Evaluation of Absolute Neutrophil, Lymphocyte and Platelet Count and Their Ratios as Predictors of Thrombotic Risk in Patients with Prefibrotic and Overt Myelofibrosis.

AIM: To investigate the prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC), platelet count and their ratios, neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), to thrombotic risk in patients with prefibrotic and overt fibrotic myelofibrosis (MF). METHODS: We retrospectively analyzed a cohort of 256 patients with prefibrotic (85 patients) and overt fibrotic MF (171 patients) treated in six Croatian hematological centers. RESULTS: Prefibrotic compared to overt fibrotic MF patients presented with significantly higher ALC, platelet count and PLR, and experienced longer time to thrombosis (TTT). Among prefibrotic patients, ANC > 8.33 × 109/L (HR 13.08, p = 0.036), ALC > 2.58 × 109/L (HR 20.63, p = 0.049) and platelet count > 752 × 109/L (HR 10.5, p = 0.043) remained independently associated with shorter TTT. Among overt fibrotic patients, ANC > 8.8 × 109/L (HR 4.49, p = 0.004), ALC ≤ 1.43 × 109/L (HR 4.15, p = 0.003), platelet count ≤ 385 × 109/L (HR 4.68, p = 0.004) and chronic kidney disease (HR 9.07, p < 0.001) remained independently associated with shorter TTT. CONCLUSIONS: Prognostic properties of ANC, ALC and platelet count are mutually independent and exceed those of NLR and PLR regarding thrombotic risk stratification. ALC and platelet count associate in opposite directions with thrombotic risk in prefibrotic and overt fibrotic MF patients.

Higher estimated plasma volume status is associated with increased thrombotic risk and impaired survival in patients with primary myelofibrosis.

Introduction: Blood plasma represents a large reservoir of cytokines and other mediators of inflammation. Higher estimated plasma volume status (ePVS) has been shown to correlate with increased thrombotic risk in polycythemia vera patients, but its clinical and prognostic associations in patients with myelofibrosis are unknown which we aim to evaluate in this study. Materials and methods: We retrospectively analysed a multicentric cohort of 238 patients with primary (PMF) and secondary myelofibrosis (SMF). Estimated plasma volume status was calculated using the Strauss-derived Duarte formula. Overall survival (OS) and time to thrombosis (TTT) considering both arterial and venous thromboses were primary endpoints of interest. Results: Median ePVS was 5.8 dL/g and it did not significantly differ between PMF and SMF patients. Patients with more advanced disease features, more pronounced inflammation and higher comorbidity burden had higher ePVS. Higher ePVS (> 5.6 dL/g) was associated with shorter OS in PMF (unadjusted hazard ratio, HR = 2.8, 95% confidence interval, CI (1.79-4.41), P < 0.001) and SMF (unadjusted HR = 2.55, 95% CI (1.1-5.71), P =0.025) and with shorter TTT in PMF (> 7 dL/g, unadjusted HR = 4.1, 95% CI (1.44-11.59), P = 0.009) patients. Associations with OS diminished in multivariate analyses after adjustments for the dynamic-international-prognostic-scoring-system (DIPSS) and myelofibrosis-secondary-to-PV-and ET-prognostic-model (MYSEC-PM), respectively. Association with TTT remained significant independently of JAK2 mutation, white blood cell count and chronic kidney disease. Conclusions: Myelofibrosis patients with more advanced disease features and more pronounced inflammation have higher ePVS, indicative of expanded plasma volume. Higher ePVS is associated with impaired survival in PMF and SMF and higher thrombotic risk in PMF patients.

Dose-adjusted EPOCH and rituximab (DA-EPOCH-R) in older patients with high-risk aggressive diffuse large B-cell lymphoma: A real-life multicenter study by the Croatian Cooperative Group for Hematologic diseases (KroHem).

PURPOSE: Dose-adjusted EPOCH and rituximab (DA-EPOCH-R) is a regimen used for the treatment of high-risk diffuse large B-cell lymphoma (DLBCL) designed to overcome resistance to standard R-CHOP by combining prolonged exposure of lymphoma cells to cytotoxic agents and dose-adjustment based on toxicity. Data on outcomes of older patients are scarce. PATIENTS AND METHODS: We collected data on patients with newly diagnosed high-risk DLBCL older than 60 years treated with DA-EPOCH-R. High-risk patients were defined by the age-adjusted international prognostic index score 2 or 3. RESULTS: A total of 120 patients were included. Median age was 69 years (range 60-82). Response rate was 74%; with 59% complete responses. Dose of DA-EPOCH-R was escalated in 50 patients (42%). Three-year progression-free survival (PFS) and overall survival (OS) was 53% and 58%, respectively, with treatment-related mortality (TRM) of 13%. In univariate analysis, favorable prognostic factors were performance status (PS) (0-2 vs. 3-4), age (<70 vs. ≥70 years), and center. In multivariate analysis, PS and center retained prognostic significance. Patients with PS 0-2 had 3-year PFS and OS of 58% and 64%, respectively, with TRM of 6%. CONCLUSION: DA-EPOCH-R is efficacious in sufficiently fit older high-risk DLBCL patients. Patients with poor PS have unacceptable toxicity and require less intensive therapy.

Clinical Dilemmas in the Treatment of Elderly Patients Suffering from Hodgkin Lymphoma: A Review.

Elderly patients make up a significant number of cases of newly diagnosed Hodgkin lymphoma. However, unlike in young patients, the outcomes of elderly patients are poor, and they are under-represented in phase III trials. Prior to treatment initiation, geriatric assessment should ideally be performed to address the patient's fitness and decide whether to pursue a curative or palliative approach. The ABVD regimen is poorly tolerated in unfit patients, with high treatment-related mortality. Alternative chemotherapy approaches have been explored, with mixed results obtained concerning their feasibility and toxicity in phase II trials. The introduction of brentuximab vedotin-based regimens led to a paradigm shift in first- and further-line treatment of elderly Hodgkin lymphoma patients, providing adequate disease control within a broader patient population. As far as checkpoint inhibitors are concerned, we are only just beginning to understand the role in the treatment of this population. In relapsed/refractory settings there are few options, ranging from autologous stem cell transplantation in selected patients to pembrolizumab, but unfortunately, palliative care is the most common modality. Importantly, published studies are frequently burdened with numerous biases (such as low numbers of patients, selection bias and lack of geriatric assessment), leading to low level of evidence. Furthermore, there are few ongoing studies on this topic. Thus, elderly Hodgkin lymphoma patients are hard to treat and represent an unmet need in hematologic oncology. In conclusion, treatment needs to be personalized and tailored on a case-by-case basis. In this article, we outline treatment options for elderly Hodgkin lymphoma patients.

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.

CDC25c expression in patients with myelofibrosis is associated with stronger myeloproliferation and shorter overall survival.

BACKGROUND: Cell division cycle 25c (CDC25c) is a gene coding a phosphatase controlling entry into mitosis upon activation through Polo-like kinase 1 (PLK1) and serves as a key regulator of cell division. The CDC25c was reported to be dysregulated in some malignant diseases, but its role in myelofibrosis has not yet been elucidated. METHODS: We have retrospectively investigated CDC25c mRNA expression in bone marrow aspirates of 43 patients with myelofibrosis (28 primary [PMF] and 15 secondary myelofibrosis [SMF]) and 12 controls. RESULTS: CDC25c mRNA expression did not significantly differ between PMF, SMF and controls (median ∆CT 3.08 vs 2.86 vs 2.29 for PMF, SMF and controls, respectively; P = 0.162). Patients presenting with higher CDC25c mRNA expression were of older age (P = 0.037), had statistically significantly higher white-blood-cells (P = 0.017), larger liver size (P = 0.022), higher absolute neutrophil (P = 0.010), monocyte (P = 0.050), basophil (P = 0.012), and eosinophil counts (P = 0.013). Patients presenting with high CDC25c mRNA expression had statistically significantly inferior overall survival compared to low CDC25c expression group (HR = 2.99; P = 0.049). Median overall survival was not reached in patients with low and was 44 months in patients with high CDC25c expression. CONCLUSION: Our data suggest that higher CDC25c expression is associated with more proliferative phenotype of myelofibrosis and is prognostic of worse survival. Future studies investigating these interesting associations are warranted.

Higher serum uric acid is associated with higher risks of thrombosis and death in patients with primary myelofibrosis.

BACKGROUND: Serum uric acid (SUA) can promote inflammation and is associated with increased cardiovascular morbidity. Primary (PMF) and secondary myelofibrosis (SMF) are myeloproliferative neoplasms characterized by high cellular turnover and substantial risk of thrombosis and death. METHODS: We have retrospectively investigated SUA in 173 patients with myelofibrosis (125 PMF; 48 SMF) and 30 controls. RESULTS: The PMF patients had significantly higher SUA in comparison to SMF and controls. In both PMF and SMF higher SUA was significantly associated with arterial hypertension and decreased renal function. Among PMF patients, higher SUA was significantly associated with older age, larger spleen, higher white blood cell counts, higher lactate dehydrogenase, lower immunoglobulin G levels, allopurinol use and non-smoking. Among SMF patients, higher SUA was associated with male sex (P < 0.05 for all analyses). In PMF higher SUA was univariately associated with inferior survival (> 427 µmol/L hazard ratio (HR) = 2.22; P = 0.006) and shorter time to thrombosis (> 444 µmol/L HR = 5.05; P = 0.006), which could be shown separately for arterial (> 380 µmol/L; HR = 4.9; P = 0.013) and venous thromboses (> 530 µmol/L; HR = 17.9; P < 0.001). In multivariate analyses, SUA remained significantly associated with inferior survival independent of the Dynamic International Prognostic Staging System and with shorter time to thrombosis independent of age in PMF patients; however, the prognostic significance of SUA was diminished after including serum creatinine in the models. SUA was not prognostic in SMF patients. CONCLUSION: The PMF patients present with higher SUA levels, which are associated with features of more advanced disease and higher risks of arterial and venous thrombosis and death.

Reduced renal function strongly affects survival and thrombosis in patients with myelofibrosis.

We retrospectively investigated a cohort of 176 myelofibrosis patients (128 primary-PMF; 48 secondary-SMF) from five hematology centers. The presence of chronic kidney disease (CKD) was determined in addition to other clinical characteristics. CKD was present in 26.1% of MF patients and was significantly associated with older age (P < 0.001), higher WBC (P = 0.015), and its subsets (neutrophil, monocyte, and basophil counts), higher platelets (P = 0.001), lower albumin (P = 0.018), higher serum uric acid (P = 0.001), higher LDH (P = 0.022), and the presence of CV risk factors (P = 0.011). There was no significant association with driver mutations, degree of bone marrow fibrosis, PMF/SMF, or DIPSS risk categories (P > 0.05 for all analyses). The presence of CKD was significantly associated with shorter time to arterial (HR = 3.49; P = 0.041) and venous thrombosis (HR = 7.08; P = 0.030) as well as with shorter overall survival (HR 2.08; P = 0.009). In multivariate analyses, CKD (HR = 1.8; P = 0.014) was associated with shorter survival independently of the DIPSS (HR = 2.7; P < 0.001); its effect being more pronounced in lower (HR = 3.56; P = 0.036) than higher DIPSS categories (HR = 2.07; P = 0.023). MF patients with CKD should be candidates for active management aimed at the improvement of renal function. Prospective studies defining the optimal therapeutic approach are highly needed.

C reactive protein to albumin ratio as prognostic marker in primary and secondary myelofibrosis.

We retrospectively investigated C reactive protein to albumin ratio (CAR) in a cohort of 142 patients with myelofibrosis [101 primary (PMF); 41 secondary (SMF)] and compared it to hematological and clinical parameters. Among other associations, higher CAR was significantly associated with higher grade of bone marrow fibrosis, lower frequency of Calreticulin (CALR) mutations, presence of constitutional symptoms, massive splenomegaly, transfusion dependency, blast phase disease, lower hemoglobin, lower platelets, higher ferritin and higher lactate dehydrogenase (LDH) (p < .05 for all analyses). Higher CAR was able to predict inferior survival in PMF independently of DIPSS [hazard ratio (HR)=2.17; p = .015 for high CAR and HR = 2.05; p < .001 for DIPSS] and in SMF independently of Mysec-PM (HR = 6.48; p = .022 for high CAR and HR = 2.63; p = .013 for Mysec-PM) demonstrating its good prognostic potential. CAR seems to be an independent and prognostically relevant parameter, both in PMF and SMF, and might aid in timely recognition of most vulnerable patients.

Patterns of Glucose Fluctuation are Challenging in Patients Treated for Non-Hodgkin's Lymphoma.

PURPOSE: This cohort study aimed to determine patterns of glycemic fluctuation and changes in metabolic parameters during and after corticosteroid administration in newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP chemotherapy. PATIENTS AND METHODS: The study was performed in 20 patients of whom 11 had diabetes and 9 were nondiabetics. Anthropometric parameters were collected, and blood samples were taken four times during the study to analyze metabolic parameters. Capillary glucose was measured seven times a day (fasting, before mean meals, postprandial, and before bedtime) to evaluate the glycemic profile. RESULTS: In all 20 patients, acute glucocorticoid administration resulted in the elevation of average glucose levels, dominantly postprandial in the afternoon which correlates with corticosteroid peak action. In 7 out of 11 diabetics, prandial insulin was started during corticosteroid administration and discontinued afterward. Although none of our nondiabetic patients met diabetes criteria, evident is the elevation in average glycemia levels six weeks after corticosteroid administration. Potentially, even transient corticosteroid administration reduces insulin sensitivity and contributes to later glycemic disturbances. HbA1c levels were higher at the end of the study while fructosamine levels were higher during the study. CONCLUSION: Patients and health-care professionals need to be aware of corticosteroid-induced hyperglycemia. We recommend identifying risk factors, measuring glycemia before, during, and after corticosteroid administration, and starting the adequate therapy as soon as possible.

Higher AURKA and PLK1 expression are associated with inferior overall survival in patients with myelofibrosis.

Aurora-kinase-A (AURKA), BORA and Polo-like-kinase-1 (PLK1) are regulating cell-cycle control and promotion of mitosis entry. AURKA contributes to Janus-kinase-2 (JAK2) activation and increased AURKA protein levels were reported in CD34+ and CD41+ cells of myeloproliferative neoplasm patients, leading to aneuploidy and aberrant megakaryopoiesis. We aimed to investigate AURKA, BORA and PLK1 mRNA expression in unfractionated bone-marrow aspirates of 43 patients with myelofibrosis (28 primary-/PMF, 15 secondary-myelofibrosis/SMF) and 12 controls and to assess their clinical correlations. AURKA expression did not significantly differ between myelofibrosis and controls (P = 0.466). Higher AURKA expression was significantly associated with higher absolute monocyte-count (P = 0.024) and shorter overall survival (HR = 3.77; P = 0.012). Patients with both PMF and SMF had lower BORA expression than controls (P = 0.009). Higher BORA expression was significantly associated with absence of constitutional symptoms (P = 0.049), absence of circulatory blasts (P = 0.047), higher monocyte- (P = 0.040) and higher eosinophil-counts (P = 0.016) and had neutral effect on survival (P > 0.05). PLK1 expression did not significantly differ between myelofibrosis and controls (P = 0.103). Higher PLK1 expression was significantly associated with higher white-blood-cell-count (P = 0.042) and inferior overall survival (HR = 5.87; P = 0.003). In conclusion, AURKA, BORA and PLK1 are involved in pathogenesis of myelofibrosis and may affect survival. Future studies investigating these interesting associations are warranted.

[Has femoral neck fracture in older patients to be treated with reposition of fragments and osteosynthesis or with primary aloarthroplasty?]. / Treba li prijelom vrata femura u starijih bolesnika lijeciti repozicijom i osteosintezom ulomaka ili primarnom aloartroplastikom kuka?

In this article we analised and compared the efficiency of operative treatment of the femoral neck fracture in two groups of patients, over 70 years of age, treated on different way. The first group were the patients treated by osteosynthesis of the fracture site, and the second group were the patients treated by aloarthroplasty of the hip. All patients had surgery over three days after injury. We found that the group of patients with osteosynthesis had twice bigger unsuccessful results (62.5%) in relation to the group treated with hip aloarthroplasty (31.8%). The relation between the number of reoperations after osteosynthesis and hip aloarthroplasty was 8:1. We also found that radiological healing ot the fracture site after osteosynthesis happened only in 10% cases. Patients treated with hip aloarthroplasty earlier started to walk without help (1.9 months after surgery) and the patients treated with osteosynthesis could walk five times later (10.59 months after surgery). Although neck femoral fractures in older patients are treated ten times more with hip aloarthroplasty than with osteosynthesis, int his article we showed that hip aloarthroplasty must be the first choice in mostly all patients over 70 years of age. Osteosynthesis has to be used very rare, in patients with lateral neck fractures without dislocations, and it must be done as emergency procedure, not later then 48 hours of injury.