph⫹ metaphases
⫹
Partial (PCyR)
1%-35% Ph metaphases
Minor
36%-65% Ph⫹ metaphases ⫹
Minimal
66%-95% Ph metaphases
Check at diagnosis, 3 and 6 months until CCyR achieved, then every 12 months if regular molecular monitoring not assured
1%-35% Ph⫹ metaphases ⬎35% Ph⫹ metaphases –
⬎ 95% Ph⫹ metaphases
–
Undetectable BCR-ABL by qRTPCR in 2 consecutive samples
BCR-ABL mRNA undetectable by qRT-PCR
None
Pretreatment, then at 6 and 12 months after treatment initiation; 12-month test not needed if CCyR achieved at 6 months; test at 18 months if CCyR not achieved at 12 months
Molecular Complete (CMR)
Major (MMR)
Ratio of BCR-ABL to ABL ⱕ 0.1% on the International Scale
qRT-PCR every 3 months until MMR, then every 6 months
Pretreatment and then every 3 months. If CCyR is reached, BCR-ABL transcript levels should be measured every 3 ⱖ 3-log reduction in months for 3 years, then every 3-6 International Scale of BCR-ABL months thereafter. mRNA
Abbreviations: CCyR ⫽ complete cytogenetic response; CMR ⫽ complete molecular response; ELN ⫽ European LeukemiaNet; MMR ⫽ major molecular response; NCCN, National Comprehensive Cancer Network; PCyR ⫽ partial cytogenetic response; Ph⫹ ⫽ Philadelphia chromosome–positive; qRT-PCR ⫽ quantitative real-time polymerase chain reaction. a Reproduced with permission from Baccarani M, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009; 27:6041-6051. © 2008 American Society of Clinical Oncology. All rights reserved. b Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Chronic Myelogenous Leukemia V.1.2012. © 2011 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed July 8, 2011. To view the most recent and complete version of the NCCN Guidelines, go online to http://www.NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK, NCCN, NCCN GUIDELINES, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
Table 2 European LeukemiaNet Treatment Response Criteriaa Response Optimal Suboptimal Failure
Table 3 European LeukemiaNet CML-CP Treatment Recommendations for Suboptimal Response and Failurea
Treatment Time 3 Months
6 Months
CHR, at least At least PCyR minor CyR No CyR
Less than PCyR
Less than CHR
No CyR
12 Months
18 Months
CCyR
MMR
PCyR
Less than MMR
Less than PCyR Less than CCyR
Abbreviations: CCyR ⫽ complete cytogenetic response; CHR ⫽ complete hematologic response; CyR ⫽ cytogenetic response; MMR ⫽ major molecular response; PcyR ⫽ partial cytogenetic response. a Reproduced with permission from Baccarani M, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009; 27:6041-6051. © 2008 American Society of Clinical Oncology. All rights reserved.
Abelson gene (ABL) on chromosome 9.3,5,10 This hybrid oncogene (BCR-ABL) encodes a fusion protein that increases intrinsic ABL tyrosine kinase activity and leads to increased cell proliferation, impaired cell adhesion properties, and inhibition of apoptosis.5,10 CML is a triphasic disorder, with ⬎ 90% of patients presenting in chronic phase,3 which is often asymptomatic. Without effective therapy, CML progresses within 3 to 5 years to the advanced phases, ie, accelerated phase and blast phase.5 Currently, lifelong TKI therapy is recommended.6 Because of the requirement for long-term treatment, medication adherence can be a
Treatment Responseb
Treatment Recommendation
Suboptimal Response
Continue TKI at current dose or test higher dose
Failure
Dasatinib or nilotinib; allogeneic HSCT in patients with disease progression or with T315I mutation
Abbreviations: CML-CP ⫽ chronic myelogenous leukemia– chronic phase; HSCT ⫽ hematopoietic stem cell transplant; TKI ⫽ tyrosine kinase inhibitor. a Reprinted with permission from Baccarani M, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009; 27:6041-6051. © 2008 American Society of Clinical Oncology. All rights reserved. b European LeukemiaNet recommends imatinib 400 mg daily as first-line treatment for CML-CP and dasatinib and nilotinib as second-line treatment.
challenge similar to that for other asymptomatic chronic illnesses, such as hypertension or diabetes. Indeed, a direct correlation has been observed between adherence to imatinib therapy and cytogenetic and molecular responses.14,15
Diagnostic and Response Monitoring Methods Three diagnostic methods are commercially available for the detection of BCR-ABL: conventional karyotypic analyses, fluorescence in situ hybridization (FISH), and quantitative reverse transcriptase– polymerase chain reaction (qRT-PCR). Conventional cytogenetic analyses are performed on marrow aspirates, as the yield of cells in metaphase decreases significantly when peripheral blood myeloid
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Coordinated Team Care for CML Figure 1 Graphic Used to Facilitate Discussions With Patients, Depicting a Schematic Representation of Residual Disease at Various Milestones for Newly Diagnosed Patients With CML in Chronic Phase With Optimal Response to TKI Therapy
CBC/WBC
Disease Burden
CTG
FISH
MRD qRT-PCR Diagnosis
3 Months
6 Months
12 Months
Abbreviations: CBC/WBC ⫽ complete Blood count/white blood cell; CTG ⫽ cytogenetic analysis; FISH ⫽ fluorescence in situ hybridization; qRT-PCR ⫽ quantitative reverse transcriptase polymerase chain reaction.
progenitor cells are used.16 Twenty to 50 metaphases are typically evaluated; this technique can therefore detect the Ph chromosome when it is present in 2%-5% of metaphases.17 FISH, another cytogenetic test, uses 2 probes for BCR and ABL, each labeled in a different color (red and green). The colocalization of the probes to the t(9;22) rearranged gene results in a fusion of the 2 colors. FISH can detect the Ph chromosome in blood and marrow samples in a larger number of cells (typically 100-500) than can conventional karyotypic analyses, rendering FISH more sensitive for detecting the Ph chromosome.17 There is excellent correlation between blood and marrow FISH results, which are not affected by the type of TKI, the presence of Ph chromosome variants, the presence of additional karyotypic abnormalities, or the disease phase.18 The most sensitive method to detect BCR-ABL is qRT-PCR, a molecular test. Through amplification of the BCR-ABL mRNA transcripts, qRT-PCR is capable of detecting the presence of BCR-ABL in 1 cell out of 1 million normal cells, well below the detection level of conventional cytogenetic analysis or FISH.19 Because of variations in standards for testing and reporting among laboratories, the International Scale was developed to provide consistency in the interpretation of qRT-PCR results.20,21 Correlations between blood and marrow qRT-PCR results are excellent18,22–24; blood qRT-PCR is recommended for monitoring the treatment response in CML. The European LeukemiaNet (ELN) and the National Comprehensive Cancer Network (NCCN) have published guidelines defining milestones in the monitoring of response to therapy (Table 1).6,7,25 The ELN defines optimal and suboptimal responses, as well as treatment failure, based on hematologic, cytogenetic (conventional cytogenetic analysis), and molecular (qPCR) responses measured at these mile-
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stones (Table 2) and provides guidelines for changes in therapy (Table 3).7,25 Understanding the sensitivity of the different methods used to measure BCR-ABL is important to avoid over- and undertreatment.
Coordinated Team Care for CML In 2005, we established an outpatient coordinated team care approach for patients with CML to maximize the benefits of TKI therapy through education and by engaging patients in disease management. First, we created a dedicated, consistent team with excellent communication skills: a hematologist, a physician assistant (PA), a nurse coordinator, a social worker, a pharmacist, and a research coordinator; the referring oncologist was also incorporated into the team as an integral member. The rationale for developing this team approach was to address patient issues—including psychosocial, financial, insurance coverage, and transportation— comprehensively from the first visit through the long course of the disease. In an era of readily accessible information, empowering patients to participate in their care requires reliable educational materials and a good understanding of monitoring results. Hematologist. The hematologist, the first team member patients meet on the initial visit, is an experienced leukemia specialist with expertise in all CML treatment modalities, including allogeneic HSCT. Hematologists provide a global explanation of CML, discuss various treatment options, and recommend human leukocyte antigen (HLA) typing and early identification of an HLA-compatible donor for HSCT-eligible patients with advanced-phase disease or those in chronic phase receiving a ⱖ second-line agent; also high-
Stacie Holloway et al Figure 2 CML Summary-and-Response Tracking Sheet, Summarizing Pertinent Presentation Features, Treatment History, Presence of ABL Kinase Domain Mutations, Presence or Absence of an HLA-Compatible Donor, and Results of Monitoring
Winship Cancer Institute CML Flow Sheet Addressograph
Diagnosis: Date: / Splenomegaly: Y / N WBC , % blast Hgb , PLT LDH: Treatment: IFN pre-Imatinib: N / Y Imatinib started: Dose Changes: Dasatinib started: Dose Changes: Nilotinib started: Dose Changes: Bosutinib started: Dose Changes: Ponatinib started: Dose Changes: started: Dose Changes:
/ / / / / / / / / / / / / / / / /
started: /
/
/
/
/
/
/
IFN Stop:
/
Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose:
IM Stop:
/ /
DAS Stop:
/
NIL Stop:
ADD CHR
PB PCR
/
Date Stopped: / /
BM PCR
/
PONA Stop:
on on
PB FISH
/
BOS Stop:
Mutation Analysis:
BM FISH
/
/ /
HLA matched sibling: N / Y Name: URD donor: DATE
DRUG DOSE
Matched / Mismatched ( BM%
BM
CTG
MONTH CELL. BLASTS Ph+/20
ADD CHR
) BM FISH
PB FISH
BM PCR
PB PCR
Abbreviations: BM ⫽ bone marrow; CTG ⫽ cytogenetics; FISH ⫽ fluorescence in situ hybridization; Hgb ⫽ hemoglobin; IFN ⫽ interferon; LDH ⫽ lactate dehydrogenase; PB ⫽ peripheral blood; PCR ⫽ polymerase chain reaction; Ph⫹ ⫽ Philadelphia chromosome positive; PLT ⫽ platelets; URD ⫽ unrelated donor; WBC ⫽ white blood cells.
lighted is the importance of treatment adherence and response monitoring at all milestones. Visual tools facilitate good understanding across all educational backgrounds (Figure 1). The hematologist introduces the other team members and explains their respective functions. Open communication channels with the referring oncologist and/or primary care physician are also established through verbal and/or electronic communication and the timely transmission of clinic notes, thus providing community on-
cologists, who normally have limited exposure to this rather uncommon disease, a general framework for patient management and extending the plan of care closer to the patient’s home. At subsequent visits, the hematologist provides perspective for response to therapy by noting results on a CML-specific summaryand-response tracking sheet (Figure 2) to track responses at various milestones and provide a rationale for therapy adjustment should these milestones not be reached. When other treatments are indi-
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Coordinated Team Care for CML cated, the hematologist works with other team members, such as the transplant nurse coordinator, so that the patient maintains a consistent health care team throughout the disease course, regardless of treatment modality. To ensure consistent coordinated care, the hematologist leads the team’s preclinic conferences, during which the CML-specific summary-and-response tracking sheet is reviewed, updated, and if applicable the plan of care is adjusted. These meetings are not only essential for sharing information and concerns but also provide a venue for continuing education of the team, given the evolving and complex field of CML. Physician Assistant. In the United States, PAs practice medicine independently but under the supervision of attending physicians. PAs conduct physical examinations, diagnose and treat concurrent illnesses, manage adverse events (AEs), order and interpret tests, counsel on preventive health, perform procedures (bone marrow biopsies), and prescribe medications. In this team, PAs are an independent extension of the physician and implement the plan of care established by the hematologist. The PA addresses adherence and inquires about TKI-related AEs, recommends remedies for these symptoms, and adapts follow-up by scheduling additional visits or communicating with patients between visits. The PA manages patient expectations by ensuring understanding of test results and engages the patient in tracking these results. The PA also keeps the referring physician updated through timely transmission of clinic notes. Nurse Coordinator. The nurse coordinator is the patient’s primary point of contact through electronic communications and/or phone calls and is the anchor of the relationship between the patient and the health care team. The nurse exchanges contact information with the patient, provides CML-specific educational materials (booklets and a DVD), and instructs the patient to bring in prescribed medications at each clinic visit. The nurse informs the patient of common TKI-specific AEs, specifically highlighting early warning signs (Table 426 –28), meets patients at every clinic visit, discusses adherence to the prescribed doses of TKIs, ensures that no lapses in therapy occur by checking medication refills, and coordinates insurance preapproval and enrollment in patient-assistance programs. The nurse also coordinates return clinic visits, procedure appointments, and verification of molecular monitoring. After team discussion, the nurse reports the monitoring test results promptly and provides the patient with an assessment of the various response milestones. These frequent interactions between patient and nurse help build close relationships and ensure open lines of communication. Other Health Professionals. A social worker, clinical pharmacist, and dedicated CML research coordinator are also involved in the management of patients with CML. The social worker provides a list of educational websites, patient assistance programs, and peer support group meetings and addresses issues related to transportation to and from the medical center, psychosocial issues, child care options during the clinic visit day, and information for sperm banking and surrogacy when appropriate. Pharmacists counsel patients about complex medication schedules and drug interactions. If the patient is enrolled in a clinical trial, the research coordinator is integrated into the team and assists with all aspects associated with screening, enrollment, and conduct of the trial.
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Table 4 Common Adverse Events Associated With TKI Therapy: Patient Informationa TKI-Associated Adverse Event
Patient Information
Hematologic Anemia
Shortness of breath, fatigue
Thrombocytopenia
Bleeding, bruising, petechiae
Leukopenia
Fever
Fluid Retention
Weight gain, facial and/or lower extremity swelling
Gastrointestinal
Nausea, vomiting, heartburn Diarrhea
Musculoskeletal
Muscular cramps Joint pain
Dermatologic Pleural Effusion Neurologic
Rash Shortness of breath, dry cough Headaches
Hepatic
Darkening of the urine, epigastric pain, nausea, vomiting
Cardiac
Electrocardiographic finding often, occasionally irregular heartbeat, feeling light-headed or faint
Abbreviation: TKI ⫽ tyrosine kinase inhibitor. a Please consult individual full prescribing information before prescribing any of these agents.
Discussion The primary reasons for establishing this coordinated team approach are to coach patients throughout their long journey with CML and to help them navigate the complexities of their disease. In this model, patients are empowered through education to better understand their illness and are engaged as active team members in monitoring their responses to therapy. A multidisciplinary approach in cancer has been shown to improve patients’ adherence with treatment appointments and the treatment regimen,29 reduce anxiety about their overall care, enhance quality of life, and improve the outcomes of certain malignancies.30,31 A recent study has shown that patients with CML progress through 5 distinct stages: crisis, hope, adaptation, new normalcy, and uncertainty,32 and the ability to cope with these stages is affected by the degree of knowledge about the disease, comfort level with the physician, and optimism about the success of treatment.32 In an era of readily available and easily accessible information, patients can easily become confused and anxious, effectively suffering from “information overload.”33 Providing basic education through educational booklets, DVDs, and trusted websites may attenuate this anxiety. In our team model, the patient’s understanding of response monitoring results is used to tailor additional education at each subsequent clinic visit. Through frequent communication between the leukemia specialist and the referring physician, knowledge about the disease and monitoring is relayed beyond the academic medical center to community providers. Including the community oncologist in the team establishes a collaborative partnership that leads to early referral without the concern of losing the patient from the practice.
Stacie Holloway et al In our experience, this approach has led to targeted referral of patients for clinical trials or for allogeneic HSCT. Exposing the patient at each clinic visit to friendly team members who deliver a consistent message throughout the course of the disease has improved relationships between patients and the team, and in some cases has improved patient adherence with clinic visits. The use of a simple graphic and a disease-monitoring flow chart has allowed patients to visualize their progress with therapy, which in turn increases the chances of adherence to treatment with TKIs. The impact of a dedicated and coordinated team care approach is difficult to quantify. Disease-free survival correlates with adherence to therapy, but in some cases this is hindered by the underlying biological characteristics of CML.34 Our approach can be evaluated indirectly by measuring adherence to clinic visits: among the 178 patients with CML referred between 2005 and 2010 to our institution, only 6 (3.3%) were nonadherent with clinic visits and/or were lost to follow-up. Another indirect measure is adherence to therapy: lacking methods to directly measure daily adherence to TKI therapy, nurses count the number of remaining pills before prescription renewal. Finally, patient enrollment in CML-specific clinical trials can also indirectly measure the partnership between community physicians and the leukemia team: between January 2005 and May 2011, 95 patients were enrolled in 8 trials testing experimental agents in CML.
Conclusion We have described a coordinated team care approach for the management of patients with CML at a tertiary center. This team consists of dedicated and specialized health care providers with expertise in all aspects of CML management. Patients and their referring oncologists are integral members of this team. This approach can help to improve overall management of CML by providing patient education, improved alliances with the health care team, and a good understanding of response monitoring.
8. 9.
10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
22. 23.
Acknowledgments Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Mariana Ovnic, PhD, and Claudette Knight, PharmD, of Percolation Communications LLC for their medical editorial assistance.
24. 25. 26.
Disclosure All authors report that they have no relevant relationships to disclose.
27. 28.
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www.leukemia-net.org/content/leukemias/cml/recommendations/. Accessed January 25, 2011. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007; 109:2303-9. Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 2007; 110:3540-6. National Cancer Institute. Cancer Topics—PDQ Summaries: Chronic myelogenous leukemia treatment. Available at: http://www.cancer.gov/cancertopics/pdq/ treatment/CML/healthprofessional/allpages. Accessed March 7, 2011. Quintás-Cardama A, Cortes JE, O’Brien S, et al. 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Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006; 108:28-37. Kantarjian HM, Talpaz M, Cortes J, et al. Quantitative polymerase chain reaction monitoring of BCR-ABL during therapy with imatinib mesylate (STI571; gleevec) in chronic-phase chronic myelogenous leukemia. Clin Cancer Res 2003; 9:160-6. Lundan T, Juvonen V, Mueller MC, et al. Comparison of bone marrow high mitotic index metaphase fluorescence in situ hybridization to peripheral blood and bone marrow real time quantitative polymerase chain reaction on the International Scale for detecting residual disease in chronic myeloid leukemia. Haematologica 2008; 93:178-85. Hochhaus A, Lin F, Reiter A, et al. Quantification of residual disease in chronic myelogenous leukemia patients on interferon-alpha therapy by competitive polymerase chain reaction. Blood 1996; 87:1549-55. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009; 27:6041-51. Gleevec (imatinib mesylate) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp. 2010. Available at: http://www.pharma.us.novartis.com/ product/pi/pdf/gleevec_tabs.pdf. Accessed March 7, 2011. Tasigna (nilotinib) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp, 2011. Available at: http://www.pharma.us.novartis.com/product/ pi/pdf/tasigna.pdf. Accessed March 7, 2011. Sprycel (dasatinib) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co, 2010. Available at: http://packageinserts.bms.com/pi/pi_sprycel.pdf. Accessed March 7, 2011. Boxer MM, Vinod SK, Shafiq J, et al. 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Managing Chronic Myeloid Leukemia: A Coordinated Team Care Perspective Stacie Holloway,1 Katharine Lord,1 Beverly Bethelmie-Bryan,2 Marian W. Shepard,2 Jessica Neely,2 Morgan McLemore,2 Satyanarayan K. Reddy,3 Aldemar Montero,4 William S. Jonas,5 Sara Pierson Gladney,5 Shyam L. Khanwani,6 Silpa C. Reddy,7 Anup K. Lahiry,8 Leonard T. Heffner,2 Elliott Winton,2 Martha Arellano,2 Hanna Jean Khoury2 Abstract Treatment of chronic myeloid leukemia (CML) has seen dramatic progress in recent years with the development of tyrosine kinase inhibitors (TKIs). To take maximum advantage of therapy with TKIs, compliance and good understanding of monitoring response to therapy are essential. We established a team that included a hematologist, a physician assistant (PA), and a nurse who work closely with a social worker, a pharmacist, and a research coordinator to assist patients throughout their journey with CML. The patient and the referring community oncologist were incorporated into this team. This coordinated team care approach takes advantage of each member’s specific skills to provide patients with education about CML, encourage patients’ strong involvement in tracking/monitoring results/response to therapy, and support patients with issues that arise throughout the long course of the disease. A low rate of noncompliance with clinic visits (3%) was an indirect measure of the impact of this approach. The inclusion of the referring oncologist in the team extended the tracking of monitoring results to the community practice. We conclude that a coordinated team care approach is feasible in the management of patients with CML. This approach provided patients with education and a good understanding of response to therapy and improved relations with the health care team. Clinical Lymphoma, Myeloma & Leukemia, Vol. 12, No. 2, 88-93 © 2012 Elsevier Inc. All rights reserved. Keywords: Adherence, BCR-ABL, Multidisciplinary team, Patient education, Tyrosine kinase inhibitor
Introduction Targeting BCR-ABL with tyrosine kinase inhibitors (TKIs) has revolutionized outcomes in patients with chronic myeloid leukemia (CML),1– 4 practically replacing allogeneic hematopoietic stem cell transplantation (HSCT) as first-line therapy.5–7 Three TKIs are commercially available in the United States for the treatment of CML: imatinib, dasatinib, and nilotinib. These agents have remarkable activity when given as first-line therapy,1–3 and dasatinib or nilotinib produce 1
Emory Healthcare, Atlanta, GA Winship Cancer Institute of Emory University, Atlanta, GA 3 South Atlanta Hematology Oncology, Riverdale, GA 4 Suburban Hematology Oncology Associates, Lawrenceville, GA 5 Atlanta Hematology and Oncology Associates, Atlanta, GA 6 Georgia Cancer Specialists, Fayetteville, GA 7 Atlanta Cancer Care, Atlanta, GA 8 Longstreet Cancer Center, Gainesville, GA 2
Submitted: Sept 2, 2011; Revised: Oct 24, 2011; Accepted: Oct 27, 2011 Address for correspondence: H. Jean Khoury, MD, 1365 Clifton Road, C1152, Atlanta, GA 30322 Fax: 404-778-4755; e-mail contact: [email protected]
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impressive responses when administered after imatinib failure or intolerance.8 –10 Monitoring of response and timely implementation of second-line therapy are essential to maximize the benefit of these highly effective agents.11 Multidisciplinary care is an integrated team approach to health care in which medical and allied health care professionals from various specialties collaborate to develop an individualized treatment plan for each patient, after considering all relevant options. This well-recognized approach relies on the unique talents and specific skills of each team member to optimize care in chronic and complex illnesses.12 In this article, we describe, within the specialty of hematology at a tertiary center, the functionality of a coordinated team care approach for patients with CML.
Background CML is a clonal myeloproliferative hematopoietic stem cell disorder characterized by the presence of the Philadelphia (Ph) chromosome, or t(9;22).5,13 The Ph chromosome is the result of a reciprocal translocation of the breakpoint cluster region (BCR) on chromosome 22 and the
2152-2650/$ - see frontmatter © 2012 Elsevier Inc. All rights reserved. doi: 10.1016/j.clml.2011.10.004
Table 1 Definitions of Treatment Response and Recommended Monitoring Intervals ELN7,25,a Definition
NCCN6,b Monitoring
Definition
Monitoring
Hematologic
Complete (CHR)
Complete normalization of blood Platelet count ⬍ 450 ⫻ 109/L, At diagnosis, then every 15 days counts, leukocytes ⬍ 10 ⫻ no immature granulocytes, until response achieved, then every 109/L, platelets ⬍ 450 ⫻ 109/ basophils ⬍ 5%, nonpalpable 3 months as needed L, no immature cells, spleen nonpalpable spleen
–
Cytogenetic No Ph⫹ metaphases
Complete (CCyR)
No Ph⫹ metaphases
⫹
Partial (PCyR)
1%-35% Ph metaphases
Minor
36%-65% Ph⫹ metaphases ⫹
Minimal
66%-95% Ph metaphases
Check at diagnosis, 3 and 6 months until CCyR achieved, then every 12 months if regular molecular monitoring not assured
1%-35% Ph⫹ metaphases ⬎35% Ph⫹ metaphases –
⬎ 95% Ph⫹ metaphases
–
Undetectable BCR-ABL by qRTPCR in 2 consecutive samples
BCR-ABL mRNA undetectable by qRT-PCR
None
Pretreatment, then at 6 and 12 months after treatment initiation; 12-month test not needed if CCyR achieved at 6 months; test at 18 months if CCyR not achieved at 12 months
Molecular Complete (CMR)
Major (MMR)
Ratio of BCR-ABL to ABL ⱕ 0.1% on the International Scale
qRT-PCR every 3 months until MMR, then every 6 months
Pretreatment and then every 3 months. If CCyR is reached, BCR-ABL transcript levels should be measured every 3 ⱖ 3-log reduction in months for 3 years, then every 3-6 International Scale of BCR-ABL months thereafter. mRNA
Abbreviations: CCyR ⫽ complete cytogenetic response; CMR ⫽ complete molecular response; ELN ⫽ European LeukemiaNet; MMR ⫽ major molecular response; NCCN, National Comprehensive Cancer Network; PCyR ⫽ partial cytogenetic response; Ph⫹ ⫽ Philadelphia chromosome–positive; qRT-PCR ⫽ quantitative real-time polymerase chain reaction. a Reproduced with permission from Baccarani M, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009; 27:6041-6051. © 2008 American Society of Clinical Oncology. All rights reserved. b Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Chronic Myelogenous Leukemia V.1.2012. © 2011 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed July 8, 2011. To view the most recent and complete version of the NCCN Guidelines, go online to http://www.NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK, NCCN, NCCN GUIDELINES, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
Table 2 European LeukemiaNet Treatment Response Criteriaa Response Optimal Suboptimal Failure
Table 3 European LeukemiaNet CML-CP Treatment Recommendations for Suboptimal Response and Failurea
Treatment Time 3 Months
6 Months
CHR, at least At least PCyR minor CyR No CyR
Less than PCyR
Less than CHR
No CyR
12 Months
18 Months
CCyR
MMR
PCyR
Less than MMR
Less than PCyR Less than CCyR
Abbreviations: CCyR ⫽ complete cytogenetic response; CHR ⫽ complete hematologic response; CyR ⫽ cytogenetic response; MMR ⫽ major molecular response; PcyR ⫽ partial cytogenetic response. a Reproduced with permission from Baccarani M, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009; 27:6041-6051. © 2008 American Society of Clinical Oncology. All rights reserved.
Abelson gene (ABL) on chromosome 9.3,5,10 This hybrid oncogene (BCR-ABL) encodes a fusion protein that increases intrinsic ABL tyrosine kinase activity and leads to increased cell proliferation, impaired cell adhesion properties, and inhibition of apoptosis.5,10 CML is a triphasic disorder, with ⬎ 90% of patients presenting in chronic phase,3 which is often asymptomatic. Without effective therapy, CML progresses within 3 to 5 years to the advanced phases, ie, accelerated phase and blast phase.5 Currently, lifelong TKI therapy is recommended.6 Because of the requirement for long-term treatment, medication adherence can be a
Treatment Responseb
Treatment Recommendation
Suboptimal Response
Continue TKI at current dose or test higher dose
Failure
Dasatinib or nilotinib; allogeneic HSCT in patients with disease progression or with T315I mutation
Abbreviations: CML-CP ⫽ chronic myelogenous leukemia– chronic phase; HSCT ⫽ hematopoietic stem cell transplant; TKI ⫽ tyrosine kinase inhibitor. a Reprinted with permission from Baccarani M, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009; 27:6041-6051. © 2008 American Society of Clinical Oncology. All rights reserved. b European LeukemiaNet recommends imatinib 400 mg daily as first-line treatment for CML-CP and dasatinib and nilotinib as second-line treatment.
challenge similar to that for other asymptomatic chronic illnesses, such as hypertension or diabetes. Indeed, a direct correlation has been observed between adherence to imatinib therapy and cytogenetic and molecular responses.14,15
Diagnostic and Response Monitoring Methods Three diagnostic methods are commercially available for the detection of BCR-ABL: conventional karyotypic analyses, fluorescence in situ hybridization (FISH), and quantitative reverse transcriptase– polymerase chain reaction (qRT-PCR). Conventional cytogenetic analyses are performed on marrow aspirates, as the yield of cells in metaphase decreases significantly when peripheral blood myeloid
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Coordinated Team Care for CML Figure 1 Graphic Used to Facilitate Discussions With Patients, Depicting a Schematic Representation of Residual Disease at Various Milestones for Newly Diagnosed Patients With CML in Chronic Phase With Optimal Response to TKI Therapy
CBC/WBC
Disease Burden
CTG
FISH
MRD qRT-PCR Diagnosis
3 Months
6 Months
12 Months
Abbreviations: CBC/WBC ⫽ complete Blood count/white blood cell; CTG ⫽ cytogenetic analysis; FISH ⫽ fluorescence in situ hybridization; qRT-PCR ⫽ quantitative reverse transcriptase polymerase chain reaction.
progenitor cells are used.16 Twenty to 50 metaphases are typically evaluated; this technique can therefore detect the Ph chromosome when it is present in 2%-5% of metaphases.17 FISH, another cytogenetic test, uses 2 probes for BCR and ABL, each labeled in a different color (red and green). The colocalization of the probes to the t(9;22) rearranged gene results in a fusion of the 2 colors. FISH can detect the Ph chromosome in blood and marrow samples in a larger number of cells (typically 100-500) than can conventional karyotypic analyses, rendering FISH more sensitive for detecting the Ph chromosome.17 There is excellent correlation between blood and marrow FISH results, which are not affected by the type of TKI, the presence of Ph chromosome variants, the presence of additional karyotypic abnormalities, or the disease phase.18 The most sensitive method to detect BCR-ABL is qRT-PCR, a molecular test. Through amplification of the BCR-ABL mRNA transcripts, qRT-PCR is capable of detecting the presence of BCR-ABL in 1 cell out of 1 million normal cells, well below the detection level of conventional cytogenetic analysis or FISH.19 Because of variations in standards for testing and reporting among laboratories, the International Scale was developed to provide consistency in the interpretation of qRT-PCR results.20,21 Correlations between blood and marrow qRT-PCR results are excellent18,22–24; blood qRT-PCR is recommended for monitoring the treatment response in CML. The European LeukemiaNet (ELN) and the National Comprehensive Cancer Network (NCCN) have published guidelines defining milestones in the monitoring of response to therapy (Table 1).6,7,25 The ELN defines optimal and suboptimal responses, as well as treatment failure, based on hematologic, cytogenetic (conventional cytogenetic analysis), and molecular (qPCR) responses measured at these mile-
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stones (Table 2) and provides guidelines for changes in therapy (Table 3).7,25 Understanding the sensitivity of the different methods used to measure BCR-ABL is important to avoid over- and undertreatment.
Coordinated Team Care for CML In 2005, we established an outpatient coordinated team care approach for patients with CML to maximize the benefits of TKI therapy through education and by engaging patients in disease management. First, we created a dedicated, consistent team with excellent communication skills: a hematologist, a physician assistant (PA), a nurse coordinator, a social worker, a pharmacist, and a research coordinator; the referring oncologist was also incorporated into the team as an integral member. The rationale for developing this team approach was to address patient issues—including psychosocial, financial, insurance coverage, and transportation— comprehensively from the first visit through the long course of the disease. In an era of readily accessible information, empowering patients to participate in their care requires reliable educational materials and a good understanding of monitoring results. Hematologist. The hematologist, the first team member patients meet on the initial visit, is an experienced leukemia specialist with expertise in all CML treatment modalities, including allogeneic HSCT. Hematologists provide a global explanation of CML, discuss various treatment options, and recommend human leukocyte antigen (HLA) typing and early identification of an HLA-compatible donor for HSCT-eligible patients with advanced-phase disease or those in chronic phase receiving a ⱖ second-line agent; also high-
Stacie Holloway et al Figure 2 CML Summary-and-Response Tracking Sheet, Summarizing Pertinent Presentation Features, Treatment History, Presence of ABL Kinase Domain Mutations, Presence or Absence of an HLA-Compatible Donor, and Results of Monitoring
Winship Cancer Institute CML Flow Sheet Addressograph
Diagnosis: Date: / Splenomegaly: Y / N WBC , % blast Hgb , PLT LDH: Treatment: IFN pre-Imatinib: N / Y Imatinib started: Dose Changes: Dasatinib started: Dose Changes: Nilotinib started: Dose Changes: Bosutinib started: Dose Changes: Ponatinib started: Dose Changes: started: Dose Changes:
/ / / / / / / / / / / / / / / / /
started: /
/
/
/
/
/
/
IFN Stop:
/
Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose: Dose:
IM Stop:
/ /
DAS Stop:
/
NIL Stop:
ADD CHR
PB PCR
/
Date Stopped: / /
BM PCR
/
PONA Stop:
on on
PB FISH
/
BOS Stop:
Mutation Analysis:
BM FISH
/
/ /
HLA matched sibling: N / Y Name: URD donor: DATE
DRUG DOSE
Matched / Mismatched ( BM%
BM
CTG
MONTH CELL. BLASTS Ph+/20
ADD CHR
) BM FISH
PB FISH
BM PCR
PB PCR
Abbreviations: BM ⫽ bone marrow; CTG ⫽ cytogenetics; FISH ⫽ fluorescence in situ hybridization; Hgb ⫽ hemoglobin; IFN ⫽ interferon; LDH ⫽ lactate dehydrogenase; PB ⫽ peripheral blood; PCR ⫽ polymerase chain reaction; Ph⫹ ⫽ Philadelphia chromosome positive; PLT ⫽ platelets; URD ⫽ unrelated donor; WBC ⫽ white blood cells.
lighted is the importance of treatment adherence and response monitoring at all milestones. Visual tools facilitate good understanding across all educational backgrounds (Figure 1). The hematologist introduces the other team members and explains their respective functions. Open communication channels with the referring oncologist and/or primary care physician are also established through verbal and/or electronic communication and the timely transmission of clinic notes, thus providing community on-
cologists, who normally have limited exposure to this rather uncommon disease, a general framework for patient management and extending the plan of care closer to the patient’s home. At subsequent visits, the hematologist provides perspective for response to therapy by noting results on a CML-specific summaryand-response tracking sheet (Figure 2) to track responses at various milestones and provide a rationale for therapy adjustment should these milestones not be reached. When other treatments are indi-
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Coordinated Team Care for CML cated, the hematologist works with other team members, such as the transplant nurse coordinator, so that the patient maintains a consistent health care team throughout the disease course, regardless of treatment modality. To ensure consistent coordinated care, the hematologist leads the team’s preclinic conferences, during which the CML-specific summary-and-response tracking sheet is reviewed, updated, and if applicable the plan of care is adjusted. These meetings are not only essential for sharing information and concerns but also provide a venue for continuing education of the team, given the evolving and complex field of CML. Physician Assistant. In the United States, PAs practice medicine independently but under the supervision of attending physicians. PAs conduct physical examinations, diagnose and treat concurrent illnesses, manage adverse events (AEs), order and interpret tests, counsel on preventive health, perform procedures (bone marrow biopsies), and prescribe medications. In this team, PAs are an independent extension of the physician and implement the plan of care established by the hematologist. The PA addresses adherence and inquires about TKI-related AEs, recommends remedies for these symptoms, and adapts follow-up by scheduling additional visits or communicating with patients between visits. The PA manages patient expectations by ensuring understanding of test results and engages the patient in tracking these results. The PA also keeps the referring physician updated through timely transmission of clinic notes. Nurse Coordinator. The nurse coordinator is the patient’s primary point of contact through electronic communications and/or phone calls and is the anchor of the relationship between the patient and the health care team. The nurse exchanges contact information with the patient, provides CML-specific educational materials (booklets and a DVD), and instructs the patient to bring in prescribed medications at each clinic visit. The nurse informs the patient of common TKI-specific AEs, specifically highlighting early warning signs (Table 426 –28), meets patients at every clinic visit, discusses adherence to the prescribed doses of TKIs, ensures that no lapses in therapy occur by checking medication refills, and coordinates insurance preapproval and enrollment in patient-assistance programs. The nurse also coordinates return clinic visits, procedure appointments, and verification of molecular monitoring. After team discussion, the nurse reports the monitoring test results promptly and provides the patient with an assessment of the various response milestones. These frequent interactions between patient and nurse help build close relationships and ensure open lines of communication. Other Health Professionals. A social worker, clinical pharmacist, and dedicated CML research coordinator are also involved in the management of patients with CML. The social worker provides a list of educational websites, patient assistance programs, and peer support group meetings and addresses issues related to transportation to and from the medical center, psychosocial issues, child care options during the clinic visit day, and information for sperm banking and surrogacy when appropriate. Pharmacists counsel patients about complex medication schedules and drug interactions. If the patient is enrolled in a clinical trial, the research coordinator is integrated into the team and assists with all aspects associated with screening, enrollment, and conduct of the trial.
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Table 4 Common Adverse Events Associated With TKI Therapy: Patient Informationa TKI-Associated Adverse Event
Patient Information
Hematologic Anemia
Shortness of breath, fatigue
Thrombocytopenia
Bleeding, bruising, petechiae
Leukopenia
Fever
Fluid Retention
Weight gain, facial and/or lower extremity swelling
Gastrointestinal
Nausea, vomiting, heartburn Diarrhea
Musculoskeletal
Muscular cramps Joint pain
Dermatologic Pleural Effusion Neurologic
Rash Shortness of breath, dry cough Headaches
Hepatic
Darkening of the urine, epigastric pain, nausea, vomiting
Cardiac
Electrocardiographic finding often, occasionally irregular heartbeat, feeling light-headed or faint
Abbreviation: TKI ⫽ tyrosine kinase inhibitor. a Please consult individual full prescribing information before prescribing any of these agents.
Discussion The primary reasons for establishing this coordinated team approach are to coach patients throughout their long journey with CML and to help them navigate the complexities of their disease. In this model, patients are empowered through education to better understand their illness and are engaged as active team members in monitoring their responses to therapy. A multidisciplinary approach in cancer has been shown to improve patients’ adherence with treatment appointments and the treatment regimen,29 reduce anxiety about their overall care, enhance quality of life, and improve the outcomes of certain malignancies.30,31 A recent study has shown that patients with CML progress through 5 distinct stages: crisis, hope, adaptation, new normalcy, and uncertainty,32 and the ability to cope with these stages is affected by the degree of knowledge about the disease, comfort level with the physician, and optimism about the success of treatment.32 In an era of readily available and easily accessible information, patients can easily become confused and anxious, effectively suffering from “information overload.”33 Providing basic education through educational booklets, DVDs, and trusted websites may attenuate this anxiety. In our team model, the patient’s understanding of response monitoring results is used to tailor additional education at each subsequent clinic visit. Through frequent communication between the leukemia specialist and the referring physician, knowledge about the disease and monitoring is relayed beyond the academic medical center to community providers. Including the community oncologist in the team establishes a collaborative partnership that leads to early referral without the concern of losing the patient from the practice.
Stacie Holloway et al In our experience, this approach has led to targeted referral of patients for clinical trials or for allogeneic HSCT. Exposing the patient at each clinic visit to friendly team members who deliver a consistent message throughout the course of the disease has improved relationships between patients and the team, and in some cases has improved patient adherence with clinic visits. The use of a simple graphic and a disease-monitoring flow chart has allowed patients to visualize their progress with therapy, which in turn increases the chances of adherence to treatment with TKIs. The impact of a dedicated and coordinated team care approach is difficult to quantify. Disease-free survival correlates with adherence to therapy, but in some cases this is hindered by the underlying biological characteristics of CML.34 Our approach can be evaluated indirectly by measuring adherence to clinic visits: among the 178 patients with CML referred between 2005 and 2010 to our institution, only 6 (3.3%) were nonadherent with clinic visits and/or were lost to follow-up. Another indirect measure is adherence to therapy: lacking methods to directly measure daily adherence to TKI therapy, nurses count the number of remaining pills before prescription renewal. Finally, patient enrollment in CML-specific clinical trials can also indirectly measure the partnership between community physicians and the leukemia team: between January 2005 and May 2011, 95 patients were enrolled in 8 trials testing experimental agents in CML.
Conclusion We have described a coordinated team care approach for the management of patients with CML at a tertiary center. This team consists of dedicated and specialized health care providers with expertise in all aspects of CML management. Patients and their referring oncologists are integral members of this team. This approach can help to improve overall management of CML by providing patient education, improved alliances with the health care team, and a good understanding of response monitoring.
8. 9.
10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
22. 23.
Acknowledgments Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Mariana Ovnic, PhD, and Claudette Knight, PharmD, of Percolation Communications LLC for their medical editorial assistance.
24. 25. 26.
Disclosure All authors report that they have no relevant relationships to disclose.
27. 28.
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