Anti‐CD20 immunotherapy as a bridge to tolerance, after allogeneic stem cell transplantation for patients with chronic lymphocytic leukaemia: results of the CLLX4 trial (2018)

Treatment failure after allogeneic haematopoietic cell transplantation (HCT) in patients with high risk chronic lymphocytic leukaemia (CLL) is almost equally distributed between relapse and non-relapse mortality (van Gelder et al, 2017). Pre-clinical and clinical evidence suggests anti-CD20 immunotherapy may be promising for the prevention and treatment of chronic graft-versus-host disease (GVHD) (Kharfan-Dabaja & Cutler, 2011; Zeiser & Blazar, 2016). Moreover, anti-CD20 antibodies are routinely used in the treatment of CLL. The objective of the CLLX4 trial was to harness the anti-CD20 antibody, ofatumumab, for the dual-purpose of disease-control peri-transplantation and prevention of chronic GVHD. Here, we report final results from the CLLX4 trial, a multicentre, single arm, open phase II study for elderly patients with advanced CLL (NCT01809847). Patients were enrolled into the trial between June 2013 and August 2014. Major eligibility criteria were a diagnosis of CLL according to World Health Organisation criteria confirmed by flow cytometry of peripheral blood or bone marrow, age > 55 years, active high-risk disease according to the 2007 European Society for Blood and Marrow Transplantation CLL Transplant Consensus, and a physical performance which allowed for allogeneic HCT. All patients signed written informed consent. The trial was approved by the Ethical Review Board (EK 291092012) and conducted in accordance with the Declaration of Helsinki. Treatment comprised 8 weeks of induction therapy (1 × 300 mg ofatumumab, then 7 × 2000 mg ofatumumab weekly, combined with 4 days of dexamethasone 40 mg in weeks one, three, five and seven) followed by six monthly doses of ofatumumab as maintenance for patients with at least stable disease at 8 weeks assessment (Supporting Information). Patients with a human leucocyte antigen (HLA)-allele-matched (referring to HLA-A, -B, -C, and -DRB1) related or unrelated donor proceeded to allogeneic HCT during the maintenance part of the trial after conditioning with 30 mg/m2 fludarabine (days −6 to −2), 4 × 1 mg/kg busulphan orally (days −3 and −2) and 10 mg/kg antithymocyte-globulin (ATG Fresenius®; days −4 to −1, for patients with unrelated donors). GVHD prophylaxis consisted of ciclosporin adjusted to plasma trough levels starting on day −1 and mycophenolate mofetil starting on day 0 at a dose of 2 × 15 mg/kg for all patients. Co-primary endpoints were the rates of overall response after induction therapy and negative minimal residual disease (MRD). The trial was stopped in 2014 after the enrolment of 17 patients due to a steep decline in accrual after marketing approval of ibrutinib for patients with relapsed or refractory CLL in Europe. Baseline patient characteristics are given in Table 1. Compliance was good and 98% of scheduled ofatumumab infusions were administered. Twenty-one adverse events (AE)s Common Toxicity Criteria grade ≥3 (39%) were observed prior to alloHCT or in patients who did not receive alloHCT, whereas 33 AEs grade ≥3 (61%) were observed after alloHCT. No new safety signals for ofatumumab were identified and none of the AEs after alloHCT were assigned to ofatumumab (Table SI). The overall response rate after induction therapy was 47% [90% confidence interval (CI) 26–69%]. Twelve patients started maintenance therapy after induction therapy. Seven patients received per protocol alloHCT. Of these seven patients, five (71%, 90% CI 34–95%) experienced acute GVHD grade I-IV and two patients developed mild chronic GVHD. Five patients completed maintenance therapy and passed the 14-month assessment for MRD according to protocol (Figure S1). The main reasons to go off study during maintenance therapy were AEs (N = 3) in patients after alloHCT and progressive disease (N = 3) in patients on ofatumumab maintenance therapy without alloHCT. Altogether, 3 out of 17 patients (18%, 90% CI 5–40%) achieved MRD-negativity by 14 months after the start of the study. All three patients had been transplanted and were alive and well at last follow-up. Two-year overall (OS) and event-free survival (EFS) for all patients was 53% (90% CI 33–73%) and 18% (90% CI 2–33%). Two-year survival was 63% (90% CI 34–91%) for responders and 44% (90% CI 17–72%) for non-responders after ofatumumab induction. From start of maintenance therapy, 2-year OS was 57% (90% CI 26–88%) in transplanted patients and 100% (90% CI not available) in patients with ofatumumab only (Figure S2). Nine patients died, including all patients who did not receive maintenance therapy. Causes of death for all patients and sequential therapy of CLL after end of study treatment are listed in Table 2. B cell reconstitution after alloHCT is characterized by the expansion of activated, potentially allo- and auto-reactive B cells that would physiologically undergo negative selection (Sarantopoulos & Ritz, 2015). Anti-CD20 antibody therapy after alloHCT aims to restore B cell homeostasis by postponing B cell reconstitution until less immunological alarm signals are prevalent. Two independent phase II trials, where rituximab was used for GVHD prevention, reported promisingly low rates of steroid-requiring chronic GVHD (Cutler et al, 2013; Michallet et al, 2013). Data collected in this study contribute to the growing body of information on the safety and efficacy of anti-CD20 antibody use in this indication. In line with the critical role of B-cell receptor activation for the survival of auto-reactive B cells, ibrutinib has demonstrated activity in patients with steroid-refractory chronic GHVD (Zeiser & Blazar, 2016; Miklos et al, 2017). These options for tuning B cell reconstitution after alloHCT deserve further evaluation in randomized controlled trials. None of the new pathway inhibitors, ibrutinib, idelalisib, and venetoclax, had been approved during the enrolment period into the CLLX4 trial. In this trial, alloHCT had no significant impact on OS in pathway inhibitor-naïve patients. In contrast, survival was probably determined by access to pathway inhibitors after failure of maintenance therapy. Given the beneficial safety profile and efficacy of these drugs, alloHCT should be postponed. It is likely that alloHCT will remain an attractive salvage option after failure of one or even more pathway inhibitors. Some patients, however, will be lost during sequential treatment due to Richter transformation and/or infectious complications (Mato et al, 2016; Jones et al, 2018). Given the sustained disease control after alloHCT in a significant percentage of patients, recommendation of alloHCT to good risk transplant candidates who are refractory or intolerant to either BTK- or BCL2-inhibition may still be a wise clinical decision (van Gelder et al, 2017; Schetelig et al, 2017). We are grateful to the study coordinator, Angelika Bitter, and the local study nurses as well as the dedicated staff of the participating transplant centres. This trial was supported by an unrestricted grant from Glaxo Smith Kline (Brentford, Middlesex, United Kingdom). After the transfer of ofatumumab to Novartis (Basel, Switzerland) this grant was provided by the new owner of the market authorisation. All authors made substantial contributions to the acquisition, analysis and interpretation of the data, revised the manuscript critically and approved the final version. In detail, JS, StS, MH, and MB designed the study. JS, CSL, GS, EMW, MH, GK, SB, JMM, KS, RT, MVB, FS, and StS treated patients according to the protocol. SB and KAK performed central diagnostics. JS was the clinical coordinator and wrote the paper. Table SI. Adverse events CTC grade ≥3. Fig S1. Modified consort diagram. Fig S2. Overall survival by type of maintenance therapy. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.