Measurable Residual Disease–Guided Therapy for Chronic Lymphocytic Leukemia

Author(s): Talha Munir, Ph.D.¹; Sean Girvan, M.Sc.²; David A. Cairns, Ph.D.²; Adrian Bloor, Ph.D., F.R.C.Path.^3,4; David Allsup, Ph.D.⁵; Abraham M. Varghese, Ph.D.¹; Satyen Gohil, Ph.D.⁶; Shankara Paneesha, F.R.C.Path.⁷; Andrew Pettitt, F.R.C.Path.^8,9; Toby Eyre, M.D.¹⁰; Christopher P. Fox, Ph.D.¹¹; Francesco Forconi, F.R.C.Path.^12,13; Ben Kennedy, F.R.C.Path.¹⁴; Constantine Balotis, M.D.¹⁴; Nicholas Pemberton, F.R.C.Path.¹⁵; Oonagh Sheehy, M.B., F.R.C.Path.¹⁶; John Gribben, M.D., D.Sc.¹⁷; Nagah Elmusharaf, F.R.C.Path.¹⁸; Simona Gatto, Ph.D.¹⁸; Gavin Preston, Ph.D.¹⁹; Anna Schuh, M.D.¹⁰; Renata Walewska, Ph.D.²⁰; Lelia Duley, M.Sc.²¹; Nichola Webster, B.Sc.^22,23; Surita Dalal, Ph.D.^22,23; Andrew Rawstron, Ph.D.²²; Dena Howard, Ph.D.²; Anna Hockaday, B.Sc.²; Sharon Jackson, Ph.D.²; Natasha Greatorex, B.Sc.²; Sue Bell, D.Phil.²; David Stones, M.Sc.²; Julia M. Brown, M.Sc.²; Piers E.M. Patten, F.R.C.Path., Ph.D.^24,25; Peter Hillmen, Ph.D.¹; the UK CLL Trials Group;

Source: N Engl J Med 2025;393:1177-1190

Dr. Anjan Patel's Thoughts

The phase 3 FLAIR trial compared MRD-guided ibrutinib–venetoclax (I+V) to ibrutinib (I) alone and FCR in previously untreated chronic lymphocytic leukemia (CLL). I+V achieved undetectable minimal residual disease (MRD) in bone marrow at 2 years in 66.2% of patients, versus 0% with I and 48.3% with FCR. At 5 years, PFS was 93.9% with I+V, 79.0% with I, and 58.1% with FCR; OS was 95.9%, 90.5%, and 86.5%, respectively. These data suggest that MRD-guided I+V not only deepens remissions but also translates to superior long-term outcomes—this could be a real game-changer for our frontline CLL management, especially for those with unmutated immunoglobulin heavy chain variable (IGHV).

BACKGROUND

An interim analysis of progression-free survival in this trial showed that ibrutinib–venetoclax was superior to fludarabine–cyclophosphamide–rituximab (FCR) among patients with chronic lymphocytic leukemia (CLL). Whether ibrutinib–venetoclax is more effective than ibrutinib alone is unclear.

METHODS

In this phase 3, multicenter, open-label trial, we randomly assigned patients with CLL to receive ibrutinib–venetoclax, ibrutinib alone, or FCR. The primary end points were undetectable measurable residual disease (MRD) in bone marrow within 2 years in the ibrutinib–venetoclax group as compared with the ibrutinib-alone group and progression-free survival in the ibrutinib–venetoclax group as compared with the FCR group. A powered secondary end point was progression-free survival in the ibrutinib–venetoclax group as compared with the ibrutinib-alone group. Other secondary end points included overall survival. Research Summary Measurable Residual Disease–Guided Therapy for CLL

RESULTS

A total of 172 of the 260 participants (66.2%) in the ibrutinib–venetoclax group had undetectable MRD in bone marrow within 2 years, as compared with none of the 263 participants in the ibrutinib-alone group (P

CONCLUSIONS

With extended follow-up and increased enrollment, our trial showed that undetectable MRD and extended progression-free survival were more common with ibrutinib–venetoclax than with ibrutinib alone or FCR. The results for overall survival were also consistent with a benefit of ibrutinib–venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.)

Author Affiliations

¹Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom; ²Leeds Cancer Research UK Clinical Trials Unit, University of Leeds, Leeds, United Kingdom; ³Christie Hospital NHS Foundation Trust, Manchester, United Kingdom; ⁴University of Manchester, Manchester, United Kingdom; ⁵Hull University Teaching Hospitals NHS Trust, Hull, United Kingdom; ⁶University College London Hospitals NHS Foundation Trust, London; ⁷University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; ⁸Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, United Kingdom; ⁹University of Liverpool, Liverpool, United Kingdom; ¹⁰Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom; ¹¹University of Nottingham, School of Medicine, Nottingham, United Kingdom; ¹²Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; ¹³Haematology Department, Cancer Care Directorate, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; ¹⁴University Hospitals of Leicester NHS Trust, Leicester, United Kingdom; ¹⁵Worcestershire Acute Hospitals NHS Trust, Worcester, United Kingdom; ¹⁶Belfast City Hospital, Belfast, United Kingdom; ¹⁷Queen Mary University of London, London; ¹⁸University Hospital of Wales, Cardiff, United Kingdom; ¹⁹Aberdeen Royal Infirmary, Aberdeen, United Kingdom; ²⁰University Hospitals Dorset NHS Foundation Trust, Bournemouth, United Kingdom; ²¹CLL Support, Chippenham, United Kingdom; ²²Haematological Malignancy Diagnostic Service, Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom; ²³Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom; ²⁴Comprehensive Cancer Centre, King’s College London, London; ²⁵King’s College Hospital NHS Foundation Trust, London

A phase 2 trial of CHOP with anti-CCR4 antibody mogamulizumab for older patients with adult T-cell leukemia/lymphoma Available to Purchase

The phase 2 trial of Moga-CHOP (CHOP + mogamulizumab) in older patients with aggressive adult T-cell leukemia/lymphoma (ATL) demonstrated a significant improvement in 1-year PFS (36.2% vs 16% historical control), with a 1-year OS of 66.0% and a CR rate of 64.6%. The overall response rate (ORR) was high at 91.7%, and the median overall survival (OS) reached 1.6 years. Notably, CCR4 mutations and Moga-associated cutaneous AEs correlated with better OS, and the regimen was generally tolerable with no unexpected toxicities. Bottom line: Moga-CHOP is now a strong first-line option for older, transplant-ineligible ATL patients, and it’s encouraging to see these survival gains in a population with historically poor outcomes.

Phase III Trial of Pirtobrutinib Versus Idelalisib/Rituximab or Bendamustine/Rituximab in Covalent Bruton Tyrosine Kinase Inhibitor–Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-321)

Pirtobrutinib improved progression-free survival (PFS) to 14 months compared to 8 months with Idelalisib/Rituximab or Bendamustine/Rituximab (IdelaR/BR), with a hazard ratio of 0.54, in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had previously been treated with covalent BTK inhibitors (cBTKi). It also demonstrated favorable tolerability. With acalabrutinib and venetoclax emerging as preferred first-line therapies, Pirtobrutinib represents a strong second-line option for eligible patients.

Phase II Study of Acalabrutinib, Venetoclax, and Obinutuzumab in a Treatment-Naïve Chronic Lymphocytic Leukemia Population Enriched for High-Risk Disease

Triple therapy for CLL, AVO, is highly active and has very high MRD-negative rates compared to other studies using Ven+Obi or BTKi therapy alone. The battle between indefinite BTKi therapy vs more intense combination therapy will continue as we don’t know if one paradigm is better from a bigger picture.

Influence of Nucleophosmin (NPM1) Genotypes on Outcome of Patients With AML: An AIEOP-BFM and COG-SWOG Intergroup Collaboration

It does not seem that all NPM1 mutations are created equally. Type A and B mutations had favorable outcomes and type D mutations do much worse, something to consider when risk stratifying in patients with AML.

Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia

This study was done with and without obinutuzumab, both arms beat obinutuzumab and chlorambucil. There were more deaths in the obinutuzumab arm even though it was superior because of COVID, so it is immunosuppressive.