Current treatment approaches in CLL aim at achieving the best clinical response without detectable minimal residual disease (MRD) in order to prolong the duration of response and potentially overall survival. Such a goal could be achieved by combining chemotherapy and monoclonal antibodies. This phase II trial was designed to evaluate the safety and the efficacy of alemtuzumab given as consolidation therapy after 3 courses of oral fludarabine and cyclophosphamide (FC)(F 40 mg/m2 and C 250 mg/m2 D1 to D3 every 4 weeks) in patients (pts) aged 65 to 70 years with previously untreated Binet stage B or C CLL. Pts who had achieved either complete response (CR) or partial response (PR) after FC were eligible for consolidation with alemtuzumab. Alemtuzumab was administered subcutaneously (SC) at the dose of 10 mg thrice a week for 8 consecutive weeks. Cytomegalovirus (CMV) antigenemia was monitored every week and alemtuzumab should be discontinued in pts with more than 3 positive nuclei. Such stringent stopping rules for CMV reactivation, as well as the limitation of FC regimen to 3 courses and of the duration of alemtuzumab treatment to 8 weeks, were adopted in this trial targeting elderly patients in first-line treatment because of the severe infectious toxicities reported by others with similar strategies. MRD was evaluated by 6-color flow cytometry before, during and after alemtuzumab treatment and all samples were centralized in 1 center (Avicenne hospital, Bobigny). From June 2004 to January 2008, 55 patients with advanced (stage B or C) fully annotated CLL have been recruited in 14 French centers. Response to induction was evaluable in 51 of them (suicide before FC 1 pt and missing data 3 (Table presented) pts). CR was achieved in 18 pts (34.6%) and PR in 22 pts (42.3%) for an overall response rate (ORR) of 77% after 3 courses of FC. FC regimen was discontinued in 6 pts (progression 1 pt, renal carcinoma 1 pt, neutropenia 2 pts, pure red cell aplasia (PRCA) 1 pt, myocardial infarction 1 pt) and stable disease was observed in 5 pts. All the responding pts except 2 (breast cancer in 1CRpt and lung carcinoma in 1 PR pt) proceeded to alemtuzumab consolidation after a planned 2-month period of rest (median 63 days, range 33 to 152). Alemtuzumab treatment was fully completed in 29/38 pts (76%), while it was stopped prematurely (mainly between the 6th and 8th weeks) in 9 pts (24%). CMV reactivation occurred in 8 pts (21%) but it was associated with systemic symptoms in only 1 case (pneumonia). Grade 3-4 neutropenia was observed in 9 pts at some point during alemtuzumab treatment. Eleven of the 21 PR pts (52%) converted from PR to CR after lemtuzumab consolidation while 2 patients went from CR to PR. Overall, 26 pts were in CR after the whole treatment strategy (FC followed by alemtuzumab), accounting for 51% of the entire cohort. BloodMRDcould be assessed sequentially in two-thirds of pts. While all patients but 1(33/34 pts) were MRD positive after chemotherapy and before alemtuzumab treatment, only 5/22 pts (23%) had detectable MRD at the sensitivity level of 10-4 after the end of alemtuzumab consolidation, and 12 of the 25 assessed pts (48%) still had undetectable MRD at 6 months after the end of treatment. With a median follow up of 34 months (range 2 to 58), only 6 out of the 38 pts (16%) who received FC followed by alemtuzumab consolidation had CLL disease progression. Five patients have died (CLL 1 pt, solid tumors 3 pts, stroke 1 pt). No serious delayed infectious complication was observed and 2 patients developed auto-immune cytopenia. Because of the low number of events (disease progression) observed so far, no correlation between the duration of response and the MRD status could be made until now. In conclusion, the administration of only 3 courses of FC yielded a rather high response rate in previously untreated elderly CLL patients and a short (8 weeks) alemtuzumab consolidation course could be thereafter administered safely, leading to a high rate of PR to CR switches, a high proportion of patients without detectable blood MRD after the end of treatment, and durable responses.

INTERVENTION:

Trade Name: MabCampath Product Name: alemtuzumab Pharmaceutical Form: Concentrate for solution for injection

CONDITION:

Primary therapy of patients with Alk‐negative T‐NHL in patients aged 61 ‐ 80 years ICD classification codes : ICD‐O 9702/3; 9717/3; 9716/3; 9708/3; 9705/3; 9714/3 ; MedDRA version: 18.1 Level: LLT Classification code 10025632 Term: Malignant lymphoma System Organ Class: 100000004864 ; MedDRA version: 18.1 Level: LLT Classification code 10002464 Term: Angiomimmunoblastic (AILD, LgX (Kiel Classification) System Organ Class: 100000004864 Therapeutic area: Diseases [C] ‐ Cancer [C04]

PRIMARY OUTCOME:

Main Objective: Improvement of the efficacy of chemotherapy with CHOP‐14 by the additional use of the CD52 monoclonal antibody alemtuzumab measured on the basis of Event‐free Survival Primary end point(s): event‐free survival (EFS) at 3 years Secondary Objective: Comparison of +/‐ alemtuzumab addition concerning further endpoints of efficacy, short term and long term side effects, adherence to protocol and withdrawal from therapy Timepoint(s) of evaluation of this end point: Interim analysis in 2012; Final Analysis in 2016

SECONDARY OUTCOME:

Secondary end point(s): CR and OR rate, rate of primary progression, relapse rate, treatment‐related deaths, overall survival, progression free survival, tumour control, disease‐free survival, safety, protocol adherence, immune reconstitution after therapy Timepoint(s) of evaluation of this end point: Interim analysis in 2012; Final Analysis in 2016

INCLUSION CRITERIA:

1. Age: 61 ‐ 80 years 2. Risk group: All risk groups, including stage I with bulk (= 7.5 cm) and stages II to IV, exept stage I with no further IPI risk factor (LDH, ECOG, stage, E>1) beside the age over 60 3. Histology: Diagnosis of aggressive non‐Hodgkin's lymphoma, confirmed by an excisional biopsy of a lymph node or by a sufficiently extensive biopsy of an extranodal involvement if there is no lymph node involvement. It will be possible to treat all peripheral T‐lineage lymphomas with the exception of ALK‐positive anaplastic large cell lymphoma and primary cutaneous T‐cell lymphomas (Mycosis fungoides, Sezary syndrome and primary cutaneous CD30‐positive lymphoproliferations, and transformed primary cutaneous T‐cell lymphomas). These lymphomas comprise: T cell ‐

NHL:

peripheral T‐cell lymphoma PTCL‐NOS Lennert's lymphoma T‐zone lymphoma T‐cell lymphoma of the AILD type anaplastic large cell lymphoma, ALK negati

When multiple treatments are available, network meta-analysis can synthesize evidence and rank relative effectiveness. We applied this approach to current treatments for previously untreated chronic lymphocytic leukaemia. Data search was conducted in PubMed and websites of regulatory agencies (year 2000 through present time). Our analysis included randomized controlled trials assessing treatments for previously untreated chronic lymphocytic leukaemia. The endpoint of the analysis was the rate of progression-free survival at 3 years. At least two reviewers abstracted study data and outcomes. Agents examined for their relative effectiveness included four monotherapies (chlorambucil, fludarabine, bendamustine, alemtuzumab) and four combination treatments (cyclophosphamide + fludarabine, cyclophosphamide + cladribine, cyclophosphamide + fludarabine + rituximab, cyclophosphamide + fludarabine + alemtuzumab). A Bayesian network meta-analysis was conducted to comparatively evaluate these treatments. Nine trials (3620 patients) were included in the analysis. Odds ratio (with 95 % credible intervals) was estimated for all direct and indirect comparisons. Combinations treatments were found to be significantly more effective than single-agent treatments. Ranking in effectiveness was as follows: (1) cyclophosphamide + fludarabine + rituximab, (2) alemtuzumab, (3) cyclophosphamide + fludarabine + alemtuzumab, (4) cyclophosphamide + fludarabine and (at same ranking) cyclophosphamide + cladribine, (6) fludarabine, (7) bendamustine and (8) chlorambucil. Bendamustine fared worse in our analysis than in its pivotal trial. Overall, the estimated rankings appeared to be robust according to probabilistic analysis. Numerous indirect comparisons were assessed in the absence of RCTs. In conclusion, we generated an updated synthesis of the effectiveness of these treatments and we ranked them according to a Bayesian probabilistic model. In our probabilistic analysis, cyclophosphamide + fludarabine + rituximab ranked first in the base case while the worst-case scenario of this analysis placed this treatment at a remarkable second place.

The increase of fludarabine-resistant chronic lymphocytic leukemia (CLL) presents a new treatment challenge. The aim of this review is to evaluate the efficacy and safety of rituximab for patients with fludarabine-refractory CLL. Medline, Embase, The Cochrane Library and selected conference proceedings were searched. Seventeen relevant publications reporting stratified data were identified. Treatments included: rituximab in combination with etanercept, alemtuzumab, bendamustine or methylprednisolone alone, with fludarabine and cyclophosphamide (FCR), with oxaliplatin as well as fludarabine and cytarabine, with cyclophosphamide as well as fludarabine and alemtuzumab (CFAR), and with cytarabine, cisplatinum and dexamethasone (DHAP). One study evaluated rituximab with granulocyte-macrophage colony-stimulating factor in combination with alternating cyclophosphamide, liposomal daunorubicin, vincristine, dexamethasone and methotrexate plus Ara-C. One study evaluated rituximab as monotherapy. Of the nine studies considering overall response, eight reported rates above 50% (four reported rates above 75%). Median overall survival was 37 months for FCR, 11 months for CFAR, 20 months for rituximab with methylprednisolone, 30 months for rituximab with alemtuzumab and 44 months for an FCR/CFAR mixed treatment. The identified studies indicate that regimens containing rituximab may be highly efficacious in the fludarabine-refractory CLL setting. Nevertheless, further research is needed to facilitate the choice of treatment for the clinician.

Background: Prolonging kidney transplant survival is an important clinical priority. Induction immunosuppression with antibody therapy is recommended at transplantation and non-depleting interleukin-2 receptor monoclonal antibodies (IL2Ra) are considered first line. It is suggested that recipients at high risk of rejection should receive lymphocyte-depleting antibodies but the relative benefits and harms of the available agents are uncertain. Objectives: We aimed to: evaluate the relative and absolute effects of different antibody preparations (except IL2Ra) when used as induction therapy in kidney transplant recipients; determine how the benefits and adverse events vary for each antibody preparation; determine how the benefits and harms vary for different formulations of antibody preparation; and determine whether the benefits and harms vary in specific subgroups of recipients (e.g. children and sensitised recipients). Search methods: We searched the Cochrane Kidney and Transplant's Specialised Register to 29 August 2016 through contact with the Information Specialist using search terms relevant to this review. Selection criteria: Randomised controlled trials (RCTs) comparing monoclonal or polyclonal antibodies with placebo, no treatment, or other antibody therapy in adults and children who had received a kidney transplant. Data collection and analysis: Two authors independently extracted data and assessed risk of bias. Dichotomous outcomes are reported as relative risk (RR) and continuous outcomes as mean difference (MD) together with their 95% confidence intervals (CI). Main results: We included 99 studies (269 records; 8956 participants; 33 with contemporary agents). Methodology was incompletely reported in most studies leading to lower confidence in the treatment estimates. Antithymocyte globulin (ATG) prevented acute graft rejection (17 studies: RR 0.63, 95% CI 0.51 to 0.78). The benefits of ATG on graft rejection were similar when used with (12 studies: RR 0.61, 0.49 to 0.76) or without (5 studies: RR 0.65, 0.43 to 0.98) calcineurin inhibitor (CNI) treatment. ATG (with CNI therapy) had uncertain effects on death (3 to 6 months, 3 studies: RR 0.41, 0.13 to 1.22; 1 to 2 years, 5 studies: RR 0.75, 0.27 to 2.06; 5 years, 2 studies: RR 0.94, 0.11 to 7.81) and graft loss (3 to 6 months, 4 studies: RR 0.60, 0.34 to 1.05; 1 to 2 years, 3 studies: RR 0.65, 0.36 to 1.19). The effect of ATG on death-censored graft loss was uncertain at 1 to 2 years and 5 years. In non-CNI studies, ATG had uncertain effects on death but reduced death-censored graft loss (6 studies: RR 0.55, 0.38 to 0.78). When CNI and older non-CNI studies were combined, a benefit was seen with ATG at 1 to 2 years for both all-cause graft loss (7 studies: RR 0.71, 0.53 to 0.95) and death-censored graft loss (8 studies: RR 0.55, 0.39 to 0.77) but not sustained longer term. ATG increased cytomegalovirus (CMV) infection (6 studies: RR 1.55, 1.24 to 1.95), leucopenia (4 studies: RR 3.86, 2.79 to 5.34) and thrombocytopenia (4 studies: RR 2.41, 1.61 to 3.61) but had uncertain effects on delayed graft function, malignancy, post-transplant lymphoproliferative disorder (PTLD), and new onset diabetes after transplantation (NODAT). Alemtuzumab was compared to ATG in six studies (446 patients) with early steroid withdrawal (ESW) or steroid minimisation. Alemtuzumab plus steroid minimisation reduced acute rejection compared to ATG at one year (4 studies: RR 0.57, 0.35 to 0.93). In the two studies with ESW only in the alemtuzumab arm, the effect of alemtuzumab on acute rejection at 1 year was uncertain compared to ATG (RR 1.27, 0.50 to 3.19). Alemtuzumab had uncertain effects on death (1 year, 2 studies: RR 0.39, 0.06 to 2.42; 2 to 3 years, 3 studies: RR 0.67, 95% CI 0.15 to 2.95), graft loss (1 year, 2 studies: RR 0.39, 0.13 to 1.30; 2 to 3 years, 3 studies: RR 0.98, 95% CI 0.47 to 2.06), and death-censored graft loss (1 year, 2 studies: RR 0.38, 0.08 to 1.81; 2 to 3 years, 3 studies: RR 2.45, 95% CI 0.67 to 8.97) compared to ATG. Creatinine clearance was lower with alemtuzumab plus ESW at 6 months (2 studies: MD -13.35 mL/min, -23.91 to -2.80) and 2 years (2 studies: MD -12.86 mL/min, -23.73 to -2.00) compared to ATG plus triple maintenance. Across all 6 studies, the effect of alemtuzumab versus ATG was uncertain on all-cause infection, CMV infection, BK virus infection, malignancy, and PTLD. The effect of alemtuzumab with steroid minimisation on NODAT was uncertain, compared to ATG with steroid maintenance. Alemtuzumab plus ESW compared with triple maintenance without induction therapy had uncertain effects on death and all-cause graft loss at 1 year, acute rejection at 6 months and 1 year. CMV infection was increased (2 studies: RR 2.28, 1.18 to 4.40). Treatment effects were uncertain for NODAT, thrombocytopenia, and malignancy or PTLD. Rituximab had uncertain effects on death, graft loss, acute rejection and all other adverse outcomes compared to placebo. Authors' conclusions: ATG reduces acute rejection but has uncertain effects on death, graft survival, malignancy and NODAT, and increases CMV infection, thrombocytopenia and leucopenia. Given a 45% acute rejection risk without ATG induction, seven patients would need treatment to prevent one having rejection, while incurring an additional patient experiencing CMV disease for every 12 treated. Excluding non-CNI studies, the risk of rejection was 37% without induction with six patients needing treatment to prevent one having rejection. In the context of steroid minimisation, alemtuzumab prevents acute rejection at 1 year compared to ATG. Eleven patients would require treatment with alemtuzumab to prevent 1 having rejection, assuming a 21% rejection risk with ATG. Triple maintenance without induction therapy compared to alemtuzumab combined with ESW had similar rates of acute rejection but adverse effects including NODAT were poorly documented. Alemtuzumab plus steroid withdrawal would cause one additional patient experiencing CMV disease for every six patients treated compared to no induction and triple maintenance, in the absence of any clinical benefit. Overall, ATG and alemtuzumab decrease acute rejection at a cost of increased CMV disease while patient-centred outcomes (reduced death or lower toxicity) do not appear to be improved. © 2017 The Cochrane Collaboration.

OBJECTIVE:

To present the current clinical evidence on ofatumumab for use in refractory chronic lymphocytic leukemia (CLL).

DATA SOURCES:

A literature search was performed using MEDLINE and PubMed (both 1966-May 2011), as well as the American Society of Hematology abstracts (2000-May 2011), using the primary search terms ofatumumab and HuMax-CD20.

STUDY SELECTION AND DATA EXTRACTION:

Clinical studies and abstracts available in the English language, describing the pharmacology, pharmacokinetics, clinical activity, and safety of ofatumumab in CLL were included in this review.

DATA SYNTHESIS:

Ofatumumab is a human immunoglobulin monoclonal antibody that binds to B-lymphocytes expressing CD-20 cell surface antigens. Ofatumumab was granted accelerated approval by the Food and Drug Administration in October 2009 for the treatment of CLL refractory to fludarabine and alemtuzumab. A Phase 1/2 trial has established the safety and tolerability of single-agent ofatumumab at an initial dose of 300 mg intravenously on week 1, followed by 2000 mg once weekly for 7 doses (weeks 2-8), followed by 2000 mg once every 4 weeks for 4 doses (weeks 9-12), for a total of 12 doses. The final analysis of a pivotal international multicenter trial has shown promising activity in patients with CLL refractory to fludarabine and alemtuzumab, demonstrating overall response rates of 44-51%, with prolonged progression-free and overall survival. Ofatumumab activity has also been shown in a variety of other malignant and nonmalignant conditions, including non-Hodgkin lymphoma, rheumatoid arthritis, and multiple sclerosis. The most common adverse effect is grade 1 and 2 infusion reactions. Other adverse effects include infection, neutropenia, anemia, rash, fever, and diarrhea.

CONCLUSIONS:

Clinical evidence suggests that ofatumumab is an effective agent in patients with CLL refractory to fludarabine and alemtuzumab. Data are awaited comparing ofatumumab to other salvage regimens. Until results of head-to-head trials are conducted comparing ofatumumab to existing regimens, it cannot be said whether ofatumumab is more efficacious or tolerable than currently available therapies.