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.

Venous thromboembolism in Croatia - Croatian Cooperative Group for Hematologic Diseases (CROHEM) study.

AIM: To analyze the incidence and characteristics of venous thromboembolism (VTE) in Croatia. METHODS: The Croatian Cooperative Group for Hematologic Diseases conducted an observational non-interventional study in 2011. Medical records of patients with newly diagnosed VTE hospitalized in general hospitals in 4 Croatian counties (Sibenik-Knin, Koprivnica-Krizevci, Brod-Posavina, and Varazdin County) were reviewed. According to 2011 Census, the population of these counties comprises 13.1% of the Croatian population. RESULTS: There were 663 patients with VTE; 408 (61.54%) had deep vein thrombosis, 219 (33.03%) had pulmonary embolism, and 36 (5.43%) had both conditions. Median age was 71 years, 290 (43.7%) were men and 373 (56.3%) women. Secondary VTE was found in 57.3% of participants, idiopathic VTE in 42.7%, and recurrent VTE in 11.9%. There were no differences between patients with secondary VTE and patients with idiopathic VTE in disease recurrence and sex. The most frequent causes of secondary VTE were cancer (40.8%), and trauma, surgery, and immobilization (38.2%), while 42.9% patients with secondary VTE had ≥2 causes. There were 8.9% patients ≤45 years; 3.3% with idiopathic or recurrent VTE. Seventy patients (10.6%) died, more of whom had secondary (81.4%) than idiopathic (18.6%) VTE (P<0.001), and in 50.0% VTE was the main cause of death. Estimated incidence of VTE in Croatia was 1.185 per 1000 people. CONCLUSION: Characteristics of VTE in Croatia are similar to those reported in large international studies. Improved thromboprophylaxis during the presence of risk factors for secondary VTE might substantially lower the VTE burden.

Hip and Knee Osteoarthritis in Patients with Chronic Myeloproliferative Neoplasms: A Cross-Sectional Study.

BACKGROUND: Osteoarthritis (OA) is a progressive degenerative disease with an inflammatory background. Chronic myeloproliferative neoplasms (MPN) are clonal hematopoietic disorders characterized by chronic inflammation and a tendency for connective tissue remodeling. AIM: This study aimed to investigate the prevalence and associated risk factors of symptomatic OA (sOA) in MPN patients. PATIENTS AND METHODS: A total of 100 consecutive MPN (39 essential-thrombocythemia, 34 polycythemia-vera, 27 myelofibrosis) patients treated in two community hematologic centers were cross-sectionally evaluated. Patients were required to have both symptoms attributable to hip and/or knee OA and radiographic confirmation to be considered as having sOA. RESULTS: The prevalence of hip and/or knee sOA was significantly higher among MPN patients than the previously reported prevalence in the general population of similar age (61% vs. 22%, p < 0.001). Hip sOA was present in 50%, knee sOA in 51% and sOA of both localizations in 41% of patients. A high proportion of MPN patients had radiographic signs of hip OA (94%) and knee OA (98%) in the presence of attributable symptoms. Among the other factors, sOA was univariately associated with the presence of JAK2 mutation, myelofibrosis phenotype, older age, higher body weight, and higher MPN-SAF score (p < 0.050 for all analyses). In the multivariate analysis, older age (odds ratio = 1.19, 95% confidence interval-CI 1.06-1.33) and higher body weight (OR = 1.15, 95% CI 1.06-1.25) were recognized as independent risk factors for sOA. On the other hand, cytoreductive treatment was a protective factor for sOA (OR = 0.07, 95% CI 0.006-0.86). CONCLUSIONS: The prevalence of sOA in MPN patients was higher than that in the general population and seems to correlate with older age, increased myeloproliferation and a higher inflammatory state. Whether cytoreductive treatment may postpone OA development in MPN patients warrants additional confirmation.

Apocrine carcinoma of the scalp with aggressive clinical course--a case report and review of the literature.

Primary cutaneus apocrine carcinoma is a rare malignancy with about 50 cases reported in the literature. Axilla is the most common site of occurrence, but locations like scalp, anogenital region, ear canal, chest, wrist, finger and eyelid have been described. The neoplasm presents itself as an asymptomatic, slow-growing, solid or cystic mass that varies in color. Most patients have a history of a long-standing neoplasm before the diagnosis is made. The disease is considered to have an indolent clinical course with favorable outcome although more than half of reported patients had regional lymph node metastases at the time of diagnosis. Systemic dissemination to lung, bones, liver and brain is extremely rare with only 14 cases documented in the literature. Wide surgical excision with lymph node dissection upon confirmation of the lymph node metastases remains the only curable treatment. Care and management of the disseminated disease is still challenging. We report a case of a 65-year-old woman with a very aggressive apocrine carcinoma of the scalp prone to local recurrence and distant metastases to lung and bones.

High platelet-to-lymphocyte ratio may differentiate polycythemia vera from secondary polycythemia.

Discriminating polycythemia vera (PV) from secondary polycythemia (SP) is crucial due to the inherent risk of thrombosis in PV and different treatment approaches. The majority of PV patients have subnormal serum erythropoietin levels and harbor Janus kinase 2 (JAK2) mutations; however, serum erythropoietin levels may be normal in approximately one third of PV patients and mutational analysis is costly and requires access to specialized laboratories. Recently, neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios (PLR) emerged as rapidly available biomarkers to identify PV patients under an increased risk of thrombosis and death. This multicenter retrospective study investigated whether these two biomarkers may also be used to differentiate PV from SP. A total of 207 subjects were included (103 PV and 104 SP) with both baseline NLR (median 4.33 vs. 1.89) and PLR (median 259.12 vs. 81.11) being significantly higher in PV than in SP (p < 0.001 for both analyses). According to the receiver operating curve analysis, PLR (area under the curve, AUC 0.936, the optimal cut-off value of > 138.1 had 82.5% sensitivity and 91.67% specificity for the detection of PV) outperformed other tested variables (NLR, total leukocytes, neutrophils, lymphocytes and platelets) and its cut-off values with 100% specificity and sensitivity were able to confirm (PLR > 224.56; 31% patients) and to exclude (PLR < 68.8; 13% patients) the highest proportions of PV patients. Therefore, PLR may represent a cheap and a rapidly available biomarker with valuable diagnostic and prognostic properties. This information may be particularly useful in resource-limited settings; however, our results need validation on larger datasets.

Hematocrit to hemoglobin ratio as a prognostic marker in polycythemia vera.

BACKGROUND: The hematocrit to hemoglobin ratio (HHR) is frequently used in everyday practice to measure hemoconcentration; however, clinical associations of HHR in the context of polycythemia vera (PV) have not been investigated so far. PATIENTS AND METHODS: We retrospectively assessed HHR at the time of diagnosis in 107 PV and 40 secondary polycythemia (SP) patients from three community hospitals. RESULTS: Median HHR was higher in PV than in SP patients (3.131 vs. 2.975, p = 0.041). Among PV patients, higher HHR correlated with splenomegaly, higher total leukocyte and absolute granulocyte counts, higher red blood cell counts, lower hemoglobin, higher red blood cell distribution width, lower mean corpuscular hemoglobin and lower ferritin levels, whereas in SP patients higher HHR correlated with older age, female sex and lower hemoglobin (p < 0.050 for all analyses). Using the receiver operating curve analysis-defined cut-off points, higher HHR in PV was associated with a shorter time to thrombosis (hazard ratio-HR 5.20, p = 0.022) independently of high-risk disease status (HR 4.48, p = 0.034) and shorter overall survival (HR 6.69, p = 0.009) independently of leukocytosis (HR 4.48, P = 0.034) and the absence of aspirin use (HR 15.53, p < 0.001). CONCLUSION: Higher HHR may represent iron deficiency and a stronger clonal myeloproliferation in PV and could provide additional prognostic information to the classical risk assessment.

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.

Non-Myelofibrosis Chronic Myeloproliferative Neoplasm Patients Show Better Seroconversion Rates after SARS-CoV-2 Vaccination Compared to Other Hematologic Diseases: A Multicentric Prospective Study of KroHem.

Disease- and treatment-mediated immunodeficiency might render SARS-CoV-2 vaccines less effective in patients with hematologic diseases. We performed a prospective non-interventional study to evaluate humoral response after one and two doses of mRNA-1273, BNT162b2, or ChAdOx1 nCoV-19 vaccine in 118 patients with different malignant or non-malignant hematologic diseases from three Croatian treatment centers. An electrochemiluminescent assay was used to measure total anti-SARS-CoV-2 S-RBD antibody titers. After one vaccine dose, 20/66 (33%) achieved seropositivity with a median antibody titer of 6.1 U/mL. The response rate (58/90, 64.4%) and median antibody titer (>250 U/mL) were higher after two doses. Seropositivity varied with diagnosis (overall p < 0.001), with the lowest rates in lymphoma (34.6%) and chronic lymphocytic leukemia (52.5%). The overall response rate in chronic myeloproliferative neoplasms (CMPN) was 81.3% but reached 100% in chronic myeloid leukemia and other non-myelofibrosis CMPN. At univariable analysis, age > 67 years, non-Hodgkin's lymphoma, active treatment, and anti-CD20 monoclonal antibody therapy increased the likelihood of no vaccine response, while hematopoietic stem cell recipients were more likely to respond. Age and anti-CD20 monoclonal antibody therapy remained associated with no response in a multivariable model. Patients with the hematologic disease have attenuated responses to SARS-CoV-2 vaccines, and significant variations in different disease subgroups warrant an individualized approach.

Beneficial effect of ACE inhibitors on kidney function in polycythemia vera.

BACKGROUND: Reduced kidney function has been associated with worse clinical outcomes in patients with myeloproliferative neoplasms (MPN). Statins and angiotensin-converting enzyme inhibitors (ACE-i) have renoprotective properties and their pleiotropic effects might also affect the malignant MPN clone; however, whether concomitant use of statins and ACE­i has a positive effect on estimated glomerular filtration rate (eGFR) in polycythemia vera (PV) patients is currently unknown. METHODS: This multicenter retrospective study investigated effects of statins and ACE­i on 12-month eGFR dynamics in 75 PV patients. RESULTS: Of the patients 25 (33.3%) had a 10% or more increase in eGFR at 12 months. Univariately, statins (55.5% vs. 16.3%; p = 0.022), ACE­i (61% vs. 24.6%; p = 0.004), male sex (54.3%, vs. 15%; p < 0.001) and the absence of chronic kidney disease (CKD, 45.5% vs. 16.1%; p = 0.008) were statistically significantly associated with an improvement in eGFR. ACE­i (p = 0.008), CKD (p < 0.001), male sex (p = 0.004) and higher baseline eGFR (p = 0.007) remained statistically significantly associated with an improvement in eGFR in the multivariate logistic regression model also including statins, hydroxyurea, high-risk disease, cardiovascular risk factors, chronic heart failure and baseline hematocrit. CONCLUSION: The ACE­i might have renoprotective properties in PV. Further studies are needed to elucidate whether the use of these drugs could also affect other MPN-related outcomes.

A correlative study of histology and imprint cytology of gastric mucosa biopsy in the diagnosis gastric cancer.

The purpose of this paper is to show the importance of gastric mucosa imprint cytology in detecting stomach cancer. Analyzed were 364 cytological and pathohistiological samples taken from 335 patients having suspected diagnosis of gastric cancer. Every specimen was submitted to slide imprinting and then fixed in formalin for further processing with routine histopathology. The imprints were air dried for cytological analysis, stained according to May-Grünwald-Giemsa and analyzed by light microscope. By pathohistological punch-biopsy samples analysis stomach cancer was found in 45 samples. With cytological samples analysis the cancer was detected in 48 samples and 13 cytological samples were suspected of cancer With combining these two methods cancer was found in 68 cases. Patients with positive cytological finding and negative pathohistologic finding underwent gastroscopy with punch-biopsy. All patients with positive pathohistological findings were operated. All materials were histologically examined. Cancer was found in 68 patients. Cytological analysis of stomach mucosa bioptic material imprints, increases the number of positive findings in preoperative stage of gastric cancer diagnosis. The greatest advantage of this method is short period for preparation of material, simplicity and low price. Every data on morphological changes in mucosa has been also pathohistologically checked, because taking imprints does not damage the specimen.

[Diagnosis and therapy for patients with essential thrombocythemia. Guidelines of Croatian Cooperative Group for hematologic disorders--KROHEM]. / Dijagnosticko-terapijski pristup u bolesnika s esencijalnom trombocitemijom. Smjernice Hrvatske kooperativne grupe za hematoloske bolesti--KROHEM.

Essential thrombocythemia (ET) is a clonal myeloproliferative neoplasm. Croatian Cooperative Group for hematologic disorders, KROHEM proposes the diagnostic and treatment guidelines for ET. Diagnosis of ET is based on the criteria and classification of World Health Organization (WHO). The level of treatment recommendation is based on the UpToDate (web based medical community database) criteria. For ET diagnosis it is mandatory to show sustained increased number of platelets with typical histomorphological changes of megakaryopoiesis in bone marrow. Secondary thrombocytosis and other chronic myeloproliferative neoplasms have to be excluded. Therapy is based on risk factors for ET. The risk factors are number of platelets, patient's age, and the risk levels for thrombosis and bleeding. Patients with low risk (age < 60 years and platelets < 1000 x 10(9)/L) arw not candidates for therapy. In younger group of patients with platelets between 1000 and 1500 x 10(9)/L or more than 1500 x 10(9)/L treatment with anagrelide or hydroxyurea is recommended respectively. In high risk patients hydroxyurea is the first line treatment. Anagrelide is indicated in these patients in the absence of treatment response. Alpha-interferon is recommended for pregnant women with ET and high platelet counts.

Chronic kidney disease could be a risk factor for thrombosis in essential thrombocythemia and polycythemia vera.

Chronic kidney disease (CKD) is a well-known risk factor for venous thromboembolism and cardiovascular (CV) disease development in the general population, but its role in thrombotic risk in essential thrombocythemia (ET) and polycythemia vera (PV) remains poorly understood. This retrospective multicenter study analyzed clinical correlations and the potential impact of CKD on thrombosis development in ET and PV patients. We included 167 patients (76 ET and 91 PV); 25.7% had CKD at diagnosis, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 for ≥ 3 months. Lower eGFR correlated with advanced age, female sex, higher granulocytes, higher serum C-reactive protein, history of thrombosis, CV risk factors, and the presence of palpable splenomegaly. CKD was univariately associated with inferior thrombosis-free survival in the entire cohort, as well as in both ET and PV patients. These results remained significant in the multivariate Cox regression models when adjusted to disease-specific risk models. Therefore, CKD could be a risk factor for thrombosis in ET and PV patients. Additional studies on a larger number of patients are needed to confirm our findings and to elucidate whether the addition of CKD to the current risk stratification models might improve prognostication in ET and PV patients.

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.

Serum chitotriosidase: a circulating biomarker in polycythemia vera.

OBJECTIVES: Serum chitotriosidase activity (CHIT1) is a biomarker of macrophage activation with an important role in inflammation-induced tissue remodeling and fibrosis. Macrophages have been described to play a crucial role in regulating pathological erythropoiesis in polycythemia vera (PV). The aim of this study was to evaluate CHIT1 in patients diagnosed with Philadelphia-negative myeloproliferative neoplasms (MPNs). METHODS: Using fluorometric assay, we measured CHIT1 in 28 PV, 27 essential thrombocythemia (ET), 17 primary myelofibrosis (PMF), 19 patients with secondary myelofibrosis and in 25 healthy controls. RESULTS: CHIT1 was significantly higher in PV (p < .001) and post-PV myelofibrosis (MF) transformation (post-PV MF) (p = .020), but not in ET (p = .080), post-ET MF transformation (p = .086), and PMF patients (p = .287), when compared to healthy controls. CHIT1 in PV was positively correlated with hemoglobin (p = .026), hematocrit (p = .012), absolute basophil count (p = .030) and the presence of reticulin fibrosis in the bone marrow (p = .023). DISCUSSION: A positive correlation between CHIT1 and these distinct laboratory PV features might imply macrophages closely related to clonal erythropoiesis as cells of CHIT1 origin. In addition, a positive association between CHIT1 and reticulin fibrosis might indicate its potential role in PV progression. CONCLUSION: CHIT1 might be considered as a circulating biomarker in PV. Additional studies are needed to clarify the role of CHIT1 in promoting disease progression and bone marrow fibrosis in PV.

The effect of granulocyte colony-stimulating factor on engraftment in patients with lymphoproliferative malignancies and solid tumors undergoing autologous peripheral stem cell transplantation.

The effects of granulocyte colony-stimulating factor (G-CSF) and engraftment quality on the rate of hematopoietic system recovery were assessed in patients with solid tumors and lymphoproliferative diseases after autologous hematopoietic stem cell ransplantation. Treatment with autologous hematopoietic stem cell transplantation was performed in 40 patients for non- Hodgkin's lymphoma (n= 20), Hodgkin's lymphoma (n= 8), multiple myeloma (n= 8), and breast cancer (n=4). In 20 patients with solid tumors and ymphoproliferative diseases, treatment with autologous hematopoietic stem cell transplantation was followed by G-CSF therapy (experimental group). Another 20 patients with solid tumors and lymphoproliferative diseases were treated with autologous hematopoietic stem cell transplantation without G-CSF therapy (control group). The two patient groups were matched for age, sex, diagnosis, number of chemotherapy courses, and engraftment quality (nucleated cells or CD34+ cells). The experimental group received G-CSF in a dose of 5 µg/kg body weight subcutoneous from day 1 of autologous hematopoietic stem cell transplantation until leukocyte count increase to > 1.0 x 109/L over three consecutive days. Nonparametric tests (x2-test, median test, extended median test) were used in statistical analysis. The hematopoietic system showed rapid recovery. Leukocyte count > 1.0 x 109/L was recorded on median day 11 (range 8-21) in the experimental group vs median day 12 (range 9-16) in the control group; gra-nulocyte count > 0.5 x 109/L on median day 12 (range 8-23) vs day 14 (range 10-16) in the control group; and platelet count > 20 x 109/L on median day 13 (range 8-80) vs day 11 (range 7-15) in the control group. Differences between the two patient groups were not statistically significant. G-CSF therapy administered after autologous hematopoietic stem cell transplantation did not result in faster leukocyte, granulocyte or platelet recovery. The patients receiving a relatively lower number of cells showed the same rate of recovery as those who received a higher cell number. The number of CD34+ cells per kg body weight did not correlate with the rate of leukocyte, granulocyte or platelet recovery.

Death caused by possible unrecognized (too Late Recognized) Mycobacterium gordonae infection in a patient with angioimmunoblastic T-cell lymphoma.

Here, we present possible death caused by Mycobacterium gordonae infection in a patient with angioimmunoblastic T-cell lymphoma. Our patient was severely immunocompromised in whom we suspect to an infection, but we did not have isolates until she died. After she died, we received a positive sputum culture of M. gordonae. We conclude that when having severely immunocompromised patients with suspicion of infection but without isolates we should always consider the saprophytic mycobacteria. These mycobacteria require a long period of isolation, but patients with these mycobacteria are potentially curable if appropriate treatment is applied for a sufficiently long period.