NE Oncology Issue – August 2011
Treatment with rituximab in combination with fludarabine plus cyclophosphamide (FCR) has dramatically improved the outcome of patients with chronic lymphocytic leukemia (CLL). For patients who can tolerate it, first-line treatment with FCR is now considered to be the standard of care in CLL across Canada. Despite the success of the FCR regimen, a number of questions exist on its optimal administration. The following paper is the second of a series examining key challenges faced in the administration of FCR in Canada. Future papers will address issues such as supportive care for patients receiving FCR and use of the oral formulations of fludarabine and cyclophosphamide. By addressing the challenges related to the administration of FCR, patients are more likely to complete all treatment cycles, thereby increasing efficacy and resulting in improved outcomes.
Managing hematological toxicities with FCR
Tina Crosbie, BSc Pharm, ACPR;1 James Johnston, MD (FRCP);2 Jennifer Daley-Morris, BSc Pharm;3 Marc Geirneart, BSc Pharm2
1The Ottawa Hospital, Ottawa, Ontario; 2CancerCare Manitoba, Winnipeg, Manitoba; 3Stronach Regional Cancer Centre
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world, representing approximately 30% of all leukemias.1,2 Although predominantly characterized by neoplastic B-cells, CLL is clearly distinctive from other leukemic diseases and B-cell tumours.2 In CLL, an accumulation of abnormal B-lymphocytes in the blood, bone marrow, lymph nodes, and spleen causes overcrowding, suppressing the formation and function of blood and immune cells. In addition, malignant lymphocytes do not function normally, further reducing the body’s ability to fight infection. Bone marrow infiltration by CLL cells can result in a number of cytopenias, which are predictive of poor prognosis in patients with CLL.2,3 In addition, CLL is characterized by a high prevalence of autoimmune disease such as autoimmune hemolytic anemia (AIHA), immune thrombocytopenia purpura (ITP), pure red cell aplasia (PRCA), and autoimmune agranulocytosis (AIG). Immune incompetence is another key feature of CLL, characterized by progressive hypogammaglobulinemia and impaired ability of cell-mediated immunity to recall antigens.2 Patients with CLL are therefore at increased risk of infections, which are a common cause of morbidity and mortality.1 In CLL patients, especially those with neutropenia, bacteremia and pneumonia are commonly seen. The addition of rituximab to fludarabine and cyclophosphamide (FCR) has dramatically improved remission duration and survival of patients with CLL, as evidenced in the landmark CLL-8 study by Hallek, et al. (2010).4 However, chemotherapeutic regimens such as FCR also increase the risk of cytopenias and opportunistic infections.1,4,5 Effective monitoring and management of cytopenias and infections is therefore of key importance in the treatment of CLL. Given the impact of CLL and its treatment on the bone marrow and the immune system, it is important to effectively manage hematologic toxicities. Despite the recognition of this concern, strategies to manage these complications vary within and between Canadian institutions. This paper is a general discussion on the management of hematological toxicities in CLL patients treated with FCR. However, it does not reflect a true evidence-based guideline process with a systematic literature review and is not meant to be used as a consensus guideline. The management and prevention of infections through appropriate prophylaxis is beyond the scope of this paper but is an important focus for future discussions.
Selecting patients for treatment with FCR
Patient fitness and comorbidities should be considered in treatment decisions to determine whether aggressive therapies such as FCR can be tolerated. Several systems exist for determining patient fitness, two of the most common being the Eastern Cooperative Oncology Group (ECOG) Performance Status and the Cumulative Illness Rating Scale (CIRS). In determining whether a patient can be categorized as fit, a combination of these scoring systems should be used.6 In 1982, ECOG developed a set of performance status criteria that categorizes patients into one of five categories from high to low levels of physical function. (Table 1) These categories were designed to assess how the patient’s disease affects daily living.7 The ECOG Performance Status categories are also commonly used within the context of CLL to assess treatment intensity and determine whether elderly patients could be included in specific clinical trials.7 A second system for assessing patient fitness is the CIRS tool. The CIRS assesses comorbidities in different organ systems by assigning points to various conditions, such as heart disease. The physician tabulates the number of points in a variety of body systems, where a low score indicates optimal health.8 In addition to using the ECOG system, the CIRS was also used in combination with creatinine clearance (CrCl) in the CLL-8 study to determine eligibility of patients for treatment with FCR.4 Therefore, using a combination of both scoring systems may be the ideal strategy for selecting patients. See Appendix A for a detailed description of how to calculate the CIRS score.9 Once a fitness score has been determined based on a combination of the systems discussed, it is possible to group patients into a fit or frail group. (Table 2) By using the methods described above to determine patient fitness, treatment decisions can be made that balance efficacy and individual patient tolerability. If patients are determined to be fit according to the above criteria, FCR is a reasonable first-line treatment option. However, if patients are identified as frail, alternative, less toxic treatment regimens should be used. Less aggressive treatment options that can be considered in frail patients include fludarabine; chlorambucil; or cyclophosphamide, vincristine, and prednisone (CVP); with or without rituximab. For patients with a CIRS score ≤6 and/or ECOG >2 but with renal dysfunction, FCR may still be appropriate in some patients (e.g., CrCl 50–70 mL/min). Fludarabine with rituximab (FR) can be considered with a reduced dose of fludarabine for patients with poor renal function. In addition, for patients falling in between the fit and frail categories, or for those requiring a less aggressive regimen, FR is also a reasonable option. By using these selection methods to eliminate frail patients, hematological toxicities may be minimized or even eliminated completely with the use of FCR.
In determining the appropriate strategy for managing CLL patients with hematological toxicities, it is important to determine whether these are related to the disease itself or to treatment with chemotherapeutic regimens such as FCR. Prior to treatment, bone marrow suppression as a result of CLL itself can lower blood counts due to overcrowding with abnormal lymphocytes. Thus, it is important to treat the disease to restore blood counts. As treatment with FCR also causes myelosupression, low counts seen with later treatments (cycles 4–6) may occur as a result of chemotherapy itself. At later points in the disease, delaying treatment is therefore appropriate to ensure bone marrow recovery and prevent further toxicity. Since patients with CLL have low blood counts to begin with, standard criteria for grading hematologic toxicities cannot be applied.6 Therefore, to adequately monitor blood counts and manage cytopenias effectively, it is important to assess baseline counts prior to treatment to establish a basis for comparison. Once treatment is initiated, periodic blood counts should be documented and compared to baseline levels rather than to normal lab values in order to assess progress. A grading scale of hematologic toxicities for use in CLL was developed by the International Workshop for CLL (IWCLL) and is presented in Table 3.6 For lower risk patients, blood counts should be monitored 1–2 times per cycle, with more extensive monitoring in earlier cycles. In higher risk patients, such as those with low platelet levels at baseline, weekly blood counts are recommended.10-14 (Figure 1)
Neutropenia is the most common hematologic toxicity seen in patients with cancer.10 The administration of cytotoxic chemotherapies, such as cyclophosphamide and fludarabine, generally results in a white blood cell nadir after 5–14 days, with recovery by days 7–21. However, high-dose chemotherapy can extend the duration and deepen the nadir of the neutropenia, increasing the risk of infection. Careful monitoring of absolute neutrophil counts (ANC) and comparison to baseline levels is therefore important to ensure neutropenia is managed appropriately. Although cytopenias associated with cyclophosphamide are well known, treatment with fludarabine can lead to additional myelosupression.5,15 Myelosupression with fludarabine generally has a time to nadir of 10–14 days, with recovery between 5–7 weeks.16 A phase I study in solid tumour patients showed that the median time to nadir counts after treatment with fludarabine was 13 days (range: 3–25 days) for granulocytes and 16 days (range: 2–32 days) for platelets.5 Although most patients had hematologic impairment at baseline either as a result of their disease or prior therapy, use of fludarabine may cause cumulative myelosuppression. Since patients are already immuno-compromised, administration of fludarabine and cyclophosphamide (FC) requires careful hematologic monitoring. Recombinant granulocyte colony-stimulating factor (rG-CSF) is a supportive care agent that stimulates neutrophil proliferation, differentiation, and activation.10 The 2006 American Society of Clinical Oncology (ASCO) guidelines on the use of white blood cell growth factors recommends the use of G-CSF when the anticipated frequency of febrile neutropenia exceeds 20% or in patients considered at high-risk because of comorbidities (e.g., extensive prior chemotherapy or pelvic radiotherapy, neutropenia existent prior to chemotherapy, or active infection).17 In addition, the protocol for the CLL-8 study mandated the use of G-CSF in the event of neutropenia with fever >38.5 °C or hypothermia with or without suspected or documented infection.4 In the CLL-8 study, 45% of patients treated with FCR and 23% of patients treated with FC received G-CSF during the course of their disease. Use of growth factors may be useful in certain patients with infection or disease-related bone marrow suppression. However, when neutrophil counts are reduced after cytotoxic therapy, administering growth factors may elevate ANCs, giving physicians a false sense of security that continuing treatment can be done safely. When treatment is resumed prematurely, complete recovery may not have occurred, causing further damage to bone marrow. Further bone marrow damage can impede the ability to give subsequent treatments, resulting in a poorer prognosis for these patients. Therefore, when neutrophil counts are reduced as a result of treatment, FCR should be delayed to allow for adequate recovery before resuming therapy. (Figure 1) Determining the cause of neutropenia is necessary to determine the correct course of action. Generally, when neutropenia occurs early in the disease course, such as between cycles 1 and 3, growth factors may be considered while waiting for bone marrow clearance. Beyond early disease, growth factors should only be used to prevent recurring infections when neutropenia is accompanied by fever. Appropriate upfront selection of patients for treatment with FCR should dramatically reduce the risk of cytopenias in patients with CLL. Therefore, eliminating cyclophosphamide completely to increase neutrophil counts is not recommended. To manage patients with severe neutropenia, treatment delays and dose reductions are appropriate to allow for marrow recovery. In the CLL-8 study, treatment with FCR was delayed and the dose of fludarabine and cyclophosphamide was reduced in patients with grade 3/4 neutropenia.4 (Table 4) Therefore, when the first grade 3/4 cytopenia is reported, FCR treatment should be delayed for up to two weeks until counts reach or exceed baseline levels. Once counts have recovered, treatment with FCR may be resumed, but the dose of fludarabine and cyclophosphamide should be reduced by 25%. If grade 3/4 neutropenia continues to occur, fludarabine and cyclophosphamide should continue to be reduced. If, however, severe neutropenia occurs for three or more cycles, treatment with FCR should be discontinued and less marrow suppressive rituximab combinations, such as FR or cyclophosphamide, rituximab, dexamethasone (RCD), may be considered if the patient can tolerate them and they have active disease. (Figure 1)
Before beginning treatment with FCR, patients may have thrombocytopenia as a result of marrow replacement by their leukemia; the majority have high-risk disease with platelet levels <100,000/mm3.6 As with neutropenia, thrombocytopenia may also occur as a result of treatment with FCR.5,15 When severe thrombocytopenia (grades 3/4) occurs after treatment with FCR, treatment delays and dose reductions of fludarabine and cyclophosphamide should be implemented as per the recommendations above for neutropenia. (Table 4 and Figure 1) Treatment for thrombocytopenia typically involves platelet transfusions, which are commonly given when platelet levels fall below 20,000/μL.10 Common risks associated with platelet transfusions include infection, allergic reactions, transfusionassociated lung injury, and alloimmunization. In addition, refractoriness to platelet transfusion can occur due to the development of antibodies. The development of antibodies can become a significant problem for patients who become dependent upon transfusions, although leukocyte filtration can decrease the incidence of this complication.
Anemia is a common consequence of cancer and its treatment, occurring in approximately 40% of patients.10 Potential causes of cancer-associated anemia may include direct tumour infiltration of bone marrow; reduced levels of endogenous erythropoietin production; an increase in inflammatory cytokines, such as tumour necrosis factor (TNF) that may directly inhibit erythropoiesis by curbing stored iron utilization; and other contributory factors, such as nutritional deficiencies, hemorrhage, and hemolysis. The primary treatments for cancer-induced anemia include blood transfusions, erythropoiesis stimulating agents (ESA), such as epoetin alfa; darbepoetin alfa; and iron therapy.10 Decisions regarding treatment must be tailored to each patient based on the degree of anemia, clinical status, and comorbidities. For patients with severe anemia with continued symptoms such as poor cardiac or respiratory function manifesting as dyspnea, cardiac failure, or angina, treatment should include transfusion of packed red blood cells (RBCs). However, for mild to moderate anemia, blood transfusions are not recommended due to the increased risk of infection, allergic responses, transfusion-associated lung injury, and alloimmunization. The 2010 ASCO/ASH guidelines on treating cancer-induced anemia recommend that iron stores be checked at baseline and periodically to optimize symptom improvement.11,12 (Table 3 and Figure 1) The use of epoetin or darbepoetin is recommended as a treatment option for patients with chemotherapy-associated anemia and a hemoglobin (Hb) concentration that has decreased to <100 g/L in order to decrease RBC transfusions. Transfusions are also an option, depending on the severity of the anemia or clinical circumstances. An optimal level at which to initiate ESA therapy in patients with anemia whose Hb is between 100–120 g/L cannot be definitively determined from the available evidence. Under these circumstances, the decision to initiate ESA treatment should be determined by clinical judgment, consideration of the risks and benefits of ESAs, and patient preferences. Hb can be increased to the lowest concentration needed to avoid transfusions, which may vary by patient and condition. However, the Hb concentration should not exceed 120 g/L during ESA therapy.14 The guidelines also state that epoetin or darbepoetin are equally effective when treatment calls for ESAs. Regardless of the supportive drug chosen, iron supplementation is advised to augment the response to ESAs.
Autoimmune complications of CLL
Autoimmune complications occur in around 10–25% of patients with CLL at some point during their disease.2,3,18 Blood constituents are the main target, resulting in a number of disorders, including AIHA, ITP, PRCA, and AIG. Of these phenomena, AIHA is the most common. Patients with CLL receiving FCR should be evaluated and closely monitored for signs of autoimmune cytopenias, which occur in around 6.5% of treated patients and may be confused with cytopenias related to marrow suppression.19 Typically, immune cytopenias should be suspected in patients when there is an isolated fall or delayed recovery in Hb, platelets, or neutrophils. The development of AIHA following FCR is typically associated with a negative Coomb’s test. The diagnosis of PRCA or ITP usually requires a marrow confirmation.6 These conditions usually respond to prednisone with discontinuation of FCR. Patients not responding to prednisone, or relapsing following tapering of the steroid, usually respond to cyclosporine or to combination treatment with RCD.20
CLL is a B-cell malignancy that is distinct from other leukemic diseases and B-cell tumours, with important consequences for its management. The disease itself leads to a number of cytopenias due to overcrowding of bone marrow with abnormal lymphocytes. Although treatment with FCR has improved overall and progression-free survival, cytotoxic regimens such as these can worsen cytopenias through treatment-related myelosupression. Upfront selection of fit patients who are better able to tolerate more aggressive regimens such as FCR can effectively reduce the risk of cytopenias. Further, by using a combination of tools such as the ECOG and CIRS to categorize patients, treatment decisions can be made based on fitness level to ensure therapy is well tolerated. Given the distinct nature of CLL from other diseases, standard criteria for grading the severity of cytopenias are not appropriate. It is therefore important to monitor blood counts before and during treatment to effectively manage toxicities. When cytopenias occur as a result of the disease itself, treatment with chemotherapy is important to reduce lymphocyte burden. However, when hematologic toxicities occur as a result of treatment, dose delays and reductions may be necessary to allow adequate recovery of bone marrow. Given the impact of hematological toxicities on adherence to treatment, effective management is crucial to ensure optimal treatment response and remission.
References: 1. Tsiodras S, Samonis G, Keating MJ, Kontoyiannis DP. Infection and immunity in chronic lymphocytic leukemia. Mayo Clin Proc 2000;75:1039- 54. 2. Caligaris-Cappio F, Hamblin TJ. B-cell chronic lymphocytic leukemia: a bird of a different feather. J Clin Oncol 1999;17:399-408. 3. Zent CS, Ding W, Schwager SM, et al. The prognostic significance of cytopenia in chronic lymphocytic leukaemia/small lymphocytic lymphoma. Br J Haematol 2008;141:615- 21. 4. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376:1164-74. 5. Novopharm Limited. PrFludarabine Phosphate. Product Monograph 2006. 6. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008;111:5446-56. 7. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55. 8. Linn BS, Linn MW, Gurel L. Cumulative illness rating scale. J Am Geriatr Soc 1968;16:622-6. 9. Hudon C, Fortin M, Soubhi H. Abbreviated guidelines for scoring the Cumulative Illness Rating Scale (CIRS) in family practice. J Clin Epidemiol 2007;60:212. 10. Capo G, Waltzman R. Managing hematologic toxicities. J Support Oncol 2004;2:65-79. 11. Sabbatini P, Cella D, Chanan-Khan A, et al. Cancer and Treatment-Related Anemia. National Comprehensive Cancer Network 2003. 12. Rizzo JD, Brouwers M, Hurley P, et al. American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol 2010;28:4996-5010. 13. Rizzo JD, Lichtin AE, Woolf SH, et al. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 2002;20:4083-107. 14. Janssen Inc. PrEPREX®* (epoetin alfa). Product Monograph September, 2010. 15. Baxter Corporation. PROCYTOX® (Cyclophosphamide). Product Monograph October, 2003. 16. The Merk Manual. Fludarabine. May, 2011. 17. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24:3187-205. 18. Dearden C. Disease-specific complications of chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program 2008:450-6. 19. Borthakur G, O’Brien S, Wierda WG, et al. Immune anaemias in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab- -incidence and predictors. Br J Haematol 2007;136:800-5. 20. Kaufman M, Limaye SA, Driscoll N, et al. A combination of rituximab, cyclophosphamide and dexamethasone effectively treats immune cytopenias of chronic lymphocytic leukemia. Leuk Lymphoma 2009;50:892-9.
Bernard Lemieux, MD, FRCPC
Dr. Bernard Lemieux is a Medical Oncologist in the Department of Hematology at the Centre Hospitalier de l’Université de Montreal (CHUM) and Hôpital NotreDame. He received his medical degree from the University of Montreal in 1996 and completed his medical specialty in hematology and medical oncology, followed by a clinical fellowship in lymphoproliferative disorders from 2002–2003 at the Centre Hospitalier Lyon-sud, France. He is past president of the Quebec HematoOncology Association (AMHOQ). Currently, he is Medical Director of the Hematologic Disorders Team and the Lymphoproliferative Disease Clinic and co-director of the Medical Oncology Clinical Research Unit (URCOH) at CHUM.
Laurie H. Sehn, MD, MPH
Dr. Laurie H. Sehn is a Clinical Assistant Professor at the BC Cancer Agency and the University of British Columbia in Vancouver. She has been a medical oncologist and clinical investigator with the Lymphoma Tumour Group since 1998. Dr. Sehn has served on the Board of Directors of Lymphoma Foundation Canada (LFC) since 2002 and is currently Director of Research Fellowships for the LFC. Dr. Sehn’s research interests include all of the lymphoid cancers, with particular interest in the biology and treatment of large-cell lymphoma, the application of new imaging techniques such as PET scanning to lymphoma management, and innovative new approaches to treatment.
Douglas A. Stewart, BMSc, MD, FRCPC
Dr. Douglas A. Stewart is currently a professor in the Departments of Oncology and Medicine, and Chief of the Division of Hematology and Hematological Malignancies at the University of Calgary. Since July 1994, he has been practising medical oncology at the Tom Baker Cancer Centre in Calgary, where he is a member of the Breast Cancer and Hematology Tumour Groups, Leader of the Hematology/Blood and Marrow Transplant Program, and Provincial Leader of the Hematology Tumour Team for the Alberta Health Services Cancer Care Program. His research interests focus on clinical trials involving hematological malignancies and hematopoietic stem cell transplantation. Dr. Stewart has authored over 80 peer-reviewed manuscripts and over 120 abstracts.
Martin Dreyling, MD, PhD
Dr. Martin Dreyling is an attending physician and associate professor in the Medical Department of the University of Munich, Grosshadern, Germany. His primary interests include the molecular biology and clinical care of lymphoma. Dr. Dreyling’s research activities relate to the molecular basis of malignant transformation, cell cycle dysregulation in mantle cell lymphoma (MCL), secondary genetic alterations and biological prognostic factors in malignant lymphoma, and innovative therapeutic approaches in indolent lymphoma. He is actively involved in a number of national and European study groups, and is currently the Coordinator of the European MCL Network. Dr. Dreyling has co-authored over 300 scientific papers, book chapters, and published abstracts in international peer-reviewed journals.
Liat Vidal, MD
Dr. Liat Vidal is a senior physician at the Institute of Hematology in the Beilinson Hospital, Rabin Medical Center in Israel. She received her medical degree from the Hebrew University in Jerusalem in 1998 and completed her residency in internal medicine at the Beilinson Hospital, Rabin Medical Center in 2004. From 2006 to 2007 she worked as a physician in hematology/oncology at the Hasharon Hospital, Rabin Medical Center. Dr. Vidal has a Master’s degree in epidemiology and her research interests include evidence-based medicine, systematic review, and meta-analysis.