QUESTIONS: With respect to outcomes such as survival, response rate, response duration, time to progression, and quality of life, is alemtuzumab a beneficial treatment option for patients with B-cell chronic lymphocytic leukemia (cll)?What toxicities are associated with the use of alemtuzumab?Which patients are more likely-or less likely-to benefit from treatment with alemtuzumab? PERSPECTIVES: Evidence was selected and reviewed by one member of the Hematology Disease Site Group (dsg) of Cancer Care Ontario's Program in Evidence-Based Care (pebc) and by methodologists. The practice guideline report was reviewed and approved by the Hema-tology dsg, which comprises hematologists, medical and radiation oncologists, and a patient representative. As part of an external review process, the report was disseminated to obtain feedback from practitioners in Ontario. OUTCOMES: Outcomes of interest were overall survival, quality of life, response rates and duration, and adverse event rates. METHODOLOGY: A systematic review of the medline, embase, HealthStar, cinahl, and Cochrane Library databases was conducted to search for primary articles and practice guidelines. The evidence informed the development of clinical practice recommendations. The evidence review and recommendations were appraised by a sample of practitioners from Ontario, Canada, and were modified in response to the feedback received. The systematic review and modified recommendations were approved by a review body within the pebc. RESULTS: The literature review found no published randomized controlled trials (rcts) that evaluated alem-tuzumab alone or in combination with other chemotherapeutic agents for the treatment of relapsed or refractory cll. One rct evaluated alemtuzumab administered to consolidate a complete or partial response to first-line fludarabine-containing chemotherapy. That study was stopped early because of excessive grades 3 and 4 infection-related toxicity in the alemtuzumab arm. Patients receiving alemtuzumab experienced significantly improved progression-free survival as compared with patients undergoing observation. Six single-arm studies evaluated disease response with administration of alemtuzumab as a single agent in the treatment of patients with relapsed or refractory cll post-fludarabine. The pooled overall response rate was 38% (complete response: 6%; partial response: 32%). Adverse events associated with the use of alemtuzumab were commonly reported and included serious infusion-related, hematologic, and infection-related toxicities. RECOMMENDATION: This evidence-based recommendation applies to adult patients with B-cell cll. Treatment with alemtuzumab is a reasonable option for patients with progressive and symptomatic cll that is refractory to both alkylator-based and fludarabine-based regimens. QUALIFYING STATEMENTS: The evidence supporting treatment with alemtuzumab comes principally from case series that evaluated disease response as the primary outcome measure. Patients should be informed that any possible beneficial effect of alemtuzumab on other outcome measures such as duration of response, quality of life, and overall survival are not supported in evidence and currently remain speculative. Treatment with alemtuzumab is associated with significant and potentially serious treatment-related toxicities. Patients must be carefully informed of the uncertain balance between potential risks of harm and the chance for benefit reported in studies. Given the current substantial uncertainty in this balance, patient preferences will likely play a large role in determining the appropriate treatment choice. Given the potential toxicities associated with alemtuzumab, and given the limited nature of the agent's testing in clinical trials in broad populations of patients with cll, the use of alemtuzumab in patients with important comorbidities may be associated with excessive risks.

RECORD STATUS: None CITATION: Canadian Coordinating Office for Health Technology Assessment. Alemtuzumab. Canadian Coordinating Office for Health Technology Assessment (CCOHTA). 2001

BACKGROUND: Chronic lymphocytic leukaemia (CLL) accounts for 25% of all leukaemias and is the most common lymphoid malignancy in Western countries. Standard treatment  includes mono- or poly-chemotherapies. Nowadays, monoclonal antibodies are added, especially alemtuzumab and rituximab. However, the impact of these agents remains unclear, as there are hints of an increased risk of severe infections. OBJECTIVES: To assess alemtuzumab compared with no further therapy, or with other anti-leukaemic therapy in patients with CLL. SEARCH METHODS: We searched CENTRAL and MEDLINE (from January 1985 to November 2011), and EMBASE (from 1990 to 2009) as well as conference proceedings for randomised controlled trials (RCTs). Two review authors (KB, NS) independently screened search results. SELECTION CRITERIA: We included RCTs comparing alemtuzumab with no further therapy or comparing alemtuzumab with anti-leukaemic therapy such as chemotherapy or monoclonal antibodies in patients with histologically-confirmed B-cell CLL. Both pretreated and chemotherapy-naive patients were included. DATA COLLECTION AND ANALYSIS: We used hazard ratios (HR) as an effect measure for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) for response rates, treatment-related mortality (TRM) and adverse events. Two review authors independently extracted data and assessed the quality of trials. MAIN RESULTS: Our search strategies led to 1542 potentially relevant references. Of these, we included five RCTs involving 845 patients. Overall, we judged the quality of the five trials as moderate. All trials were reported as randomised and open-label studies. However, two trials were published as abstracts only, therefore, we were unable to assess the potential risk of bias for these trials in detail. Because of the small number of studies in each analysis (two), the quantification of heterogeneity was not reliable. Two trials (N = 356) assessed the efficacy of alemtuzumab compared with no further therapy. One trial (N = 335), reported a statistically significant OS advantage for all patients receiving alemtuzumab (HR 0.65 (95% confidence interval (CI) 0.45 to 0.94; P = 0.021). However, no improvement was seen for the subgroup of patients in Rai stage I or II (HR 1.07; 95% CI 0.62 to 1.84; P = 0.82). In both trials, the complete response rate (CRR) (RR 2.61; 95% CI 1.26 to 5.42; P = 0.01) and PFS (HR 0.58; 95% CI 0.44 to 0.76; P < 0.0001) were statistically significantly increased under therapy with alemtuzumab. The potential heterogeneity seen in the forest plot could be due to the different study designs: One trial evaluated alemtuzumab additional to fludarabine as relapse therapy; the other trial examined alemtuzumab compared with no further therapy for consolidation after first remission.There was no statistically significant difference for TRM between both arms (RR 0.57; 95% CI 0.17 to 1.90; P = 0.36). A statistically significant higher rate of CMV reactivation (RR 10.52; 95% CI 1.42 to 77.68; P = 0.02) and infections (RR 1.32; 95% CI 1.01 to 1.74; P = 0.04) occurred in patients receiving alemtuzumab. Seven severe infections (64%) in the alemtuzumab arm in the GCLLSG CLL4B study led to premature closure. Two trials (N = 177), evaluated alemtuzumab versus rituximab. Neither study reported OS or PFS. We could not detect a statistically significant difference for CRR (RR 0.85; 95% CI 0.67 to 1.08; P = 0.18) or TRM (RR 3.20; 95% CI 0.66 to 15.50; P = 0.15) between both arms. However, the CLL2007FMP trial was stopped early due to an increase in mortality in the alemtuzumab arm. More serious adverse events occurred in this arm (43% versus 22% (rituximab), P = 0.006). One trial (N = 297), assessed the efficacy of alemtuzumab compared with chemotherapy (chlorambucil). For this trial, no HR is reported for OS. Median survival has not yet been reached, 84% of patients were alive in each arm at the data cut-off or at the last follow-up date (24.6 months). The TRM between arms shows no statistical significant difference (0.6% versus 2.0%; P = 0.34). Alemtuzumab statistically significantly improves PFS (HR 0.58; 95% CI 0.43 to 0.77; P = 0.0001), time to next treatment (23.3 compared with 14.7 months; P = 0.0001), ORR (83.2% versus 55.4%; P < 0.0001), CRR (24.2% versus 2.0%; P < 0.0001), and minimal residual disease rate (7.4% versus 0%; P = 0.0008) compared with chlorambucil. Statistically, significantly more asymptomatic (51.7% versus 7.4%) and symptomatic cytomegalovirus (CMV) infections (15.4% versus 0%) occurred in the patients treated with alemtuzumab. AUTHORS' CONCLUSIONS: In summary, the currently available evidence suggests an OS, CRR and PFS benefit for alemtuzumab compared with no further therapy, but an increased risk for infections in general, CMV infections and CMV reactivations. The role of alemtuzumab versus rituximab still remains unclear, further trials with longer follow-up and overall survival as primary endpoint are needed to evaluate the effects of both agents compared with each other. Alemtuzumab compared with chlorambucil seems to be favourable in terms of PFS, but a longer follow-up period and trials with overall survival as primary endpoint are needed to determine whether this effect will translate into a survival advantage.

Alemtuzumab (Campath-1H) is a powerful antilymphocyte antibody that produces profound and long-lasting lymphopenia. It is being used with increasing frequency for induction in organ transplantation, with the aim of allowing steroid-free and/or calcineurin-free/sparing maintenance immunosuppressive protocols. Despite a considerable experience with this agent, mostly in kidney transplantation, there are only two relatively small randomized controlled trials available, and therefore the level of evidence for its role in transplantation is limited. Nevertheless, it does appear that the incidence of acute rejection is low after induction with alemtuzumab, perhaps if used with a calcineurin inhibitor, and that steroid-free and calcineurin-sparing protocols are possible. Although there is a profound and long-lasting T cell lymphopenia after administration of alemtuzumab, there is no apparent increase in infection, posttransplantation lymphoproliferative disease, or other side effects, other than perhaps autoimmune disease. Whether alemtuzumab is more effective than Thymoglobulin or anti-interleukin 2 receptor antibodies cannot be answered at this time. However from a cost aspect, the use of alemtuzumab for induction compares more than favorably with other lymphocyte-depleting agents. Alemtuzumab is an attractive agent for induction in organ transplantation, but there is a need for more and larger randomized trials with long-term follow-up before its true role can be established, particularly with respect to safety.

OBJECTIVE: To review available evidence about the safety and efficacy of alemtuzumab for induction of immunosuppression in heart transplant recipients. DATA SOURCES: Searches of MEDLINE, EMBASE, and Cochrane databases were conducted. Key search terms included alemtuzumab, Campath-1H, CD52, lymphocyte, cytolytic, induction, immunosuppression, rejection, and cardiac transplantation. Additional pertinent data were identified through a search of abstracts from major transplant meetings. STUDY SELECTION AND DATA EXTRACTION: All English-language articles and abstracts identified from the data sources were evaluated. All primary data were eligible for inclusion if they evaluated the safety or efficacy of alemtuzumab for induction of immunosuppression in heart transplant patients. One retrospective cohort, 1 case series, 1 case-control series, and 1 open-label trial were identified and included for review. DATA SYNTHESIS: Acute cellular rejection occurs in 40% to 70% of heart transplant recipients within the first 6 months after transplant and is associated with significant morbidity and mortality. Depleting and nondepleting antibodies have displayed positive outcomes in inducing immunosuppression; however, the ideal induction strategy that balances efficacy and toxicity remains elusive. Alemtuzumab, a cytolytic anti-CD52 antibody, has been used to induce immunosuppression in kidney, pancreas, liver, intestine, and lung transplant recipients, and its use in heart transplant has been investigated. Studies of use of alemtuzumab to induce immunosuppression in heart transplant patients have shown low rates of rejection; however, it has not been directly compared with other immunosuppression-inducing agents and safety data are limited. CONCLUSIONS: Although alemtuzumab may be a practical option for inducing immunosuppression, data are insufficient to recommend its routine use in deference to more established agents. Large, randomized clinical trials with extended durations of follow-up must be conducted to characterize its efficacy and safety further.

RECORD STATUS: None CITATION: Hadj Tahar A. Alemtuzumab for B-cell chronic lymphocytic leukemia. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA) 2005: 4

RECORD STATUS: None CITATION: Fajemisin B. Alemtuzumab for chronic lymphocytic leukaemias. London: Bazian Ltd (Editors), Wessex Institute for Health Research and Development, University of Southampton 2003: 10

OBJECTIVE: To compare the efficacy and safety of alemtuzumab versus traditional antibodies for induction therapy in renal transplantation. METHODS: Literature searches for all randomized controlled trials comparing alemtuzumab with traditional antibodies for post renal transplant induction therapy were performed using MEDLINE, EMBASE and the Cochrane Library. Quality assessment was performed in each trial. Meta-analyses were performed to demonstrate the pooled effects of relative risk (RR) with 95% confidence intervals (CI). RESULTS: A total of 808 participants from six randomized controlled trials (RCTs) were included. Alemtuzumab was associated with lower incidence of biopsy-proven acute rejection over traditional antibodies (RR 0.63, CI 0.45-0.87, p=0.005). This difference remained when only studies comparing alemtuzumab with rabbit antithymocyte globulin were included (RR 0.32, CI 0.11-0.91, p=0.03), but lost significance when only patients at high-risk were included (RR 0.86, CI 0.48-1.55, p=0.62). No significant differences were detected between alemtuzumab and traditional antibodies in terms of delayed graft function, patient death, graft loss, and safety profile. CONCLUSIONS: Alemtuzumab induction is superior to traditional antibodies in preventing AR in renal transplantation, but this benefit may not extend to recipients at high immunologic risk. The lower rejection rates do not translate into a uniform increase in graft or patient survival.

BACKGROUND: Alemtuzumab (MabCampath or Campath; Genzyme, Cambridge, MA) is a CD52-specific monoclonal antibody that causes profound and sustained lymphocyte depletion. Its use as an induction therapy in organ transplantation is increasing. Since our last systematic review in 2006, where we identified the need for good-quality randomized controlled trials (RCTs), several RCTs have been published that examine its efficacy and safety in kidney transplantation. The aim of this study was to evaluate the current evidence for alemtuzumab induction therapy in kidney transplantation. METHODS: We performed a systematic literature search using Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Transplant Library from the Centre for Evidence in Transplantation, and International Clinical Trials Registry Platform. Inclusion criteria specified all RCTs in which kidney transplant recipients receiving induction with alemtuzumab were compared with those receiving another induction agent or no induction. Studies were assessed for methodological quality. The primary outcome was the incidence of biopsy-proven acute rejection (BPAR) (Banff grade ≥1), and secondary outcomes included graft loss, renal function, delayed graft function (DGF), patient death, and the incidence of infection, autoimmunity, malignancy, and new-onset diabetes mellitus after transplantation. RESULTS: Ten RCTs, with a total of 1223 patients, were included. Studies were grouped according to induction regimens. Alemtuzumab induction has a lower risk of BPAR compared with induction with the interleukin-2 receptor antibodies (IL-2RAs): basiliximab (Simulect; Novartis, Basel, Switzerland) and daclizumab (Zenapax; Roche, Basel, Switzerland) combined (relative risk, 0.54; 95% confidence interval, 0.37-0.79; P<0.01). No significant difference was observed in the risk of BPAR when alemtuzumab induction was compared with rabbit antithymocyte globulin (rATG) (Thymoglobulin [Genzyme] or ATG-Fresenius S [Fresenius, Munich, Germany]) (relative risk, 0.79; 95% confidence interval, 0.52-1.21; P=0.28). There was no difference in graft loss, DGF, patient death, and new-onset diabetes mellitus after transplantation when alemtuzumab was compared with IL-2RAs or rATG induction. The effect of alemtuzumab induction on renal function and the incidence of infection, malignancy, and autoimmunity were limited by the data available. There were two trials comparing alemtuzumab with no induction, but neither trial reported a significant reduction in BPAR at 12 months. CONCLUSIONS: Alemtuzumab induction reduces the risk of BPAR compared with IL-2RAs but not rATG. Because the incidence of other efficacy outcomes (graft loss, DGF, and patient death) was similar, if it is felt that an induction agent is necessary, then our analysis suggests that it is more acceptable to base the choice of induction agent on safety outcomes and/or costs.

BACKGROUND: Alemtuzumab, a humanized CD52 monoclonal antibody, with its profound lymphocyte depletion property, was expected to be a promising induction therapy agent for kidney transplantation (KTx). However, currently no consensus is available about its efficacy and safety. The aim of this meta-analysis was to make a profound review and an objective appraisal of this issue. METHODS: Relevant papers were searched, essentially in the PubMed database and the Cochrane library. After a thorough review, randomized controlled trials (RCTs) comparing the outcome of KTx using alemtuzumab induction therapy (test group) with a control group were collected according to the inclusion criteria. Data of general characteristic of studies and major outcomes of Ktx were extracted and meta-analyses were performed with RevMan 4.2 software. The odds ratio (OR) with a 95% confidence intervals (CI) was the principle measurement of effect. RESULTS: Five RCTs were included. The chi square test showed no significant between-study heterogeneity, thus fixed effect model was employed. Sub-group analysis with studies including alemtuzumab induction followed by a tacrolimus-based immunosuppressive regimen showed that the acute rejection rate (ARR) was lower relative to the control (OR = 0.59, 95% CI 0.34 - 1.01, P = 0.05). However, meta-analysis with all included studies revealed that neither ARR nor patient/graft survival rates differ significantly between the test and the control group, but the cytomegalovirus (CMV) infection rate was higher in the test group (OR 2.50, 95% CI 1.22 - 5.12, P = 0.01). A great number of the test group recipients safely remained on a regimen that was steroid-free and with a reduced dose of conventional immunosuppressive drugs. CONCLUSIONS: Alemtuzumab induction therapy for KTx was an effective and safe protocol in the tested follow-up period. Steroid avoidance and a dose reduction of conventional immunosuppressive drugs after alemtuzumab induction therapy may have clinical importance. However, high quality RCTs with larger population and longer follow-up are needed for a more accurate and objective appraisal of this novel protocol.