Emerging Management Strategies for Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS Sponsored by the This activity is supported by educational grants from GlaxoSmithKline, Genentech and Genzyme Emerging Management Strategies for Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS Faculty Thomas J. Kipps, MD, PhD is the Evelyn and Edwin Tasch Chair in Cancer Research, a UCSD Professor of Medicine, and the Deputy Director of Research at the Moores UCSD Cancer Center in La Jolla, California. He received his PhD in Immunology and MD from Harvard University and completed his residency and fellowship training in Internal Medicine, Hematology, and Genetics at Stanford University. Prior to serving in his current positions, Dr. Kipps was Head of Hematology and Oncology, Associate Director of the Gene Therapy Program, Director of the Translational Research Program, and Director of the Immunology Department at UCSD. Dr. Kipps has a national and international reputation for his work in cancer research, immunology, and gene therapy. He is the author of more than 200 publications and is the PI on several peer-reviewed grants, including an award from NCI/NIH to fund the Chronic Lymphocytic Leukemia Consortium (CRC). The CRC involves collaboration with 8 other Cancer Centers around the nation. Dr. Kipps has over 20 years experience in combining research and clinical care responsibilities. Kanti R. Rai, MD is Chief, Division of Hematology- Oncology at the Long Island Jewish Medical Center in New Hyde Park, New York, and the Joel Finkelstein Cancer Foundation Professor of Medicine at the Albert Einstein College of Medicine in the Bronx, New York. In 1955, he received his MB, BS from SMS Medical College, University of Rajasthan, Jaipur, India, after which he did his residency in pediatrics at Lincoln Hospital of the City of New York, Bronx, New York. Dr. Rai then became Chief Resident in Pediatrics at the North Shore Hospital, in Manhasset, New York in 1958. He followed his residency as a Fellow in Nuclear Medicine and Hematology at the Long Island Jewish Hospital in 1959, and then became Research Associate in Hematology at Brookhaven National Laboratory Medical Research Center in Upton, New York. Before assuming his current position, Dr. Rai served as Chief, Division of Experimental Medicine, Institute of Nuclear Medicine, New Delhi, India, and then as Associate Scientist at Brookhaven National Laboratory. He has also served as Associate Professor of Medicine (1972-80) and Professor of Medicine (1980-1989) at the School of Medicine, State University of New York at Stony Brook, as well as Joel Finkelstein Cancer Foundation Professor of Medicine (1989-2004), Albert Einstein College of Medicine. He has been Chief at the Division of Hematology-Oncology at Long Island Jewish Medical Center since 1981. Dr. Rai is Certified by the American Board of Pediatrics. Dr. Rai has received numerous awards, among which are the Eastern Leukemia Society Scholar, National Leukemia Association Scholar, Helena Rubenstein Foundation Leukemia Research Award, Joel Finkelstein Cancer Foundation Man of the Year Award, and the Peter Jay Sharp Foundation Award for CLL Research. He has served as Co-chair on the Medical Advisory Board of the Lauri Strauss Leukemia Foundation, and he is a Founding Member and Co-chair of the International Workshop on CLL, as well as a member of the NCI-sponsored Working Group on CLL. Dr. Rai’s major interests focus on hematological malignancies, prognostic markers and improved therapy for CLL. Lead Nurse Planner Carol Marietta, NP Nurse Practitioner Rancho Mirage, California 1 Emerging Management Strategies for Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS Intended Audience This activity was developed for hematologists, oncologists, NPs, RNs, and other health care professionals working with patients with CLL. Statement of Need A number of new therapies have become available and new combination regimens have been studied for the treatment of CLL in the past few years, yet standard first- and second-line treatments have yet to be established. Community hematologists/oncologists are challenged to keep abreast of the latest clinical study data and expert recommendations on these new treatments or emerging combination regimens. There are also new tools available for testing for prognostic markers, and recommendations about which treatment regimens should be used based on individual patient risk profiles. Learning Objectives Upon completion of this activity, participants should be able to: ■ Utilize appropriate tests and biomarkers to quickly and accurately diagnose, stage, and do risk assessment for patients with CLL ■ Design optimal treatment protocols for individual patients ■ Provide appropriate supportive care for patients ■ Incorporate data from clinical trials to guide adoption of new treatment options when available and appropriate Nursing Learning Objectives Upon completion of this activity, participants should be able to: ■ Incorporate new data into their work to enhance their care of patients and families This activity will address professional practice gaps in knowledge. 2 Emerging Management Strategies for Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS Accreditation and Certification The Annenberg Center for Health Sciences at Eisenhower is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Annenberg Center designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit . Physicians should only claim credit commensurate with the extent of their participation in the activity. Annenberg Center for Health Sciences is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. The faculty for this activity have disclosed that there will be discussion about the use of products for non-FDA approved indications. Additional content planners: In accordance with the Accreditation Council for Continuing Medical Education Standards, parallel documents from other accrediting bodies, and Annenberg Center policy, the following disclosures have been made: The following have no significant relationship to disclose: Joel Legunn (Medical Writer) Carol Marietta, NP (Lead Nurse Planner) A maximum of 1 contact hour may be earned for successful completion of this activity. All staff at the Annenberg Center for Health Sciences at Eisenhower have nothing to disclose. There is no charge for this activity. Statements of Credit may be printed online. The ideas and opinions presented in this educational activity are those of the faculty and do not necessarily reflect the views of the Annenberg Center and/or its agents. As in all educational activities, we encourage practitioners to use their own judgment in treating and addressing the needs of each individual patient, taking into account that patient’s unique clinical situation. The Annenberg Center disclaims all liability and cannot be held responsible for any problems that may arise from participating in this activity or following treatment recommendations presented. Disclosure It is the policy of the Annenberg Center to ensure fair balance, independence, objectivity, and scientific rigor in all programming. All faculty and planners participating in sponsored programs are expected to identify and reference off-label product use and disclose any relationship with those supporting the activity or any others with products or services available within the scope of the topic being discussed in the educational presentation. In accordance with the Accreditation Council for Continuing Medical Education Standards, parallel documents from other accrediting bodies, and Annenberg Center policy, the following disclosures have been made: Thomas J. Kipps, MD Research Support Consultant Speakers Bureau Biogen-Idec; Celgene Corporation; Cephalon, Inc.; Memgen, LLC; sanofi-aventis Igenica, Inc. Educational Concepts; PER; University of Utah This activity is supported by educational grants from GlaxoSmithKline, Genentech and Genzyme. This activity is an enduring material and consists of a web activity. Successful completion is achieved by reading and viewing the material, reflecting on its implications in your practice, and completing the assessment component. The estimated time to complete the activity is 1 hour. This activity was originally released in March 2010 and is eligible for credit through February 28, 2011. Kanti R. Rai, MD Consultant Biogen Idec; Cephalon, Inc.; Genentech; GlaxoSmithKline 3 Emerging Management Strategies for Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS Introduction The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous. Whereas some patients require treatment relatively soon after diagnosis, others may enjoy a relatively indolent course, free of symptoms, and not require therapy for many years. Because studies in the 1990s found that early treatment may actually compromise patient survival, and because there are no studies that show early treatment can provide a survival benefit, it is currently recommended to withhold therapy until the patient develops progressive and/or symptomatic disease.1 In recent years, an impressive number of prognostic markers have been identified that can stratify patients into subgroups that have different prognoses. Some of these markers can help assess the relative risk for disease progression independent of clinical stage. At the same time, there has been progress in the treatment of CLL that is providing for an improved survival benefit. Recent years have witnessed the use of newer drugs, monoclonal antibodies, and monoclonal antibody/drug combinations (so called “chemoimmunotherapy”) that have provided for TABLE 1 improved response rates and longer progression-free survival times after treatment. Even in the face of these advances, however, there are still no standard protocols for first-line CLL therapy. This discussion highlights risk categories most often encountered in clinical practice, the prognostic markers used for risk stratification, and the approaches to applying both prognostic markers and new therapeutic options to achieve optimal patient outcomes in each risk category. Prognostic Markers – The Key to Risk Stratifications Based on a better understanding of the biology of CLL, we can better stratify patients into different prognostic subgroups. It is possible to identify features of CLL cells (Table 1) that are associated with the tendency for progressive disease that requires treatment relatively soon after diagnosis. Among these are the mutation status of the expressed immunoglobulin variable region (heavy chain) genes (IgHV genes), or expression of the 70-kD zeta-chain-associated protein kinase (ZAP-70), or CD38. In addition, there are many other markers that are associated with more aggressive disease, such as high level expression of thymidine kinase or lipoprotein lipase. Prognostic Markers for CLL2 MARKER LOW RISK HIGH RISK Thymidine-kinase Low or normal High Soluble CD23 levels Low or normal High Beta-2 microglobulin Low or normal High IgV(H) mutational status Mutated Unmutated Lactate dehydrogenase Low or normal High CD38 expression <20% -30% >20% -30% ZAP-70 expression <20% -30% >20% -30% Lymphocytic doubling time >12 months ≤12 months Serum markers FISH cytogenetics (see Table 2) Adapted with permission from Yee KWL, O’Brien SM, Chronic Lymphocytic Leukemia Diagnosis and Treatment. Mayo Clin Proc 2006;81:1105-1129. 4 Emerging Management Strategies for Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS Using one or a combination of these prognostic markers, we can now stratify patients into subgroups that have significantly different risks for disease progression. For example, patients with leukemia cells that express ZAP-70 and/or that use unmutated IgHV gene will have, on average, a greater tendency for early disease progression requiring treatment than patients with CLL cells that do not express ZAP-70, or that use mutated IgHV. More recently, the former subgroup of patients also has been noted to have a shorter progression-free survival after successful treatment with chemoimmunotherapy than that latter subgroup. with a relatively good prognosis. Less common is the finding of an extra copy of chromosome 12 (trisomy 12), which is associated with atypical cell morphology, higher leukemia-cell expression levels of CD20, and a strong tendency for relatively rapid disease progression. Other common abnormalities include deletions in the long arm of chromosome 11 at 11q22.3, or deletions in the short arm of chromosome 17 at 17p13.1. Each of these chromosomal abnormalities, particularly deletions at 17p13.1, is associated with a poorer response to certain types of treatment, particularly those that require active P53 to function. Nevertheless, the expression of these prognostic markers has not been shown to influence the response to treatment. For example, the relatively complete response rates to various treatment regimens appear to be the same in both subsets of patients. The gene located at 17P13.1 encodes TP53, an important transcription factor that is activated by a number of alkylating agents and purine analogs. This activation induces a range of changes in genes that are involved in regulating growth arrest, and in genes that encode proteins that may initiate apoptosis. Therefore, the absence or deletion of the TP53 gene typically causes the leukemic cells to be less responsive to these chemotherapeutic agents, and to demonstrate chemo-resistance. In contrast, there are certain recurrent genetic changes identified in CLL cells that are associated with differences in response to standard therapies and/or survival. These genetic changes can be identified in blood or marrow CLL cells through standard cytogenetics or via Fluorescence In Situ Hybridization (FISH), and are thought to occur during the development or evolution of the disease (Table 2). The most common genetic lesion is deletion of a segment in the long arm of chromosome 13 at 13q14, which, if found to be the sole genetic abnormality, is associated TABLE 2 The exact cause of the genetic lesion at 11q22.3 is still uncertain. There is active investigation of regulatory RNAs or micro RNAs that map to this region and that might account for the relative resistance to certain types of drug therapy. Several clinical trials have demonstrated that patients with del 11q have a lower response to single-agent Fluorescence In Situ Hybridization (FISH) Tests for CLL3-5 CYTOGENETIC ABERRATION/LOCUS PARAMETER DETECTED IMPLICATION 11q22.3 Deletions of the ATM gene Found in 11%-18% of cases. Marked by lymphadenopathy and poor survival. 12cen Gain of chromosome 12 Found in 16%-25% of cases. Unresolved pathogenic outcome, but has been shown to be a negative prognostic factor with median survival approx 5 yrs. 13q14.3 Deletions of the RB1 region Found in 36%-64% of cases. Good prognosis as sole abnormality. Disease-free interval and overall survival is better than cases with normal karyotype because of slow disease progression. 17p13.1 Deletions of the TP53 gene Found in 7%-8% of cases that are resistant to chemotherapy and have a short survival. 5 Emerging Management Strategies for Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS fludarabine therapy, or to the combination of fludarabine and rituximab, than do patients who do not have either this or the 17p deletion abnormality. However, these patients appear to have a response equivalent to that of patients without del 11q, if treated with chemotherapy regimens that include fludarabine and an alkylating agent, such as cyclophosphamide. CASE 1 2. a. be placed on wait-and-watch status b. have treatment started immediately Correct Answer: (b) This patient is in need of therapy. He has symptomatic disease and evidence for compromised marrow function. Left untreated he probably would develop worsening cytopenia and increasingly symptomatic disease. Studies have shown that patients with high-risk stage disease benefit from therapy. An Older Patient With High-Risk Features MR is a 70-year-old man with CLL diagnosed 3 years ago. He had been doing well until about 4 months ago when he began experiencing progressive fatigue, night sweats, and abdominal fullness with early satiety after eating. He otherwise maintains an excellent performance status of 0/5 by the ECOG criteria and lacks significant medical co-morbidities. On exam he is noted to have significant palpable cervical lymphadenopathy and a spleen palpable 7 cm below the left costal margin. His white blood cell count (WBC) was noted to be 125,000 with 97% well differentiated lymphocytes, which was significantly increased from that of his WBC of 13,000 noted at diagnosis. His hemoglobin was 10.1 gm% and his platelet count 98,000. His leukemia cells were noted to express high levels of ZAP-70 and to use unmutated IgHV. Cytogenetic analyses demonstrated the cells to have deletions at 11q22.3. Interactive Questions (circle your answer before reading the correct answer below.) This patient should: 3. High risk patients without significant symptoms should: a. be placed under observation b. given a therapeutic regimen that will stop progression c. treated with the goal of achieving a complete response Correct Answer: (c) Even if prognostic markers are favorable, symptomatic high-risk patients should be placed on a therapeutic regimen with the goal of a complete, or maximally achievable response. 4. A preferred therapy for this patient would be: a. Fludarabine + cyclophosphamide + rituximab 1. This patient is: a. high risk b. low risk (FCR) b. Fludarabine + rituximab (FR) c. Bendamustine-rituximab Correct Answer (a) The patient is at high risk (Stage IV), as the patient’s platelet count is below 100,000. He also has anemia, most likely reflecting disease-related marrow suppression. In addition, his prognostic markers are unfavorable—unmutated IgV(H) gene, and ZAP-70 positive—and he is symptomatic. Correct Answer: (a) In view of his adverse leukemia-cell cytogenetics, namely the deletion at 11q, he should be considered for combination chemoimmunotherapy (Table 3 on next page). Clinical studies comparing the outcome of treatment with fludarabine versus fludarabine and cyclophosphosphamide have 6 Emerging Management Strategies for Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS demonstrated the combination of the purine analog with an alkylating agent to yield higher complete response rates and longer progression free survival times after therapy than treatment with fludarabine alone.6-8 TABLE 3 Therapeutic Regimens Used in CLL DRUG CLASS Chemotheraphy Purine analogs The difference in outcome is particularly apparent for patients with CLL cells that have the 11q deletion. A retrospective review of patient outcomes,9 and prospective randomized phase III clinical studies10 have demonstrated that the addition of rituximab to the combination of fludarabine and cyclophosphamide significantly improves response rates, progression-free survival after treatment, and overall survival relative to response achieved from treatment with the combination of fludarabine and cyclophosphamide alone. It is important to bear in mind that many of the clinical CLL treatment trials described in the literature usually involve patients of a younger median age than the typical CLL patient. The median ages of the patients in many studies are typically in the 50s, whereas the median age at diagnosis for all patients with CLL is closer to 70. However, age can be a factor in the expected tolerance to treatment. Older patients generally have a limited myeloid reserve. A rule of thumb is that marrow cellularity is generally 100 minus a patient’s age, reflecting the age-related decline in marrow function. Because elderly patients have less myeloid reserve than younger patients, they might have a lower tolerance to myelosuppressive therapy. In addition, elderly patients often have one or more co-morbidities, such as impaired renal function, cardiovascular disease, or diabetes. Renal function needs to be considered because a number of therapeutic agents used in the treatment of CLL undergo renal clearance. Thus, dosage reductions should be implemented in patients with renal impairment to avoid toxicity. Patients with cardiovascular disease may not tolerate anemia, and patients with diabetes have an increased risk for infection that is independent of the CLL-related decline in immune function. Thus, older patients’ profiles, with regard to often compromising co-morbidities and age-related decline, need to be included as an additional factor when stratifying the patients into different prognostic groups. Fludarabine (Fludara®) Pentostatin (Nipent®) 2-chlorodeoxyadenosine Alkylating agents Cyclophosphamide (Cytoxan®) Chlorambucil (Leukeran®) Bendamustine (Treanda®) Biologic Immunotherapies Rituximab (Rituxan®) Alemtuzumab (Campath®) Investigational Agents Ofatumumab Lenalidomide (Revlimid®) Flavopiridol Combination Therapies Fludarabine-cyclophosphamide-rituximab (FCR) Fludarabine-rituximab (FR) Fludarabine-cyclophosphamide (FC) Pentostatin-cyclophosphamide-rituximab (PCR) Oxaliplatin-fludarabine-cytarabine-rituximab (OFAR) To reduce the myelotoxicity of the treatment regimens, investigators at the University of Pittsburgh developed what they called an “FCR light” regimen, which calls for using a reduced dose of fludarabine and cyclophosphamide, but an increased dose of rituximab.11 These investigators also gave patients rituximab maintenance therapy every 6 months after completing the 6 courses of therapy, in a fashion similar to how patients are treated with follicular lymphoma. Because this regimen included rituximab maintenance therapy, it is difficult to assess progression free survival after treatment. Nevertheless, the reported complete response and overall response rates were on a par with those of the conventional FCR regimen, making this regimen a potential option for elderly patients with del 11q. 7 Emerging Management Strategies for Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS Another treatment regimen that is well tolerated in patients with limited myeloid reserve is that involving use of high-dose methylprednisolone and rituximab, the so-called HDMP+R regimen. Excellent response rates of good duration were observed for patients treated with HDMP+R without inducing significant myelotoxicity.12, 13 Alemtuzumab There are newer immune therapies being developed to address the treatment difficulties encountered with highrisk patients. One of these is alemtuzumab (Campath®), a monoclonal antibody that appears to have activity in the treatment of patients who have CLL cells with del(17p).14 In a phase II study involving 93 CLL patients who had failed treatment with fludarabine, treatment with alemtuzumab resulted in a 50% reduction in disease burden in 33% of the patients and a complete response in 2%.15 Responses to therapy lasted about 7 months on average. These results were similar to those of 2 smaller studies conducted previously, demonstrating an overall response rate of over 30% in patients previously treated with chemotherapy.16, 17 However, all 3 studies were single-arm trials lacking controls and making it difficult to fully assess efficacy and safety. Nevertheless, these results prompted the FDA to provide accelerated approval in 2001. The FDA mandated a phase 3 clinical trial, CAMC307, in which approximately 300 CLL patients were randomized to receive therapy with either chlorambucil or alemtuzumab.18 Because there was a nearly 30 percent greater (83% vs 55%) overall response rate among patients treated with alemtuzumab versus chlorambucil (p< 0.0001), and a 12-fold increase (24% vs 2%) in complete response rates in patients receiving alemtuzumab (p< 0.0001), the FDA approved the use of alemtuzumab for the initial treatment of patients with CLL in September 2007. Although alemtuzumab is highly effective in clearing blood and marrow leukemic cells, it appears to be less effective in clearing cells in the large lymph nodes.19 The probability of achieving a complete response to treatment with alemtuzumab decreases in patients with large lymph nodes. Treatment of patients with lymph nodes less than 2 cm in diameter apparently can provide for complete response rates of up to 50%. However, the probability of achieving a complete response to treatment with alemtuzumab apparently falls to less than 20% in patients with lymph nodes between 2 and 5 cm, and to virtually 0% in patients with lymph nodes greater than 5 cm in diameter. As such, alemtuzumab may be best suited for patients who lack bulky lymphadenopathy or who have resolution of bulky adenopathy following treatment with other agents. For patients without bulky adenopathy, treatment with alemtuzumab may be the most effective therapy for eradicating minimal residual disease in the marrow after therapy. A challenging toxicity that results from use of alemtuzumab is immune suppression. The anti-CD52 antibody is cytotoxic for both T cells and B cells, and typically causes significant lymphopenia. Patients treated with alemtuzumab experience immune suppression that enhances their risk for opportunistic infection. As such, there is a need to implement anti-microbial prophylaxis and to monitor the patient for signs or symptoms of de novo infections, as well as reactivation of latent virus infection, such as those caused by cytomegalovirus (CMV). Surprisingly, the incidence of opportunistic infections was similar in patients within the two arms of the CAM307 trial who were treated with either alemtuzumab or chlorambucil, with the exception of reactivation of CMV.18 Therefore, careful monitoring for CMV is needed in patients treated with alemtuzumab. Reactivation of CMV can be difficult to diagnose as alemtuzumab-treated patients may fail to produce detectable levels of antibodies against CMV. As such, monitoring for CMV using sensitive measures such as polymerase chain reaction (PCR) is necessary. Conceivably, patients who are seropositive for CMV infection prior to treatment with alemtuzumab might benefit from preemptive therapy with valgancyclovir similar to that administered to solid organ transplant recipients.20 8 Emerging Management Strategies for Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS CASE 2 An Asymptomatic Older Patient CZ, an 80-year-old white woman has been referred by her hematologist-oncologist for a second opinion regarding management decisions/options. She was diagnosed with CLL about 5 years earlier and, since she has been symptom free, she has been on “wait-and-watch” for these past 5 years. She was in clinical stage 0 at diagnosis. About a year prior to this consultation the lymph nodes had become clinically palpable, but they have all remained small in size. Her hemogram has been monitored at 3to 6-month intervals in the past, showing normal platelets and hemoglobin/hematocrit. However, her white blood cell count and absolute lymphocyte count (ALC), which were 28,000 and 20,000 respectively at the time of initial diagnosis, had increased steadily thereafter. At 1 year, the ALC was 30,000, at 3 years it was 38,000 and now, 5 years later, it is 50,000. The patient has no symptoms and leads an active life for an 80-year-old. The markers show typical phenotype of CLL that uses a mutated IgV(H) gene and is ZAP-70 negative. Correct Answer: (a) Wait-and-watch is the preferred protocol. Studies have shown that patients given early treatment do not have an increased life expectancy compared with those who are placed under observation. Notably, those patients given early treatment were at higher risk of developing second malignancies. 3. a. be placed under observation b. given a therapeutic regimen that will stop progression c. treated with the goal of achieving a complete response Correct Answer: (c) Even if prognostic markers are favorable, symptomatic low-risk patients should be placed on a therapeutic regimen with the goal of a complete, or maximally achievable response. Interactive Questions (circle your answer before reading the correct answer below.) 1. This patient is: a. high risk b. low risk Correct Answer (b) The patient is at low risk (Stage 1). Although the patient has some lymph node enlargement, the nodes remain small in size. Platelets and hemoglobin are normal. In addition, her prognostic markers are favorable—mutated IgV(H) gene, and ZAP-70 negative—and she is asymptomatic. Her lymphocytosis, however, has increased. 2. This patient should: a. be placed on wait-and-watch status b. have treatment started immediately Low-risk patients with significant symptoms should: 4. If this low-risk patient was symptomatic, the preferred therapy should be: a. FCR b. FR c. Bendamustine-rituximab Correct Answer (b): FR is preferred in view of the advanced age of the patient. Low-risk CLL patients are those who are in clinical stages zero, 1, or 2, (Table 4 on next page) and can be either asymptomatic or symptomatic. If these patients present with mutated IgV(H) gene status, then the prognosis is more favorable, and a watch-and-wait protocol can be followed. Moreover, if these patients also have other good prognostic markers such as negative (ZAP-70), or a del 13q as the sole aberration evident 9 Emerging Management Strategies for Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS Staging of Chronic Lymphocytic Leukemia21. TABLE 4 Rai Lymphocytosis Lymph Node Enlargement Spleen/Liver Enlargement Hemoglobin < 11 g/dL Platelet < 100 x 109/L Survival (years) 0 Yes No No No No >13 I Yes Yes No No No 8 II Yes ± ± No No 5 III Yes ± ± Yes No 2 IV Yes ± ± ± Yes 1 This research was originally published in Hematology. Kay N, Hamblin TJ, Jelinek DF, et al. Chronic Lymphocytic Leukemia. Hematology. 2002:193-213. © American Society of Hematology from a FISH panel, then the clinician should feel confident in placing these patients under an observationonly status. Unfortunately, to date, there are no clinical trials that clearly define observation as the standard of care for these patients versus some effective treatment. In a French study conducted several years ago, asymptomatic CLL patients were randomized to treatment with chlorambucil or wait-and-watch.22 It was found that there was no difference in overall life expectancy whether the patients were in the treatment or observation arm. Of note is that in the early treatment group there was a higher incidence of second malignancies, such as epithelial cancers. As a result, most clinicians do not favor early treatment in low-risk patients with favorable prognostic markers. A trial is currently in progress (CALGB) that is randomizing asymptomatic, low-risk CLL patients with poor prognostic markers to either early treatment with FR, or observation only. The results will be available in a few years, and until then, the recommended approach is to keep these patients under observation only. In an asymptomatic patient with unfavorable prognostic markers, such as unmutated IgV(H) gene, positive ZAP-70, positive CD 38 co-expression on leukemic cells, del 11q, 12 trisomy, or del(17p), the disease is likely to progress sooner, which mandates treatment intervention. Low-risk CLL patients with symptoms are another matter. Weight loss is one such symptom, particularly a 10% loss in baseline body weight within a period of 6 months without dieting or other effort to lose weight. Profound drenching sweats, profound fatigue that interferes with normal lifestyle, and frequent bacterial infections requiring antibiotic intervention are also among the constellation of symptoms to monitor. If a patient in the early stage of disease presents with one or more of these symptoms, therapeutic intervention becomes justifiable, regardless of prognostic marker status. It is necessary to consider, when initiating treatment for the first time, what the therapeutic endpoint should be, that is, what is the objective of treatment? A recent report from the international workshop on CLL has updated existing guidelines and criteria for diagnosis, prognosis, and treatment of CLL.1 There is emerging evidence suggesting that those patients who achieve a better response are more likely to have a longer life expectancy and a better quality of life, in addition to a longer interval before the next treatment is required. So, whether the patients are given FR or FCR, for example, the objective should be to achieve a complete, or maximally achievable remission without any undue toxicities. Determining Remission Status It would be instructive, at this point, to discuss what is meant by a complete remission. Up until now, the principal criterion has been the absence of clinical evidence of disease. Among these are absence of palpable disease, 10 Emerging Management Strategies for Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS such as palpably enlarged lymph nodes, spleen or liver, and normalization of blood count. Recently, however, owing to the success of FR or FCR regimens to achieve complete remission, attention is being focused on minimal residual disease (MRD) levels in patients who have achieved complete remission by clinical criteria. Investigators are beginning to look for the presence of residual CLL cells in circulating blood or in the bone marrow using two- or four-color flow cytometry, or with PCR to uncover any molecular markers of residual CLL. These tests would, of course, have to be negative to consider the remission complete. Whether such negative molecular marker status is achievable is under investigation. At present, then, the best level of achievable clinical remission without undue toxicity is the accepted standard. CASE 3 Interactive Questions (circle your answer before reading the correct answer below.) 1. a. low risk b. high risk Correct Answer (b) This patient has unfavorable prognostic markers— unmutated IgV(H) gene and positive ZAP 70— which implies high risk even though the patient is asymptomatic. 2. A Younger Patient With High White Cell Count and Poor Prognostic Markers MJ, a 53-year-old white male is referred by his internist because of a high blood white cell count discovered upon a routine annual check-up. MJ had been watched by his internist over a period of one year before this referral. He has no symptoms and maintains an active and busy professional and social life. The TWBC a year ago was 62,000 with an ALC of 40,000, hemoglobin, hematocrit, platelets, and neutrophils were all within normal limits. Six months later, the ALC had increased to 66,000, and now, at the time of this referral a year after the initial discovery, the ALC had further increased to 78,000. There are still no symptoms, and the rest of the blood counts have remained normal. Upon examination, there were palpably enlarged small nodes, measuring about 1 to 1.5 cm diameter in the neck, axillae, and groin bilaterally. Spleen and liver were not clinically palpable. Flow cytometry of blood lymphocytes showed a phenotype characteristic of CLL—CD19+, CD20+, CD23+, CD5+, lambda light chains with sIGM and sIGD positivity. IgV(H) showed unmutated genes and ZAP-70 was positive. This patient is: Should this patient be placed on therapy? a. yes b. no Correct Answer (a) Because of the clinical stage, and presence of unfavorable prognostic markers, this high-risk younger patient will have more to gain by being placed on an aggressive therapeutic regimen. Without such aggressive treatment, the patient has a high probability of developing a more rapidly progressing disease. 3. The preferred therapy for this patient should be: a. FCR b. Alemtuzumab c. Bendamustine-rituximab Correct Answer (a) FCR is preferred because 1) There is experience with a large number of patients, 2) The patient is relatively young and has a good performance status, 3) Our overall objective is to try to reach a complete remission. (b) and (c) are also good options, but our experience is with a lower number of patients. 11 Emerging Management Strategies for Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS It should be emphasized that high-risk younger patients (age 40 to 55 years) have more to gain and less to lose by receiving a much more aggressive approach to treatment. For these patients, prognostic markers are critically important if these patients are being categorized as high risk because of the clinical stage and the presence of unfavorable markers, such as an unmutated IgV(H) gene. The objective of their treatment is twofold: 1) to achieve a complete clinical response, and 2) once the response has been achieved, to discuss with the patient the option of receiving an allogeneic hemopoietic stem cell transplant (SCT); this would be a human-leukocyte-antigen (HLA)-matched sibling transplant, or if a sibling is not available, an unrelated HLA-matched donor transplant. A caveat here is that these transplants should be done with a nonmyeloablative-conditioning-based treatment. A number of institutions are conducting prospective clinical trials with patients who meet these criteria to determine whether a complete remission and good success with a marrow transplant will be of benefit.23 There are, in fact, somewhere under 100 patients who are alive today as a result of allogeneic SCTs done with nonmyeloablative conditioning. The reason for emphasizing nonmyeloablative conditioning is that the success of this particular transplant method is based on immune modulation rather than on replacing or seeding an aplastic marrow—that is, one that has been rendered aplastic by prior preparatory chemotherapy. As a result of myeloablative conditioning, there has been an unacceptable mortality rate (40% to 50%), within 100 days of the transplant. In contrast, the mortality rate has gone down significantly with nonmyeloablative conditioning. Recently published reports indicate that with nonmyeloablative conditioning-based allogeneic transplants, not only is the mortality rate reduced, but also the morbidity with chronic and acute graft-versus-host disease has been in an acceptable range, and there is rapid patient recovery.24, 25 Thus, for high-risk younger patients, first-line options should be very aggressive, since these CLL patients have a high probability of dying because of the disease. A 5-year follow-up study evaluated for factors that influence the outcomes of patients undergoing allogeneic transplantation for CLL.26 It was found that younger patients with no concomitant morbidities, and without bulky disease—such as lymph nodes >5 cm in diameter—fare much better with allogeneic SCT than do patients who do not have these characteristics. Investigational Therapies There are investigational agents that appear to be effective in treating elderly high-risk patients. One of these is lenalidomide (Revlimid®) an immune modulator derived from thalidomide, which was banned in the 1960s for causing birth defects in the babies of pregnant women who were taking it as a sedative. This class of agent inhibits angiogenesis, a mechanism required by cancer cells. Lenalidomide does not appear to have cytotoxic effects against leukemic cells. In two trials of previously treated CLL patients, however, lenalidomide was shown to have activity in this disease.27, 28 Another group of novel agents are the BCL2 antagonists, which are involved in initiating apoptosis. As such, they may obviate the need for induction of P53, which ordinarily is required for the induced expression of pro-apoptotic molecules, such as PUMA, that are responsible for the cytotoxic effects of anti-leukemia drugs, such as fludarabine.29 The use of agents that can emulate the effects of such molecules as PUMA might obviate the need to induce P53 to provide for leukemia-cell apoptosis. In addition, there are the newer monoclonal antibodies, such as the humanized anti-CD20 agent ofatumumab, which has striking activity, but has not been compared with rituximab. Refractory or relapse patients have already been treated with first-line agents, and now require carefully structured second-line therapeutic regimens. With regard to patients who have fludarabine-refractory CLL, or who have Richter’s Syndrome (RS), a group at the MD Anderson Cancer Center developed a regimen that employs varying combinations of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy (OFAR).30 This regimen has the advantage of reduced myelotoxicity compared with standard FC combinations, and has demonstrated very strong activity in RS patients, as well as activity in fludarabine-refractory CLL patients. Given the activity 12 Emerging Management Strategies for Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS of OFAR, particularly in patients with del(17p) and in patients older than 70 years, a larger study of OFAR is currently being pursued by this group. In high-risk elderly patients with del(17p), alkylating agents and purine analogs do not have high activity. A retrospective review of the literature by the MD Anderson group found that there may be some heterogeneity among these patients who have del(17p) regarding their response patterns to an FCR regimen.31 A note of caution here is that the presence of del(17p) in CLL cells does not necessarily indicate that the leukemia cell lacks functional P53.32, 33 Conversely, CLL cells that lack del(17p) can have dysfunctional P53.34 As such, the association between del(17p) and dysfunctional P53 is not absolute. Conceivably, the patients with CLL cells that harbored del(17p), and who have a favorable response to chemoimmunotherapy had CLL cells with functional P53. This is possibly reflected in a retrospective analysis of the CLL4 trial patients, which found that the adverse outcome associated with del(17p) was observed for patients who have more than 20% of their leukemia cells harboring deletions at 17p.35 A sizable subset of patients, who had fewer than 20% of their CLL cells with del(17p) as defined by FISH analysis, had outcomes similar to those of patients who had CLL cells that did not have any detectable deletions at 17p. As such, patients who are noted to have fewer than 20% of their CLL cells with del(17p) by FISH might respond well to more standard chemoimmunotherapy regimens. Conclusion The management of CLL has advanced from palliative measures to newer therapeutic options such as biologic immune modulators, purine analogs and chemo-immunotherapeutic combinations. At the same time, the evolution of prognostic markers has provided for a greater degree of certainty in applying risk-adapted first-line therapy. As a result, the perspective of first-line treatment has changed to one in which complete remission is now a clinically realistic goal, with the possibility of increased survival time for CLL patients. Click here to go online to go to the Posttest and Evaluation for this activity and to obtain CE credit. Or, you can use this case-sensitive URL to go to the online Posttest and Evaluation for this activity: http://www.medpagetoday.com/pdf/Annenberg01/posttest.cfm. You may also simply return to the MedPage Today Web site and log in to the activity to access the Posttest/Evaluation. 13 Emerging Management Strategies for Chronic Lymphocytic Leukemia IN HIGH-RISK PATIENTS References 1. 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;111:5446-5456. 2. Yee KWL, O’Brien SM. 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