Skip to main content
NCBI home page
JAMA Network logoLink to JAMA Network
. 2024 Jul 11;10(9):1221–1227. doi: 10.1001/jamaoncol.2024.2122

Measurable Residual Disease and Clinical Outcomes in Chronic Lymphocytic Leukemia

A Systematic Review and Meta-Analysis

Fausto Alfredo Rios-Olais 1, Alyssa K McGary 2, Mazie Tsang 3, Diana Almader-Douglas 4, Jose F Leis 3, Matthew R Buras 5, Talal Hilal 3,✉
PMCID: PMC11240229  PMID: 38990562

Key Points

Question

What is the association between measurable residual disease (MRD) and progression-free survival in chronic lymphocytic leukemia?

Findings

In this systematic review and meta-analysis of 11 prospective clinical trials including 2765 patients with chronic lymphocytic leukemia treated with targeted agents or obinutuzumab-based therapy, MRD status was associated with progression-free survival in the first-line treatment setting and with time-limited therapy.

Meaning

These findings may have implications for clinical trial design and provide a rationale for using MRD as an end point for accelerated drug registration.

This systematic review and meta-analysis assesses the association between measurable residual disease and progression-free survival in chronic lymphocytic leukemia treated with targeted agents.

Abstract

Importance

Measurable residual disease (MRD) refers to the presence of disease at low levels not detected by conventional pathologic analysis. The association of MRD status as a surrogate end point of clinical outcome in chronic lymphocytic leukemia (CLL) has not been established in the era of targeted agents. Assessing the association of MRD with progression-free survival (PFS) may improve its role as a surrogate marker and allow its use to accelerate drug development.

Objective

To assess the association between MRD and PFS in CLL using data from prospective clinical trials that studied targeted agents or obinutuzumab-based treatment.

Data Sources

Clinical studies on CLL were identified via searches of PubMed, Embase, Scopus, and Web of Science from inception through July 31, 2023.

Study Selection

Prospective, single-arm, and randomized clinical trials that assessed targeted agents or obinutuzumab-based treatment and reported PFS by MRD status were included. Studies with insufficient description of MRD information were excluded.

Data Extraction and Synthesis

Study sample size, median patient age, median follow-up time, line of treatment, MRD detection method and time points, and survival outcomes were extracted.

Main Outcomes and Measures

Analyses of survival probabilities and hazard ratios (HRs) were conducted for PFS according to MRD status. Meta-analyses were performed using a random-effects model.

Results

A total of 11 prospective clinical trials (9 randomized and 2 nonrandomized) including 2765 patients were analyzed. Achieving undetectable MRD (uMRD) at 0.01% was associated with an HR of 0.28 (95% CI, 0.20-0.39; P < .001) for PFS. Median PFS was not reached in both groups (uMRD vs MRD), but the estimated 24-month PFS was better in the uMRD group (91.9% [95% CI, 88.8%-95.2%] vs 75.3% [95% CI, 64.7%-87.6%]; P < .001). The association of uMRD with PFS was observed in subgroup analyses in the first-line treatment setting (HR, 0.24; 95% CI, 0.18-0.33), relapsed or refractory disease setting (HR, 0.34; 95% CI, 0.16-0.71), and trials using time-limited therapy (HR, 0.28; 95% CI, 0.19-0.40).

Conclusions and Relevance

The findings of this systematic review and meta-analysis suggest that assessing MRD status as an end point in clinical trials and as a surrogate of PFS may improve trial efficiency and potentially allow for accelerated drug registration.

Introduction

The treatment of chronic lymphocytic leukemia (CLL) has seen important advances in the past decade. Targeted agents, including Bruton tyrosine kinase inhibitors (BTKis) such as ibrutinib, acalabrutinib, and zanubrutinib as well as venetoclax (a B-cell lymphoma 2 inhibitor) and obinutuzumab (a humanized anti-CD20 monoclonal antibody), have been introduced for first-line treatment and the management of relapsed and refractory disease.1,2,3,4,5 However, disease response categories in CLL have not changed substantially and rely primarily on clinical and radiographic variables. The standard response criteria are based on that of the 2018 International Workshop on Chronic Lymphocytic Leukemia, which include history, physical examination, bone marrow examination, and imaging.6 In the past decade, higher-sensitivity measurable residual disease (MRD) assays have emerged as a clinical trial end point and have since been incorporated into most CLL trials evaluating targeted therapies. Measurable residual disease refers to the detection of disease after treatment using highly sensitive techniques (eg, 10−4 or 1 per 10 000 cells), including multiparameter flow cytometry (MFC); allele-specific oligonucleotide polymerase chain reaction (ASO-PCR); and more recently, next-generation sequencing (NGS). Next-generation sequencing–based methods can track patient-specific clonal sequences at a rate of 10−6 or 1 per 1 million cells.7 Measurable residual disease can be measured in peripheral blood or bone marrow.7

Unlike diseases such as acute lymphoblastic leukemia, in which achieving undetectable MRD (uMRD) at established time points during treatment is associated with disease-free survival and overall survival (OS),8 the association of MRD with clinical outcomes in CLL is not well defined. In CLL, prospective trials have shown improved progression-free survival (PFS) when reaching uMRD after established time points for targeted agents used in first-line5,9,10,11 and relapsed and refractory12,13 treatment settings. However, some caveats exist when interpreting these results, as some trials did not test for MRD unless patients achieved a complete response (CR),12,14 which introduces bias. There is also substantial heterogeneity in the methods (eg, MFC vs NGS) and tissue compartments tested (eg, peripheral blood vs bone marrow).7 Additionally, BTKi monotherapy has rarely achieved uMRD, but treatment until disease progression or unsustainable toxic effects has translated into excellent PFS and OS regardless of MRD status.15 Therefore, MRD has primarily been used to understand the effect of CLL treatment in the context of clinical trials.6 To understand the association between MRD and PFS derived from recent clinical trials that evaluated targeted agents and obinutuzumab-based treatment, we conducted a systematic review and meta-analysis of the existing literature.

Methods

Eligibility Criteria

This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline.16 The study of published trials did not involve individual-level data and was exempt from institutional review board approval. Informed consent was not required.

Articles that reported prospective single-arm and randomized clinical trials (RCTs) of CLL that evaluated a targeted agent in at least 1 arm or obinutuzumab-based treatment were included. Trials must have reported PFS according to MRD status and an MRD at the 0.01% cutoff (ie, 10−4 or 1 per 10 000 cells) (as suggested by most guidelines17) due to lack of data for other cutoffs (eg, 10−6 or 1 per 1 million cells). To exclude duplicate reporting of patients, we included only the most recent update of an RCT with the longest follow-up. Abstracts, retrospective studies, review articles, case reports, case series, maintenance treatment studies, duplicate studies, non–English language publications, and studies lacking comprehensive details on MRD and/or survival outcomes (ie, PFS) categorized by MRD status were excluded. We also excluded studies that used MRD to guide treatment decisions since they introduced bias by treating until achievement of uMRD and did not report PFS by MRD status (Figure 1).

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses Literature Search Flow Diagram.

Figure 1.

Open in a new tab

Data Sources and Search Strategies

A comprehensive literature search was performed for abstracts and full-text articles published in print or online from electronic databases (PubMed, Embase, Scopus, and Web of Science) from inception through July 31, 2023. The detailed search strategy is described in the eMethods in Supplement 1. The search strategy was designed and conducted by an experienced librarian (D.A.-D.) with input from the study investigators and used different combinations of the following keywords: chronic lymphocytic leukemia, small lymphocytic lymphoma, measurable residual disease, minimal residual disease, overall survival, and progression-free survival.

Data Extraction

Prespecified data elements were extracted from each article by 2 reviewers (F.A.R.-O. and T.H.). The following variables were collected: study population, tissue compartment tested (peripheral blood and/or bone marrow), MRD assessment technique (ASO-PCR, MFC, and/or NGS), time point of MRD measurement, treatment arm, median age and age range, median follow-up time, uMRD rate, course of treatment (first-line vs relapsed or refractory), Rai stage, Eastern Cooperative Oncology Group performance status, sex, immunoglobulin heavy variable gene status, presence of del(17p), TP53 variant status, and survival outcome. Data on race and ethnicity were mostly not reported and were not collected.

Two strategies were used to extract hazard ratios (HRs) comparing patients who reached uMRD with those who did not. If a study included HRs, we used them with their 95% CIs. If HRs were not included in a study, we used DigitizeIt, version 2.5.10 graph digitizer software (Bormisoft) to record the coordinates of data points of Kaplan-Meier curves for PFS for the uMRD and MRD groups. After graphing, we ran the coordinates through WebPlotDigitizer, version 4.6 (Ankit Rohatgi), an online tool that uses an algorithm to compute HRs along with their 95% CIs. We excluded studies if neither of these data points were for PFS.

Data Synthesis

Searches of electronic databases yielded 557 articles after excluding duplicates. Two investigators (F.A.R.-O. and T.H.) identified and reviewed full-text articles that were deemed relevant by screening the list of titles. Disagreements between the 2 reviewers were resolved through consensus. A total of 11 studies with 16 treatment arms were included. All studies used an MRD cutoff of less than 0.01% (ie, 10−4 or 1 per 10 000 cells). The literature search flow diagram is shown in Figure 1. Patients with MRD were pooled together in studies that reported MRD according to response criteria (eg, uMRD for a CR and uMRD for a partial response [PR]). Characteristics of the individual studies are presented in the eTable in Supplement 1.

Quality Assessment

The revised Cochrane risk-of-bias tool18 was used to evaluate internal validity of each randomized study included in the meta-analysis. The Cochrane Risk of Bias in Non-Randomized Studies–of Interventions tool19 was used to evaluate the remaining 2 nonrandomized prospective trials. Quality assessment was conducted by 2 investigators separately (F.A.R.-O. and T.H.).

Statistical Analysis

The primary end point was PFS. For each study, we obtained HRs (uMRD vs MRD) and corresponding 95% CIs according to the strategies described previously.

Meta-analyses were performed using the restricted maximum likelihood random-effects model from the R package metafor.20 Cochran Q statistic, the variance of the reported study effect sizes, was used to quantify heterogeneity. The I2 statistic was used to estimate the percentage of variation across studies that is due to heterogeneity rather than chance. The pooled HR estimates and their 95% CIs are reported. For the pooled survival estimates and estimated pooled survival curves, the implementation of the DerSimonian-Laird random-effects model from the R package RISCA21 was used. All analyses were performed using R, version 4.1.2 (R Project for Statistical Computing).

We performed subgroup analyses according to line of treatment, inclusion or exclusion of del(17p), class of therapy agent, treatment duration (time limited vs indefinite), MRD evaluation method, and inclusion or exclusion of patients according to functional status. Sensitivity analyses were performed by excluding BTKi monotherapy or BTKi combination therapy to focus on time-limited therapies. Statistical significance was set at a 2-sided P < .05 by χ2 test.

Results

Study Characteristics

A total of 11 trials5,9,10,11,12,13,22,23,24,25,26 reported data on 2765 patients who had MRD testing. Study characteristics are shown in the eTable in Supplement 1. Different tissues were tested for MRD: 1 trial evaluated MRD exclusively in peripheral blood22 and the remaining in both peripheral blood and bone marrow.5,9,10,11,12,13,23,24,25,26 None of the trials evaluated MRD in bone marrow only. There were different time points of MRD measurement, the most common being 3 months after the end of treatment (3 studies10,24,25). Seven studies reported on first-line treatment.5,9,10,11,22,24,25 Some trials used different levels of MRD12,13 (uMRD <0.01%; low MRD, 0.01%-0.1%; and high MRD >0.1%). When those cutoffs were reported, we pooled low MRD and high MRD groups together into an MRD-positive group. In addition, some studies reported MRD according to treatment response (CR or PR),5,11 so we pooled uMRD values together regardless of clinical response. No study included had as its primary end point the association of MRD and PFS, but MRD testing was a primary, secondary, or exploratory end point (eTable in Supplement 1). Only 1 study did not report MRD PFS according to the treatment arm of the trial,5 with the remaining pooling all patients of the study together according to MRD.9,10,11,12,13,22,23,24,25,26 Obinutuzumab was used as part of the treatment in 6 studies,9,10,11,24,25,26 while 5 studies each used venetoclax5,13,24,25,26 and ibrutinib.11,12,22,23,24

Risk-of-Bias Assessment

One RCT was considered as having a low risk of bias.12 The remaining 8 RCTs were categorized as having some concerns of bias, which were mainly due to the unmasked nature of the treatment interventions and lack of concealment.5,10,11,13,22,23,24,25 The Risk of Bias in Non-Randomized Studies–of Interventions assessment of the 2 prospective nonrandomized trials9,26 showed both to have low risk of bias. The revised risk-of-bias assessment results are shown in eFigure 1 in Supplement 1 using a traffic light plot produced by the R package robvis.27

MRD Status and PFS

The PFS curves according to MRD status are shown in Figure 2A. There was a statistically significant difference in the pooled survival estimates between the uMRD and MRD groups, with an estimated 24-month PFS of 91.9% (95% CI, 88.8%-95.2%) in the uMRD arm compared with 75.3% (95% CI, 64.7%-87.6%) in the MRD arm (P < .001) and a pooled HR estimate for PFS of 0.28 (95% CI, 0.20-0.39; P < .001). A forest plot estimating each individual study’s HR is shown in eFigure 2A in Supplement 1.

Figure 2. Pooled Progression-Free Survival (PFS) by Measurable Residual Disease (MRD) Status.

Figure 2.

Open in a new tab

The dashed lines represent the median survival, where 50% of the study population is expected to have experienced progression. BTKi indicates Bruton tyrosine kinase inhibitor; uMRD, undetectable measurable residual disease.

MRD Status and PFS According to Line of Treatment

The PFS curves according to MRD status for the first-line and relapsed or refractory treatment settings are shown in Figure 2B and C. Median PFS was not reached by any group according to MRD status and line of treatment. In the first-line treatment setting, there was a statistically significant difference in the pooled survival estimates between the uMRD and MRD groups, with an estimated 24-month PFS of 93.5% (95% CI, 90.9%-96.2%) in the uMRD arm compared with 77.7% (95% CI, 64.9-93) in the MRD arm (P < .001) and with a pooled HR of 0.24 (95% CI, 0.18-0.33) (eFigure 2B in Supplement 1).

In the relapsed or refractory treatment setting, the estimated 24-month PFS was 83.5% (95% CI, 70.8%-98.4%) in the uMRD arm compared with 68.8% (95% CI, 50.2%-94.4%) in the MRD arm, with a pooled HR of 0.34 (95% CI, 0.16-0.71) (eFigure 2C in Supplement 1). Not all studies included in the forest plot reported survival estimates, so those studies could not be pooled.23,26 Therefore, there was no statistically significant difference in the pooled survival estimates between the uMRD and MRD groups in this setting.

MRD Status and PFS in Patients Receiving Time-Limited Therapy

The PFS curves according to MRD status are shown in Figure 2D. In studies excluding the use of BTKis, there was a statistically significant difference in the pooled survival estimates between the uMRD and MRD groups, with an estimated 24-month PFS of 90.7% (95% CI, 86.3%-95.3%) in the uMRD arm compared with 55.5% (95% CI, 46.8%-65.9%) in the MRD arm (P < .001) and pooled HR estimate of 0.28 (95% CI, 0.19-0.40) (eFigure 2D in Supplement 1). Forest plots showing the HR estimates for study arms using chemoimmunotherapy and ibrutinib included in the meta-analysis are shown in eFigure 3 in Supplement 1.

MRD Status and PFS by Study Characteristics

Measurable residual disease status was consistently associated with PFS except in the relapsed or refractory setting and in studies that excluded del(17p) (Figure 3). For the MRD method subgroups, NGS was excluded as only 1 trial24 used this methodology to assess for MRD (eTable in Supplement 1).

Figure 3. Forest Plot of Progression-Free Survival by Subgroups.

Figure 3.

Open in a new tab

The size of the boxes represents the relative weights assigned to each study, as determined by sample size. ASO-PCR indicates allele-specific oligonucleotide polymerase chain reaction; HR, hazard ratio; MFC, multiparameter flow cytometry; and MRD, measureable residual disease.

MRD Status and PFS by Clinical Response Criteria

Only 2 studies5,11 reported MRD-associated PFS according to standard response criteria, comprising 4 subgroups: patients with a CR and detectable MRD, patients with a PR and detectable MRD, patients with a CR and uMRD, and patients with a PR and uMRD. The best PFS was observed in patients with a CR and uMRD; PFS was similar in patients with a PR and uMRD and those with a CR and detectable MRD and the worst in patients with a PR and detectable MRD (eFigure 4 in Supplement 1).

Discussion

The findings of this systematic review and meta-analysis of prospective clinical trials including 2765 patients with CLL show that MRD is consistently associated with PFS, especially in the first-line treatment setting and with time-limited therapy. The magnitude of benefit associated with uMRD was substantial, corresponding to a 72% reduction in the risk of death or progression for patients achieving uMRD. In almost every subgroup analysis, the association between MRD and PFS persisted regardless of the treatment used, duration of therapy, MRD testing method, cytogenetic risk, and enrolled patient population.

This meta-analysis is the first, to our knowledge, to be done in the era of targeted therapies, as the previous effort included 11 studies in which all patients were treated with chemoimmunotherapy and none were treated with venetoclax and/or BTKis.28 In the previous meta-analysis, the estimated 3-year PFS for the patients with uMRD was 86% compared with 32% in patients with MRD. In our analysis, the estimated 2-year PFS was substantially better in each subgroup (91.9% in the uMRD group vs 75.3% in the MRD group), reflecting that the incorporation of novel agents has substantially transformed and improved the management of CLL.28

Although ibrutinib therapy is rarely associated with CR or uMRD, when achieved, the association of MRD with PFS persisted in this class of agents as well, suggesting that the association is agnostic of choice of therapy. Another finding is that International Workshop on Chronic Lymphocytic Leukemia response criteria may not be enough to help in prognostication, as incorporating MRD data resulted in differing outcomes between different clinical response categories, suggesting that incorporating MRD results in response assessment may help to risk stratify patients more accurately.

These data have several implications for clinical practice and trial design. First, timing and frequency of assessment, tissue tested, and technique used to assess MRD should be standardized so that more homogeneous evidence continues to grow. The robust association of MRD with PFS supports the consideration of MRD as a surrogate end point of PFS and its incorporation in trials to guide fixed-duration treatment discontinuation or intensification according to MRD status, which is already being done with promising results.29,30,31 Although a reasonable primary end point for accelerated approval, MRD benefit needs to be confirmed by assessing PFS and OS.

Limitations

This study has several limitations. First, the reported effect sizes from the studies included in the various meta-analyses are heterogeneous. However, the forest plots also indicate that virtually all studies reported a best point effect size estimate in the same direction. The model used to pool the reported effect sizes in each forest plot allowed for the population effect size estimated by each study to vary. When considering the choice of model used to pool the effect size estimates and the consistency with which the effect sizes point in the same direction, we did not consider the observed between-study heterogeneity to be concerning. Second, some trials only measured MRD in patients with a CR,12,14 underrepresenting those who achieved a PR with uMRD. Patients in this subgroup have a prognosis that is at least as good as for those achieving a CR but with MRD.5,11,32,33 Third, although MRD is associated with PFS, PFS is a surrogate end point, and the association of MRD with OS is less clear largely due to scarcity of data. As such, the use of MRD as a primary end point for accelerated approval needs to be confirmed by assessing PFS and OS. Long-term outcomes of pragmatic CLL trials might provide more information on whether uMRD is also prognostic of OS.

Conclusions

In this large systematic review and meta-analysis, MRD in patients with CLL was found to be associated with PFS, especially in the first-line treatment setting and with time-limited therapy. Given this association, the use of MRD status as an end point in clinical trials and a surrogate of PFS may improve the efficiency and design of future trials and introduce MRD-guided strategies in clinical practice.

Supplement 1.

eMethods. Search Strategy

eTable. Individual Characteristics of the Studies Included in the Meta-Analysis With Prespecified MRD End Point

eFigure 1. Risk-of-Bias Assessment Using RoB2.0 and ROBINS-I

eFigure 2. Forest Plots of PFS HRs by Measurable Residual Disease Status for All Studies Included, Studies of Frontline Therapy, Studies in the Relapsed/Refractory Setting, and All Studies Excluding Indefinite BTKi Arms

eFigure 3. Forest Plots Showing HR Estimates for Study Arms With Chemoimmunotherapy and Study Arms With Ibrutinib Included in the Meta-Analysis

eFigure 4. Progression-Free Survival of All Patients According to MRD Status and Clinical Response (PR vs CR)

jamaoncol-e242122-s001.pdf (1.6MB, pdf)
Supplement 2.

Data Sharing Statement

jamaoncol-e242122-s002.pdf (12.4KB, pdf)

References

  • 1.Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443. doi: 10.1056/NEJMoa1817073 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi: 10.1016/S0140-6736(20)30262-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043. doi: 10.1016/S1470-2045(22)00293-5 [DOI] [PubMed] [Google Scholar]
  • 4.Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi: 10.1056/NEJMoa1815281 [DOI] [PubMed] [Google Scholar]
  • 5.Eichhorst B, Niemann CU, Kater AP, et al. ; GCLLSG, HOVON and Nordic CLL Study Groups; SAKK; Israeli CLL Association; Cancer Trials Ireland . First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754. doi: 10.1056/NEJMoa2213093 [DOI] [PubMed] [Google Scholar]
  • 6.Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. doi: 10.1182/blood-2017-09-806398 [DOI] [PubMed] [Google Scholar]
  • 7.Rios-Olais FA, Hilal T. Measurable residual disease in chronic lymphocytic leukemia: current understanding and evolving role in clinical practice. Curr Treat Options Oncol. 2023;24(8):907-928. doi: 10.1007/s11864-023-01103-1 [DOI] [PubMed] [Google Scholar]
  • 8.Berry DA, Zhou S, Higley H, et al. Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis. JAMA Oncol. 2017;3(7):e170580. doi: 10.1001/jamaoncol.2017.0580 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Stilgenbauer S, Leblond V, Foà R, et al. Obinutuzumab plus bendamustine in previously untreated patients with CLL: a subgroup analysis of the GREEN study. Leukemia. 2018;32(8):1778-1786. doi: 10.1038/s41375-018-0146-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-1110. doi: 10.1056/NEJMoa1313984 [DOI] [PubMed] [Google Scholar]
  • 11.Moreno C, Greil R, Demirkan F, et al. First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase III iLLUMINATE trial. Haematologica. 2022;107(9):2108-2120. doi: 10.3324/haematol.2021.279012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Fraser G, Cramer P, Demirkan F, et al. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia. 2019;33(4):969-980. doi: 10.1038/s41375-018-0276-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Seymour JF, Kipps TJ, Eichhorst BF, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022;140(8):839-850. doi: 10.1182/blood.2021015014 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25(35):5616-5623. doi: 10.1200/JCO.2007.12.9098 [DOI] [PubMed] [Google Scholar]
  • 15.Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528. doi: 10.1056/NEJMoa1812836 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. J Clin Epidemiol. 2021;134:178-189. doi: 10.1016/j.jclinepi.2021.03.001 [DOI] [PubMed] [Google Scholar]
  • 17.Wierda WG, Rawstron A, Cymbalista F, et al. Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations. Leukemia. 2021;35(11):3059-3072. doi: 10.1038/s41375-021-01241-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Higgins JP, Savović J, Page MJ, Sterne JA. Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). Accessed October 31, 2023. https://www.riskofbias.info/welcome/rob-2-0-tool/current-version-of-rob-2
  • 19.Sterne J, Higgins J, Reeves B. Current version of ROBINS-I. Accessed November 1, 2023. https://www.riskofbias.info/welcome/home/current-version-of-robins-i
  • 20.Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36(3):1-48. doi: 10.18637/jss.v036.i03 [DOI] [Google Scholar]
  • 21.Foucher Y, Le Borgne F, Chatton A, Sabathe C. RISCA: causal inference and prediction in cohort-based analyses, version 1.0.4. R package documentation, 2023. Accessed November 15, 2023. https://rdrr.io/cran/RISCA
  • 22.Wang XV, Hanson CA, Tschumper RC, et al. Measurable residual disease does not preclude prolonged progression-free survival in CLL treated with ibrutinib. Blood. 2021;138(26):2810-2827. doi: 10.1182/blood.2020010146 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Sharman JP, Brander DM, Mato AR, et al. Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial. Lancet Haematol. 2021;8(4):e254-e266. doi: 10.1016/S2352-3026(20)30433-6 [DOI] [PubMed] [Google Scholar]
  • 24.Munir T, Moreno C, Owen C, et al. Impact of minimal residual disease on progression-free survival outcomes after fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in the GLOW study. J Clin Oncol. 2023;41(21):3689-3699. doi: 10.1200/JCO.22.02283 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Al-Sawaf O, Zhang C, Lu T, et al. Minimal residual disease dynamics after venetoclax-obinutuzumab treatment: extended off-treatment follow-up from the randomized CLL14 study. J Clin Oncol. 2021;39(36):4049-4060. doi: 10.1200/JCO.21.01181 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. J Clin Oncol. 2018;36(19):1973-1980. doi: 10.1200/JCO.2017.76.6840 [DOI] [PubMed] [Google Scholar]
  • 27.McGuinness LA, Higgins JPT. Risk-of-bias visualization (robvis): an R package and Shiny web app for visualizing risk-of-bias assessments. Res Synth Methods. 2021;12(1):55-61. doi: 10.1002/jrsm.1411 [DOI] [PubMed] [Google Scholar]
  • 28.Molica S, Giannarelli D, Montserrat E. Minimal residual disease and survival outcomes in patients with chronic lymphocytic leukemia: a systematic review and meta-analysis. Clin Lymphoma Myeloma Leuk. 2019;19(7):423-430. doi: 10.1016/j.clml.2019.03.014 [DOI] [PubMed] [Google Scholar]
  • 29.Wierda WG, Allan JN, Siddiqi T, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: primary analysis results from the minimal residual disease cohort of the randomized phase II CAPTIVATE study. J Clin Oncol. 2021;39(34):3853-3865. doi: 10.1200/JCO.21.00807 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Kater AP, Levin MD, Dubois J, et al. Minimal residual disease-guided stop and start of venetoclax plus ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia (HOVON141/VISION): primary analysis of an open-label, randomised, phase 2 trial. Lancet Oncol. 2022;23(6):818-828. doi: 10.1016/S1470-2045(22)00220-0 [DOI] [PubMed] [Google Scholar]
  • 31.Munir T, Cairns DA, Bloor A, et al. ; National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup . Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. 2024;390(4):326-337. doi: 10.1056/NEJMoa2310063 [DOI] [PubMed] [Google Scholar]
  • 32.Strati P, Keating MJ, O’Brien SM, et al. Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL. Blood. 2014;123(24):3727-3732. doi: 10.1182/blood-2013-11-538116 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Thompson PA, Srivastava J, Peterson C, et al. Minimal residual disease undetectable by next-generation sequencing predicts improved outcome in CLL after chemoimmunotherapy. Blood. 2019;134(22):1951-1959. doi: 10.1182/blood.2019001077 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eMethods. Search Strategy

eTable. Individual Characteristics of the Studies Included in the Meta-Analysis With Prespecified MRD End Point

eFigure 1. Risk-of-Bias Assessment Using RoB2.0 and ROBINS-I

eFigure 2. Forest Plots of PFS HRs by Measurable Residual Disease Status for All Studies Included, Studies of Frontline Therapy, Studies in the Relapsed/Refractory Setting, and All Studies Excluding Indefinite BTKi Arms

eFigure 3. Forest Plots Showing HR Estimates for Study Arms With Chemoimmunotherapy and Study Arms With Ibrutinib Included in the Meta-Analysis

eFigure 4. Progression-Free Survival of All Patients According to MRD Status and Clinical Response (PR vs CR)

jamaoncol-e242122-s001.pdf (1.6MB, pdf)
Supplement 2.

Data Sharing Statement

jamaoncol-e242122-s002.pdf (12.4KB, pdf)

Articles from JAMA Oncology are provided here courtesy of American Medical Association

RESOURCES