This report on a second line treatment for CLL from Lancet Oncology today
Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial
Despite the increasing number of treatment options, chronic lymphocytic leukaemia (CLL) remains an incurable disease. Estimates of median survival range from more than 10 years for patients with early-stage CLL to less than 1 year for patients with fludarabine-resistant disease. 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 fludarabine-based regimens could have a synergistic effect due to their complementary modes of action. In a report by Kennedy and colleagues, five of six patients with CLL who were refractory to both drugs when administered as single agents achieved remission with the combination of fludarabine and alemtuzumab.
Results from a single-group phase 2 study further suggested that fludarabine 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 35·6 months. Therefore, we compared the efficacy and safety of this combination treatment with fludarabine monotherapy in patients with relapsed or refractory CLL.
The study was done in five centres in North America and 43 in Europe. Eligible patients had relapsed or refractory CLL according to the National Cancer Institute Working Group's 1996 criteria, with evidence of progressive disease that required therapy after one previous line of treatment for CLL. Patients could have had past treatment with fludarabine or alemtuzumab provided the duration of their response was longer than 12 months. Additional inclusion criteria were Binet stage A, B, or C or Rai stage I–IV 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-effects 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 fludarabine and alemtuzumab; positive Coombs test and active haemolysis; absolute neutrophil count (ANC) of less than 1·5×10e9 cells per L or platelet count of less than 75×10e9 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, Richter's 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.
An interactive voice response system (IVRS) was used to randomly assign patients in a 1:1 ratio to fludarabine plus alemtuzumab or fludarabine monotherapy in an open-label trial. At call-in from the site to enrol the patients, IVRS conveyed stratification data to a computer system and initiated the randomisation program. The system retrieved stratification and treatment assignment data for previously enrolled patients, and a computer-generated next random number was provided by the sponsor's statistician. The system used the minimisation method9 with the probability parameter 0·80 to assign patients to treatment. The stratification 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 fludarabine therapy (yes vs no), and maximum lymph node size (≥5 vs <5 cm or none).
During the first treatment cycle, patients in the combination group were given escalating doses of alemtuzumab; 3 mg/day, 10 mg/day, 30 mg/day, intravenously over 2 h. If grade 3 or 4 infusion-related 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 fludarabine; 30 mg/m2 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 4–6 h for the first day of each new cycle and over 2 h during days 2 and 3. Patients randomly assigned to the fludarabine monotherapy were treated with 25 mg/m2 per day for 5 days, intravenously, over 15–30 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 fludarabine plus alemtuzumab group were administered paracetamol 500–1000 mg orally 30 min before alemtuzumab infusion for control of infusion-related events 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 first day of the study treatment and continuing until CD4+ cell counts were at least 200 cells per μL.
If patients developed haematological toxicities with a recovery time (ie, retreatment criteria ANC ≥1·0×10e9 cells per L, platelet count ≥100×10e9 per L, and no active infection) from the scheduled start of the new cycle of 14 days or less (days 29–43 of previous cycle), no dose modification was required in those assigned to combination treatment or monotherapy; 15–28 days (days 44–57 of previous cycle), patients assigned to combination treatment were given fludarabine 30 mg/m2 per day plus alemtuzumab 30 mg/day for 2 days every 28 days, and those assigned to monotherapy were administered 16·75 mg/m2 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 modification was required with combination treatment or monotherapy; grade 3, patients assigned to combination treatment were given fludarabine 30 mg/m2 per day plus alemtuzumab 30 mg/day for 2 days every 28 days, and those assigned to monotherapy were administered 16·75 mg/m2 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 0·50–1·17 mL/s per 1·73 m2 were treated with fludarabine 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 μL. 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.
The primary endpoint was progression-free survival (PFS), defined 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 definition 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, fludarabine pharmacokinetics, and health-related quality of life. The main analysis of efficacy 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 Group's 1996 guidelines for CLL; criteria for disease progression were specified in the study protocol and were in accordance with these guidelines.8 The health-related quality-of-life instrument was a five-dimensional questionnaire about health status and a visual analogue scale thermometer for self-rating current health-related quality of life. The five 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 investigate the effect of prespecified prognostic factors on efficacy 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.
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 α of 0·05. Two interim analyses were planned to assess safety and efficacy at a third and two-thirds of the total planned events under the jurisdiction of a data safety monitoring board. To protect the overall α of 0·05 for the analysis of the primary endpoint, a Lan and DeMets error spending function with an O'Brien–Fleming boundary was used to allow flexibility with the timing of the interim analyses.
Differences in PFS and overall survival between the treatment groups were tested by use of the Cox proportional hazard model, stratified by Rai stage (I or II vs III or IV). Differences in ORR and CR were tested with the Cochran-Mantel-Haenzsel method stratified 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 0·05 level, a multiple-tests' adjustment with the Hochberg procedure12 was prespecified 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
From July, 2004, to October, 2008, 335 patients were enrolled (18 in centres in North America and 317 in Europe) and randomly assigned to fludarabine alone or with alemtuzumab. 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 stratification were well balanced between the treatment groups.
In both groups, patients were given a median of six treatment cycles (range 1–6), 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 3–653) and fludarabine 494·5 mg/m2 (0–568·4) in the combination treatment group, and fludarabine 687·5 mg/m2 (20·6–776·5) in the monotherapy group.
Fludarabine plus alemtuzumab significantly prolonged PFS compared with fludarabine. The ORR was non-significantly higher in the combination treatment group than in the monotherapy group. The CR rate was significantly higher in the fludarabine plus alemtuzumab group than in the fludarabine alone group. The independent response review panel identified six patients in the combination treatment group and none in the monotherapy group as MRD negative (p=0·014).
With a median follow-up for all enrolled patients of 29·5 months (IQR 16·5 to 42·1 months), the median overall survival was significantly improved in the fludarabine 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 cutoff or last follow-up date. After the predefined multiple testing adjustment, the comparisons between groups for CR rate and overall survival remained significant (p=0·018 and p=0·042, respectively). There was no apparent treatment difference in the quality-of-life indicators.
The significantly improved PFS in patients treated with combination treatment compared with monotherapy was consistent for all prespecified subgroups, including those judged to be high risk (advanced disease and older patients). Patients with advanced disease (Rai stage III or IV) who were given combination treatment had a longer median PFS than did those given fludarabine. The ORR and CR rate were also significantly higher. Notably, patients with Rai stage III or IV who were given fludarabine plus alemtuzumab also had significantly improved median overall survival compared with those treated with fludarabine alone, indicating survival benefit in favour of the combination treatment. Improvement in overall survival was not noted in patients with Rai stage I or II CLL (HR 1·07, 95% CI 0·62–1·84; p=0·82). There was evidence of differential treatment benefit 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=0·011). In older patients (age ≥65 years), median PFS was significantly longer with the combination treatment than with fludarabine alone. Median overall survival for this older population was not reached in the group assigned to fludarabine plus alemtuzumab, whereas it was 40·9 months in the monotherapy group.
161 (98%) of 164 patients in the fludarabine plus alemtuzumab group and 149 (90%) of 165 in the fludarabine group had all-cause adverse events. 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 non-haematological all-cause adverse events arose in more than 10% of patients. The most common all-cause serious adverse events that arose in more than 2% of patients in the fludarabine plus alemtuzumab group were neutropenia, febrile neutropenia, pneumonia, pyrexia, thrombocytopenia, diarrhoea, and leucopenia. In the fludarabine group, these were febrile neutropenia and anaemia.
Ten patients in the fludarabine plus alemtuzumab group and 12 in the fludarabine group died as a result of adverse events (irrespective of cause). During the treatment period (date of first 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. The causes of these deaths were similar (acute respiratory and circulatory insufficiency [n=2], acute haemolysis [n=1], and cardiopulmonary insufficiency [n=1] in the fludarabine plus alemtuzumab group; disease related [n=2], acute respiratory and circulatory insufficiency [n=2], septic shock syndrome [n=1], acute myocardial infarction [n=1], and pulmonary oedema in the fludarabine 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 insufficiency [n=2]) and three in the fludarabine group (acute respiratory and circulatory insufficiency [n=2] and septic shock syndrome [n=1]).
The overall incidence of severe haematological toxicity (defined 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 μL) was 3·0 months (95% CI 2·7–4·7) in the fludarabine plus alemtuzumab group and 2·0 months (1·8–2·6) in the fludarabine 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 fludarabine plus alemtuzumab group. Additionally, the incidences of infections that were greater than grade 3 were similar in both groups—19 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 fludarabine 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 fludarabine plus alemtuzumab group and in one (<1%) asymptomatic patient in the fludarabine group. Study drug was not discontinued for any of the patients with asymptomatic cytomegalovirus PCR positivity. The median time to first occurrence of a PCR-positive test was 30 days (range 20–52) for patients in the fludarabine plus alemtuzumab group; only one patient in the fludarabine 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 fludarabine 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.
121 (74%) of 164 patients in the fludarabine plus alemtuzumab group had at least one potentially alemtuzumab infusion-related event (defined 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 1–6 compared with 24 (15%) of 165 in the fludarabine group. Potentially alemtuzumab infusion-related adverse events were most common in the initial treatment cycles for the fludarabine plus alemtuzumab group. For chills, pyrexia, nausea, and urticaria, the incidences were highest in cycle 1 and seemed to show a general reduction with progression from cycle 1 to cycle 6 for the fludarabine plus alemtuzumab group. 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 fludarabine plus alemtuzumab group. 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 fludarabine plus alemtuzumab group had a grade 4 event (pyrexia), and there were no fatal infusion-related events.
No clinically relevant differences 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 profile of combination treatment in patients 65 years and older was similar to that of the overall patient population.
The combination of fludarabine and alemtuzumab resulted in a significant improvement in PFS, CR rate, and overall survival compared with fludarabine alone in patients with previously treated relapsed or refractory CLL. Although the difference in ORR between these regimens was not significant, the improvement in PFS and overall survival shows the clinical benefit of the combination treatment. This combination also seemed to provide significant clinical benefit 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 fludarabine, treatment with fludarabine 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 first-line alemtuzumab monotherapy given three times a week. 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 infusion-associated reactions). Despite the difference 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 first-line treatment for patients with CLL, the disease remains incurable, thus treatment decisions require that benefit-to-risk assessments are undertaken for each 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.
Systematic review
A search of the literature identified an earlier phase 2 trial in which excellent results were reported for three times weekly alemtuzumab used in combination with 4-weekly fludarabine, suggesting superadditive effects. 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 fludarabine in a 4-week schedule in patients with relapsed and refractory CLL; they also reported high response rates with tolerable toxicity. Since the monthly fludarabine 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.
The findings of our randomised phase 3 study suggest that the monthly administration of alemtuzumab plus fludarabine results in excellent response rates and prolonged progression-free survival and overall survival with a tolerable side-effect profile. 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, benefited from this treatment approach. Thus, we view this combination as an important treatment option for patients with relapsed or refractory CLL.
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. O'Brien and colleagues reported an ORR of 65% with fludarabine plus cyclophosphamide and 80% with fludarabine plus cyclophosphamide plus oblimersen in patients with relapsed or refractory CLL. It has been reported that in previously treated patients with CLL, compared with fludarabine plus cyclophosphamide, the three-drug combination of fludarabine plus cyclophosphamide plus rituximab extended median PFS (21·9 months vs 27·0 months), and increased ORR (49% vs 61%) and CR rates (3% vs 9%) as assessed by independent review. This comparability is important because fludarabine plus cyclophosphamide and fludarabine 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. However, fludarabine-based combination regimens have been increasingly used as first-line or subsequent treatments. Although no conclusion can be drawn about the benefit of the combination treatment in the subset of patients with previous exposure to fludarabine because of the small sample size (25 in fludarabine plus alemtuzumab group and 26 in fludarabine monotherapy group], the HR of 0·82 suggests that the combination treatment is beneficial. Additionally, the significant overall treatment benefit noted from all the enrolled patients suggests that the combination treatment provided benefit to all enrolled patients previously given different 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 defined on the basis of these data, and restricting the ability to make conclusions about any effect of cytogenetics on response.
For second-line therapy, the fludarabine plus alemtuzumab regimen has several potential advantages. First, unlike fludarabine plus cyclophosphamide and fludarabine plus cyclophosphamide plus rituximab, the fludarabine 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. Second, patients treated with fludarabine 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 fludarabine 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 fludarabine plus alemtuzumab regimen improves patient convenience compared with the standard dosing regimen of three times per week for up to 12 weeks.
The fludarabine plus alemtuzumab combination provides clinical benefits with an acceptable safety profile in previously treated patients with CLL when compared with single-agent fludarabine. This combination might become an important additional treatment option for patients with relapsed or refractory CLL
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