BACKGROUND:

Monoclonal antibodies may be used more effectively in combination. A previous study of intravenous (iv) bolus alemtuzumab plus rituximab in patients with chronic lymphocytic leukemia (CLL) recurrence produced a response rate of 54% after a 4-week treatment period.

METHODS:

To optimize dose, schedule, and route of alemtuzumab, a study was designed exploring continuous intravenous infusion (civ) followed by subcutaneous (sc) alemtuzumab together with weekly iv rituximab in patients with previously treated CLL.

RESULTS:

Data from 40 patients with a median age of 59 years, and a median of 3 prior regimens (range, 1-8 regimens) were evaluable. Approximately 64% of patients were fludarabine-refractory. Seven patients (18%) achieved a complete response (CR), 4 (10%) a nodular partial response (nPR), and 10 (25%) a partial response for an overall response rate of 53%. Of 11 major responses (CR, nPR), 8 occurred after cycle 1. Response rates were highest in blood (94%), followed by liver/spleen (82%), bone marrow (68%), and lymph nodes (51%). The combination did not generate unexpected toxicities. Cytomegalovirus (CMV) reactivations occurred in 6 patients (15%) and responded well to anti-CMV therapy. High titers of anti-idiotype antibodies after sc alemtuzumab were demonstrated in 1 patient, but remained without clinical sequelae.

CONCLUSIONS:

The combination of civ/sc alemtuzumab plus rituximab has activity in some patients with recurrent/refractory CLL and maximum response is achieved after 1 cycle (4 weeks) in 73% of patients. Further exploration in other settings of CLL together with accompanying pharmacokinetic studies is recommended.

BACKGROUND:

The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment.

METHODS:

In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405.

FINDINGS:

202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39-0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38-0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia.

INTERPRETATION:

For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity.

FUNDING:

Genzyme (Sanofi) and Bayer Schering Pharma.

Although retreatment with alemtuzumab in relapsing B-cell chronic lymphocytic leukemia (CLL) may be beneficial, there has thus far been no thorough analysis available on this topic. Data were collected from 30 chemotherapy-pretreated patients with progressive CLL who had received alemtuzumab twice in consecutive, distinct therapy lines. The median dose of alemtuzumab retreatment was 402 mg (range, 43-1,090 mg). Retreatment with alemtuzumab induced an overall response rate of 47%. From the start of alemtuzumab retreatment, median progression-free survival (PFS) and overall survival (OS) were 6.3 and 20.0 months, respectively. Response rates, PFS and OS upon alemtuzumab retreatment were correlated with response to initial alemtuzumab treatment, the time interval between the initial course of alemtuzumab and start of retreatment, and the hemoglobin concentration prior to retreatment. Reported toxicities from 24 cases included infections (50%), febrile reactions upon alemtuzumab administration (38%), exanthema (21%), and grade 4 neutropenia (13%) and thrombocytopenia (17%). We conclude that alemtuzumab retreatment represents an effective and tolerable therapeutic option for selected patients with CLL.

The treatment of patients with chronic lymphocytic leukemia (CLL) who fail purine analogues is sub optimal. CLL lymphocytes express two antigens, namely CD 20 and CD 52, for which monoclonal antibodies are readily available. Rituximab is a chimeric monoclonal antibody targeted against CD 20, which has some activity in refractory CLL, with primary effect on nodal disease. Alemtuzumab is a humanized anti-CD 52 antibody that is approved for the treatment of CLL in patients who fail alkylating agents and purine analogues. Alemtuzumab has better activity in the peripheral blood and the bone marrow compared to nodal disease. We investigated whether combining both antibodies is safe in refractory CLL. Both antibodies were given to a total of 12 patients divided into 3 cohorts with escalating alemtuzumab doses (3 mg, 10 mg, and 30 mg). The combination was proven to be safe, not toxic, feasible, and active. One patient attained PR by NCI criteria while all other patients had stable disease lasting a median of 101.5 days. All patients normalized their peripheral lymphocytosis within a median of 23.5 days. No treatment-related mortality was identified. No CMV reactivation occurred. Additional studies are needed to investigate the clinical significance of such a combination in this patient population, and whether this combination can be administered safely with systemic chemotherapy. These studies are currently underway.

Background: Chronic lymphocytic leukaemia (CLL) is an incurable and chronic disorder, with worsening prognosis for patients as their disease progresses. We compared the efficacy and safety of the combination of fludarabine and alemtuzumab with fludarabine 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 I-IV were randomly assigned in a 1:1 ratio according to a computer-generated allocation schedule to open-label combination treatment (fludarabine 30 mg/m 2 per day and alemtuzumab 30 mg per day on days 1-3) or monotherapy (fludarabine 25 mg/m 2 on days 1-5) 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 fludarabine monotherapy (n=167; median 23·7 months [95% CI 19·2-28·4] vs 16·5 months [12·5-21·2]; hazard ratio 0·61 [95% CI 0·47-0·80]; p=0·0003) and overall survival (median not reached vs 52·9 months [40·9-not reached]; 0·65 [0·45-0·94]; p=0·021) compared with fludarabine alone. All-cause adverse events occurred in 161 (98%) of 164 patients in the combination treatment group and 149 (90%) of 165 in the fludarabine alone group. Patients in the fludarabine 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 fludarabine and alemtuzumab is another treatment option for patients with previously treated CLL. Funding: Genzyme. © 2011 Elsevier Ltd.

RECORD STATUS:

This is a bibliographic record of a published health technology assessment. No evaluation of the quality of this assessment has been made for the HTA database.

CITATION:

All Wales Medicines Strategy Group (AWMSG). Alemtuzumab (MabCampath®) for the treatment of patients with B-cell chronic lymphocytic leukaemia for whom fludarabine combination chemotherapy is not appropriate Penarth: All Wales Therapeutics and Toxicology Centre (AWTTC), secretariat of the All Wales Medicines Strategy Group (AWMSG). AWMSG Secretariat Assessment Report Advice No. 2208. 2008

Alemtuzumab is active in chronic lymphocytic leukaemia (CLL) patients refractory to alkylators and fludarabine. The aim of this study was to determine the efficacy and safety of subcutaneous alemtuzumab at low dose (10 mg three times per week, for 18 weeks) to 49 patients with pre-treated CLL. The overall response rate was 53%, including 27% of complete responses; it was 42% in patients over 70 years, and 54% in the fludarabine-resistant patients. Forty-five percent of the patients with an unfavourable karyotype responded, including 60% of those with the 17p- aberration. After a median follow-up of 25 months, the median overall time to disease progression was 8 months (responders 12 months, non-responders 4 months). The median overall time to alternative treatment was 9 months (responders 17 months, non-responders 6 months) and median overall survival was 30 months. The treatment was well tolerated: grade IV neutropenia was observed in 17%, and cytomegalovirus (CMV) reactivation in 24% of the patients, with no CMV disease. We observed a total of 30 infections (50% during treatment and 50% during the 12-month follow-up), only one-third of which was severe. This study confirms that low-dose subcutaneous alemtuzumab is effective in poor prognosis CLL, and has a particularly favourable toxicity profile.

In 45, ≤ 60 years old patients with CLL and an adverse biologic profile, a front-line treatment with Fludarabine and Campath (Alemtuzumab(®)) was given. The overall response rate was 75.5%, the complete response rate (CR) 24.4% with the lowest CR rates, 16.7% and 8.3%, in 11q and 17p deleted cases. The 3-year progression-free survival (PFS) and overall survival were 42.5% and 79.9%, respectively. PFS was significantly influenced by CLL duration, beta2-microglobulin, and improved by post-remissional stem cell transplantation. Front-line fludarabine and alemtuzumab showed a manageable safety profile and evidence of a benefit in a small series of CLL patients with adverse biologic features.

INTRODUCTION:

A long-term prospective randomized trial evaluating alemtuzumab, a humanized anti-CD52 monoclonal antibody, in a predominantly non-Caucasian population has yet to be reported.

METHODS:

Ninety deceased donor (DD) first renal transplant recipients were randomized into three different antibody induction groups: group A, thymoglobulin (Thymo); group B, alemtuzumab; group C, daclizumab (Dac). In groups A and C, the target trough levels of tacrolimus were 8-10 ng/mL, mycophenolate mofetil (MMF) 1 g administered twice daily, and maintenance methylprednisolone. In group B, target tacrolimus trough levels were 4-7 ng/mL, 500 mg MMF administered twice-daily, without methylprednisolone. African-Americans and Hispanics comprised more than 50% in each group.

RESULTS:

A minimum follow-up of 27 months showed no overall group differences in patient or graft survival (p = 0.89 and 0.66), but a trend towards worse death-censored graft survival in group B (p = 0.05). Acute rejection rates were not significantly different: six (20%), seven (23%), and seven (23%) in groups A, B, and C, respectively. The incidence of chronic allograft nephropathy was higher in group B than in A and C (p = 0.008). The mean calculated creatinine clearance at 24 months was 81.1 +/- 5.5, 64.4 +/- 4.5, and 80.7 +/- 5.7 in groups A, B, and C, respectively (p = 0.01 for B vs. average of A and C).

CONCLUSION:

In this randomized 27-month minimum follow-up trial of predominantly non-Caucasian DD renal transplant recipients with alemtuzumab induction, lower maintenance tacrolimus, MMF, and steroid avoidance appear less effective than either Thymo or Dac with higher maintenance immunosuppression.

Although single-agent fludarabine is associated with high response rates (60%-80%) in patients with previously untreated B-cell chronic lymphocytic leukemia (B-CLL), this therapy is not curative and patients will relapse from persistence of minimal residual disease. Response rates to subsequent lines of therapy drop dramatically, as does survival. Antibodies including alemtuzumab and rituximab act in synergy with fludarabine and improve responses in salvage CLL therapy. In an effort to identify an effective chemoimmunotherapy regimen for patients with relapsed CLL, a phase II, multicenter, open-label, randomized trial was initiated. B-CLL patients who had failed prior therapy were randomized to treatment with either fludarabine combined with alemtuzumab or fludarabine combined with rituximab. Four patients randomized to the cohort received fludarabine 25 mg/m2 IV and alemtuzumab 30 mg SC, on Days 1-5. Eight patients received fludarabine 25 mg/m2 IV on Days 1-5, and rituximab 375 mg/m2 IV on Days 1 and 4 of the first cycle, followed by fludarabine 25 mg/m2 IV on Days 1-5, and rituximab 375 mg/m2 IV on Day 1 in subsequent cycles. Patients were assessed monthly for response while on therapy, and interim restaging occurred at cycle 4. Those who achieved a CR received no further therapy, whereas those who achieved a PR or SD received 2 additional cycles. 12 patients (7 male and 5 female) participated in this trial and the median age was 67 years. Nine patients had Rai III/IV (2 patients in alemtuzumab arm and 7 patients in rituximab arm). All patients had failed 1 course of therapy; 9 had failed treatment with a fludarabine-based regimen, and 3 had failed treatment with alkylating agents. In the alemtuzumab arm, 2 patients developed a CMV reactivation, one of whom developed CMV viremia, which was successfully treated with gancyclovir. Of the 8 patients in the rituximab plus fludarabine arm, 6 withdrew due to adverse events and 2 patients died while on study. In the alemtuzumab plus fludarabine arm, 1 person withdrew due to adverse events and 1 patient died after the trial was closed. Overall, 3 of 4 patients in the alemtuzumab arm responded (2 complete response [CR], 1 partial response [PR]), and 3 of 7 patients in the rituximab arm (1 CR, 2 PR). Recently published data has prompted a shift in CLL therapy. Increased numbers of patients are receiving chemoimmunotherapy combinations earlier in treatment. An increased use of FR and FCR in the first-line setting made further recruitment difficult. The potential of randomizing patients to the FR arm of the study prompted low accrual and the subsequent closing of the study.