One more point for ibrutinib plus rituximab over fludarabine, cyclophosphamide and rituximab (FCR)

Chronic lymphocytic leukemia (CLL) is an incurable B-cell neoplasm characterized by T-cell dysfunction, which is responsible for increased risk of cancers and infections. In the first-line setting, ibrutinib plus rituximab has already won the match against fludarabine, cyclophosphamide and rituximab (FCR) by demonstrating improved progression-free survival (PFS) and overall survival (OS) at 5.8 years, with hazard ratios (HR) of 0.37 (P<0.001) and 0.47 (P=0.018), respectively (1). Notwithstanding these impressive results, a possibility of long-term disease control with FCR has been reported in a small subset of patients (giving hope for a cure), and some physicians could believe that this regimen still has a place in frontline CLL treatment (2). However, it is important to note that this long-term control is limited to a fraction of the minority of fit, IGHV mutated patients that reach undetectable minimal residual disease (MRD) after completing six FCR cycles, and does not prevent late relapses (2,3); moreover, at the population level, ibrutinib plus rituximab is a better option than FCR even in the case of IGHV mutated status (HR for PFS, 0.27, P=0.001; HR for OS, 0.72, P=0.68) (1). Eventually, FCR is associated with a high risk of infections and second primary malignancies, with high-risk myeloid neoplasms being an issue (4,5). With this ancillary analysis of E1912 study, the first phase 3 randomized trial that demonstrated the superiority of ibrutinib plus rituximab over FCR, no doubt that those physicians will change their minds (6). Indeed, Papazoglou and colleagues show that ibrutinib, apart from inhibiting CLL cells proliferation by its action on Bruton tyrosine kinase (BTK), can reinvigorate CD8 T-cells and partially restore in vitro the immunological disorders observed in CLL (6).

CLL is a good illustration that the immune microenvironment plays a major role in lymphoma pathophysiology; the best illustration of this being that CD4 T-cells are necessary for CLL cell survival in mice lymph nodes (7).

Moreover, T-cells play a central role in disease persistence and progression. A remarkable hallmark is that the CD4/CD8 ratio is diminished in CLL because of (I) increased number of CD4 in proliferation centers, and (II) blood CD8 T-cells expansion, with CD8 T-cells being ineffective in this case (8,9). Maybe as a result, the results of immune checkpoint inhibitors are disappointing in CLL.

Concerning CD4, regulatory T-cells (Tregs) are increased, and CLL Tregs are more immunosuppressive than normal Tregs (10,11). Their role in disease progression and in relapse kinetics after FCR has been suggested (12). Moreover, Th2 are overexpressed and attempts to reverse the skewed Th1 to Th2 T-cell differentiation, with the goal of restoring immune function alongside with the immunological synapse reconstitution with the use of lenalidomide failed, with the development of acute lymphoblastic leukemias while using this drug in maintenance (10,13-15).

Hence, attempts to drive immune system to better control the disease did not succeed. Readers of the analyses from Papazoglou and colleagues might hope that things are changing. This work analyzed T-cell subpopulations and natural killer (NK) cells at baseline, at 6 months and at 12 months of treatment in both arms of E1912, and allowed exploration of the correlation between immune cell subpopulation modifications and outcomes (6).

In the FCR arm, the authors observed a deep lymphodepletion after treatment completion, with an increased Treg to CD4 ratio.

Conversely, in the ibrutinib plus rituximab arm at baseline, the presence of an elevated absolute effector memory CD8⁺PD-1⁺ T-cells was associated with improved PFS (HR =0.266, P=0.0448); so was the presence of a higher percentage of PD-L1⁺CD19 B-cells (HR =0.070, P=0.0108), which can suggest the reversion of T-cell exhaustion and the ‘re-mobilization’ of previously exhausted T-cells to eventually kill CLL cells. This hypothesis is supported by (I) the positive impact of a higher percentage of effectors in the CD8⁺ subset at 6 months of ibrutinib plus rituximab (HR =0.267, P=0.0449 for PFS), and (II) the observation of restored T-cell exhaustion in patients from the ibrutinib plus rituximab arm: the authors observed enhanced killing functions compared to baseline, and improvement of immunological synapse as compared to baseline (with an augmentation of the proportion of CD8⁺ T-cell: CLL cell synapses compared to CD4⁺ T-cell: CLL cell synapses).

The authors then performed killing assays of CLL cells with and without the association of the T-cell-engaging bispecific antibody glofitamab (CD20×CD3) with T-cells from patients treated with ibrutinib plus rituximab, and showed a significant increase in T-cell mediated CLL cell death compared to baseline, at any point from 6 months of treatment; such an increase was not seen in FCR-treated patients, with no modifications in killing assays results. However, even if the authors of that study are experts in performing killing assays, patients treated with FCR had lower CD8 levels, which can diminish the T-cell mediated CLL death while using glofitamab.

Thus, findings from Papazoglou and colleagues indicate that the already known ability of ibrutinib to reverse T-cell exhaustion (16), translates into a restoration of immune-mediated disease control (6).

However, immune functions do not seem completely recovered as in vitro assays of adding anti-PD-1 to ibrutinib-exposed T-cells did not translate into cytotoxicity restoration; hence future studies will be necessary to decipher what happens within proliferation centers while using ibrutinib, but there is no doubt that this study allowed a step forward towards immunomodulation in CLL with the development of associations of ibrutinib and other immunotherapies.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-56/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-56/coif). M.G. received payment/honoraria from Astrazenecca, and Abbvie. The other author has no conflicts of interest to declare.

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