Bertoni, Francesco

Abstract Aggressive B-cell non-Hodgkin lymphomas represent a clinically heterogeneous group of malignancies characterized by rapid progression and varied molecular features. Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive B-cell non-Hodgkin lymphoma and encompasses a biologically diverse group of diseases, now classified into 18 molecular subtypes (Alaggio et al. Leukemia, 2022). While first-line R-CHOP therapy cures approximately 60% of patients (Coiffier et al. N Engl J Med. 2002), those with relapsed or refractory (R/R) disease face poor outcomes. Although CAR T-cell therapies (e.g. axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) have improved outcomes, access remains limited due to logistical and disease-related constraints (Locke et al. N Engl J Med. 2022). More recently, bispecific CD20xCD3 antibodies such as epcoritamab and glofitamab have shown clinical activity in the R/R setting after ≥2 prior lines, with complete response (CR) rates of ~40% (Dickinson et al. N Engl J Med. 2022; Thieblemont et al. J Clin Oncol. 2023). However, treatment sequencing and mechanisms of resistance to CD20-targeted therapies remain areas of active investigation. One emerging resistance mechanism to CD20 bispecific antibodies is the downregulation or loss of CD20 expression, which has been associated with treatment failure and disease progression (Bannard et al. Clin. Cancer Research, 2022). This highlights the need for novel strategies to overcome CD20 resistance. Dapolsertib (MEN1703) is a first-in-class dual PIM/FLT3 kinase inhibitor that targets key oncogenic and survival pathways in hematologic malignancies. PIM kinases (PIM1, PIM2, PIM3) regulate translation, metabolism, apoptosis, and immune modulation. Overexpression and mutations in PIM genes are associated with poor prognosis in DLBCL, particularly in the ABC subtype, and are known to cooperate with MYC and BCL6 (Szydłowski et al. Cancer Res. 2021). Simultaneous inhibition of all three PIMs downregulates MYC and induces marked cytotoxicity in preclinical models. In AML, dapolsertib has demonstrated preliminary clinical single-agent activity, with ~10% CR/CRi reported in the DIAMOND study (NCT03008187; Martinelli et al. Blood Neoplasia, in press). Dapolsertib has also shown strong antitumor activity in lymphoma models, both in vitro and in vivo (Bellon et al. Mol Cancer. 2023). Notably, dapolsertib demonstrated synergy with anti-CD20 antibody, rituximab, providing a rationale for combination strategies (Szydłowski et al. Cancer Res. 2021). The rationale for combining dapolsertib with a CD20 bispecific antibody lies in its potential to modulate survival pathways, sensitize malignant B-cells to immunotherapy, and circumvent resistance mechanisms such as CD20 loss by inducing CD20 expression. JASPIS-01 (NCT06534437) is an ongoing, international multicenter, Phase 2 study evaluating dapolsertib as monotherapy or in combination with glofitamab in patients with R/R aggressive B-cell lymphoma after ≥2 prior lines of therapy. The trial consists of three parts: a safety run-in (Part 1), optional enrichment (Part 2), and a potential randomized comparison vs. glofitamab (Part 3). Part 1 will include 2 groups of patients. Group 1 comprises bispecific-naïve patients randomized to a prospective dose-optimization evaluation of the combination with dapolsertib. Patients receive either 125 mg on a 2 weeks on / 1 week off schedule or 150 mg on a 1 week on / 2 weeks off schedule for up to 12 cycles to investigate optimal therapeutic window. Group 2 comprises patients who exhausted therapeutic standard options and who will receive dapolsertib monotherapy at 125 mg on a 2 weeks on / 1 week off schedule until intolerable toxicity or disease progression. The initial safety run-in (Parts 1 of both groups) informs dose selection for Part 2. Dose continuation in Part 2 will be guided by Data and Safety Monitoring Board safety assessments after ≥2 completed treatment cycles. The primary objectives are to assess safety, tolerability, and preliminary anti-lymphoma activity. Key endpoints include incidence of adverse events, overall/complete response rates, and duration of response. As of July 11, 2025, Part 1 is enrolling in France, Poland, Spain and the UK with additional sites activation ongoing.

ABSTRACT The PIM family of serine/threonine kinases (PIM1, PIM2, and PIM3) are involved in the development of cancer and represent promising therapeutic targets. We investigated the therapeutic potential of targeting PIM kinases in diffuse large B‐cell lymphoma (DLBCL), particularly the activated B‐cell‐like (ABC) subtype, using the pan‐PIM inhibitor AZD1208. We demonstrated that PIM1 and PIM2 are more highly expressed in ABC‐ cells than in germinal center B‐cell‐like (GCB) ‐DLBCL cells, and that ABC‐DLBCL cell lines are more sensitive to PIM inhibition with AZD1208. Transcriptome analysis of ABC‐DLBCL cell lines treated with AZD1208 revealed a downregulation of genes involved in NF‐κB signaling, a crucial pathway for ABC‐DLBCL. We also explored synergistic drug combinations using a high‐throughput screen, which identified BCL2 and glutaminase inhibitors as effective partners for AZD1208, particularly in aggressive ABC‐DLBCL and double‐hit cell lines. The combination of AZD1208 with the clinically available BCL2 inhibitor venetoclax was synergistic in most DLBCL cell lines, and this combination induced apoptosis and reduced levels of AKT and MCL1 proteins. In conclusion, our findings suggested that AZD1208, especially when combined with BCL2 inhibitors like venetoclax, holds promise as a treatment strategy for aggressive lymphomas. These combinations may enable lower doses of PIM inhibitors, leading to increased tolerability and improved anti‐tumor activity in clinical settings. The study also highlighted the potential for targeting PIM kinases in combination with other therapies to overcome drug resistance in DLBCL.