Maintenance therapy for chronic lymphocytic leukaemia

Background 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. Objectives 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. Search methods 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. Selection criteria 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. Data collection and analysis 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). Main results 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. Authors' conclusions 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.