Efficacy and Safety of Obinutuzumab-chemotherapy Combinations in Front-line Treatment of Follicular Non-Hodgkin Lymphoma During the COVID-19 Pandemic: A Study of KROHEM, the Croatian Cooperative Group for Hematologic Diseases.

Obinutuzumab (G) has become part of front-line treatment of follicular lymphoma (FL) based on results of a large randomized study. Data on patients treated outside of clinical trials are lacking. We have retrospectively investigated efficacy and safety of G-based immunochemotherapy regimens in 114 patients treated in a real-life setting during a period of 2 years, largely coinciding with the COVID-19 pandemic. The response rate was 93.8%; 18-months overall (OS) and progression-free survival (PFS) were 88% and 84%, respectively. Patients treated with G-cyclophosphamide, vincristine and glucocorticoid + doxorubicine (CHOP) had statistically significantly superior OS and PFS compared to patients treated with G-bendamustine (G-B) (P = 0.002 and P = 0.006, respectively) due to an increase in lethal infections, most notably COVID-19, in the latter group. A total of 12 patients died during follow-up; 9 of 61 treated with G-B, 1 of 49 treated with G-CHOP and 2 of 4 treated with G-cyclophosphamide, vincristine and glucocorticoid (CVP). SARS-CoV-2 infection was diagnosed in 20 (17.5%) patients. All of the 7 treated with G-CHOP recovered, while 4 of 12 treated with G-B died. Immunoglobulin levels and severity of neutropenia were similar between the groups. In multivariate analysis, G-B in comparison to G-CHOP was an independent prognostic factor (P = 0.044, hazard ratio = 9.81) after adjustment for age, sex and Follicular Lymphoma International Prognostic Index (FLIPI). Based on our experience G has excellent antilymphoma activity in patients receiving front-line treatment for FL in real-life setting, but during the COVID-19 pandemic, it should be preferentially combined with CHOP, at least in patients younger than 65.

Improvement in the outcomes of mantle cell lymphoma in the last decade: a real-life non interventional study of the Croatian Cooperative Group for Hematologic Diseases.

AIM: To compare the outcomes of Croatian patients with mantle cell lymphoma (MCL) who started treatment in 2007 and 2008 (historical cohort) and of those who started treatment between 2015 and 2017 (recent cohort). METHODS: The historical cohort consisted of 40 patients who started treatment with rituximab in 2007 and 2008. Data on the recent cohort, consisting of 89 patients, were collected retrospectively from the electronic databases of Croatian hospitals with hematology units. Demographic characteristics and data on induction regimens, autologous stem cell transplantation (ASCT), and rituximab maintenance in the first remission, event-free survival (EFS), and overall survival (OS) were available for both cohorts, and data on cell morphology, mantle cell international prognostic index (MIPI), and Ki67 expression only for the recent cohort. RESULTS: The recent cohort had significantly better two-year EFS and OS (EFS 58% vs 40%, P=0.014; OS 80% vs 56%, P=0.009), especially in patients below 65. In univariate analysis, induction regimen, ASCT, and maintenance were significant prognostic factors for EFS and the former two for OS. In the multivariate analysis, only ASCT remained significant. Bendamustine+rituximab (BR) induction improved the outcomes of non-transplantable patients over R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, steroid). Blastoid morphology and high MIPI were adverse prognostic factors for EFS and OS. CONCLUSION: In the last decade, the outcome of newly diagnosed MCL patients improved. ASCT in the first remission was the main contributor in transplantable patients and BR in non-transplantable. Regularly updated national guidelines may help in a timely adoption of new treatments, thus improving the results.

Tetraploid acute promyelocytic leukemia with double translocation t (15,17) PML/RARA: the first case report in Croatia and Europe.

Acute promyelocytic leukemia (APL) is characterized by the translocation t (15;17)(q22;q21) cytogenetic abnormality in the majority of cases. In most of the cases the cells of APL have normal, diploid karyotype. There are very few cases presented with very rare tetraploid karyotype with double translocation t(15;17)(q22;q12). We report the first case of tetraploid APL with double translocation t(15, 17) in Europe. A 66-year old male patient presented with dyspnea and unexplained dental bleeding. Blood work showed a white blood cell count of 1x109/L, hemoglobin was 124 g/ L, platelet count was 61x109/L and fibrinogen level was low (1.4 g/L). Cytogenetics showed a tetraploid karyotype. Fluorescence in situ hybridization analysis proved existence of clonal cells with translocation t (15,17) in 15% of metaphase nuclei and tetraploid subclonal cells with the same translocation in 70% of metaphase nuclei. Findings were consistent with APL, tetraploid variant and the patient started all-trans retinoic acid (ATRA) treatment. The patient achieved complete remission in 2 months and completed three consolidation therapy cycles with ATRA, idarubicin or mitraxontrate. Currently, the patient is undergoing maintenance therapy with ATRA, 6-mercaptopurine and weekly methotrexate.

Guidelines for Diagnosis and Treatment of Chronic Lymphocytic Leukemia. Krohem B-Cll 2017.

Recent developments in the diagnosis and treatment of chronic lymphocytic leukemia (B-CLL) have led to change of approach in clinical practice. New treatments have been approved based on the results of randomized multicenter trials for first line and for salvage therapy, and the results of numerous ongoing clinical trials are permanently providing new answers and further refining of therapeutic strategies. This is paralleled by substantial increase in understanding the disease genetics due to major advances in the next generation sequencing (NGS) technology. We define current position of the Croatian Cooperative Group for Hematologic Disease on diagnosis and treatment of CLL in the transition from chemo-immunotherapy paradigm into a new one that is based on new diagnostic stratification and unprecedented therapeutic results of B-cell receptor inhibitors (BRI) and Bcl-2 antagonists. This is a rapidly evolving field as a great number of ongoing clinical trials con-stantly accumulate and provide new knowledge. We believe that novel therapy research including genomic diagnosis is likely to offer new options that will eventually lead to time limited therapies without chemotherapy and more effective clinical care for B-CLL based on individualized precision medicine.

Prognostic nutritional index as a predictor of prognosis in patients with diffuse large B cell lymphoma.

BACKGROUND: The prognostic nutritional index (PNI), an indicator of nutritional status and systemic inflammation, is associated with short-term and long-term outcomes of various malignancies. The prognostic value of PNI in diffuse large B cell lymphoma (DLBCL) remains unknown. The aim of the present study was to determine the prognostic value of baseline PNI in DLBCL patients. METHODS: We retrospectively analyzed data from 103 DLBCL patients treated with R­CHOP or R­CHOP-like regimens. We evaluated the significance of PNI as a predictor of response to treatment, overall survival (OS) and event-free survival (EFS). RESULTS: Patients with a PNI ≤ 44.55, where the cut-off was calculated by receiver operating characteristics (Youden index) and the same was obtained for response to treatment with 76.2 % sensitivity and a specificity of 85.4 %, for OS with 72.4 % sensitivity and a specificity of 90.5 % and for EFS with 65.6 % sensitivity and a specificity of 90.1 %, had significantly worse 5­year OS (18.3 % vs 86.4 %, P < 0.001, log rank test) and 5­year EFS (15.1 % vs 82.3 %, P < 0.001, log rank test). Regression analysis showed that PNI ≤ 44.55 was an independent prognostic factor for response to treatment with an odds ratio (OR) of 4.88 for treatment failure, 95 % confidence interval (CI) 1.077-22.105, OS hazard ratio (HR) 4.24, 95 % CI 1.451-12.392 and EFS HR 4.007, 95 % CI 1.48-10.852. Lower PNI levels were found in patients with advanced Ann Arbor clinical stage (46.6 ± 7.77 vs. 52.7 ± 5.43) and in those with poor response to therapy (40.58 ± 7.26 vs. 50.67 ± 6.26). CONCLUSIONS: The PNI is a simple and useful marker to predict long-term survival outcome in DLBCL patients. Low PNI predicted poor outcome. A limitation of the study is its retrospective design in which the prognostic value was tested in the derivation cohort only. Notwithstanding, this is the first study suggesting that PNI is an important prognostic factor in DLBCL.

Red blood cell distribution width as a simple negative prognostic factor in patients with diffuse large B-cell lymphoma: a retrospective study.

AIM: To determine the prognostic value of baseline red blood cell distribution width (RDW) in diffuse large B cell lymphoma (DLBCL) patients. METHODS: Data from 81 DLBCL patients diagnosed from 2006 to 2013 at the University Hospital Center Osijek, Osijek, Croatia, were reviewed. We evaluated disease outcome, overall survival (OS) and event-free survival (EFS), and demographic, clinical and laboratory factors affecting outcome. Univariate analysis and Cox regression analysis were used. RESULTS: Median age of patients was 64 years, 29 were men (35.8%). Higher RDW levels (%) were found in patients with advanced Ann Arbor clinical stage (14.94±1.82 vs 13.55±1.54, P=0.001) and in those with poor response to therapy (14.94±1.82 vs 13.55±1.54, P=0.001). Patients with RDW>15% (cut-off was calculated by receiver operating characteristics) had significantly worse OS (median [range], 33 months [20-46] vs 74 months [65-82], P<0.001) and EFS (27 months [15-40] vs 68 months [59-77], P<0.001). Cox regression analysis showed that RDW>15% was an independent prognostic factor for OS (HR 3.654, 95% CI 1.128-11.836) and EFS (HR 2.611, 95% CI 1.012-6-739). CONCLUSION: High baseline RDW is an independent prognostic marker of poor outcome in patients with DLBCL. RDW could be an easily available and inexpensive marker for the risk stratification in patients with DLBCL.