In-vivo T-cell depleted reduced-intensity conditioned allogeneic haematopoietic stem-cell transplantation for patients with acute lymphoblastic leukaemia in first remission: results from the prospective, single-arm evaluation of the UKALL14 trial

Abstract

Background: The outcome of chemotherapy in patients older than 40 years with acute lymphoblastic leukaemia is poor and myeloablative allogeneic haematopoietic stem-cell transplantation (HSCT) has a high transplant-related mortality (TRM) in this age cohort. The aim of this study was to assess the activity and safety of reduced-intensity conditioned allogeneic HSCT in this patient population.

Methods: This was a single-arm, prospective study within the UKALL14 trial done in 46 centres in the UK, which recruited patients to the transplantation substudy. Participants in UKALL14 had B-cell or T-cell acute lymphoblastic leukaemia, were aged 25-65 years (BCR-ABL1-negative) or 18-65 years (BCR-ABL1-positive), and for this subcohort had a fit, matched sibling donor or an 8 out of 8 allelic matched unrelated donor (HLA-A, HLA-B, HLA-C, and HLA-DR). On June 20, 2014, the protocol was amended to allow 7 out of 8 matched unrelated donors if the patient had high risk cytogenetics or was minimal residual disease (MRD)-positive after the second induction course. Patients were given fludarabine, melphalan, and alemtuzumab (FMA; intravenous fludarabine 30 mg/m2 on days -6 to -2, melphalan 140 mg/m2 on day -2, and alemtuzumab 30 mg on day -1 [sibling donor] and days -2 and -1 [unrelated donor]) before allogeneic HSCT (aged ≥41 years patient pathway). Donor lymphocyte infusions were given from 6 months for mixed chimerism or MRD. The primary endpoint was event-free survival and secondary and transplantation-specific endpoints included overall survival, relapse incidence, TRM, and acute and chronic graft-versus-host disease (GVHD). This study is registered with ClinicalTrials.gov, NCT01085617.

Findings: From Feb 22, 2011, to July 26, 2018, 249 patients (236 aged ≥41 years and 13 younger than 41 years) considered unfit for a myeloablative allograft received an FMA reduced-intensity conditioned HSCT. 138 (55%) patients were male and 111 (45%) were female. 88 (35%) participants received transplantations from a sibling donor and 160 (64%) received transplantations from unrelated donors. 211 (85%) participants had B-precursor acute lymphoblastic leukaemia. High-risk cytogenetics were present in 43 (22%) and another 63 (25%) participants were BCR-ABL1-positive. At median follow-up of 49 months (IQR 36-70), 4-year event-free survival was 46·8% (95% CI 40·1-53·2) and 4-year overall survival was 54·8% (48·0-61·2). 4-year cumulative incidence of relapse was 33·6% (27·9-40·2) and 4-year TRM was 19·6% (15·1-25·3). 27 (56%) of 48 patients with TRM had infection as the named cause of death. Seven (15%) of 48 patients had fungal infections, 13 (27%) patients had bacterial infections (six gram-negative), and 11 (23%) had viral infections (three cytomegalovirus and two Epstein-Barr virus). Acute GVHD grade 2-4 occurred in 29 (12%) of 247 patients and grade 3-4 occurred in 12 (5%) patients. Chronic GVHD incidence was 84 (37%) of 228 patients (50 [22%] had extensive chronic GVHD). 49 (30%) of 162 patients had detectable end-of-induction MRD, which portended worse outcomes with event-free survival (HR 2·40 [95% CI 1·46-3·93]) and time-to-relapse (HR 2·41 [1·29-4·48]).

Interpretation: FMA reduced-intensity conditioned allogeneic HSCT in older patients with acute lymphoblastic leukaemia in first complete remission provided good disease control with moderate GVHD, resulting in better-than-expected event-free survival and overall survival in this high-risk population. Strategies to reduce infection-related TRM will further improve outcomes.

Funding: Cancer Research UK.

Conflict of interest statement

Declaration of interests DIM reports educational events, consulting, and advisory boards for Pfizer, Amgen, Kite, and Novartis. MC declares grants or contracts with Incyte and Cyclacel; speakers bureau or honoraria for Incyte, Novartis, Pfizer, Astellas, Jazz, and Gilead; and advisory boards for Novartis, Pfizer, Jazz, and Daiichi-Sankyo. AM received educational honoraria and payments for advisory boards and travel sponsorship from Roche; advisory board honoraria from Amgen; educational and travel payments from BMS and Celgene; and advisory board honoraria from AbbVie. TFM declares travel grants from Amgen, Jazz, Pfizer, Bayer, Kyowa Kirin, Celgene, Kite/Gilead, Janssen, and Takeda; advisory board honoraria from Kite/Gilead, Amgen, Novartis, Pfizer, Celgene, Daiichi Sankyo, Atara, and Roche; lecture honoraria from Kite/Gilead, Takeda, Janssen, Roche, Servier, Novartis, and Celgene; and research funding from Janssen, AstraZeneca, and Novartis. AVM received honoraria for an educational event for Amgen. MNP received honoraria and meeting support from Kite. NM received speaker fees from Amgen, Janssen, and AbbVie; attended advisory boards of AbbVie and Kite; and had conference support from AbbVie and Takeda. CJR reports paid educational events for Kite and Incyte; and advisory boards for Kite, Novartis, Amgen, and Pfizer. AKF reports consulting for Amgen. BP received honoraria from Pfizer and Amgen. 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

Study profile ALL=acute lymphoblastic leukaemia. DLBCL=diffuse large B-cell lymphoma. FMA=fludarabine, melphalan, and alemtuzumab. GVHD=graft-versus-host disease. HSCT=haematopoietic stem-cell transplantation. *Patient taken off trial for non-protocol conditioning or donor. †Clinician choice based on patient fitness (excluded from univariable and multivariable survival analysis).

Figure 2

Major outcomes of reduced-intensity conditioned allogeneic haematopoietic stem-cell transplantation (A) Event-free survival. (B) Overall survival. (C) Cumulative incidence of relapse. (D) Cumulative incidence of transplant-related mortality.