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.

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.

No Evident Prognostic Benefit of Statin Use in Diffuse Large B-Cell Lymphoma Patients with Unfavorable Disease Features Treated with R-DA-EPOCH.

Recent reports indicate that patients with aggressive non-Hodgkin lymphomas might benefit if concomitantly receiving statins with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine (Oncovin) and prednisone immunochemotherapy. We retrospectively analyzed a cohort of 130 newly diagnosed diffuse large B-cell lymphomas with unfavorable clinical features treated with first-line rituximab, dose-adjusted etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, hydroxydaunorubicin (R-DA-EPOCH) immunochemotherapy in period 2005-2019. A total of 17/130 (13.1%) patients received statins concomitantly with immunochemotherapy, mostly atorvastatin and in intermediate statin dose intensity. Besides tendency to be associated with older age (p = 0.070), there were no other significant associations of statins use with neither sex, disease stage, R-IPI, or other unfavorable disease features (p > 0.05 for all analyses). Also, no significant differences were present considering feasibility (number of cycles with dose escalation/reduction), toxicity (number of cycles with anemia, thrombocytopenia, neutropenia, febrile neutropenia, and septic complications) nor efficacy (response rates) of R-DA-EPOCH regimen (p > 0.05 for all analyses). Also, statin use had no significant association with neither OS (p = 0.480) nor PFS (p = 0.891). Lack of associations of statin use with relevant clinical outcomes was further corroborated by multivariate analyses.

Venetoclax combinations delay the time to deterioration of HRQoL in unfit patients with acute myeloid leukemia.

Phase 3 trials Viale-A and Viale-C evaluated health-related quality of life (HRQoL) in patients with AML unfit for intensive chemotherapy who received venetoclax (VEN) + (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C) or placebo (PBO) + AZA or LDAC. Patient-reported outcomes included: EORTC QLQ-C30 global health status (GHS/QoL) and physical functioning (PF), PROMIS Cancer Fatigue Short Form 7a (Fatigue), and EQ-5D-5L health status visual analog scale (HS-VAS). Time to deterioration (TTD), defined as worsening from baseline in meaningful change thresholds (MCT) of ≥10, 5, or 7 points for GHS/QoL or PF, fatigue, and HS-VAS, respectively, was assessed; differences between groups were analyzed using Kaplan-Meier and unadjusted log-rank analyses. VEN + AZA vs PBO + AZA patients had longer TTD in GHS/QoL (P = 0.066) and fatigue (P = 0.189), and significantly longer TTD in PF (P = 0.028) and HS-VAS (P < 0.001). VEN + LDAC vs PBO + LDAC patients had significantly longer TTD in GHS/QoL (P = 0.011), PF (P = 0.020), and fatigue (P = 0.004), and a trend in HS-VAS (P = 0.057). Approximately 43%, 35%, 32%, and 18% of patients treated with VEN + AZA, AZA + PBO, VEN + LDAC, or LDAC + PBO, respectively, saw improvements >MCT in GHS/QoL. Overall, VEN may positively impact HRQoL in patients with AML ineligible for intensive chemotherapy, leading to longer preservation of functioning and overall health status.

Baseline and progressive adipopenia in newly diagnosed patients with diffuse large B-cell lymphoma with unfavorable features are associated with worse clinical outcomes.

We retrospectively analyzed perirenal and subcutaneous fat thickness and their dynamics from baseline to end-of-treatment computerized-tomography scans in a cohort of 118 newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients with unfavorable features treated with R-DA-EPOCH regimen. Higher revised-international-prognostic-index (R-IPI) score was significantly associated with higher baseline perirenal and lower subcutaneous fat thickness. Up to 51% patients experienced perirenal and 40% subcutaneous fat-tissue loss during immunochemotherapy period. R-DA-EPOCH feasibility, toxicity and obtained response to therapy did not significantly differ regarding baseline perirenal and subcutaneous fat measurements whereas higher number of febrile-neutropenia cycles was associated with more pronounced subcutaneous fat loss. In multivariate-analyses subcutaneous fat loss of ≥6% (hazard-ratio (HR) =4.58, p < 0.001) and achieving response to therapy (HR = 0.03, p < 0.001) predicted overall-survival, and baseline subcutaneous fat thickness ≤24 mm (HR = 3.14, p = 0.023), baseline minimal perirenal fat thickness ≤8 mm (HR = 2.44, p = 0.042) and achieving response to therapy (HR = 0.04, p < 0.001) predicted progression-free-survival independently of each other.

Psoas muscle index at the time of diagnosis might reflect the prognosis of classical Hodgkin's lymphoma patients.

We retrospectively investigated clinical and prognostic significance of psoas muscle index (PMI) calculated as total psoas muscle area at L3 vertebra level obtained from baseline computed tomography (CT) scans in 49 newly diagnosed classical Hodgkin's lymphoma (cHL) patients prior to specific treatment. Median PMI was 572.5 mm2/m2 and was significantly higher in males (P < 0.001), patients with higher body mass index (BMI, P < 0.001), absence of extranodal disease (P = 0.037), higher absolute lymphocyte count (P = 0.037), higher hemoglobin (P = 0.010) and lower lactate dehydrogenase (LDH, P = 0.050). There were no significant associations with age, disease subtype, presence of constitutional symptoms, Ann Arbor disease stage, presence of advanced disease or international prognostic score. Patients with lower PMI had significantly worse PFS (hazard ratio [HR] 4.91; P = 0.009). This phenomenon persisted in the multivariate model (HR = 5.09; P = 0.042) adjusted for International Prognostic Score (IPS) and chemotherapy type.

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.

More Pronounced Muscle Loss During Immunochemotherapy is Associated with Worse Clinical Outcomes in Newly Diagnosed Patients with Diffuse Large B-Cell Lymphoma with Unfavorable Features.

INTRODUCTION: Cancer-induced cachexia is associated with poor prognosis in patients with non-Hodgkin lymphoma, but it is unknown how and to what extent curable lymphoma treatments affect the musculoskeletal system. PATIENTS AND METHODS: We retrospectively analyzed 104 newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients with unfavorable disease features treated with the R-DA-EPOCH regimen. Psoas muscle area (PMA) measured at L3 vertebra level was compared between staging (pre-therapy) and revision (end of treatment) computerized tomography (CT) scans. RESULTS: Small but significant decline in PMA was observed during the immunochemotherapy period (average loss 5%; P=0.016) with 57.7% of patients experiencing muscle loss. Higher body surface area (OR=17.98 for each m2; P=0.034), number of cycles with dose reduction (OR=2.86 for each cycle; P=0.039) and worse response to therapy (OR=3.09 for each response category; P=0.052) were recognized as independent contributors to the PMA loss in multivariate analysis. One quarter of patients had more pronounced PMA loss (≥21%), which was associated with significantly worse overall and progression-free survival. Both ≥21% PMA loss and non-achieving response to therapy remained independently associated with inferior OS (PMA loss HR=2.98; P=0.016 and achieving response HR=0.04; P<0.001) and PFS (PMA loss HR=3.16; P=0.005 and achieving response HR=0.08; P=0.001) in multivariate analyses. DISCUSSION: Muscle loss occurs in approximately half of newly diagnosed DLBCL patients with unfavorable disease features during R-DA-EPOCH immunochemotherapy. If pronounced, this is associated with worse clinical outcomes irrespectively of achieved response to therapy. Muscle loss seems to be mostly affected by the efficacy and tolerability of the regimen.

Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia.

BACKGROUND: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study. METHODS: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival. RESULTS: The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P<0.001). The incidence of complete remission was higher with azacitidine-venetoclax than with the control regimen (36.7% vs. 17.9%; P<0.001), as was the composite complete remission (complete remission or complete remission with incomplete hematologic recovery) (66.4% vs. 28.3%; P<0.001). Key adverse events included nausea of any grade (in 44% of the patients in the azacitidine-venetoclax group and 35% of those in the control group) and grade 3 or higher thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 28%), and febrile neutropenia (in 42% and 19%). Infections of any grade occurred in 85% of the patients in the azacitidine-venetoclax group and 67% of those in the control group, and serious adverse events occurred in 83% and 73%, respectively. CONCLUSIONS: In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax-azacitidine group than in the control group. (Funded by AbbVie and Genentech; VIALE-A ClinicalTrials.gov number, NCT02993523.).

Prolonged methylprednisolone premedication prior to obinutuzumab in patients with chronic lymphocytic leukemia.

First obinutuzumab application is associated with infusion related reactions (IRRs) that may discourage further continuation of the drug. During our clinical practice we have observed that chronic lymphocytic leukemia (CLL) patients with autoimmune hemolytic anemia (AIHA) prolongedly receiving corticosteroids do not develop obinutuzumab IRRs. Therefore, we decided to apply prolonged corticosteroid premedication with methylprednisolone in dose 1-1.5 mg/kg for ≥7 days to all further obinutuzumab candidates. Here we present non-randomized comparison of 28 consecutive previously untreated CLL patients receiving prolonged corticosteroid premedication (15 patients) or standard premedication (13 patients) prior to the first obinutuzumab infusion. Prolonged corticosteroid premedication resulted in significant reduction of all-grade (20% vs 61.5%; p = .025) and grade III (0% vs 23.1%; p = .049) obinutuzumab IRRs. Prolonged corticosteroid premedication did not significantly affect occurrence of infective complications. Patients with CLL and AIHA receiving obinutuzumab showed continuous and stable increase in hemoglobin levels concomitantly with decrease in parameters of hemolysis.

Neutral effect of Glioma-associated oncogene-1 expression on survival in myelofibrosis.

This study retrospectively analyzed glioma-associated oncogene 1 (GLI­1) mRNA expression in unfractionated bone marrow aspirates of 32 patients with myelofibrosis and 16 controls. It was found that GLI­1 expression did not significantly differ between primary, secondary myelofibrosis and controls (median difference in threshold cycles ∆CT 7.2, 7.3 and 6.9, respectively; P = 0.864), as well as that survival curves of myelofibrosis patients with higher/lower GLI­1 expression showed multiple overlaps and overall comparable course (P = 0.651). The results suggest that general upregulation of GLI­1 does not seem to be a feature of the disease and are in line with modest biological and clinical effects observed with inhibitors of Hedgehog signaling pathway in patients with myelofibrosis.

Health-related quality of life in Croatian general population and multiple myeloma patients assessed by the EORTC QLQ-C30 and EORTC QLQ-MY20 questionnaires.

Background The impact of disease and treatment on the patient's overall well-being and functioning is a topic of growing interest in clinical research and practice. The aim of this study is to obtain reference data on quality of life of Croatian general population. Further, we aim to assess the impact of the disease and its primary systemic treatment on their health related quality of life (HrQoL) in multiple myeloma (MM) patients. Patients and methods Participants for the first part of the study were randomly selected from adult Croatian population. In the clinical part of the study MM patients were included as prospectively diagnosed within two years in two major Croatian haematological centres. The EORTC QLQ-C30 in both trials and QLQ-MY20 in MM patients only were applied for HrQoL assessment. Results Gender, age and place of residence have great impact on quality of life scores in Croatian population. The MM patients at the time of diagnosis have lower QLQ-C30 scores for global quality of life, functional and symptom scale scores, as well as single items. The type of disease followed by the choice of therapy options are important HrQoL determinants. Conclusions The norm values available now for Croatian population will help to interpret HrQoL for clinicians and aid in planning cancer care interventions. This study identified treatment effect consistent with those from other observational studies and provided new data on HrQoL across two different treatment choices for MM 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.

Elevated Neutrophil-to-Lymphocyte-ratio and Platelet-to-Lymphocyte Ratio in Myelofibrosis: Inflammatory Biomarkers or Representatives of Myeloproliferation Itself?

BACKGROUND/AIM: We aimed to investigate clinical associations of inflammatory biomarkers neutrophil-to-lymphocyte-ratio (NLR) and platelet-to-lymphocyte-ratio (PLR) in patients with myelofibrosis, myeloproliferative neoplasm with inflammatory background. PATIENTS AND METHODS: We retrospectively analyzed a cohort of 102 myelofibrosis patients. NLR and PLR were assessed in addition to other disease-specific parameters. RESULTS: NLR and PLR were significantly higher in myelofibrosis than in healthy controls. Higher NLR was significantly associated with Janus-kinase-2 (JAK2)-mutation, wild-type-Calreticulin (CALR), older age and parameters reflecting increased proliferative potential of disease (higher leukocytes, higher hemoglobin, larger spleen-size), whereas there was no significant association with C-reactive-protein (CRP). Higher PLR was significantly associated with absence of blast-phase-disease, absence of constitutional-symptoms, lower percentage-of-circulatory-blasts, smaller spleen-size and lower CRP. In the Cox-regression-model, higher-NLR (HR=2.76; p=0.004), lower-PLR (HR=1.99; p=0.042) and Dynamic-International-Prognostic-System (DIPSS) (HR=3.26; p<0.001) predicted inferior survival independently of each other. CONCLUSION: In the context of myelofibrosis, elevated NLR and PLR are more likely to represent myeloproliferation itself and not necessary the extent of inflammation.