Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial

Abstract

Background: Treatment for adults with acute lymphoblastic leukaemia requires improvement. UKALL14 was a UK National Cancer Research Institute Adult ALL group study that aimed to determine the benefit of adding the anti-CD20 monoclonal antibody, rituximab, to the therapy of adults with de novo B-precursor acute lymphoblastic leukaemia.

Methods: This was an investigator-initiated, phase 3, randomised controlled trial done in all UK National Health Service Centres treating patients with acute lymphoblastic leukaemia (65 centres). Patients were aged 25-65 years with de-novo BCR-ABL1-negative acute lymphoblastic leukaemia. Patients with de-novo BCR-ABL1-positive acute lymphoblastic leukaemia were eligible if they were aged 19-65 years. Participants were randomly assigned (1:1) to standard-of-care induction therapy or standard-of-care induction therapy plus four doses of intravenous rituximab (375 mg/m2 on days 3, 10, 17, and 24). Randomisation used minimisation and was stratified by sex, age, and white blood cell count. No masking was used for patients, clinicians, or staff (including the trial statistician), although the central laboratory analysing minimal residual disease and CD20 was masked to treatment allocation. The primary endpoint was event-free survival in the intention-to-treat population. Safety was assessed in all participants who started trial treatment. This study is registered with ClincialTrials.gov, NCT01085617.

Findings: Between April 19, 2012, and July 10, 2017, 586 patients were randomly assigned to standard of care (n=292) or standard of care plus rituximab (n=294). Nine patients were excluded from the final analysis due to misdiagnosis (standard of care n=4, standard of care plus rituximab n=5). In the standard-of-care group, median age was 45 years (IQR 22-65), 159 (55%) of 292 participants were male, 128 (44%) were female, one (<1%) was intersex, and 143 (59%) of 244 participants had high-risk cytogenetics. In the standard-of-care plus rituximab group, median age was 46 years (IQR 23-65), 159 (55%) of 294 participants were male, 130 (45%) were female, and 140 (60%) of 235 participants had high-risk cytogenetics. After a median follow-up of 53·7 months (IQR 40·3-70·4), 3-year event-free survival was 43·7% (95% CI 37·8-49·5) for standard of care versus 51·4% (45·4-57·1) for standard of care plus rituximab (hazard ratio [HR] 0·85 [95% CI 0·69-1·06]; p=0·14). The most common adverse events were infections and cytopenias, with no difference between the groups in the rates of adverse events. There were 11 (4%) fatal (grade 5) events in induction phases 1 and 2 in the standard-of-care group and 13 (5%) events in the standard-of-care plus rituximab group). 3-year non-relapse mortality was 23·7% (95% CI 19·0-29·4) in the standard-of-care group versus 20·6% (16·2-25·9) in the standard-of-care plus rituximab group (HR 0·88 [95% CI 0·62-1·26]; p=0·49).

Interpretation: Standard of care plus four doses of rituximab did not significantly improve event-free survival over standard of care. Rituximab is beneficial in acute lymphoblastic leukaemia but four doses during induction is likely to be insufficient.

Funding: Cancer Research UK and Blood Cancer UK.

Conflict of interest statement

Declaration of interests AKF received institutional peer-reviewed grant funding from Cancer Research UK, the Medical Research Council, and Servier; received consulting fees from Amgen; has a leadership/fiduciary role for the British Society of Haematology (unpaid); and is on a data safety and monitoring board for Novartis. AAK has received honoraria from Kite and Gilead; has received institutional peer-reviewed grant funding from Millennium pharmaceutics, Bristol Myers Squibb, Amgen, Celgene, Merck Sharp and Dohme, Janssen-Cilag, Pfizer, and Cancer Research UK; and is on a data safety and monitoring board or advisory committee for the University of Birmingham. AKM has received honoraria form Amgen, Roche, Abbvie, and Celgene; has received institutional peer-reviewed grant funding from Janssen and AstraZeneca; has received meeting support from Roche, Celgene, and Abbvie; and is on a data safety and monitoring board or advisory committee for Novartis. AVM has received institutional peer-reviewed grant funding from Cancer Research UK, Blood Cancer UK, the EU Innovative Medicines Initiative, and North East Children's Cancer Fund; has a leadership/fiduciary role for the ALLTogther Consortium Board and the Genetics Committee and Science Committee (unpaid); and has received honoraria from Amgen. AZC has received honoraria from Pfizer, Amgen, and Hartley Taylor; and is on a data safety and monitoring board or advisory committee for Pfizer. BB has received institutional peer-reviewed grant funding from Novartis/Haematology Society of Australia and New Zealand (New Investigator Scholarship). CJR has received honoraria from Kite; is on a data safety and monitoring board or advisory committee for Incyte, Gilead, and Pfizer; and has a leadership/fiduciary role as the National Cancer Research Institute Adult ALL Group Chair (unpaid). DIM has received consulting fees from Amgen, Pfizer, Kite, and Novartis; and honoraria from Amgen, Pfizer, and Kite. DY has received meetings support from Amgen, Servier, and Jazz; and is on a data safety and monitoring board or advisory committee for the University of Birmingham, Gilead, and Pfizer. KEB has received research grant support from Blood Cancer UK. LC-H has received institutional peer-reviewed grant funding from Millennium pharmaceutics, Bristol Myers Squibb, Amgen, Celgene., Merck Sharp and Dohme, Janssen-Cilag, Pfizer, and Cancer Research UK. MC has received institutional peer-reviewed grant funding from Cure Leukaemia, Blood Cancer UK, Cyclacel, and Incyte; has received consulting fees from Pfizer, Novartis, and Jazz; has received payment or honoraria from Pfizer, Novartis, Jazz, and Astellias; and has received meeting support from Novartis. PS has received institutional peer-reviewed grant funding from Cancer Research UK, Blood Cancer UK, and Servier. RK has received honoraria from Amgen and Pfizer; and is on a data safety and monitoring board or advisory committee for Amgen. TFM has received honoraria from Amgen, Pfizer, Kite, Gilead, Janssen, Roche, Servier, Novartis, and Celgene; has received institutional peer-reviewed grant funding from Janssen and AstraZeneca; and has received meeting support from Novartis, Amgen, Pfizer, Kite, Gilead, Celgene, Daiichi Sankyo, and Atara. All other authors declare no competing interests.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Trial profile AML=acute myeloid leukaemia. AUL=acute undifferentiated leukaemia. HSCT=haematopoietic stem-cell transplantation. POQR=positive outside quantifiable range. *Standard of care: biphenotypic leukaemia n=1, diffuse large B-cell lymphoma n=1, acute myeloid leukaemia n=1, Burkitt lymphoma n=1; standard of care plus rituximab: diffuse large B-cell lymphoma n=2, chronic myeloid leukaemia blast phase n=1, lymphoma not otherwise specified n=2. †Deviations from protocol conditioning or donor. ‡Deviation from trial maintenance pathway. §Minimal residual disease data availability for risk assessment: at the end of phase 1, 422 had a result (negative, positive, POQR, or indeterminate), 57 had specimen processed but no target was identified, 98 had insufficient or missing diagnostic specimen or end of phase 1 specimen not received or patient off trial; at the end of phase 2, 393 had a result (negative, positive, POQR, or indeterminate), 43 had specimen processed but no target was identified, 122 had insufficient or missing diagnostic specimen or end of phase 2 specimen not received or patient off trial. ∥Post-induction maintenance pathway includes intensification and four blocks of consolidation before the start of maintenance. ||Post-induction reduced intensity conditioned allogeneic HSCT pathway also includes intensification before HSCT.

Figure 2

Event-free survival (A) and subgroup analysis of event-free survival (B) HR=hazard ratio. *GRAALL group cutoff.