Background
Chronic lymphocytic leukaemia (CLL) accounts for 25% of all leukaemias and is the most common lymphoid malignancy in western countries. Standard treatments include mono‐ or ...polychemotherapies, usually combined with monoclonal antibodies such as rituximab or alemtuzumab. However, the impact of these agents remains unclear, as there are hints for increased risk of severe infections.
Objectives
The objectives of this review are to provide an evidence‐based answer regarding the clinical benefits and harms of monoclonal anti‐CD20 antibodies (such as rituximab, ofatumumab, GA101) compared to no further therapy or to other anti‐leukaemic therapies in patients with CLL, irrespective of disease status.
Search methods
We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 12, 2011), MEDLINE (from January 1990 to 4 January 2012), and EMBASE (from 1990 to 20 March 2009) as well as conference proceedings (American Society of Hematology, American Society of Clinical Oncology, European Hematology Association and European Society of Medical Oncology) for randomised controlled trials (RCTs).
Selection criteria
We included RCTs examining monoclonal anti‐CD20 antibodies compared to no further therapy or to anti‐leukaemic therapy such as chemotherapy or monoclonal antibodies in patients with newly diagnosed or relapsed CLL.
Data collection and analysis
We used hazard ratios (HR) as effect measures for overall survival (OS), progression‐free survival (PFS) and time to next treatment, and risk ratios (RR) for response rates, treatment‐related mortality (TRM) and adverse events (AEs). Two review authors independently extracted data and assessed quality of trials.
Main results
We screened a total of 1150 records. Seven RCTs involving 1763 patients were identified, but only five could be included in the two separate meta‐analyses we performed. We judged the overall the quality of these trials as moderate to high. All trials were randomised and open‐label studies. However, two trials were published as s only, therefore we were unable to assess the potential risk of bias for these trials in detail.
Three RCTs (N = 1421) assessed the efficacy of monoclonal anti‐CD20 antibodies (i.e. rituximab) plus chemotherapy compared to chemotherapy alone. The meta‐analyses showed a statistically significant OS (HR 0.78, 95% confidence interval (CI) 0.62 to 0.98, P = 0.03, the number needed to treat for an additional beneficial effect (NNTB) was 12) and PFS (HR 0.64, 95% CI 0.55 to 0.74, P < 0.00001) advantage for patients receiving rituximab. In the rituximab‐arm occurred more AEs, World Health Organization (WHO) grade 3 or 4 (3 trials, N = 1398, RR 1.15, 95% CI 1.08 to 1.23, P < 0.0001; the number needed to harm for an additional harmful outcome (NNTH) was 9), but that did not lead to a statistically significant difference regarding TRM (3 trials, N = 1415, RR 1.19, 95% CI 0.70 to 2.01, P = 0.52).
Two trials (N = 177) evaluated rituximab versus alemtuzumab. Neither study reported OS or PFS. There was no statistically significant difference between arms regarding complete response rate (CRR) (RR 1.21, 95% CI 0.94 to 1.58, P = 0.14) or TRM (RR 0.31, 95% CI 0.06 to 1.51, P = 0.15). However, the CLL2007FMP trial was stopped early owing to an increase in mortality in the alemtuzumab arm. More serious AEs occurred in this arm (43% with alemtuzumab versus 22% with rituximab; P = 0.006).
Two trials assessed different dosages or time schedules of monoclonal anti‐CD20 antibodies. One trial (N = 104) evaluated two different rituximab schedules (concurrent arm: fludarabine plus rituximab (Flu‐R) plus rituximab consolidation versus sequential arm: fludarabine alone plus rituximab consolidation). The comparison of the concurrent versus sequential regimen of rituximab showed a statistically significant difference of the CRR with 33% in the concurrent‐arm and 15% in the sequential‐arm (P = 0.04), that did not lead to statistically significant differences regarding OS (HR 1.14, 95% CI 0.20 to 6.65, P = 0.30) or PFS (HR 0.96, 95% CI 0.43 to 2.15, P = 0.11). Furthermore results showed no differences in occurring AEs, except for neutropenia, which was more often observed in patients of the concurrent arm. The other trial (N = 61) investigated two different dosages (500 mg and 1000 mg) of ofatumumab in addition to FluC. The arm investigating ofatumumab did not assess OS and a median PFS had not been reached owing to the short median follow‐up of eight months. It showed no statistically significant differences between arms regarding CRR (32% in the FCO500 arm versus 50% in the FCO1000 arm; P = 0.10) or AEs (anaemia, neutropenia, thrombocytopenia).
Authors' conclusions
This meta‐analysis showed that patients receiving chemotherapy plus rituximab benefit in terms of OS as well as PFS compared to those with chemotherapy alone. Therefore, it supports the recommendation of rituximab in combination with FluC as an option for the first‐line treatment as well as for the people with relapsed or refractory CLL. The available evidence regarding the other assessed comparisons was not sufficient to deduct final conclusions.
Patients with transplantation-ineligible relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) fare poorly, with limited treatment options. The antibody-drug conjugate polatuzumab vedotin ...targets CD79b, a B-cell receptor component.
Safety and efficacy of polatuzumab vedotin with bendamustine and obinutuzumab (pola-BG) was evaluated in a single-arm cohort. Polatuzumab vedotin combined with bendamustine and rituximab (pola-BR) was compared with bendamustine and rituximab (BR) in a randomly assigned cohort of patients with transplantation-ineligible R/R DLBCL (primary end point: independent review committee IRC assessed complete response CR rate at the end of treatment). Duration of response, progression-free survival (PFS), and overall survival (OS) were analyzed using Kaplan-Meier and Cox regression methods.
Pola-BG and pola-BR had a tolerable safety profile. The phase Ib/II pola-BG cohort (n = 27) had a CR rate of 29.6% and a median OS of 10.8 months (median follow-up, 27.0 months). In the randomly assigned cohort (n = 80; 40 per arm), pola-BR patients had a significantly higher IRC-assessed CR rate (40.0%
17.5%;
= .026) and longer IRC-assessed PFS (median, 9.5
3.7 months; hazard ratio HR, 0.36, 95% CI, 0.21 to 0.63;
< .001) and OS (median, 12.4
4.7 months; HR, 0.42; 95% CI, 0.24 to 0.75;
= .002; median follow-up, 22.3 months). Pola-BR patients had higher rates of grade 3-4 neutropenia (46.2%
33.3%), anemia (28.2%
17.9%), and thrombocytopenia (41%
23.1%), but similar grade 3-4 infections (23.1%
20.5%), versus the BR group. Peripheral neuropathy associated with polatuzumab vedotin (43.6% of patients) was grade 1-2 and resolved in most patients.
Polatuzumab vedotin combined with BR resulted in a significantly higher CR rate and reduced the risk of death by 58% compared with BR in patients with transplantation-ineligible R/R DLBCL.
Background & Aims Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn’s disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based ...on therapeutic drug monitoring increases rate of remission and whether continued concentration-based dosing is superior to clinically based dosing of infliximab for maintaining remission in patients with CD and UC. Methods We performed a 1-year randomized controlled trial at a tertiary referral center, including 263 adults (178 with CD and 85 with UC) with stable responses to maintenance infliximab therapy. Doses were escalated or reduced using an algorithm to reach a target trough concentration (TC) of 3–7 μg/mL in all patients (optimization phase). Patients were randomly assigned (1:1) to groups that received infliximab dosing based on their clinical features (n = 123) or continued dosing based on TCs (n = 128) (maintenance phase). The primary end point was clinical and biochemical remission at 1 year after the optimization phase. Results At screening, 115 of 263 patients had a TC of infliximab of 3–7 μg/mL (43.7%). Of 76 patients with TCs <3 μg/mL, 69 patients (91%) achieved TCs of 3–7 μg/mL after dose escalation. This resulted in a higher proportion of CD patients in remission than before dose escalation (88% vs 65%; P = .020) and a decrease in the median concentration of C-reactive protein, compared with before the dose increase (3.2 vs 4.3 mg/L; P < .001); these changes were not observed in patients with UC. Of 72 patients with TCs >7 μg/mL, 67 patients (93%) achieved TCs of 3–7 μg/mL after dose reduction. This resulted in a 28% reduction in drug cost from before dose reduction ( P < .001). Sixty-six percent of patients whose dosing was based on clinical features and 69% whose dosing was based on TC achieved remission, the primary end point ( P = .686). Disease relapsed in 21 patients who received clinically based dosing (17%) and 9 patients who received concentration-based dosing (7%) ( P = .018). Conclusions Targeting patients’ infliximab TCs to 3–7 μg/mL results in a more efficient use of the drug. After dose optimization, continued concentration-based dosing was not superior to clinically based dosing for achieving remission after 1 year, but was associated with fewer flares during the course of treatment. ClinicalTrialsRegister.eu number: 2011-002061-38.
Objective
The efficacy and safety of subcutaneous tocilizumab (TCZ‐SC) versus subcutaneous placebo (PBO‐SC) was evaluated in patients with rheumatoid arthritis who had an inadequate response to ...disease‐modifying antirheumatic drugs in the BREVACTA study.
Methods
Patients (n = 656) were randomized 2:1 to receive TCZ‐SC 162 mg every other week or PBO‐SC every other week for 24 weeks; 20% previously received anti–tumor necrosis factor treatment. Escape therapy with TCZ‐SC 162 mg weekly was offered from week 12 for inadequate response. The primary end point was the American College of Rheumatology 20% improvement (ACR20) response at week 24. The key secondary outcomes were radiographic progression and safety.
Results
TCZ‐SC was superior to PBO‐SC for ACR20 response at week 24 (60.9% versus 31.5%; P < 0.0001). All secondary end points showed TCZ‐SC to be superior to PBO‐SC, including ACR50 and ACR70 response (40% and 20% for TCZ‐SC, respectively, and 12% and 5% for PBO‐SC, respectively; P < 0.0001 for both) and Disease Activity Score in 28 joints (DAS28) remission (DAS28 <2.6; 32% versus 4% P < 0.0001). The mean change in modified Sharp/van der Heijde score was significantly lower in the TCZ‐SC group than the PBO‐SC group (0.62 versus 1.23; P = 0.0149). Adverse events (AEs) and serious AEs (SAEs) were comparable between the TCZ‐SC and PBO‐SC groups; 4.6% and 3.7% of patients had at least 1 SAE, respectively, and infection was the most common SAE in 2.1% and 1.8% of patients, respectively. More injection site reactions occurred with TCZ‐SC than PBO‐SC (7.1% versus 4.1%). No anaphylaxis or serious hypersensitivity reactions occurred. There were 3 deaths in the TCZ‐SC group and 0 in the PBO‐SC group.
Conclusion
TCZ‐SC every other week had significantly greater efficacy, including ACR end points and inhibition of joint damage, compared with PBO‐SC. TCZ‐SC was well tolerated and its safety profile was comparable with that of previous intravenous TCZ studies.
The role of co-medication with tumour necrosis factor inhibitors (TNFi) is well established in rheumatoid arthritis and ankylosing spondylitis. In psoriatic arthritis (PsA) there is little evidence ...available on this issue.
The analyses were based on data from the Norwegian longitudinal observational study on disease-modifying antirheumatic drugs (NOR-DMARD). Patients with PsA starting their first TNFi, either as monotherapy or with concomitant methotrexate (MTX), were selected. Baseline characteristics, responses after 3, 6 and 12 months, and drug survival were compared between those with and without MTX co-medication. A secondary analysis was performed on patients who had confirmed swollen joints at baseline. Cox regression was used to identify predictors of discontinuation.
We included 440 patients, 170 receiving TNFi as monotherapy and 270 receiving concomitant MTX. The groups had similar baseline characteristics, except for number of swollen joints, which was higher in the concomitant MTX group. Responses were similar in the two groups in both analyses. Drug survival analyses revealed a borderline significant difference in favour of patients receiving co-medication (p=0.07), and this was most prominent for patients receiving infliximab (IFX) (p=0.01). In the Cox regression analysis lack of concomitant MTX and current smoking were independent predictors of discontinuation of TNFi.
We found similar responses to TNFi in patients with and without concomitant MTX, but drug survival was superior in patients receiving co-medication. The effect of MTX on drug survival was most prominent in patients receiving IFX. Smoking at baseline and use of TNFi as monotherapy were identified as independent predictors of drug discontinuation.
Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based ...immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.
Reports on the regulation of neutrophil function by IL-6 are often conflicting. Therapeutic inhibition of IL-6 in RA is associated with occasional neutropenia, but the mechanisms underlying this ...observation are poorly understood. This study investigated interactions between IL-6, the anti-IL-6 receptor agent tocilizumab (TCZ) and neutrophils in vitro and in vivo.
Neutrophils were isolated from healthy controls and incubated in vitro with pharmacologically relevant concentrations of IL-6 or TCZ. Neutrophils were also isolated from RA patients, including a cohort following TCZ therapy. Apoptosis was measured by annexin V/propidium iodide (PI) flow cytometry; phagocytosis was measured by incubating apoptotic neutrophils with THP-1-derived macrophages; chemotaxis was measured using cell migration through hanging-cell inserts towards IL-8 and cell surface proteins, including adhesion molecules CD11b (αMβ2 integrin) and CD62L (L-selectin) were measured by flow cytometry.
IL-6 (10-100 ng/ml) did not affect the rate of neutrophil apoptosis, priming of the respiratory burst or adhesion molecule expression nor act as a neutrophil chemoattractant. However, IL-6 enhanced signal transducer and activator of transcription 3 (STAT3) activation and neutrophil migration towards IL-8. TCZ in vitro did not induce apoptosis or phagocytosis of neutrophils, nor did it have a significant effect upon apoptosis or cell surface molecule expression. Neutrophil functions in ex vivo neutrophils from RA patients receiving TCZ treatment were unaffected.
Therapeutic blockade of IL-6, while inducing a transient neutropenia, does not directly affect neutrophil functions associated with host defence. TCZ-associated neutropenia cannot be explained by direct induction of apoptosis by TCZ, induction of apoptosis following depletion of IL-6, nor increased phagocytosis of neutrophils.
Antibody drug conjugates (ADCs) have recently been proven to be highly potent anti-tumor drugs, typically exceeding the efficacy of conventional monoclonal antibodies (mAbs). ADCs are currently ...produced by chemical conjugation of a small-molecule toxin to the mAb through lysine or cysteine side chains. This leads to heterogeneous mixtures of ADCs in which variable numbers of drugs are conjugated to individual antibodies and in which the site of conjugation cannot be defined. Consequently, there is currently significant interest in further development of drug conjugation technologies, with a particular focus on site-specific payload conjugation. Here, we present an enzymatic conjugation platform based on the S. aureus sortase A-mediated transpeptidation reaction, allowing the efficient generation of ADCs with toxins conjugated to pre-defined sites at pre-defined drug-to-antibody ratios. For this, two modifications were introduced: first, immunoglobulin heavy (IgH) and light (IgL) chains were modified at their C-termini by addition of the sortase A recognition motif LPETG, and second, the small molecule tubulin polymerization inhibitors monomethylauristatin E (MMAE) and maytansine were modified by addition of a pentaglycine peptide, thus making them suitable substrates for sortase A-mediated transpeptidation. We demonstrate efficient generation and characterization of the anti-CD30 ADC Ac10-vcPAB-MMAE, an enzymatically conjugated counterpart of brentuximab vedotin (Adcetris), as well as several anti-HER-2 ADCs including trastuzumab-maytansine, the counterpart of trastuzumab emtansine (Kadcyla). ADCs generated in this manner were found to display in vitro cell killing activities indistinguishable from the classic conjugates. Further, when tested in vivo in a HER-2-overexpressing ovarian cancer xenograft mouse model, enzymatically generated trastuzumab-maytansine was found to lead to complete regression of established tumors, similar to Kadcyla.
Tumor necrosis factor (TNF) has a pathogenic role in juvenile rheumatoid arthritis. We evaluated the efficacy and safety of adalimumab, a fully human monoclonal anti-TNF antibody, in children with ...polyarticular-course juvenile rheumatoid arthritis.
Patients 4 to 17 years of age with active juvenile rheumatoid arthritis who had previously received treatment with nonsteroidal antiinflammatory drugs underwent stratification according to methotrexate use and received 24 mg of adalimumab per square meter of body-surface area (maximum dose, 40 mg) subcutaneously every other week for 16 weeks. We randomly assigned patients with an American College of Rheumatology Pediatric 30% (ACR Pedi 30) response at week 16 to receive adalimumab or placebo in a double-blind fashion every other week for up to 32 weeks.
Seventy-four percent of patients not receiving methotrexate (64 of 86) and 94% of those receiving methotrexate (80 of 85) had an ACR Pedi 30 response at week 16 and were eligible for double-blind treatment. Among patients not receiving methotrexate, disease flares (the primary outcome) occurred in 43% of those receiving adalimumab and 71% of those receiving placebo (P=0.03). Among patients receiving methotrexate, flares occurred in 37% of those receiving adalimumab and 65% of those receiving placebo (P=0.02). At 48 weeks, the percentages of patients treated with methotrexate who had ACR Pedi 30, 50, 70, or 90 responses were significantly greater for those receiving adalimumab than for those receiving placebo; the differences between patients not treated with methotrexate who received adalimumab and those who received placebo were not significant. Response rates were sustained after 104 weeks of treatment. Serious adverse events possibly related to adalimumab occurred in 14 patients.
Adalimumab therapy seems to be an efficacious option for the treatment of children with juvenile rheumatoid arthritis. (ClinicalTrials.gov number, NCT00048542.)
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