Ozren Jaksic

The impact of venetoclax‐based therapies on autoimmune cytopenias (AIC) in patients with chronic lymphocytic leukemia (CLL) is largely unknown. This study aimed to evaluate preexisting and treatment‐emergent AIC in patients with CLL treated with venetoclax, focusing on the differential impact of venetoclax monotherapy versus venetoclax‐based combinations. In this retrospective multicenter study, data from 1720 patients were collected; 23.1% received venetoclax single agent and 76.9% venetoclax combinations (mostly containing anti‐CD20 monoclonal antibodies and/or BTK inhibitors). Combination regimens were used in 97.7% of treatment‐naïve (TN) patients and 65.8% of patients with relapsed/refractory (R/R) CLL. Preexisting AIC were reported in 11.7% of patients (8.7% in TN and 13.4% in R/R, P = 0.005). CLL‐related genetic risk factors and disease outcomes did not differ in patients with and without preexisting AIC. Irrespective of treatment type, venetoclax therapy resulted in AIC resolution or improvement in 63% of patients with active or controlled AIC. Treatment‐emergent AIC occurred in 2.6% of patients (2% in TN and 2.9% in R/R, not statistically significant). AIC episodes were reported in 4.3% of patients treated with venetoclax monotherapy and in 2.1% of those treated with venetoclax‐based combinations (P = 0.02). After standard management, AIC was considered resolved or controlled in 82% of the patients, with no substantial difference between treatment groups. Venetoclax‐based therapies have a beneficial impact on the outcome of CLL‐associated preexisting AIC. Treatment‐emergent AIC is a rare and generally manageable event. Although more frequent with venetoclax monotherapy in unadjusted analysis, this association was attenuated after adjustment for baseline prognostic factors.

Background: Late-onset neutropenia (LON) and hypogammaglobulinemia are recognized sequelae of rituximab therapy in B-cell non-Hodgkin lymphoma, and both may leave patients vulnerable to infection once treatment has ended. Methods: Fifty-three patients with newly diagnosed, unfavorable diffuse large B-cell lymphoma (DLBCL) who entered remission on dose-adjusted (DA) R-EPOCH immunochemotherapy were retrospectively evaluated. Neutropenia (absolute neutrophil count < 1.5 × 10⁹/L, CTCAE-graded), hypogammaglobulinemia and infections were registered at treatment completion and 6 and 12 months later. Results: All laboratory parameters changed significantly over time. Most reached their nadir at the end of treatment, whereas the absolute neutrophil count alone reached its lowest value later, at 6 months. Neutropenia, largely mild to moderate, affected 17.6% of patients at treatment completion, 22.4% at 6 months and 7.9% at 12 months. Neutropenia at 6 months was a new event, with no overlap with end-of-treatment neutropenia, and was mostly transient. Hypogammaglobulinemia (IgG < 5 g/L) occurred in 33.3%, 16.7% and 20.0%, respectively; median IgG declined to a nadir at the end of treatment and recovered thereafter, although the deficit tended to persist in the same patients. Post-treatment infections were recorded in 73.6% of patients (mostly respiratory); neutropenia was not associated with infection at any time point, whereas end-of-treatment hypogammaglobulinemia was associated with respiratory infection (p = 0.040). The independent predictors of 6-month neutropenia were a greater number of dose-escalated cycles, lower baseline leukocyte count and the absence of on-treatment infection, whereas 6-month hypogammaglobulinemia was predicted by autologous transplantation and the absence of B symptoms. In exploratory body composition analyses, lower baseline psoas muscle mass was associated with end-of-treatment neutropenia (p = 0.042) and greater muscle loss with other site (skin and gastrointestinal) infection (p = 0.004). Conclusions: After DA-R-EPOCH, LON is a delayed and largely transient event separate from end-of-treatment neutropenia, whereas hypogammaglobulinemia is more persistent and clinically relevant for respiratory infections.

Background/Objectives: Bortezomib, a proteasome inhibitor, is one of the key agents in the first-line treatment of multiple myeloma (MM). Although its hepatotoxic potential has been described in case reports and registration trials, systematic real-life studies quantifying the incidence, dynamics and prognostic significance of liver injury during bortezomib-based therapy are lacking. We aimed to characterize the hepatotoxicity profile of first-line bortezomib-based regimens. Methods: We retrospectively analyzed 115 consecutively treated MM patients at University Hospital Dubrava (2016–2023) who received first-line bortezomib-based regimens (VCD, VD, VMP, VRD, VTD). Liver function parameters (bilirubin, albumin, AST, ALT, GGT, ALP) were recorded at baseline and after 1 and 3 months, and abnormalities were graded according to CTCAE v5.0. Predictors of liver injury and its association with IMWG response and overall survival (OS) were assessed. Results: Elevation of any liver transaminase was observed in 33% of patients at baseline, 40.2% at 1 month and 24% at 3 months. De novo worsening developed in 23.4% of patients, predominantly (88%) within the first month, with a dominantly cholestatic pattern (96%). Liver injury was not associated with the antimyeloma regimen, the class of supportive therapy, or most comorbidities (besides second malignancy for 3-month derangement), whereas higher tumor burden and baseline liver injury were identified among the predictors. Transaminase abnormalities were not associated with the likelihood of achieving a response, but liver injury at 3 months independently predicted shorter OS (HR 2.83; p = 0.011) after adjustment for age, sex and ISS stage. Conclusions: Liver injury in bortezomib-treated MM patients is frequent and predominantly associated with the biology of the underlying disease rather than necessarily with the antimyeloma therapy itself; abnormalities persisting at 3 months deserve attention as an independent adverse prognostic marker.

During the pre-Omicron phases of the COVID-19 pandemic, patients with hematological neoplasms were characterized by very high morbidity and mortality rates. Remdesivir, a viral RNA-polymerase inhibitor, interferes with key SARS-CoV-2 enzymes, preventing the virus from multiplying. The use of convalescent plasma (CP) in treating patients with COVID-19 has been shown to be beneficial in patients with an impaired humoral response to infection, including most of those on active treatment for hematologic malignancies. This retrospective, non-interventional study was performed using the Croatian Cooperative Group for Hematological Diseases database of patients with hematological malignancies infected with SARS-CoV-2. Patients treated with remdesivir and/or CP were matched to those untreated according to age, disease type, and antineoplastic therapy. We identified 119 patients treated with remdesivir and/or CP fulfilling entry criteria and matched 116 according to our established criteria to one of the 374 untreated patients. Treatment significantly reduced COVID-19 mortality. The beneficial effect of antiviral therapy was limited to those who started antiviral treatment within 7 days of the onset of symptoms. Due to the exclusive enrolment of hematological patients with COVID-19, our study provides unique insights into the benefits of early application of both antiviral and CP therapy. It emphasizes the need for early administration before the infection has transformed into the hyperinflammatory phase.

Background/Objectives: Ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia but has off-target side effects, most notably cardiac. In order to evaluate the efficacy and toxicity of ibrutinib treatment, risk factors for adverse outcomes and the influence of pretreatment cardiologic evaluation, KroHem collected data on Croatian patients with chronic lymphocytic leukemia treated with this drug. Methods: This is a retrospective survey performed in order to analyze the efficacy and toxicity of ibrutinib in a real-life setting. Patients starting therapy with ibrutinib for chronic lymphocytic leukemia between the time the drug became reimbursable in 2015 and 31 December 2021 were included, irrespective of treatment line. Results: We identified 436 patients fulfilling entry criteria; 404 (92.7%) responded to treatment. Cardiovascular side effects occurred in 25.0% of patients and hemorrhagic in 15.6%. The dose of ibrutinib was permanently reduced in 22.2% of patients. Median follow-up of the cohort was 29 months (IQR 18–41 months), estimated median overall survival 75 months (IQR 36 months–not reached), progression-free survival 54 months (IQR 24–81 months) and time on ibrutinib treatment 44 months (IQR 14–78 months). Factors significantly related to overall survival in multivariate analysis were stage, treatment line and age. Factors significantly related to progression-free survival in multivariate analysis were treatment line, age and pretreatment history or ECG finding of cardiac arrhythmia. Factors significantly related to time on ibrutinib treatment in multivariate analysis were age, pretreatment history or ECG finding of cardiac arrhythmia, and permanent dose reduction for toxicity. Sex, FISH and the presence of arterial hypertension were not independently significantly related to any of these outcomes. Pretreatment cardiologic consultation did not improve time on ibrutinib therapy, progression-free survival, overall survival, risk of stopping treatment due to cardiovascular side effects or risk of cardiovascular or sudden death, neither in the whole cohort nor in the subgroup of patients with and without pretreatment cardiac arrhythmia. Conclusions: Our analysis confirms the efficacy and tolerability of ibrutinib for the treatment of chronic lymphocytic leukemia. Patients older than 75 do significantly less well. Routine pretreatment cardiologic consultation does not improve outcomes and should not be considered part of standard pretreatment assessment without additional proof of its usefulness. Future investigations should aim at identifying predictive factors, mechanisms, and preventive strategies for reducing cardiotoxicity in chronic lymphocytic leukemia patients taking Bruton tyrosine kinase inhibitors.

Background/Objectives: Obinutuzumab was approved for front-line treatment of chronic lymphocytic leukemia in combination with chlorambucil pulses administered every 2 wks. Alternative schedules of chlorambucil enable the administration of higher total chlorambucil doses, and have better antileukemia activity. So far, evidence on the feasibility of combining obinutuzumab with alternative chlorambucil schedules is lacking. We performed this retrospective analysis to analyze real life outcomes in chronic lymphocytic leukemia patients receiving a combination of obinutuzumab with different chlorambucil schedules. Methods: This was a retrospective survey performed in order to analyze the feasibility and efficacy of different obinutuzumab and chlorambucil combinations in a real-life setting. Patients receiving this combination as a front-line therapy for chronic lymphocytic leukemia in participating centers, outside of clinical trials, in 2017 and 2018 were included. Results: Seventy-three patients fulfilling entry criteria were identified. Their median age was 76 years, and ranged from 58 to 90 years. The median follow up time was 59 months. The response rate was 89%, with a median progression-free survival time of 27 months, and an overall survival time of 49 months. Chlorambucil was administered as planned in 15 of the 22 (79%) patients treated with chlorambucil pulses every 2 weeks; in 15 of the 42 (34%) patients treated with 7-day courses of chlorambucil administered every 4 weeks; and in 0 of the 10 patients treated with a continuous high dose of chlorambucil (p = 0.002). Changes in treatment schedules were made due to side effects. The progression-free and overall survival rates were similar between the three groups. Conclusions: The combinations of obinutuzumab with more intensive chlorambucil schedules are less feasible, preventing the administration of the intended higher total dose of chlorambucil, and do not improve outcomes in comparison to chlorambucil pulses administered every 2 weeks.

Hrvatska B-stanična kronična limfocitna leukemija (B-KLL) karakterizirana je varijabilnom infiltracijom B-KLL limfocitima različitih limfnih odjeljaka, tj. periferne krvi (PK), koštane srži (KS) i limfnih čvorova (LČ) i limfoidnih organa. Interakcije s različitim mikrookolišima mogu rezultirati različitom aktivnošću bolesti i otpornošću na apoptozu. Novi agensi koji ciljaju Btk i Bcl-2 pokazuju izvanrednu aktivnost u B-CLL. Međutim, oni mogu imati različitu aktivnost u različitim limfnim odjeljcima, dok inhibitori Btk također mogu uzrokovati značajnu redistribuciju B-CLL limfocita između odjeljaka. Cilj ovog istraživanja je procijeniti: 1) postoji li različita ekspresija Bcl-2 obitelji anti-i pro-apoptotskih proteina (Bcl-2, Bax, Bim, mcl-1) i Btk u B-KLL limfocitima iz različitih limfoidnih odjeljaka; 2) odnos promatranih ekspresija prema parametrima bolesti (TTM, TD, stadij, B2MG, LDH); 3) promjene tijekom liječenja Btk inhibitorima. Rezultati: Uključeno je 28 bolesnika s B-KLL (18/10 M/Ž, medijan dobi 71 godina, raspon 48-85) liječenih inhibitorima btk (ibrutinib 24, acalabrutinib 4). Medijan TTM bio je 10,2 (raspon 3,4-23,9), a TD 0,68. Rai stadij III/IV imao je 8 bolesnika. Ekspresija Bcl-2, Mcl-1, Bim, Bax i Btk određena je protočnom citometrijom u CD19+CD5+ limfocitima Ustanovljena je veća ekspresija Bcl-2, Mcl-1 u LN u usporedbi s PK i KS (p<0,05), dok nema promjene u PK praćenju tijekom liječenja ibrutinibom/akalbrutinibom. Nema značajne razlike u ekspresiji Bim između odjeljaka, dok postoji trend veće ekspresije u PB uzorku za praćenje (p=0,054). Nema značajne razlike u ekspresiji Baxa između PB, BM i LN odjeljaka, dok postoji značajan pad ekspresije Baxa u PB uzorku za praćenje tijekom liječenja (p<0,05). p-Btk ima veću ekspresiju u LN u odnosu na PB i BM (p<0,05). Naknadna ekspresija PB p-Btk usporediva je s ekspresijom prije tretmana u PB (unatoč redistribuciji). Nismo pronašli značajnu korelaciju ekspresije obitelji Bcl-2 i ekspresije p-Btk s parametrima tumorske mase i distribucije. Zaključci: postoji različit obrazac ekspresije anti-apoptotskih i pro-apoptotskih članova obitelji bcl-2 i Btk između limfoidnih odjeljaka. Naši rezultati mogu ukazivati na veću BCR signalizaciju i veću antiapoptotičku

As novel substances, short time windows, and limits of detection increasingly challenge direct methods of doping detection in sports, indirect tools inevitably take a greater role in the fight against it. One such tool is the athlete biological passport (ABP) – a longitudinal profiling of the measured haematological and biochemical biomarkers, combined with calculated scores, against the background of epidemiological data crucial for doping detection. In both of its modules, haematological and steroidal, ABP parameters are analysed with the Bayesian adaptive model, which individualises reference and cut-off values to improve its sensitivity. It takes into account the confounding factors with proven and potential influence on the biomarkers, such as race and altitude exposure. The ABP has already changed the fight against doping, but its importance will further grow with the new modules (e.g., endocrinological), parameters (e.g., plasma volume-independent parameters), and complementing indirect methods (e.g., transcriptomic).