What is the aim of this review?
We aimed to determine whether the currently available maintenance treatments for disease control in adults with chronic lymphocytic leukaemia (CLL) have an acceptable balance between benefits and harms following previous treatment.
Key messages
We found that maintenance therapy in adults with CLL after previous therapy probably has little to no effect on long-term survival. We also found that maintenance therapy probably increases the disease control period, but is associated with an increase in drug-related serious adverse events and all adverse events.
What was studied in this review?
CLL is a blood cancer that affects the lymphocytes, a group of white blood cells that help the body fight infection and disease. In the past 20 years, the control rate and survival of patients have significantly improved due to the use of chemotherapy plus immunotherapy, followed by the introduction of novel oral targeted therapy as the mainstream treatment for CLL. Despite these advancements, CLL patients may still develop disease that is resistant to treatment. Maintenance treatments aim to improve treatment response and extend survival, but may also increase the risk of adverse events. Available drugs for maintenance intervention include anti-CD20 monoclonal antibodies (mAbs), immunomodulatory drugs, and anti-CD52 mAbs. These drugs carry risks of serious side effects due to prolonged administration. It remains unclear whether the benefits of maintenance treatments outweigh the risks, as they may not achieve a satisfactory balance between disease control and prolonged survival without increasing treatment-related death or adverse events. CLL patients who achieve remission after the first phase of treatment must therefore weigh the benefits and risks of medical observation or maintenance therapy carefully.
What did we want to find out?
We wanted to know if maintenance therapy following previous treatment is effective in controlling disease for adults with CLL and if it causes any adverse effects.
What did we do?
We searched for studies that compared maintenance therapy with placebo (dummy treatment) or observation, or head-to-head comparisons of maintenance therapies. We compared and summarised the results and rated our confidence in the evidence based on factors such as study methods and sizes.
What did we find?
We identified 11 studies (2393 participants) for inclusion in the review. All studies were randomised controlled trials (RCTs), which are the most reliable clinical studies as they randomly allocate people to receive treatment (intervention group) or no treatment (control group). We synthesised the evidence from 10 studies (2341 participants) to assess the benefits and harms of maintenance therapy for CLL when compared with control groups receiving observation or placebo (dummy treatment).
Compared to observation, anti-CD20 mAbs probably have little to no effect on overall survival (evidence from 3 studies with 1152 participants), but probably increase the time in which the disease is controlled (progression-free survival) (evidence from 5 studies with 1255 participants).
Compared to placebo/observation, IMiD probably has little to no effect on overall survival (evidence from 3 studies with 461 participants), but probably results in a large increase in progression-free survival (evidence from 3 studies with 461 participants).
Compared to observation, anti-CD20 mAbs may result in increased serious side effects (evidence from 5 studies with 1284 participants), but may not affect the chance of dying from treatment (evidence from 4 studies with 1189 participants). Anti-CD20 mAbs may slightly reduce the number of people who stopped treatment (evidence from 6 studies with 1321 participants), but may slightly increase the overall number of side effects (evidence from 6 studies with 1321 participants).
Compared to placebo/observation, IMiD may result in increased serious side effects (evidence from 2 studies with 400 participants), and may slightly increase the number of people who died due to maintenance treatment (evidence from 3 studies with 458 participants). The evidence for the effect of IMiD on number of people who stopped treatment is very uncertain (evidence from 2 studies with 400 participants), but IMiD probably increases the overall number of side effects (evidence from 3 studies with 458 participants).
There was insufficient evidence to determine whether anti-CD20 mAbs maintenance therapy affected health-related quality of life, and our confidence in the evidence is low (evidence from 1 study with 480 participants).
No studies evaluated other new maintenance interventions, such as B-cell receptor inhibitors, B-cell leukaemia-2/lymphoma-2 inhibitors, or obinutuzumab.
What are the limitations of the evidence?
The overall certainty (confidence) of the evidence was mostly moderate to low due to issues within the trials such as the potential for bias, differences in baseline characteristics, and imprecise estimates of intervention effects.
How up-to-date is this review?
The evidence is current as of January 2022.
There is currently moderate- to very low-certainty evidence available regarding the benefits and harms of maintenance therapy in people with CLL. Anti-CD20 mAbs maintenance improved PFS, but also increased grade 3/4 AEs and all AEs. IMiD maintenance had a large effect on PFS, but also increased grade 3/4 AEs. However, none of the above-mentioned maintenance interventions show differences in OS between the maintenance and control groups. The effects of alemtuzumab maintenance are uncertain, coupled with a warning for drug-related infectious toxicity. We found no studies evaluating other novel maintenance interventions, such as B-cell receptor inhibitors, B-cell leukaemia-2/lymphoma-2 inhibitors, or obinutuzumab.
Chronic lymphocytic leukaemia (CLL) is the most common lymphoproliferative disease in adults and currently remains incurable. As the progression-free period shortens after each successive treatment, strategies such as maintenance therapy are needed to improve the degree and duration of response to previous therapies. Monoclonal antibodies, immunomodulatory agents, and targeted therapies are among the available options for maintenance therapy. People with CLL who achieve remission after previous therapy may choose to undergo medical observation or maintenance therapy to deepen the response. Even though there is widespread use of therapeutic maintenance agents, the benefits and harms of these treatments are still uncertain.
To assess the effects and safety of maintenance therapy, including anti-CD20 monoclonal antibody, immunomodulatory drug therapy, anti-CD52 monoclonal antibody, Bruton tyrosine kinase inhibitor, and B-cell lymphoma-2 tyrosine kinase inhibitor, for individuals with CLL.
We conducted a comprehensive literature search for randomised controlled trials (RCTs) with no language or publication status restrictions. We searched CENTRAL, MEDLINE, Embase, and three trials registers in January 2022 together with reference checking, citation searching, and contact with study authors to identify additional studies.
We included RCTs with prospective identification of participants. We excluded cluster-randomised trials, cross-over trial designs, and non-randomised studies. We included studies comparing maintenance therapies with placebo/observation or head-to-head comparisons.
We used standard Cochrane methodological procedures. We assessed risk of bias in the included studies using Cochrane's RoB 1 tool for RCTs. We rated the certainty of evidence for the following outcomes using the GRADE approach: overall survival (OS), health-related quality of life (HRQoL), grade 3 and 4 adverse events (AEs), progression-free survival (PFS), treatment-related mortality (TRM), treatment discontinuation (TD), and all adverse events (AEs).
We identified 11 RCTs (2393 participants) that met the inclusion criteria, including seven trials comparing anti-CD20 monoclonal antibodies (mAbs) (rituximab or ofatumumab) with observation in 1679 participants; three trials comparing immunomodulatory drug (lenalidomide) with placebo/observation in 693 participants; and one trial comparing anti-CD 52 mAbs (alemtuzumab) with observation in 21 participants. No comparisons of novel small molecular inhibitors were found.
The median age of participants was 54.1 to 71.7 years; 59.5% were males. The type of previous induction treatment, severity of disease, and baseline stage varied among the studies. Five trials included early-stage symptomatic patients, and three trials included advanced-stage patients (Rai stage III/IV or Binet stage B/C). Six trials reported a frequent occurrence of cytogenic aberrations at baseline (69.7% to 80.1%). The median follow-up duration was 12.4 to 73 months. The risk of selection bias in the included studies was unclear. We assessed overall risk of performance bias and detection bias as low risk for objective outcomes and high risk for subjective outcomes. Overall risk of attrition bias, reporting bias, and other bias was low.
Anti-CD20 monoclonal antibodies (mAbs): rituximab or ofatumumab maintenance versus observation
Anti-CD20 mAbs maintenance likely results in little to no difference in OS (hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.73 to 1.20; 1152 participants; 3 studies; moderate-certainty evidence) and likely increases PFS significantly (HR 0.61, 95% CI 0.50 to 0.73; 1255 participants; 5 studies; moderate-certainty evidence) compared to observation alone.
Anti-CD20 mAbs may result in: an increase in grade 3/4 AEs (rate ratio 1.34, 95% CI 1.06 to 1.71; 1284 participants; 5 studies; low-certainty evidence); little to no difference in TRM (risk ratio 0.82, 95% CI 0.39 to 1.71; 1189 participants; 4 studies; low-certainty evidence); a slight reduction to no difference in TD (risk ratio 0.93, 95% CI 0.72 to 1.20; 1321 participants; 6 studies; low-certainty evidence); and an increase in all AEs (rate ratio 1.23, 95% CI 1.03 to 1.47; 1321 participants; 6 studies; low-certainty evidence) compared to the observation group.
One RCT reported that there may be no difference in HRQoL between the anti-CD20 mAbs (ofatumumab) maintenance and the observation group (mean difference −1.70, 95% CI −8.59 to 5.19; 480 participants; 1 study; low-certainty evidence).
Immunomodulatory drug (IMiD): lenalidomide maintenance versus placebo/observation
IMiD maintenance therapy likely results in little to no difference in OS (HR 0.91, 95% CI 0.61 to 1.35; 461 participants; 3 studies; moderate-certainty evidence) and likely results in a large increase in PFS (HR 0.37, 95% CI 0.19 to 0.73; 461 participants; 3 studies; moderate-certainty evidence) compared to placebo/observation.
Regarding harms, IMiD maintenance therapy may result in an increase in grade 3/4 AEs (rate ratio 1.82, 95% CI 1.38 to 2.38; 400 participants; 2 studies; low-certainty evidence) and may result in a slight increase in TRM (risk ratio 1.22, 95% CI 0.35 to 4.29; 458 participants; 3 studies; low-certainty evidence) compared to placebo/observation. The evidence for the effect on TD compared to placebo is very uncertain (risk ratio 0.71, 95% CI 0.47 to 1.05; 400 participants; 2 studies; very low-certainty evidence). IMiD maintenance therapy probably increases all AEs slightly (rate ratio 1.41, 95% CI 1.28 to 1.54; 458 participants; 3 studies; moderate-certainty evidence) compared to placebo/observation.
No studies assessed HRQoL.
Anti-CD52 monoclonal antibodies (mAbs): alemtuzumab maintenance versus observation
Maintenance with alemtuzumab may have little to no effect on PFS, but the evidence is very uncertain (HR 0.55, 95% CI 0.32 to 0.95; 21 participants; 1 study; very low-certainty evidence). We did not identify any study reporting the outcomes OS, HRQoL, grade 3/4 AEs, TRM, TD, or all AEs.