Immune cells in chronic lymphocytic leukemia and Hodgkin lymphoma in relation to tumor burden and treatment

B-cell malignancies are a heterogeneous group of cancers that originate from lymphoidlineage cells that are responsible for humoral immunity. When B-cell development goes wrong, chronic lymphocytic leukemia (CLL) and classical Hodgkin lymphoma (cHL), among other malignancies, may arise. Recent advances in the treatment of these diseases, e.g., ibrutinib in CLL, have greatly improved the prognosis of patients, but also introduced new challenges. Gaining knowledge about the effects that these treatments have on immune cells might help us overcome these challenges.

In Paper I, we described our efforts to further elucidate the on- and off-target mechanisms behind ibrutinib’s common adverse events and immune effects by performing proximity extension assays to measure 265 plasma biomarkers and flow cytometry to assess the immune cell dynamics throughout 5 years of ibrutinib treatment in 13 CLL patients. In Paper II, we tested the safety and feasibility of a novel intermittent dosing strategy for ibrutinib. Treatment was interrupted in CLL patients who were in remission and resumed when early sign of progression occurred in a repetitive fashion. In paper III, we characterized the influences that cHL has on circulating lymphocytes in relation to clinical parameters and first-line treatment.

We found that numerous biomarkers changed during ibrutinib treatment and categorized them by cellular origin and related conditions. Interestingly, we discovered 6 potential mediators of ibrutinib-induced atrial fibrillation. We also showed that successful ibrutinib treatment leads to a reduction in all T-cell populations, including T helper 1 cells, Tregs and exhausted T cells, which paralleled the declining tumor burden. T helper 2 (Th2) cells remained relatively stable, causing Th2-skewing. Interrupting ibrutinib turned out to be safe in CLL patients that are in a sustained remission and resuming the drug upon early signs of progression induced new objective responses. Circulating T cells in cHL were found to be exhausted and terminally differentiated, B- and natural killer-cell numbers were low, and inflammation and tumor burden were related to distinct immune profiles. Standard first-line treatment reversed most changes. However, radiotherapy involving the mediastinum seemed to selectively reduce T cells.

We conclude from these studies that ibrutinib has broad immunomodulatory effects and that several investigated biomarkers might be involved in ibrutinib-induced atrial fibrillation. Moreover, ibrutinib can safely be interrupted in responding CLL patients, who remain drugsensitive when progressive disease occurs. The risk of serious infections seems to be lower when patients are off the drug. On top of the well-studied control that malignant cells have over the immune cells in the tumor microenvironment, cHL patients have signs of systemic immunosuppression as well, which could be solved to a large extent by standard front-line treatment.

List of scientific papers

I. Mulder TA, Peña-Pérez L, Berglöf A, Meinke S, Estupiñán HY, Heimersson K, Zain R, Månsson R, Smith CIE and Palma M. Ibrutinib has time-dependent on- and off-target effects on plasma biomarkers and immune cells in chronic lymphocytic leukemia. HemaSphere. 2021 May;5(5):e564.
https://doi.org/10.1097/HS9.0000000000000564

II. Lundin J, Mulder TA, Kättström M, Wästerlid T, Uddevik A, Mellstedt H, Heimersson K, Hansson L, Palma M and Österborg A. Temporary cessation of ibrutinib results in reduced grade 3-4 infections and durable remissions – Interim analysis of an on-off-repeat Phase 1b/2 study in patients with chronic lymphocytic leukemia. eJHaem. 2021 Aug;2(3):525-529.
https://doi.org/10.1002/jha2.261

III. Mulder TA, Andersson ML, Heimersson K, Xagoraris I, Wahlin BE, Hansson L, Rassidakis G and Palma M. Characterization of immune cells in the tumor microenvironment and peripheral blood of classical Hodgkin lymphoma patients in relation to tumor burden and treatment. [Manuscript]