Chronic lymphocytic leukemia

CHAPTER 36 Chronic lymphocytic leukemia Jorge E. Cortes, MD, Susan O Brien, MD, and Mark A. Weiss, MD Chronic lymphocytic leukemia (CLL) is a clonal malignancy that results from expansion of the mature lymphocyte compartment. This expansion is a consequence of prolonged cell survival, despite a low proliferative index. The affected lymphocytes are of B-cell lineage in 95% of cases, and the remaining cases involve T lymphocytes. CLL is the most common leukemia in adults in western countries, and it accounts for approximately 25% of all leukemias. The proportion of cases diagnosed in the early stages of the disease (Rai stage 0) has risen from 10% to 50%, probably because of improved diagnosis (routine automated blood counts). Epidemiology Gender The male-to-female ratio is 2:1. This trend appears to be lost with age; the male-to-female ratio is 2.3:1.0 for patients < 50 years old, compared with 1.1:1.0 for those 75 years old. Despite this finding, the relative risk based on gender does not change substantially with age, because as the population ages, the proportion that is female rises. In the United States, for the age group 75-87 years, there are 1.67 more females than males. Therefore, relative risk of CLL for men is relatively constant, at 2.8 times that of women. Age The median age at diagnosis is 70 years, and CLL is rarely seen before the age of 35 years. Race In the American population, the incidence of CLL is similar in different races. However, the incidence is much lower in Asia ( Japan, Korea, and China), Latin America, and Africa than in the United States. Etiology and risk factors The etiology of CLL is unclear. However, some factors associated with CLL have been identified. Genetic factors There is a high familial risk for CLL, with family members of CLL patients having a twofold to sevenfold higher risk of developing the disease. CLL with a familial association tends to occur in younger age groups with subsequent generations, perhaps because of increased screening. Association with certain HLA patterns has not been consistent. CLL CHRONIC LYMPHOCYTIC LEUKEMIA 771

Environmental factors There is no documented association of CLL with exposure to radiation, alkylating agents, or known leukemogenic chemicals. However, exposure to some chemicals used in agriculture may increase the risk of developing CLL. Viral infections Associations between CLL and several viruses, including human T-cell lymphotrophic viruses I and II (HTLV-I and HTLV-II) and Epstein-Barr virus (EBV), have been suggested. However, no conclusive evidence of a causal relationship exists. Adult T-cell leukemia/lymphoma, a T-cell disorder that can resemble CLL, is caused by HTLV-I. Signs and symptoms In approximately 20% of patients, CLL is asymptomatic at diagnosis and is discovered on a routine blood examination. When symptoms are present, they are nonspecific and include fatigue, weakness, and malaise. Constitutional B symptoms (ie, fever, weight loss, and night sweats) are not common at diagnosis but may signal disease transformation. Patients frequently notice enlarged lymph nodes or abdominal discomfort and early satiety related to splenomegaly. Patients with CLL have an increased susceptibility to infections, which may be the presenting complaint. Lymphadenopathy is common at diagnosis. Lymph nodes are usually symmetrical, mobile, and nontender. Splenomegaly and hepatomegaly The spleen and, less frequently, the liver may be enlarged. Splenomegaly may be massive in advanced cases. Only occasionally is splenomegaly found in the absence of lymphadenopathy, but recognition of such patients may identify a group who can significantly benefit from splenectomy. Other organs In advanced disease, other organs may be involved, including the GI mucosa, prostate, lungs, pleura, and bones. Rarely is such involvement clinically important unless (Richter s) transformation has occurred. Laboratory features Peripheral blood The most constant feature of CLL is marked lymphocytosis, with median values of 30-50 10 9 /L. The lymphocytes are small and mature appearing with little cytoplasm and clumped chromatin. A few larger nucleolated cells, which represent prolymphocytes, usually constitute < 10% of the total lymphocytes. Diagnostic criteria for CLL defined by the National Cancer Institute (NCI) and International Workshop on CLL (IWCLL) are presented in Table 1. A positive Coombs test is seen in as many as 30% of patients at some time during the disease course, although it is uncommon (< 5%) during early stages. Autoimmune phenomena are frequent, with hemolytic anemia and thromb- 772 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

TABLE 1: Diagnostic criteria for CLL according to the National Cancer Institute (NCI) and International Workshop on CLL (IWCLL) Cells NCI IWCLL Lymphocytes 5 x 10 9 /L + 1 B-cell 10 x 10 9 /L + marker (CD19, CD20, CD23) B-cell phenotype or bone + CD5 marrow involvement Atypical cells < 55% Not stated (eg, prolymphocytes) Bone marrow 30% > 30% lymphocytes ocytopenia occurring most commonly. Autoimmune neutropenia and other autoimmune sequelae are infrequent. Bone marrow The bone marrow can be hypercellular or normocellular, but the most characteristic feature is the presence of at least 30% mature lymphocytes. The lymphocyte infiltration can be interstitial, nodular, mixed interstitial and nodular, or diffuse. Diffuse lymphocyte infiltration is associated with a poor prognosis. Other laboratory findings Hypogammaglobulinemia is seen in > 50% of patients with CLL, usually affecting IgA first, followed by IgM and IgG. However, 5%-10% of patients may have a small monoclonal peak. Paraproteinemia is more common at disease transformation. Elevated serum levels of B 2 -microglobulin (β2m)have been associated with a poor prognosis. Elevation of serum LDH levels is found in < 10% of patients at diagnosis and may indicate autoimmune hemolytic anemia or (Richter s) transformation to large-cell lymphoma. Immunophenotyping More than 95% of all cases have a B-cell phenotype. In these patients, CD19 and/or CD20 are always coexpressed with CD5, which is expressed on T cells and a subset of normal B cells. Other markers, such as CD21 and CD22, may also be expressed. Expression of CD23 helps to differentiate CLL from mantle cell lymphoma, in which cells coexpress CD19 and CD5 but lack CD23. Expression of surface immunoglobulins is usually weak and is lower than in normal B lymphocytes or most other B-cell lymphomas. Cytogenetic and molecular findings Chromosomal abnormalities Chromosomal abnormalities occur in 50%-65% of CLL patients with analyzable metaphases. Because of the low mitotic rate in CLL, traditional karyotypic methods frequently fail. Fluorescent in situ hybridization (FISH) has improved CHRONIC LYMPHOCYTIC LEUKEMIA 773

the detection of clonal genetic abnormalities in CLL patients. In a landmark study, Dohner et al evaluated 325 patients with CLL. Using a variety of fluorescent probes, they identified chromosomal aberrations in 82%. Among these findings was the recognition that some subtypes (17p and 11q) had more pronounced lymphadenopathy as well as markedly shorter time to initiate chemotherapy and shorter overall survival than did other types. In this study, the most frequent change was a deletion in 13q14 (55% of patients). Other typical abnormalities included deletion 11q22-23 (18%), trisomy 12q13 (16%), and deletion 17p13 (7%). These genetic abnormalities help explain some of the clinical variations seen in CLL. For example, patients with 13q deletions tend to have modest or absent lymphadenopathy, whereas patients with deletion 17p or 11q frequently have bulky adenopathy. Disease progression also is heavily influenced by the underlying genetic abnormality. Time from diagnosis to treatment averaged only 9 months for patients with 17p abnormalities, compared with 92 months for patients with 13q deletions. Prognostic importance These chromosomal abnormalities were potent predictors of outcome with the following median survivals: deletion 17p = 32 months; deletion 11q = 79 months; trisomy 12 = 114 months; and deletion 13q = 133 months. Molecular abnormalities No single gene has been implicated in the pathogenesis of CLL. However, several genes are involved to some extent. Retinoblastoma gene The retinoblastoma 1 (rb1) gene is located in the long arm of chromosome 13, but despite the frequent abnormalities in this region, the retained RB1 allele is usually unaffected. A more telomeric region to the rb1 gene (D13S25) is frequently affected, and in at least some cases, the abnormality is homozygous, suggesting the presence of a tumor-suppressor gene in this region. Mutations of ras Despite the frequent involvement of chromosome 12, ras mutations are uncommon in CLL. Overexpression of bcl-2 Abnormalities of the long arm of chromosome 14 frequently involve region 14q32, the site encoding for the immunoglobulin heavy-chain gene. However, gene translocations, such as t(11;14)(q13;q32) and t(14;18)(q32;q21) (which juxtapose genes bcl-1 and bcl-2 to the heavy-chain immunoglobulin gene), are relatively uncommon and should prompt consideration of alternative diagnoses (mantle cell or follicular lymphoma). Nevertheless, increased expression of bcl-2 mrna and protein are very common in CLL. Since overexpression of bcl-2 inhibits apoptosis, it is possible that this gene participates in the pathogenesis of CLL. 774 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

Mutations in p53 Mutations in the p53 tumor-suppressor gene are seen in 15% of all patients with CLL (17p abnormality detected by FISH), but these mutations are more common in patients with advanced-stage disease or transformation. Multidrug resistance gene Approximately 40% of patients with CLL have overexpression of the multidrug resistance gene (MDR1). Staging and prognosis Staging systems Two staging systems of CLL are commonly used: one proposed and later modified by Rai and the other proposed by Binet (Table 2). Both systems include three categories of low, intermediate, and high risk, with median survival durations of approximately 10, 6, and 2 years, respectively. Other prognostic factors Stage of disease has been considered the main prognostic indicator for CLL. However, other factors have prognostic implications, such as chromosomal aberrations, serum levels of β2m, pattern of bone marrow infiltration, the lymphocyte doubling time, and serum levels of soluble CD23. Mutational status of Ig V H and expression of CD38 also have been identified as prognostic characteristics in CLL. Patients with unmutated V genes showed a significantly shorter survival irrespective of stage than those with a mutated gene. Patients with stage A disease and an unmutated V gene had a median survival of 95 months, compared with 293 months for patients with a mutated gene. Mutation of V gene is somewhat associated with expression of CD38. Patients with mutated V genes frequently have low expression of CD38. These patients appear to require minimal therapy and have prolonged survival. Treatment EARLY-STAGE DISEASE Since patients with early-stage CLL have a good long-term prognosis, and early therapy has not changed the outcome of the disease, patients in the early stages should not be treated unless specific indications exist (Table 3). Recent randomized trials comparing chlorambucil (Leukeran) vs no therapy have documented no advantage for patients with early-stage CLL who received inmmediate therapy with chlorambucil. New alternatives for treatment of highrisk early-stage CLL (eg, high plasma levels of β2m) are being investigated (eg, monoclonal antibodies). CONVENTIONAL CHEMOTHERAPY Single-agent chemotherapy Chlorambucil The most frequently used single agent for CLL is chlorambucil, given as either 0.1 mg/kg daily or 20-40 mg/m 2 every 4 weeks. Therapy is continued until the signs or symptoms requiring therapy are controlled. CHRONIC LYMPHOCYTIC LEUKEMIA 775

TABLE 2: Staging systems for CLL RAI SYSTEM Median Rai Modified Rai survival stage stage (risk) Clinical characteristics (yr) 0 Low Lymphocytosis in peripheral blood and bone > 10 marrow only I Intermediate Lymphocytosis and enlarged lymph nodes 6 II Lymphocytosis and enlarged spleen and/or liver III High Lymphocytosis and anemia (hemoglobin < 11 g/dl) 2 IV Lymphocytosis and thrombocytopenia (platelets < 100 10 9 /L) BINET SYSTEM Median Binet survival stage Clinical characteristics (yr) A Hemoglobin 10 g/dl, platelets 100 10 9 /L, > 10 and < 3 areas involved B Hemoglobin 10 g/dl, platelets 100 10 9 /L, 6 and 3 areas involved C Hemoglobin < 10 g/dl, platelets < 100 x 10 9 /L, or both 2 (independent of areas involved) Chlorambucil is frequently combined with oral prednisone (30-100 mg/m 2 /d), although there is no clear evidence that the combination improves responses or overall survival over chlorambucil alone. Prednisone is of value, however, in the management of autoimmune cytopenias. Cyclophosphamide (Cytoxan, Neosar) is an alternative to chlorambucil. The usual dose is 0.5-1 g/m 2 every 3-4 weeks together with vincristine and steroids (eg, COP [cyclophosphamide, vincristine (Oncovin), and prednisone] regimen; see below). Combination chemotherapy COP and CHOP Various drug combinations have been used in CLL, mostly in patients with advanced-stage disease. The most frequently employed combinations have been COP and these three drugs plus doxorubicin (CHOP). The dose of doxorubicin used is usually low (25 mg/m 2 ). A higher dose of doxorubicin (50 mg/m 2 ) has been employed in some regimens, such as CAP (cyclophosphamide, doxorubicin [Adriamycin], and prednisone). Response rates have been 40%-85% with these combinations. In randomized studies, COP was no better than chlorambucil plus prednisone. Although CHOP initially achieved better survival than COP (in Binet stage C) or 776 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

TABLE 3: Suggested indications for therapy for early-stage CLL Progressive disease-related symptoms (eg, fever, night sweats, weight loss) Bone marrow involvement with progressive anemia and thrombocytopenia Progressive or painful splenomegaly Progressive or bulky lymphadenopathy Rapidly increasing lymphocytosis Autoimmune hemolytic anemia or thrombocytopenia chlorambucil plus prednisone, longer follow-up has not confirmed this survival advantage. NEW APPROACHES Nucleoside analogs Fludarabine (Fludara), now perhaps the drug of choice for treating CLL, has been demonstrated in a randomized trial to be more active than chlorambucil for the treatment of CLL. When given to previously treated patients at a dose of 25-30 mg/m 2 /d for 5 days every 3-4 weeks, this nucleoside analog produced responses in 20%-50% of patients, with 5%-15% of patients achieving a complete response (CR) and an additional 5%-20%, a nodular partial response (PR), ie, a CR but with the presence of lymphoid nodules in the bone marrow (Table 4). In previously untreated patients, the response rate was 67%-80%, with 8%-35% of patients achieving a CR. The addition of prednisone or chlorambucil to fludarabine therapy did not improve the response rate and is associated with an increased incidence of opportunistic infections and other toxicities. A large randomized study comparing fludarabine, CAP, and CHOP demonstrated an increased response rate with fludarabine but no difference in survival (Table 5). Randomized trials of fludarabine vs chlorambucil in previously untreated patients showed improvements in response rate (overall and CR), duration of response, and progression-free survival with fludarabine but no survival advantage. Other nucleoside analogs Cladribine (2-chlorodeoxyadenosine, 2-CdA [Leustatin]) is also active in CLL when given at doses of 0.1 mg/kg/d (or 4 mg/m 2 /d) for 7 days. At therapeutic doses, this agent appears to be associated with more myelosuppression, particularly thrombocytopenia, than fludarabine. This finding limits its utility in treating CLL, but a direct comparison with fludarabine has not been reported. The third purine analog active against CLL is pentostatin (Nipent). Previously, toxicity limited its use as an antineoplastic agent. More recently, recognition that use of this drug requires close attention to hydration and renal function (it is both toxic to and cleared by the kidneys) has renewed interest in clinical CHRONIC LYMPHOCYTIC LEUKEMIA 777

TABLE 4: Response criteria in CLL according to the IWCLL Complete response Resolution of lymphadenopathy, splenomegaly, hepatomegaly, and constitutional symptoms Normalization of blood counts: Neutrophils > 1.5 10 9 /L Platelets > 100 10 9 /L Lymphocytes < 4 10 9 /L Normalization of bone marrow < 30% lymphocytes a Nodular or focal infiltrates b Partial response Downstaging (from Binet stages C to A or B and from B to A) b or > 50% decrease in absolute lymphocyte count, splenomegaly, lymphadenopathy, hepatomegaly neutrophils 1.5 10 9 /L platelets 100 10 9 /L hemoglobin > 11 g/dl > 50% improvement in peripheral blood counts a a NCI criteria; b IWCLL criteria evaluation with this agent. Preliminary studies of pentostatin combined with cyclophosphamide demonstrate responses in > 70% of previously treated patients with acceptable toxicity. Combination chemotherapy The combination of fludarabine (30 mg/m 2 /d for 3 days) and cyclophosphamide (300 mg/m 2 /d for 3 days) has resulted in an improved response (overall and CR) rate vs fludarabine alone. Longer followup is needed to assess the effect of this combination on survival. Recent data suggest that the addition of a monoclonal antibody to fludarabinebased therapy may markedly improve CR rates in this disease. A study conducted by the Cancer and Leukemia Group B (CALGB) randomized patients with previously untreated CLL to receive fludarabine or a combination of fludarabine and the anti-cd20 antibody rituximab (Rituxan) at standard doses. Patients in both arms subsequently received a consolidation course of rituximab for 4 weeks. Overall response rates were high in both arms, but there was a significantly higher CR rate (33%) in the concurrent arm than in the arm with fludarabine alone (15%). The CR rate increased in both groups after consolidation therapy with rituximab. The group at M. D. Anderson Cancer Center has developed a regimen combining 3 days of fludarabine and cyclophosphamide with 1 dose of rituximab given monthly. The overall response rate in previously untreated 778 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

TABLE 5: Comparison of fludarabine, CAP, and CHOP treatment for CLL Response rate Patient characteristic Fludarabine CAP CHOP Response 71% 58% 72% Complete response 8% 2% 9% Median survival 69 months 70 months 67 months CAP = Cyclophosphamide, Adriamycin, and prednisone; CHOP = Cyclophosphamide, low-dose doxorubicin, vincristine (Oncovin), and prednisone patients was 95%, and two-thirds of the patients achieved CR. More important, molecular remission, or polymerase chain reaction (PCR) negativity, in the bone marrow was detected in half of the patients in CR. Kennedy et al combined alemtuzumab (Campath 1H), a chimeric monoclonal antibody targeting the pan-lymphocyte antigen CD52, with fludarabine in six patients whose disease was refractory to each agent used singly. There were five responses, including one CR. The authors noted that the observed responses were better than the prior response after each agent used singly. Bone marrow transplantation Both allogeneic and autologous bone marrow transplantation (BMT) have produced some encouraging results in patients with CLL. Allogeneic BMT is a viable option for younger patients with CLL, particularly if they have not responded to alkylating-agent and/or nucleoside-analog therapy and are in advanced disease stages. The series reported to date, including a majority of patients with advanced, refractory disease, has documented a CR rate in excess of 70%. The response is sustained in most patients, although follow-up is still short. BMT using nonablative conditioning regimens has produced encouraging results and should be considered in the setting of a clinical trial, particularly for patients > 60 years. Autologous BMT Since the median age of CLL patients is usually higher than the age considered acceptable for allogeneic BMT, autologous transplants using purged marrow have also been investigated. In general, results have been disappointing, but some CRs have been obtained and maintained for at least 10 months. Monoclonal antibody-targeted therapy Monoclonal antibodies (MoAbs) have been Standard-dose rituximab (375 mg/ m 2 weekly 4) has moderate activity against CLL, with 25% responses (Huhn, Schilling, Wilhelm, et al: Blood 98:1326-1331, 2001). Two trials using escalated dosing, however, reported higher response rates. In one trial, the antibody was given for 4 weeks but escalated on weeks 2-4 to 500-2,250 mg/m 2. A response rate of 36% was noted in 40 previously treated CLL patients, with a dose response noted (O Brien S, Kantarjian H, Thomas DA, et al: J Clin Oncol 19:2165-2170, 2001). Another trial administered the standard dose of rituximab thrice weekly for 4 weeks. A 45% response rate was observed in 33 patients with small lymphocytic lymphoma/cll (Byrd JC, Murphy T, Howard RS, et al: J Clin Oncol 19:2153-2163, 2001). CHRONIC LYMPHOCYTIC LEUKEMIA 779

used in CLL patients in an attempt to exploit antibody-mediated cytotoxicity. Alemtuzumab was recently approved by the FDA for the treatment of refractory CLL. Alemtuzumab has produced a response rate of 44% in patients with heavily pretreated CLL. In a recent pivotal trial in fludarabine-refractory patients, alemtuzumab resulted in an overall response rate of 33%. Rituximab also has been investigated (see box on previous page) and is active both as a single agent and in combination with chemotherapy. Because of rituximab s efficacy without significant toxicity, it is assuming a greater role in the treatment of patients with CLL. Other antibodies, including an anti-cd23 antibody and HuD10, are currently in early-phase testing. Splenectomy may be beneficial for patients in whom hypersplenism is believed to be the cause of cytopenias (particularly in patients without significant lymphadenopathy) or for palliation when splenomegaly is symptomatic and refractory to chemotherapy. Cytopenias frequently respond to splenectomy, which is associated with minimal mortality in experienced hands. Treatment recommendations Traditionally, the initial therapy for CLL has been chlorambucil with or without prednisone. However, accumulating data suggest that fludarabine has significantly greater activity. This agent produces higher overall and CR rates and provides a longer remission duration than chlorambucil. Newer data suggest that combination chemotherapy, particularly a nucleoside analog combined with an alkylating agent, may provide higher response rates, and the addition of MoABs to such regimens appears to increase the CR rates. The development of nonmyeloablative transplants has provided the possibility of allogeneic transplantation for CLL, where the median age of patients is in the 60s, but this new technique should only be performed in the context of a clinical trial. An effort should be made to enroll patients in clinical trials that offer them the possibility of receiving some of the new alternatives that may eventually achieve the goal of curing CLL. Complications Infections Patients with CLL are prone to multiple infections. Hypogammaglobulinemia plays a central role in the predisposition of patients to this problem, and prophylactic IV administration of immunoglobulin preparations may reduce the incidence of infections. Autoimmune cytopenias frequently complicate CLL and may be precipitated/aggravated by therapy (eg, fludarabine) for CLL. Autoimmune hemolytic anemia can be treated successfully with prednisone in the majority of patients. Combinations of cyclophosphamide with rituximab are beneficial in cases refractory to prednisone, splenectomy, or cyclosporine (Neoral, Sandimmune). Similar approaches may be useful for autoimmune thrombocytopenia. In a study from M. D. Anderson Cancer Center, 31 patients with CLL and autoimmune anemia or thrombocytopenia received cyclosporine (300 mg/day). Sixty- 780 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

three percent of patients responded, with a median duration of response of 10 months. No grade 3-4 toxicity was seen. Pure red cell aplasia is a relatively uncommon complication of CLL, which is mediated by immune mechanisms. Therapy with cyclosporine (3-6 mg/kg/d) may be effective. TRANSFORMATION Large-cell lymphoma CLL transforms into a large-cell lymphoma (LCL) in 3%-10% of patients. This phenomenon, known as Richter s transformation, has an aggressive presentation with fever and other B symptoms and progressive lymphadenopathy. Extranodal involvement occurs in approximately 40% of patients. Paraproteinemia and a sharp rise in serum lactic dehydrogenase (LDH) levels can be frequently seen. The prognosis of patients who progress to LCL is variable and depends in part on the degree of prior treatment used for the underlying CLL. In treatmentnaive patients, standard therapy for LCL with CHOP (or CHOP and rituximab) may offer long-term control of the transformed component. In patients who have had significant prior therapy, the disease is often refractory, and combination chemotherapy including BMT is frequently ineffective. Prolymphocytic leukemia More rarely, CLL can transform into prolymphocytic leukemia, characterized by a > 55% increase in prolymphocytes. The transformation is frequently accompanied by progression of splenomegaly, cytopenias, and refractoriness to therapy. Other diseases Anecdotal cases of CLL evolving into acute lymphocytic leukemia, myeloma, low-grade and Hodgkin s lymphomas have been reported. HAIRY-CELL LEUKEMIA Hairy-cell leukemia (HCL) is an infrequent B-cell malignancy usually associated with pancytopenia and splenomegaly. About 600 cases are reported yearly in the United States. Despite its relative rarity, there are a disproportionate number of highly effective therapies available. Epidemiology and etiology The male-to-female ratio of HCL is 4:1. The median age at presentation is 50 years. The etiology is unknown. Differential diagnosis HCL can be confused with malignant lymphomas, splenic lymphoma with villous lymphocytes (SLVLs), CLL, other non-hodgkin s lymphomas in leukemic phase, and occasionally even myelodysplastic syndromes. CHRONIC LYMPHOCYTIC LEUKEMIA 781

Treatment The indications for treatment of HCL are an absolute neutrophil count (ANC) < 1,000/µL, platelet count < 100 10 3 /µl, or hemoglobin < 10 g/dl; leukemic phase of HCL; symptomatic splenomegaly; recurrent infections; or autoimmune complications. Response criteria The criteria for a CR are normalization of the CBC, with ANC > 1,500/µL, platelet count > 100,000/µL, and hemoglobin > 12 g/dl; regression of organomegaly to normal; and bone marrow and peripheral blood free of hairy cells. PRs require reduction of the hairy cells in the bone marrow to < 50%, < 5% hairy cells in peripheral blood, > 50% reduction in organomegaly, and normalization of the CBC. Splenectomy is reserved for patients with splenic rupture, infarcts, a massively enlarged spleen, severe hypersplenism, or failure to respond to systemic chemotherapy. Interferon-α α (IFN-α) at a dose of 3 mu/d administered by IM or SC injection for 6 months followed by 3 mu/d three times weekly for 12 or 24 months, induces a CR in 8%-10% of patients and a PR in 74%. The median time to response was 6 months in patients achieving a PR and 14 months in those achieving a CR. Patients frequently relapse between 12 and 24 months after discontinuation of therapy. Purine analogs Pentostatin is a purine analog that binds to adenosine deaminase (ADA). The recommended dose is 4 mg/m 2 by IV bolus every other week until a CR is obtained. Usually, patients require a median of 8 courses (range, 4-15). The CR rate varies between 59%-89% in different studies, and the PR rate varies between 4%-37%. Responses can last for many years, and patients who relapse often respond to retreatment with pentostatin. In a recent update of a large randomized trial comparing pentostatin and IFN-α, Flinn et al reported that in 241 patients with HCL treated with pentostatin, the 10-year overall survival was 81%, with only 2 deaths (1%) attributable to HCL. Similarly, Catovasky et al published follow-up data on 159 patients, which showed a 4-year event-free survival of 84%. Cladribine shows activity in treating HCL similar to that of pentostatin. Due to this finding and the fact that cladribine is given as 1 cycle of a 7-day continuous infusion or 5-day bolus, this agent usually is the preferred treatment of this disorder. Piro et al treated 144 HCL patients with cladribine, 0.1 mg/ kg/d by continuous IV infusion for 7 days. A total response rate of 97% was obtained, with 85% CRs and 12% PRs. Response was independent of previous treatment with IFN or splenectomy, and three patients whose disease was refractory to pentostatin responded to cladribine. Recovery of blood cell counts occurred by day 61 (range, 11-268 days). At M. D. Anderson Cancer Center, Estey et al treated HCL patients and noted an 89% response rate, with 78% achieving a CR. Four HCL patients who relapsed after responding to cladribine were retreated again with the same drug, resulting in two CRs and one PR. 782 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

The largest series reporting long-term follow-up results on patients with HCL treated with cladribine was from the Scripps group. A total of 349 patients, with a median duration of response follow-up of 59 months, were evaluated. Twentysix percent had relapsed at a median of 29 months, but most of them were patients who had only achieved a PR. The time-to-treatment-failure rate at 48 months was only 16% in complete responders. For patients who relapse after therapy with cladribine or pentostatin, Kreitman et al reported on an exciting new treatment with an anti-cd22 antibody fused to a truncated Pseudomonas exotoxin. In 16 patients refractory to cladribine, there were 11 CRs and 2 PRs with only 3 relapses at a median followup of 16 months (Kreitman RJ, Wyndham HW, Bergeron K, et al: N Engl J Med 345:241-247, 2001). SUGGESTED READING Immunotoxin Recently, the NCI evaluated a recombinant immunotoxin containing an anti-cd22 variable domain fused to a truncated Pseudomonas exotoxin; it was given by IV infusion every other day for a total of three doses. Sixteen patients whose disease was resistant to cladribine were treated; two achieved PR and 11 achieved CR. Three of the 11 patients who had CR relapsed and were retreated; all of these patients achieved a second CR. Byrd JC, Murphy T, Howard RS, et al: Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 19:2153 2164, 2001. Byrd JC, Peterson BL, Morrison VA, et al: Randomized phase II study of fludarabine with concurrent vs sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: Results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 101:6 14, 2003. Cortes J, O Brien S, Loscertales J, et al: Cyclosporin A for the treatment of cytopenia associated with chronic lymphocytic leukemia. Cancer 92:2016 2022, 2001. Dohner H, Stilgenbauer S, Benner A, et al: Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910 1916, 2000. Flinn IW, Kopecky KJ, Foucar MK, et al: Long-term follow-up of remission duration, mortality, and second malignancies in hairy-cell leukemia patients treated with pentostatin. Blood 96:2981 2986, 2000. Keating MJ, Flinn I, Jain V, et al: Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: Results of a large international study. Blood 99:3554 3561, 2002. Kennedy B, Rawstron A, Carter C, et al: Campath-1H and fludarabine in combination are highly active in refractory chronic lymphocytic leukemia. Blood 99:2245 2247, 2002. Kreitman RJ, Wilson WH, Bergeron K, et al: Efficacy of the anti-cd22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. N Engl J Med 345:241 248, 2001. Leporrier M, Chevret S, Cazin B, et al: Randomized comparison of fludarabine, CAP, and CHOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood 98:2319 2325, 2001. CHRONIC LYMPHOCYTIC LEUKEMIA 783

Lundin J, Kimby E, Bjorkholm M, et al: Phase II trial of subcutaneous anti-cd52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B- cell chronic lymphocytic leukemia (B-CLL). Blood 100:768 773, 2002. O Brien SM, Kantarjian H, Thomas DA, et al: Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 19:2165 2170, 2001. Rai KR, Peterson BL, Appelbaum FR, et al: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343:1750 1757, 2000. Weiss MA, Maslak PG, Jurcic JG, et al: Pentostatin and cyclophosphamide: An effective new regimen in previously treated patients with chronic lymphocytic leukemia. J Clin Oncol (in press). 784 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH