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Fludarabine plus alemtuzumab versus udarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial
Thomas Elter, Liana Gercheva-Kyuchukova, Halyna Pylylpenko, Tadesuz Robak, Branimir Jaksic, Grigoriy Rekhtman, Sawomira Kyrcz-Krzemie, Mykola Vatutin, Jingyang Wu, Cynthia Sirard, Michael Hallek, Andreas Engert

Summary
Background Chronic lymphocytic leukaemia (CLL) is an incurable and chronic disorder, with worsening prognosis for patients as their disease progresses. We compared the ecacy and safety of the combination of udarabine and alemtuzumab with udarabine monotherapy in previously treated patients with relapsed or refractory CLL. Methods Patients (aged 18 years) with CLL Binet stage A, B, or C or Rai stages IIV were randomly assigned in a 1:1 ratio according to a computer-generated allocation schedule to open-label combination treatment (udarabine 30 mg/m per day and alemtuzumab 30 mg per day on days 13) or monotherapy (udarabine 25 mg/m on days 15) by use of an interactive voice response system. Both regimens were given intravenously for a maximum of six 28-day cycles. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00086580. Findings Fludarabine plus alemtuzumab (n=168) resulted in better PFS than did udarabine monotherapy (n=167; median 237 months [95% CI 192284] vs 165 months [125212]; hazard ratio 061 [95% CI 047080]; p=00003) and overall survival (median not reached vs 529 months [409not reached]; 065 [045094]; p=0021) compared with udarabine alone. All-cause adverse events occurred in 161 (98%) of 164 patients in the combination treatment group and 149 (90%) of 165 in the udarabine alone group. Patients in the udarabine plus alemtuzumab group had more cytomegalovirus events (23 [14%] vs one [<1%]) and grade 1 or 2 potentially alemtuzumab infusion-related adverse reactions (102 [62%] vs 22 [13%]). Grade 3 or 4 toxicities in the combination treatment and monotherapy groups were leucopenia (121 [74%] of 164 vs 55 [34%] of 164), lymphopenia (149 [94%] of 158 vs 53 [33%] of 161), neutropenia (93 [59%] of 157 vs 110 [68%] of 161), thrombocytopenia (18 [11%] of 164 vs 27 [17%] of 163), and anaemia (14 [9%] of 163 vs 28 [17%] of 164). The incidence of serious adverse events was higher in the combination treatment group (54 [33%] of 164 vs 41 [25%] of 165); deaths due to adverse events were similar between the two groups (ten [6%] vs 12 [7%]). Interpretation The combination of udarabine and alemtuzumab is another treatment option for patients with previously treated CLL. Funding Genzyme.
Published Online October 11, 2011 DOI:10.1016/S14702045(11)70242-X Department of Internal Medicine, Centre of Integrated Oncology Cologne Bonn, University of Cologne, Germany (T Elter MD, Prof M Hallek MD, Prof A Engert MD); Varna Clinic of Haematology, Varna, Bulgaria (Prof L Gercheva-Kyuchukova MD); Cherkasy Oncology Centre, Cherkasy, Ukraine (H Pylylpenko MD); Medical University of Lodz, Lodz, Poland (Prof T Robak MD); Clinical Hospital Merkur, Zagreb, Croatia (Prof B Jaksic MD); Khmelnitsky Regional Hospital, Khmelnitsky, Ukraine (G Rekhtman MD); Silesian Medical University, Katowice, Poland (Prof S Kyrcz-Krzemie MD); Donetsk State Medical University, Donetsk, Ukraine (M Vatutin MD); Genzyme Corporation, Cambridge, MA, USA (J Wu MS, C Sirard MD); and Cologne Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany (Prof M Hallek) Correspondence to: Dr Thomas Elter, Department of Internal Medicine, Centre of Integrated Oncology Cologne Bonn, University of Cologne, Cologne D-50924, Germany thomas.elter@uk-koeln.de

Introduction
Despite the increasing number of treatment options, chronic lymphocytic leukaemia (CLL) remains an incurable disease.1 Estimates of median survival range from more than 10 years for patients with early-stage CLL to less than 1 year for patients with udarabine-resistant disease.2 In view of the incurable and chronic nature of CLL, and the worsening prognosis for patients as their disease becomes more advanced or refractory, the development of alternative regimens in earlier treatments is essential to improve their outcome. Preclinical data suggested that the addition of alemtuzumab to udarabine-based regimens could have a synergistic eect due to their complementary modes of action.36 In a report by Kennedy and colleagues,6 ve of six patients with CLL who were refractory to both drugs when administered as single agents achieved remission with the combination of udarabine and alemtuzumab.

Results from a single-group phase 2 study further suggested that udarabine and alemtuzumab combination could improve outcomes in patients with relapsed or refractory CLL, with an overall response rate (ORR) of 83% and a median overall survival of 356 months.7 Therefore, we compared the ecacy and safety of this combination treatment with udarabine monotherapy in patients with relapsed or refractory CLL.

Methods
Patients
The study was done in ve centres in North America and 43 in Europe. Eligible patients had relapsed or refractory CLL according to the National Cancer Institute Working Groups 1996 criteria,8 with evidence of progressive disease that required therapy after one previous line of treatment for CLL. Patients could have had past treatment with udarabine or alemtuzumab provided the duration of their response was longer than
1

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12 months. Additional inclusion criteria were Binet stage A, B, or C or Rai stage IIV disease; WHO performance status (PS) 0 or 1; life expectancy of 12 weeks or longer; age 18 years or older; anticancer treatment, major surgery, or radiation therapy more than 3 weeks before randomisation in the study; complete recovery from acute side-eects of previous therapy; and adequate renal and liver function. Exclusion criteria were previous treatment for CLL with more than one previous regimen or the combination of udarabine and alemtuzumab; positive Coombs test and active haemolysis; absolute neutrophil count (ANC) of less than 1510 cells per L or platelet count of less than 7510 per L, unless due to bone-marrow involvement with CLL; disorders requiring chronic use of corticosteroids; history of anaphylaxis to monoclonal antibodies; HIV positivity; evidence of active infection or history of grade 4 infection within 3 months before randomisation in the study; active second malignancy; known CNS involvement with CLL; other severe concurrent disease; progression due to a more aggressive B-cell cancer (eg, Richters syndrome); and a history of viral hepatitis or positive hepatitis B serology in the absence of immunisation. This study was approved by the institutional review board or ethics committee from each of the participating sites. All patients provided written informed consent before enrolment to the study.

open-label trial. At call-in from the site to enrol the patients, IVRS conveyed stratication data to a computer system and initiated the randomisation program. The system retrieved stratication and treatment assignment data for previously enrolled patients, and a computergenerated next random number was provided by the sponsors statistician. The system used the minimisation method9 with the probability parameter 080 to assign patients to treatment. The stratication factors were study centre, Rai stage (I or II vs III or IV), disease status (relapsed vs refractory), age (65 vs <65 years), sex (male vs female), past exposure to udarabine therapy (yes vs no), and maximum lymph node size (5 vs <5 cm or none).

Procedures
During the rst treatment cycle, patients in the combination group were given escalating doses of alemtuzumab (Genzyme, Cambridge, MA, USA; 3 mg/day, 10 mg/day, 30 mg/day, intravenously over 2 h). If grade 3 or 4 infusionrelated adverse events occurred, the same dose was repeated daily until it was well tolerated (grade 2 or lower toxicity) with appropriate premedication. A maximum of 14 days were allowed for alemtuzumab escalation to 30 mg. After completion of the escalation, patients were given udarabine (Bayer Schering, Berlin, Germany; 30 mg/m per day, intravenously over 30 min), followed immediately by alemtuzumab (30 mg/day, intravenously over 2 h); both were administered daily for 3 days. Cycles were repeated every 28 days. After cycle 1, alemtuzumab was infused over 46 h for the rst day of each new cycle and over 2 h during days 2 and 3. Patients randomly assigned to the udarabine monotherapy were treated with 25 mg/m per day for 5 days, intravenously, over 1530 min, every 28 days. Patients in both groups were scheduled to receive a minimum of four cycles and a maximum of six treatment cycles, depending on response and toxicity. They were assessed for response every two cycles. Patients in the udarabine plus alemtuzumab group were administered paracetamol 5001000 mg orally 30 min before alemtuzumab infusion for control of infusion-related events (or equivalent) and an antihistamine 30 min before drug administration as prophylaxis for infusion-related events. Patients were premedicated with hydrocortisone (100 mg, intravenously, or equivalent steroid) just before alemtuzumab infusion during the dose escalation phase, on day 1 of each subsequent cycle, and if clinically indicated thereafter. All patients were given prophylaxis with co-trimoxazole (trimethoprim 160 mg plus sulfamethoxazole 800 mg twice a day, three times a week, orally) or equivalent and famciclovir (500 mg twice a day, orally), starting on the rst day of the study treatment and continuing until CD4+ cell counts were at least 200 cells per L. If patients developed haematological toxicities with a recovery time (ie, retreatment criteria ANC 1010 cells per L, platelet count 10010 per L, and

Randomisation and masking


An interactive voice response system (IVRS) was used to randomly assign patients in a 1:1 ratio to udarabine plus alemtuzumab or udarabine monotherapy in an

335 patients randomly assigned

168 udarabine plus alemtuzumab 4 not treated 39 discontinued before completing four cycles 22 discontinued during cycles 5 and 6 9 not followed up* 5 died 4 withdrawn 103 completed six cycles and followed up* 73 discontinued during follow-up*

167 udarabine alone

2 not treated 46 discontinued before completing four cycles 12 discontinued cycles 5 and 6 9 not followed up* 7 died 2 withdrawn 107 completed six cycles and followed up* 84 discontinued during follow-up*

86 in follow-up* at end of study

74 in follow-up* at end of study

Figure 1: Trial prole Data for the number of patients screened and eligible for the study were not collected and hence are not presented here. *Follow-up for disease progression and survival, or survival only if patient had progressed.

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no active infection) from the scheduled start of the new cycle of 14 days or less (days 2943 of previous cycle), no dose modication was required in those assigned to combination treatment or monotherapy; 1528 days (days 4457 of previous cycle), patients assigned to combination treatment were given udarabine 30 mg/m per day plus alemtuzumab 30 mg/day for 2 days every 28 days, and those assigned to monotherapy were administered 1675 mg/m per day for 5 days every 28 days; and more than 28 days (after day 57 of previous cycle), treatment was discontinued in the combination treatment or monotherapy group. In the event of a non-haematological toxicity of grade 1 or 2, no dose modication was required with combination treatment or monotherapy; grade 3, patients assigned to combination treatment were given udarabine 30 mg/m per day plus alemtuzumab 30 mg/day for 2 days every 28 days, and those assigned to monotherapy were administered 1675 mg/m per day for 5 days every 28 days; if a patient recovered more than 28 days after the date of the originally scheduled start of the next treatment cycle, the patient was withdrawn from the study; grade 4, treatment was discontinued in patients assigned to combination treatment or monotherapy. Patients with a creatinine clearance of 050117 mL/s per 173 m were treated with udarabine at a 20% dose reduction. Other protocol-mandated reasons for treatment delay or discontinuation were neurotoxicity; serious infection; grade 3 or higher pulmonary, renal, or hepatic toxicity; autoimmune thrombocytopenia; and symptomatic autoimmune anaemia. Patients were monitored weekly with complete blood count and testing for cytomegalovirus (with quantitative PCR on peripheral blood) during cycles 1 and 2, and every 2 weeks thereafter. Monthly complete blood count, CD4+ cell count, and testing for cytomegalovirus continued after cycle 6 until blood counts recovered or stabilised and CD4+ cell counts rose to more than 200 cells per L. Patients who were PCR-positive for cytomegalovirus without clinical symptoms of cytomegalovirus infection or had rising viral transcripts on subsequent weekly PCR testing were treated with valganciclovir while on study treatment. Those with clinical manifestations of cytomegalovirus infection (fever or end-organ symptoms) were treated with ganciclovir for at least 10 days. Interruption of study treatment was allowed for up to 28 days before necessitating discontinuation from study participation. Clinical, radiographic (chest radiography or CT if clinically indicated), and laboratory assessments for response or progression were done every two cycles during treatment and every 3 months after treatment until disease progression. Thereafter, patients were followed up for survival only. Patients with a clinical complete response (CR) or partial response (PR) without recovery of blood counts underwent bone-marrow assessment and testing for minimal residual disease (MRD) 2 months after the end of treatment.

Fludarabine plus alemtuzumab (n=168) Age (years) Mean (SD) 65 <65 Sex Male Female Rai stage 0* I or II III or IV Binet stage at time of study entry A B C Time since original diagnosis (months; median, range, IQR) Disease status Relapsed Refractory Fludarabine-containing previous treatment Duration of response to previous treatment (months; median, range, IQR) Maximum lymph node (5 cm) 2 microglobulin (4 mg/L) Zeta-associated protein 70 (20%) CD38 (30%) WHO performance status 0 1 B symptoms Fever Night sweats Weight loss (>10%) Hierarchical cytogenetic subgroups Del 17p131 (TP53) Del 11q (but not del 17p) Trisomy 12 (no 11p or 17p del) Normal (no detectable abnormality) Only del 13q Other combinations Abnormal but unspecied 81 (48%) 87 (52%) 79 (47%) 3 (2%) 75 (45%) 24 (14%) n=92 4 (4%) 27 (29%) 9 (10%) 19 (21%) 29 (32%) 2 (2%) 2 (2%) 101 (60%) 67 (40%) 25 (15%) 165 (1120, 70250) 34 (20%) 60 (36%) 69 (41%) 65 (39%) 27 (16%) 89 (53%) 52 (31%) 284 (082571, 127540) 2 (1%) 104 (62%) 62 (37%) 109 (65%) 59 (35%) 600 (925) 56 (33%) 112 (67%)

Fludarabine alone (n=167)

608 (934) 60 (36%) 107 (64%) 108 (65%) 59 (35%) 2 (1%) 102 (61%) 63 (38%) 25 (15%) 89 (53%) 53 (32%) 275 (142466, 72567) 101 (60%) 66 (40%) 26 (16%) 160 (172, 60245) 31 (19%) 51 (31%) 73 (44%) 72 (43%) 72 (43%) 95 (57%) 87 (52%) 8 (5%) 82 (49%) 31 (19%) n=99 16 (16%) 21 (21%) 5 (5%) 18 (18%) 30 (30%) 5 (5%) 4 (4%)

Data are number (%), unless otherwise indicated. *Included based on Binet A eligibility. All patients in the udarabine plus alemtuzumab group had received udarabine-containing regimens previously and had achieved either a complete response (12 [48%]) or partial response (13 [52%]); 25 of 26 patients in the udarabine group had received udarabine-containing regimens previously, and had achieved either a complete response (16 [62%]) or partial response (nine [35%]). Alkylating drugs (monotherapy in 94 [56%] patients in udarabine plus alemtuzumab group and 88 in udarabine group, and combination therapy in 34 [20%] and 44 [26%], respectively), purine analogues (monotherapy in 15 [9%] patients in udarabine plus alemtuzumab group and 15 [9%] in udarabine group, and combination therapy in 23 [14%] and 18 [11%], respectively), or other drugs (two [1%] patients in udarabine plus alemtuzumab group and two [1%] in udarabine group). As dened according to Dhner and colleagues model;13 percentages were based on the number of patients assessed in the cytogenetic analysis (n=191), which was implemented with protocol amendment one, and because of the small numbers of patients in each of the cytogenetic subgroups no comparisons of the treatment groups could be made.

Table 1: Patients baseline characteristics and cytogenetics

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Progression-free survival Fludarabine plus alemtuzumab (months; median, 95% CI) All patients* CR+PR CR Rai stage III or IV CR+PR CR Age 65 years CR+PR CR 237 (192 to 284) 205 (143 to 319) 296 (205 to 378) HR (95% CI); Fludarabine alone (months; p value median, 95%CI) 165 (125 to 212) 115 (90 to 147) 154 (119 to 229) 061 (047 to 080); 00003 044 (029 to 067); 00001 040 (024 to 065); 00003

Response rate Fludarabine plus alemtuzumab 137 (82%) 21 (13%) 49 (79%) 10 (16%) 45 (80%) 4 (7%) Fludarabine Dierence (95% CI); alone p value

Overall survival Fludarabine plus alemtuzumab (months; median, 95% CI) NR (NR to NR) NR (321 to NR) NR (NR to NR) HR (95% CI); Fludarabine alone (months; p value median, 95%CI) 529 (409 to NR) 235 (178 to 403) 409 (314 to 478) 065 (045 to 094); 0021 042 (025 to 069); 00007 057 (031 to 105); 0072

126 (75%) 7 (4%) 37 (59%) 2 (3%) 44 (73%) 4 (7%)

006 (003 to 015); 018 008 (002 to 015); 0006 020 (004 to 035); 0015 013 (002 to 024); 0014 007 (008 to 022); 025 0 (010 to 011); 0914

Data are number (%), unless otherwise indicated. HR=hazard ratio. CR=complete response. PR=partial response. NR=not reached. *168 patients in udarabine plus alemtuzumab group; 167 in udarabine group. 62 patients in udarabine plus alemtuzumab group; 63 in udarabine group. 56 patients in udarabine plus alemtuzumab group; 60 in udarabine group.

Table 2: Response rate, progression-free survival, and overall survival

The primary endpoint was progression-free survival (PFS), dened as the time of randomisation to progression or death from any cause, whichever was earlier. The primary endpoint was changed from time to progression (TTP) to a more conservative denition of PFS before any of the planned interim analyses were undertaken to make the data more comparable with data from other randomised studies of patients with CLL. The main secondary endpoints were ORR, CR rate, overall survival, and safety. Additional, secondary endpoints were TTP, duration of response, time to alternative treatment, incidence of MRD negativity, udarabine pharmacokinetics, and health-related quality of life. The main analysis of ecacy was based on the assessments of response and disease progression for each patient by the independent response review panel, members of which were masked to treatment assignment. Response criteria and progression were assessed according to the National Cancer Institute Working Groups 1996 guidelines for CLL; criteria for disease progression were specied in the study protocol and were in accordance with these guidelines.8 The health-related quality-of-life instrument was a vedimensional questionnaire about health status and a visual analogue scale thermometer for self-rating current health-related quality of life. The ve dimensions were mobility, self-care, usual activities, pain or discomfort, and anxiety or depression, rated according to three possible levels (no problems, some problems, and extreme problems). Exploratory analyses to
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investigate the eect of prespecied prognostic factors on ecacy outcomes were also undertaken. Toxicities were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). All patients who were given at least one dose of study drug were included in the safety analysis.

Statistical analysis
The planned sample size for this study of 300 patients (150 per group) to observe 190 events of progression or death, irrespective of treatment group, was designed to detect a 50% improvement in PFS in either group with 80% power and a two-sided of 005. Two interim analyses were planned to assess safety and ecacy at a third and two-thirds of the total planned events under the jurisdiction of a data safety monitoring board. To protect the overall of 005 for the analysis of the primary endpoint, a Lan and DeMets10 error spending function with an OBrienFleming boundary11 was used to allow exibility with the timing of the interim analyses. Dierences in PFS and overall survival between the treatment groups were tested by use of the Cox proportional hazard model, stratied by Rai stage (I or II vs III or IV). Dierences in ORR and CR were tested with the Cochran-Mantel-Haenzsel method stratied by Rai stage (I or II vs III or IV). The main analysis was done on an intention-to-treat (ITT) basis for all patients who were randomly assigned. To control family-wise error rate at the 005 level, a multiple-tests adjustment with the

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Progression-free survival (%)

Hochberg procedure12 was prespecied for the three clinically important secondary endpoints: ORR, CR, and overall survival. Statistical analyses were done with the Statistical Application Software (version 9.1.3). The study is registered with ClinicalTrials.gov, number NCT00086580.

A
100 Fludarabine+alemtuzumab Fludarabine alone

75

Role of the funding source


The study sponsors and investigators contributed to the study concept and design; interpretation of data; preparation and review of the report; and nal approval of the report for submission for publication. The corresponding author had full access to the data and takes responsibility for the integrity of the data and the accuracy of the data analyses.

50

25

Hazard ratio 061 (95% CI 047080); p=00003 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 Time (months) 9 6 4 3 3 3 2 2 2 2 1 1 2 0

Results
From July, 2004, to October, 2008, 335 patients were enrolled (18 in centres in North America and 317 in Europe) and randomly assigned to udarabine alone or with alemtuzumab (gure 1). More patients than planned were enrolled to enable an analysis of potential drug drug interactions. Six patients were not given the study treatment and therefore were not included in the safety analysis. Baseline demographics and disease characteristics used for stratication were well balanced between the treatment groups (table 1). In both groups, patients were given a median of six treatment cycles (range 16), and 105 (64%) of 164 patients in the combination treatment group and 107 (65%) of 165 in the monotherapy group were given six cycles. The median cumulative dose of alemtuzumab was 583 mg (range 3653) and udarabine 4945 mg/m (05684) in the combination treatment group, and udarabine 6875 mg/m (2067765) in the monotherapy group. Fludarabine plus alemtuzumab signicantly prolonged PFS compared with udarabine (table 2; gure 2A). The ORR was non-signicantly higher in the combination treatment group than in the monotherapy group (table 2). The CR rate was signicantly higher in the udarabine plus alemtuzumab group than in the udarabine alone group (table 2). The independent response review panel identied six patients in the combination treatment group and none in the monotherapy group as MRD negative (p=0014). With a median follow-up for all enrolled patients of 295 months (IQR 165 to 421 months), the median overall survival was signicantly improved in the udarabine plus alemtuzumab group, with 117 (70%) of 168 patients in the combination treatment group and 100 (60%) of 167 in the monotherapy group alive at the data cuto or last follow-up date (table 2, gure 2B). After the predened multiple testing adjustment, the comparisons between groups for CR rate and overall survival remained signicant (p=0018 and p=0042, respectively). There was no apparent treat-

Number at risk Fludarabine+ 168 157 142 123 111 97 87 74 64 55 41 33 28 20 18 9 alemtuzumab Fludarabine 167 150 132 115 90 76 69 59 45 32 21 14 11 7 5 4 alone

B
100

75 Overall survival (%)

50

25

Hazard ratio 065 (95% CI 045094); p=0021 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 Time (months) 1 0

Number at risk Fludarabine+ 168 160 157 144 134 132 125 116 111 100 83 71 63 54 46 33 28 23 18 15 14 10 3 alemtuzumab Fludarabine 167 160 147 139 135 130 120 114 104 91 78 68 56 49 40 25 21 20 16 10 8 4 0 alone

C
100

Overall survival for Rai stages III and IV (%)

75

50

25

Hazard ratio 042 (95% CI 025069); p=00007 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 Time (months) 6 0 6 4 0 0 1 0 0 0

0 Number at risk Fludarabine+ 62 59 59 56 55 54 48 43 42 39 32 26 20 17 17 12 11 11 8 alemtuzumab Fludarabine 63 57 52 46 42 39 34 33 27 21 19 15 14 12 8 4 3 3 2 alone

Figure 2: Kaplan-Meier estimates of survival

ment dierence in the quality-of-life indicators (data not shown). The signicantly improved PFS in patients treated with combination treatment compared with monotherapy was consistent for all prespecied subgroups, including those
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Number

Hazard ratio (95% CI)

Fludarabine plus alemtuzumab (n=164) Adverse events

Fludarabine alone (n=165)

Rai stage I or II III or IV Age (years) <65 65 <70 70 2 microglobulin (mg/L) <3 3 and <4 4 <5 5 Sex Male Female Zeta-associated protein (%) <20 20 CD38 (%) <30 30 24 >24 to 48 >48 Baseline disease status Relapsed Refractory Previous treatment Fludarabine-containing Other treatment (months) <12 12 189 146 0 05 10 15 Favours udarabine alone 058 (041083) 073 (049108) 51 284 082 (040166) 058 (044078) 202 133 070 (049099) 050 (033076) 169 137 147 90 98 063 (043092) 057 (038086) 055 (037083) 060 (036102) 068 (042112) 164 142 063 (043092) 051 (033079) 217 118 071 (052098) 045 (028075) 136 71 111 270 65 059 (038093) 076 (044133) 059 (036095) 056 (042076) 085 (049148) 219 116 273 62 071 (052098) 040 (024065) 061 (045082) 057 (030110) 206 125 075 (053106) 044 (029067)

Any Grade 3 or 4 Serious Leading to discontinuation Resulting in deaths Resulting in deaths within 30 days of last dose Neutropenia Febrile neutropenia Pneumonia Pyrexia Thrombocytopenia Diarrhoea Leucopenia Anaemia
Data are number (%).

161 (98%) 110 (67%) 54 (33%) 37 (23%) 10 (6%) 4 (2%)

149 (90%) 91 (55%) 41 (25%) 32 (19%) 12 (7%) 7 (4%)

Serious adverse events (>2% of patients) 8 (5%) 5 (3%) 5 (3%) 5 (3%) 5 (3%) 4 (2%) 4 (2%) 1 (<1%) 2 (1%) 7 (4%) 1 (<1%) 1 (<1%) 1 (<1%) 0 1 (<1%) 6 (4%)

Maximum lymph node size (cm)

Table 3: Overview of adverse events and serious adverse events

Time since diagnosis (months)

Duration of response to previous

Favours udarabine plus alemtuzumab

Figure 3: Progression-free survival by subgroups Hazard ratio of less than 1 indicates treatment benets favouring udarabine plus alemtuzumab. No treatmentcovariate interaction was identied by use of the Cox regression model with treatment and the prognostic factor as the covariates.

judged to be high risk (advanced disease and older patients; gure 3). Patients with advanced disease (Rai stage III or IV) who were given combination treatment had a longer median PFS than did those given udarabine (table 2). The ORR and CR rate were also signicantly higher (table 2). Notably, patients with Rai stage III or IV who were given udarabine plus alemtuzumab also had signicantly improved median overall survival compared with those treated with udarabine alone (table 2, gure 2C), indicating survival benet in favour of the combination treatment. Improvement in overall survival
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was not noted in patients with Rai stage I or II CLL (HR 107, 95% CI 062184; p=082). There was evidence of dierential treatment benet in terms of overall survival with the combination treatment in the patients who were Rai stage III or IV compared with Rai stage I or II (p=0011). In older patients (age 65 years), median PFS was signicantly longer with the combination treatment than with udarabine alone (table 2). Median overall survival for this older population was not reached in the group assigned to udarabine plus alemtuzumab, whereas it was 409 months in the monotherapy group (table 2). 161 (98%) of 164 patients in the udarabine plus alemtuzumab group and 149 (90%) of 165 in the udarabine group had all-cause adverse events (table 3). In the combination treatment group, non-haematological all-cause adverse events occurring in more than 10% of patients were pyrexia, chills, rash, infusion-related reactions, urticaria, cytomegalovirus PCR positivity, and nausea. In the monotherapy group, none of the nonhaematological all-cause adverse events arose in more than 10% of patients (table 4). The most common allcause serious adverse events that arose in more than 2% of patients in the udarabine plus alemtuzumab group were neutropenia, febrile neutropenia, pneumonia, pyrexia, thrombocytopenia, diarrhoea, and leucopenia (table 3). In the udarabine group, these were febrile neutropenia and anaemia (table 3). Ten patients in the udarabine plus alemtuzumab group and 12 in the udarabine group died as a result of adverse events (irrespective of cause). During the treatment period (date of rst dose to 30 days after last dose), four patients in the combination treatment group and seven in the monotherapy group died as a result of an adverse event

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(table 3). The causes of these deaths were similar (acute respiratory and circulatory insuciency [n=2], acute haemolysis [n=1], and cardiopulmonary insuciency [n=1] in the udarabine plus alemtuzumab group; disease related [n=2], acute respiratory and circulatory insuciency [n=2], septic shock syndrome [n=1], acute myocardial infarction [n=1], and pulmonary oedema in the udarabine group [n=1]). Of these, three fatal drug-related adverse events occurred in the combination treatment group (acute haemolysis [n=1] and acute respiratory and circulatory insuciency [n=2]) and three in the udarabine group (acute respiratory and circulatory insuciency [n=2] and septic shock syndrome [n=1]). The overall incidence of severe haematological toxicity (dened as laboratory changes from less than grade 3 at baseline to grade 3 or greater post-baseline, or changes from grade 3 at baseline to grade 4 post-baseline) during the treatment period are shown in table 5. The median time to recovery of CD4+ cell counts (>200 cells per L) was 30 months (95% CI 2747) in the udarabine plus alemtuzumab group and 20 months (1826) in the udarabine group. All-cause infections occurred in 67 (41%) of 164 patients in the combination treatment group and in 58 (35%) of 165 in the monotherapy group. The types and severity of all infections were similar in the two groups with the exception of lower-respiratory-tract infections (26 [16%] vs eight [5%]) and viral infections (19 [12%] vs ten [6%]), which occurred more frequently in the udarabine plus

alemtuzumab group. Additionally, the incidences of infections that were greater than grade 3 were similar in both groups19 patients in the combination treatment group (grade 3 [n=17], grade 4 [n=1, pneumonia], grade 5 [n=1, pneumonia]) versus 17 in the monotherapy group (grade 3 [n=10], grade 4 [n=3], grade 5 [n=4]). Grade 4 infections in the udarabine group were Escherichia coli gastroenteritis (n=1) and sepsis (n=2), and grade 5 infections were pneumococcal sepsis (n=1), pyelonephritis (n=1), septic shock (n=1), and oral fungal infection (n=1). Cytomegalovirus-PCR-positive tests were reported in 19 (12%) asymptomatic patients in the udarabine plus alemtuzumab group and in one (<1%) asymptomatic patient in the udarabine group. Study drug was not discontinued for any of the patients with asymptomatic cytomegalovirus PCR positivity (table 4). The median time to rst occurrence of a PCR-positive test was 30 days (range 2052) for patients in the udarabine plus alemtuzumab group; only one patient in the udarabine monotherapy group had cytomegalovirus PCR positivity (on day 69 after the start of treatment). Symptomatic cytomegalovirus infection was reported in four patients (2%) only in the udarabine plus alemtuzumab group, and their symptoms were fever (n=2), hepatitis (n=1), and fever, fatigue, malaise, and leucopenia (n=1). One patient discontinued study treatment because of symptomatic cytomegalovirus infection. All patients with symptomatic cytomegalovirus infections were treated with ganciclovir and recovered without sequelae.
Fludarabine alone (n=165) Grade 4 1 (<1%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (<1%) 1 (<1%) 0 0 Grade 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (<1%) 0 0 Any grade Grade 1 15 (9%) 2 (1%) 5 (3%) 4 (2%) 0 13 (8%) 1 (<1%) 5 (3%) 9 (5%) 4 (2%) 3 (2%) 8 (5%) 4 (2%) 4 (2%) 6 (4%) 9 (5%) 3 (2%) 0 0 5 (3%) 2 (1%) 4 (2%) 1 (<1%) 0 12 (7%) 1 (<1%) 1 (<1%) 6 (4%) 2 (1%) 1 (<1%) 6 (4%) 4 (2%) 3 (2%) 3 (2%) 6 (4%) 1 (<1%) 0 0 Grade 2 8 (5%) 0 1 (<1%) 2 (1%) 0 1 (<1%) 0 3 (2%) 3 (2%) 2 (1%) 2 (1%) 2 (1%) 0 1 (<1%) 2 (1%) 2 (1%) 1 (<1%) 0 0 Grade 3 2 (1%) 0 0 1 (<1%) 0 0 0 1 (<1%) 0 0 0 0 0 0 1 (<1%) 1 (<1%) 1 (<1%) 0 0 Grade 4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Grade 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Fludarabine plus alemtuzumab (n=164) Any grade Pyrexia Chills Rash Urticaria Infusion-related reaction* Nausea Asymptomatic cytomegalovirus PCR positivity Bronchitis Diarrhoea Allergic dermatitis Vomiting Cough Headache Pruritus Hypertension Fatigue Pneumonia Bronchospasm Bone pain 98 (60%) 49 (30%) 25 (15%) 23 (14%) 23 (14%) 20 (12%) 20 (12%) 16 (10%) 16 (10%) 14 (9%) 15 (9%) 14 (9%) 14 (9%) 14 (9%) 12 (7%) 11 (7%) 11 (7%) 10 (6%) 9 (5%) Grade 1 50 (30%) 31 (19%) 12 (7%) 5 (3%) 6 (4%) 16 (10%) 15 (9%) 2 (1%) 8 (5%) 6 (4%) 11 (7%) 10 (6%) 8 (5%) 7 (4%) 5 (3%) 9 (5%) 3 (2%) 2 (1%) 2 (1%) Grade 2 41 (25%) 15 (9%) 12 (7%) 15 (9%) 9 (5%) 3 (2%) 4 (2%) 10 (6%) 5 (3%) 7 (4%) 2 (1%) 3 (2%) 6 (4%) 6 (4%) 5 (3%) 0 2 (1%) 1 (<1%) 7 (4%) Grade 3 6 (4%) 3 (2%) 1 (<1%) 3 (2%) 8 (5%) 1 (<1%) 1 (<1%) 4 (2%) 3 (2%) 1 (<1%) 2 (1%) 1 (<1%) 0 1 (<1%) 2 (1%) 1 (<1%) 4 (2%) 7 (4%) 0

Adverse events, irrespective of causality, are reported. Data are number (%). *Only adverse events reported by the investigator specically as infusion-related reactions (ie, single preferred terms) are presented; other individual terms, such as chills, pyrexia, urticaria, which potentially could represent infusion-related reactions, but were not reported as such by the investigator, are listed in the table as individual terms when the incidence regardless of causality was at least 5%. One patient also reported symptomatic cytomegalovirus infection; therefore, 19 patients had asymptomatic infection only.

Table 4: Non-haematological adverse events (5% of patients)

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Fludarabine plus alemtuzumab (n=164) Grade 3 and 4 Grade 3 Grade 4

Fludarabine alone (n=165) Grade 3 and 4 Grade 3 Grade 4

On-treatment laboratory haematological changes* Leucocytes Lymphocytes Neutrophils Platelets Haemoglobin Neutropenia Leucopenia Lymphopenia Thrombocytopenia Anaemia Febrile neutropenia 121/164 (74%) 149/158 (94%) 93/157 (59%) 18/164 (11%) 14/163 (9%) 73 (45%) 52 (32%) 31 (19%) 16 (10%) 11 (7%) 6 (4%) 81 (49%) 27 (17%) 50 (32%) 16 (10%) 12 (7%) 45 (27%) 33 (20%) 12 (7%) 8 (5%) 10 (6%) 5 (3%) 40 (24%) 122 (77%) 43 (27%) 2 (1%) 2 (1%) 28 (17%) 19 (12%) 19 (12%) 8 (5%) 1 (<1%) 1 (<1%) 55/164 (34%) 45 (27%) 53/161 (33%) 27/163 (17%) 28/164 (17%) 64 (39%) 16 (10%) 3 (2%) 19 (12%) 21 (13%) 9 (5%) 44 (27%) 19 (12%) 18 (11%) 34 (21%) 13 (8%) 2 (1%) 15 (9%) 15 (9%) 7 (4%) 110/161 (68%) 54 (34%) 10 (6%) 9 (6%) 56 (35%) 8 (5%) 10 (6%) 30 (18%) 3 (2%) 1 (<1%) 4 (2%) 6 (4%) 2 (1%)

Adverse events (5% of patients)

Data are number (%) or n/N (%). *Denominator is based on the number of patients with evaluable laboratory changes.

Table 5: Grade 3 and 4 haematological adverse events, irrespective of causality

from cycle 1 to cycle 6 for the udarabine plus alemtuzumab group (data not shown). The incidences of bronchospasm, infusion-related reaction, vomiting, and cytokine release were also highest in cycle 1, but the total incidence was low, and therefore a pattern could not be discerned for the udarabine plus alemtuzumab group (data not shown). The incidences of hypotension (two [1%]) and rash (21 [13%]) did not seem to be related to the cycle. Furthermore, most of the infusion-related events were mild in the combination and monotherapy groups (grade 1 and 2, 102 [62%] and 22 [13%], respectively), one patient in the udarabine plus alemtuzumab group had a grade 4 event (pyrexia), and there were no fatal infusion-related events. No clinically relevant dierences in incidence of adverse events were noted between patients with Rai stage I or II versus III or IV, patients aged 65 years and older versus younger than 65 years, or male versus female patients. Furthermore, the safety prole of combination treatment in patients 65 years and older was similar to that of the overall patient population (webappendix).

Panel: Research in context Systematic review A search of the literature identied an earlier phase 2 trial in which excellent results were reported for three times weekly alemtuzumab used in combination with 4-weekly udarabine, suggesting superadditive eects.6 At the time of initiation of this trial, results from another phase 2 trial by a German chronic lymphocytic leukaemia (CLL) study group were available, combining alemtuzumab with udarabine in a 4-week schedule in patients with relapsed and refractory CLL; they also reported high response rates with tolerable toxicity.7 Since the monthly udarabine plus alemtuzumab schedule had not been previously investigated in a large, randomised phase 3 study, we designed this study for further assessment of combination treatment. Interpretation The ndings of our randomised phase 3 study suggest that the monthly administration of alemtuzumab plus udarabine results in excellent response rates and prolonged progression-free survival and overall survival with a tolerable side-eect prole. Furthermore, the total dose of each drug is substantially reduced and is more convenient for patients. Noteworthy is that patients, especially those with advanced Rai stages, beneted from this treatment approach. Thus, we view this combination as an important treatment option for patients with relapsed or refractory CLL.

Discussion
The combination of udarabine and alemtuzumab resulted in a signicant improvement in PFS, CR rate, and overall survival compared with udarabine alone in patients with previously treated relapsed or refractory CLL (table 2). Although the dierence in ORR between these regimens was not signicant, the improvement in PFS and overall survival shows the clinical benet of the combination treatment. This combination also seemed to provide signicant clinical benet to patients with advanced disease (Rai stage III or IV), a particularly important subset of patients for whom further investigation is warranted. When compared with single-agent udarabine, treatment with udarabine plus alemtuzumab resulted in a similar overall frequency and severity of infectious complications, similar frequency of grade 3 or 4 neutropenia and thrombocytopenia, a lower frequency of anaemia, and, as expected, a higher frequency of lymphopenia. The rate of cytomegalovirus PCR positivity and infections in the combination treatment group was 14% which is lower than the previously reported frequency of 68% with rst-line alemtuzumab monotherapy given three times a week.14 Although there was a discrepancy in grade 3 or 4 adverse events between treatment groups, most of these events were anticipated and they were related to the mechanism of action of alemtuzumab (particularly lymphopenia or leucopenia and infusionassociated reactions). Despite the dierence in the occurrence of grade 3 or 4 adverse events, the percentage of patients who discontinued treatment or deaths during treatment was similar in both groups. Despite the recent advances in treatment options for rst-line treatment for patients with CLL, the disease remains incurable, thus treatment decisions require that benet-to-risk assessments are undertaken for each

See Online for webappendix

121 (74%) of 164 patients in the udarabine plus alemtuzumab group had at least one potentially alemtuzumab infusion-related event (dened as having at least one drug-related adverse event out of the following preferred terms: chills, pyrexia, nausea, vomiting, rash, urticaria, hypotension, bronchospasm, cytokine release syndrome, or infusion-related reaction) during cycles 16 compared with 24 (15%) of 165 in the udarabine group. Potentially alemtuzumab infusionrelated adverse events were most common in the initial treatment cycles for the udarabine plus alemtuzumab group (data not shown). For chills, pyrexia, nausea, and urticaria, the incidences were highest in cycle 1 and seemed to show a general reduction with progression

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patient. The National Comprehensive Cancer Network guidelines and European Society of Medical Oncology guidelines suggest consideration of a variety of therapeutic regimens to treat patients with CLL throughout the course of their illness. The substantial heterogeneity of patients with CLL with respect to disease burden, age, and comorbid illnesses means that several options should be available. As such, no one regimen had emerged as the clinical standard of care for the treatment of all patients with CLL in either rst or subsequent lines of treatment at the time the trial was designed (panel). Additionally, at the time the protocol was initiated, no combination regimens were approved for use in previously treated patients with CLL and few randomised controlled studies have been undertaken in patients with relapsed or refractory CLL. OBrien and colleagues15,16 reported an ORR of 65% with udarabine plus cyclophosphamide and 80% with udarabine plus cyclophosphamide plus oblimersen in patients with relapsed or refractory CLL. Robak and colleagues17 reported that in previously treated patients with CLL, compared with udarabine plus cyclophosphamide, the three-drug combination of udarabine plus cyclophosphamide plus rituximab extended median PFS (219 months vs 270 months), and increased ORR (49% vs 61%) and CR rates (3% vs 9%) as assessed by independent review. The results presented in this report are comparable to those of Robak and colleagues17 combination chemotherapy and immunochemotherapy regimens in previously treated patients with relapsed or refractory CLL. This comparability is important because udarabine plus cyclophosphamide and udarabine plus cyclophosphamide plus rituximab are increasingly used in the front-line setting; additional novel treatment regimens are needed for second-line therapy. Treatment of CLL has been evolving over the period this study was undertaken. For patients with relapsed or refractory CLL, various guidelines provide options for treatment but no globally recognised standard of care exists.1820 However, udarabine-based combination regimens have been increasingly used as rst-line or subsequent treatments. Although no conclusion can be drawn about the benet of the combination treatment in the subset of patients with previous exposure to udarabine because of the small sample size (25 in udarabine plus alemtuzumab group and 26 in udarabine monotherapy group], the HR of 082 suggests that the combination treatment is benecial. Additionally, the signicant overall treatment benet noted from all the enrolled patients (gure 3A) suggests that the combination treatment provided benet to all enrolled patients previously given dierent types of treatment. Also, cytogenetic testing was not required in the initial stages of the study and was added midway through the study. Therefore, cytogenetic data were available for 57% of 335 patients, restricting the statistical precision of analyses in subgroups dened on the basis of these data,

and restricting the ability to make conclusions about any eect of cytogenetics on response. For second-line therapy, the udarabine plus alemtuzumab regimen has several potential advantages. First, unlike udarabine plus cyclophosphamide and udarabine plus cyclophosphamide plus rituximab, the udarabine plus alemtuzumab regimen spares patients from additional exposure to alkylating drugs, which theoretically might be associated with serious early and late toxicities, such as leukaemia possibly associated with secondary therapy.21 Second, patients treated with udarabine plus alemtuzumab had a lower exposure to each drug than with the commonly used dosing regimen when each drug is used alone. The combination regimen uses 50% less alemtuzumab and 30% less udarabine than the dosing regimen approved by the US Food and Drug Administration for single drug use. Last, the dosing schedule for alemtuzumab of 3 days per month in the udarabine plus alemtuzumab regimen improves patient convenience compared with the standard dosing regimen of three times per week for up to 12 weeks. The udarabine plus alemtuzumab combination provides clinical benets with an acceptable safety prole in previously treated patients with CLL when compared with single-agent udarabine. This combination might become an important additional treatment option for patients with relapsed or refractory CLL.
Contributors TE and AE contributed to protocol development, recruitment of patients, data interpretation, and report development and revisions MH contributed to study concept, protocol design, and report revisions. JW and CS contributed to protocol development, data analysis, and report revisions. LG-K, HP, TR, BJ, GR, SK-K, and MV contributed to patient recruitment, data collection and interpretation and report revisions. All authors reviewed the nal report. Conicts of interest TE, AE, LG-K, HP, and TR received honoraria as members of a board of directors or advisory committees for Genzyme. TE, AE, LG-K, BJ, GR, TR, SK-K, and MV received research funding from Genzyme for another study. JW and CS are employees of Genzyme. MH declared no conicts of interest. Acknowledgments The study was funded by Genzyme, Cambridge, MA, USA. The ndings have been presented in part at the 51st Annual Meeting of the American Society of Hematology, New Orleans, LA, USA, Dec 58, 2009; 15th Congress of the European Haematology Association, Barcelona, Spain, June 1013, 2010; and 52nd Annual Meeting of the American Society of Hematology, Orlando, FL, USA, Dec 1013, 2010. We are very grateful to the patients and their families who participated in this study. We thank Monica Nicosia, Science Wordsmith, and Angela Partisano, Genzyme, for assistance in preparing and editing the report; and all the investigators and clinical trial sites for their participation in the CAM314 study. References 1 Gribben JG. How I treat CLL up front. Blood 2010; 115: 18797. 2 Maddocks KJ, Lin TS. Update in the management of chronic lymphocytic leukemia. J Hematol Oncol 2009; 2: 29. 3 Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed udarabine: results of a large international study. Blood 2002; 99: 355461. 4 Demidem A, Lam T, Alas S, Hariharan K, Hanna N, Bonavida B. Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Biother Radiopharm 1997; 12: 17786.

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OBrien S, Moore JO, Boyd TE, et al. 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of udarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol 2009; 27: 520812. OBrien S, Moore JO, Boyd TE, et al. Randomized phase III trial of udarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 2007; 25: 111420. Robak T, Dmoszynska A, Solal-Celigny P, et al. Rituximab plus udarabine and cyclophosphamide prolongs progression-free survival compared with udarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010; 28: 175665. Hallek M. State-of-the-art treatment of chronic lymphocytic leukemia. Hematology 2009; 1: 44049. NCCN. Clinical practice guidelines in oncology (NCCN guidelines). Fort Washington, PA: National Comprehensive Cancer Network, 2010. http://www.nccn.org/professionals/physician_gls/f_ guidelines.asp (accessed Sept 30, 2011). Eichhorst B, Hallek M, Dreyling M; ESMO Guidelines Working Group. Chronic lymphocytic leukemia: ESMO minimum clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; 20 (suppl 4): 10204. Leone G, Pagano L, Ben-Yehuda D, Voso MT. Therapy-related leukemia and myelodysplasia: susceptibility and incidence. Haematologica 2007; 92: 138998.

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