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The role of Pi3K inhibitors in lymphoma is diminishing due to the adverse results from trials in indolent lymphoma, but is a one-size-fits-all approach to drug development penalising some lymphoma subtypes and the newer generation of Pi3K inhibitors? The report by Soumerai et al. of zandelisib with zanubrutinib in follicular and mantle cell lymphoma is an important addition to the data. Commentary on: Soumerai et al. Safety and efficacy of zandelisib plus zanubrutinib in previously treated follicular and mantle cell lymphomas. Br J Haematol 2024;204:1762-1770.

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We report the outcome of 563 cases of newly diagnosed lymphoma registered in 2019-2021, including 176 cases (31.2%) of Hodgkin lymphoma (HL), 130 (23.1%) of diffuse large B-cell lymphoma (DLBCL), 28 (5%) of follicular lymphoma (FL), 16 (2.9%) of mantle cell lymphoma (MCL) and 20 (3.5%) of peripheral T-cell lymphoma (PTCL). After a median follow-up of 30.1 months (95% CI: 28.8-31.3), the 3-year overall survival rates were 95%, 83%, 86%, 100%, 61% and 42% for HL, DLBCL, CLL, FL, MCL and PTCL respectively. These data offer valuable information on the curability of lymphoma patients in Ukraine, in a real-world setting.

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Classical Hodgkin lymphoma (cHL) accounts for 0.4% of all new cancer cases globally. Despite high cure rates with standard treatment, approximately 15% of patients still experience relapsed or refractory (RR) disease, and many of these eventually die from lymphoma-related causes. Exciting new targeted agents such as anti-PD-1 agents and brentuximab vedotin have changed the therapeutic paradigm beyond chemotherapy and radiotherapy alone. Advances in understanding of the molecular biology are providing insights in the context of novel therapies. The signature histology of cHL requires the presence of scant malignant Hodgkin Reed-Sternberg cells (HRSCs) surrounded by a complex immune-rich tumour microenvironment (TME). The TME cellular composition strongly influences outcomes, yet knowledge of the precise characteristics of TME cells and their interactions with HRSCs is evolving. Novel high-throughput technologies and single-cell sequencing allow deeper analyses of the TME and mechanisms elicited by HRSCs to propagate growth and avoid immune response. In this review, we explore the evolution of knowledge on the prognostic role of immune cells within the TME and provide an up-to-date overview of emerging prognostic data on cHL from new technologies that are starting to unwind the complexity of the cHL TME and provide translational insights into how to improve therapy in the clinic.

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The Ukrainian Lymphoma Registry (ULR) was established in 2019 with the aim of monitoring the quality of diagnosis, staging, and treatment of lymphoma in Ukraine. Between September 2019 and October 2021, 546 patients with newly diagnosed lymphoma were prospectively registered. All cases were diagnosed according to the 2016 updated WHO lymphoma classification. The male-to-female ratio (M/F) for the whole population was 0.7, with a median age of 46 years (range 18-95). The adoption of the 2016 WHO classification resulted in the identification of 36 different lymphoma subtypes, with 132 cases (24.2%) classified differently compared to the 2008 WHO classification. Only 12 cases (2.8%) were true new entities, including seven cases of high-grade B-cell lymphoma NOS, three of anaplastic large B-cell lymphoma, ALK-negative, 1 case of HHV8+ DLBCL NOS, and 1 of high-grade B-cell lymphoma with C-MYC and BCL2/BCL6 rearrangement. Moreover, 55 (61.1%) entities, including 37 defined by WHO 2008 and 18 defined by WHO 2016, were not represented at all. The analysis of cases registered in the ULR provides a comprehensive breakdown of the subtypes, stage distribution, and treatment of malignant lymphomas (ML) in Ukraine, supporting the usefulness of prospective data collection and timely reporting. We believe that this study is the first step toward a better understanding of the real-life outcomes of patients with ML.

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BACKGROUND: Clinical outcomes of Langerhans cell histiocytosis (LCH) are highly variable. It has been suggested that mitogen-activated protein kinase (MAPK) /extracellular signal-regulated kinases (ERK) signaling pathway might be activated in LCH patients. MATERIALS AND METHODS: We investigated KRAS, BRAF and NRAS mutations in patients with LCH by qPCR. RESULTS: Eight adult patients with LCH were treated at the National Cancer Institute, Kiev, Ukraine. Five patients received chemo plus radiation therapy and three patients received only chemotherapy, resp. (p < 0.05). All patients received LCH-I study protocol, six cycles in average. A BRAF c.1799T > A, p. V600E mutation was detected in 25% (2/8) of cases - 1 patient had an early relapse in 6 months, and 1 patient - stable disease. We did not find any BRAF, KRAS or NRAS mutations in three patients with late relapses (in 15, 24 and 46 months). Notably, KRAS mutations were not revealed in any LCH samples. The NRAS c.182A > G, p. Q61R mutation was found in two cases - one patient had LCH transformed to Hodgkins lymphoma, one patient had a refractory disease. Time to relapse rate (TTR) in patients with and without BRAF V600E gene mutation was 13 vs. 28 months, resp. (p < 0.05). TTR was 31.3 vs. 6.41 months in patients with absence and presence of NRAS mutation, p < 0.05. Multivariate analysis showed the presence of NRAS Q61R mutation was associated with poor event-free survival in LCH patients with HR of 6.1 (95% CI 0.2-12.6; p = 0.008). CONCLUSION: BRAF and NRAS mutations in LCH suggest a possibility of the disease being driven by the activation of the MAPK/ERK pathway. These oncogenic mutations provide new opportunities in understanding LCH pathogenesis and may be a potential target of therapy.Key words: Langerhans cell histiocytosis - mutations - prognostic factors - relapse - survival.

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