BackgroundIbrutinib is effective for B-cell malignancies but is associated with cardiovascular adverse events, including atrial fibrillation (AF) and hypertension. Longitudinal data on left atrial (LA) remodeling during treatment are limited. We characterized serial changes in LA size and function during chronic ibrutinib therapy.MethodsIn this prospective observational cohort, 40 patients starting ibrutinib underwent clinical assessment, 24–72-hour Holter monitoring, and echocardiography with LA strain at baseline and 3, 6, 12, and long-term (nominal 36-month) follow-up. Primary analyses used observed paired data, random-intercept mixed models, standardized response means (SRMs), and Benjamini-Hochberg adjustment across 24 primary contrasts.ResultsMedian age was 65 years and 53% were female. Paired mean LAVI changes were +1.52 mL/m² at 3 months (n = 38), +1.68 at 6 months (n = 36), +2.62 at 12 months (n = 33), and +2.15 at long-term follow-up (n = 31; all q ≤ 0.020). LA reservoir strain worsened from 6 months onward (all q ≤ 0.031), while LA contractile strain, LA lateral-wall TDI, and LV GLS worsened at every follow-up (all q ≤ 0.009). Results were materially unchanged after adjustment for time-varying hypertension and in complete-case sensitivity analyses. Incident AF occurred in 5/40 patients (12.5%; 95% CI 5.5%–26.1%).ConclusionDuring chronic ibrutinib therapy, longitudinal imaging showed modest LA enlargement and consistent deterioration in several LA deformation indices. These treatment-associated observations require confirmation in controlled cohorts.Clinical trial registrationClinicalTrials.gov, identifier NCT03751410.

Diarrhea usually appears early following autologous hematopoietic stem cell transplantation (ASCT) due to toxic mucosal damage and neutropenia. Infectious agents also cause diarrhea in the post-transplantation period, with Clostridium difficile (C. difficile) being most common. In contrast, cytomegalovirus (CMV) enterocolitis is extremely rare after ASCT. We report a case of a 55-year-old male who underwent ASCT for non-Hodgkin lymphoma that was complicated by severe persistent diarrhea resulting in significant hypovolemia and electrolyte imbalance. Prior to transplantation, the patient received rituximab in combination with chemotherapy (R-CHOP/R-DHAP) followed by a bendamustine-based conditioning regimen (BeEAM). After treatment with oral metronidazole, vancomycin and fidaxomicin, diarrhea persisted despite undetectable C. difficile toxin, with elevation of hepatic enzymes. Eventually, CMV infection was diagnosed by real-time polymerase chain reaction and treated with ganciclovir and valganciclovir. Due to hypogammaglobulinemia following previous rituximab treatment, CMV immunoglobulins were also administered. The patient’s condition gradually improved with CMV DNA being undetectable in serum. This case shows that diarrhea may be caused by concurrent infection with C. difficile and CMV after ASCT. Bendamustine-induced colitis and prior rituximab treatment may have been additional risk factors in this patient. Therefore, more comprehensive workup of diarrhea is needed in ASCT recipients treated with these agents.

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.

HrvatskaB-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

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.

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.

B-cell chronic lymphocytic leukemia (B-CLL) is characterized with variable infiltration by B -CLL lymphocytes of various lymphoid compartments, i.e peripheral blood (PB), bone marrow (BM) and lymph nodes (LN) and lymphoid organs. Interactions with various microenvironments may result in different disease activity and resistance to apoptosis. Novel agents targeting Btk and Bcl-2 show remarkable activity in B-CLL. However, they may have different activity in different lymphoid compartments while Btk inhibitors also may cause significant B-CLL lymphocyte redistribution between compartments. Aim of this study was to evaluate: 1) is there a different expression of Bcl-2 family of anti- and pro-apoptotic proteins (Bcl-2, Bax, Bim, mcl-1) and Btk in B-CLL lymphocytes from different lymphoid compartments; 2) relationship of observed expressions to disease parameters (TTM, TD, stage, B2MG, LDH); 3) changes during treatment with Btk inhibitors. We have included 28 B-CLL patients (18/10 M/F, median age 71 yr, range 48-85) treated with Btk inhibitors (ibrutinib 24, acalabrutinib 4). There were 15 previously treated patients and 13 treatment naïve patients. All evaluated patients had samples from PB and BM before treatment while 19 patients had also LN samples. At least one follow-up sample from PB had 20 patients. Median TTM score was 10.2 (range 3.4-23.9) and TD score was 0.68. Rai stage III/IV had 8 patients. Expression of Bcl-2, Mcl-1, Bim, Bax and Btk was determined by flow cytometry in CD19+CD5+ lymphocytes from fresh samples taken simultaneously by venipuncture (PB) or fine needle aspiration (BM and LN). There is higher expression of Bcl-2, Mcl-1 in LN compared to PB and BM (p<0.05), while there is no change in follow-up PB during ibrutinib/acalbrutinib treatment. There is no significant difference in Bim expression between compartments, while there is trend for higher expression in PB follow-up sample (p=0.054). There is no significant difference in Bax expression between PB, BM and LN compartments, while there is significant drop in Bax expression in PB follow-up sample during treatment (p<0.05). p-Btk has higher expression in LN compared to PB and BM (p<0.05). Follow-up PB p-Btk expression is comparable to pretreatment expression in PB (despite redistribution). We haven't found significant correlation of Bcl-2 family expression and p-Btk expression to the parameters of tumor mass (TTM) and tumor distribution (TD). In conclusion, there is a different pattern of expression of anti-apoptotic and pro-apoptotic Bcl-2 family members and Btk between lymphoid compartments. Our results may indicate higher BCR signaling and higher antiapoptotic activity in B-CLL lymphocytes in lymph node microenvironment. With redistribution during Btk inhibitor treatment B-CLL lymphocytes assume PB phenotype with downregulation of Btk and anti-apoptotic Bcl-2 and Mcl-1 proteins. Downregulation of pro-apoptotic Bax and possible upregulation of Bim protein indicate that there may be more complex interplay between various proteins resulting in different disease course. These results again emphasize the role of LN microenvironment in pathogenesis of B-CLL and may provide insights for treatment strategies combining targeted agents (Btk inhibitors and Bcl-2 antagonists).

Background: There are controversial clinical data on potential benefits of statin use concomitantly with immunochemotherapy in the first line treatment of agressive Non Hodgkin lymphoma (NHL) patients. Majority of information is based on R-CHOP treated cohorts. Recent reports indicate that statins might improve chemosensitivity of tumor cells to doxorubicine and diffuse large B cell lymphoma (DLBCL) patients concomitantly treated with statins in addition to R-CHOP might experience improved response rates and improved survival. Aims: We aimed to evaluate whether concomitant statin use resulted in improved outcomes in our cohort of newly diagnosed DLBCL patients with unfavorable disease features treated with R-DA-EPOCH regimen. Methods: We retrospectively evaluated all consecutive first line DLBLC patients who presented to our institution in period 2005-2019 and who were treated with R-DA-EPOCH regimen. All patients were Caucasians and had unfavorable disease features (Ki67+ ≥80% and/or International Prognostic Index (IPI) ≥2 points). Electronic and written medical records were analyzed for statin use at the time of immunochemotherapy. Clinical and laboratory features, as well as outcome measures (response rates, progression free and overall survival) were compared between patients with and without concomitant statin use. Results: A total of 130 newly diagnosed DLBLC patients were evaluated. Median age was 62 years IQR (48-71), there was a similar proportion of male (73/130 (56.2%)) and female patients (57/130 (43.8%)). Median R-IPI score was 3 points IQR (2-3). A total of 17/130 (13.1%) patients received statins concomitantly with immunochemotherapy (atorvastatin (11/17, 65%), rosuvastatin (4/17, 24%), simvastatin (2/17, 12%)). There were no significant differences in baseline demographic and clinical characteristics between patients concomitantly exposed and non-exposed to statins. Also, there were no significant differences in number of cycles with R-DA-EPOCH dose escalation, reduction, anemia, thrombocytopenia, neutropenia, febrile neutropenia and septic complications. Also, there was no significant difference in proportion of patients achieving complete (53% vs 66%) or partial response (24% vs 19%) between patients exposed and non-exposed to statins. Median follow-up of our cohort was 48 months. Statin use had no significant association with neither OS (P=0.480) nor PFS (P=0.891) as shown in Figure. To account for potential age, sex and disease biology differences between patients with and without statin exposure we evaluated statin use in a logistic regression model assessing predictors of response to therapy where only lower R-IPI score was significantly associated with achieving the response (OR 0.44 95% CI (0.21-0.94), P=0.035), whereas statin use (P=0.909), age (P=0.119) and sex (P=0.291) had no significant associations. In a similar Cox regression model assessing predictors of PFS, achieving response to therapy was statistically significant (HR 0.08 95% CI (0.03-0.21), P<0.001) and there was a tendency for higher R-IPI (HR 1.36 95% CI (0.99-1.87), P=0.058) to be associated with PFS, whereas there were no significant associations of statin use (P=0.674), age (P=0.597) and sex (P=0.151) with PFS. Image:Summary/Conclusion: Our data on first line DLBLC patients with unfavorable disease features treated with R-DA-EPOCH regimen do not confirm previously reported observations of improved response rates nor improved PFS with concomitant statin use. Differences in immunochemotherapy regimens and underlying disease biology might play a role in observed differences.

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.

Background: There is an increasing pool of evidence describing detrimental outcomes of patients with hematological malignancies with acute COVID-19. Aims: to evaluate risk of death with acute COVID-19 in patients with various hematological malignancies in comparison to matched control patients from a large single institution registry. Methods: We retrospectively analyzed all consecutive hospitalized COVID-19 patients treated in period 3/2020-3/2021 in our institution (University hospital Dubrava) that served as a regional COVID-19 referral center during the pandemic. Data from a hospital Registry project were used. Patients with hematological malignancies were compared to the case-control matched group of patients without malignant disease. Matching was performed according to age, sex and modified Charlson comorbidity index (with subtracting points provided for hematological malignancy in hematological malignancy patients). Results: Out of total 4014 consecutive hospitalized COVID-19 patients, there were 154 patients with hematological malignancies. There were 81/154 (52.6%) male patients. Median age was 71 years and median Charlson comorbidity index was 5 points. Most represented hematologic malignancy subtype was chronic lymphocytic leukemia (CLL) present in 37/154 (24%) patients, followed by aggressive lymphomas (30/154 (19.5%)), plasma cell dyscrasias (28/154 (18.2%)), acute leukemias (21/154 (13.6%)), indolent non Hodgkin lymphomas (18/154 (11.7%)), myelodysplastic syndromes (MDS, 12/154 (7.8%)) and chronic myeloproliferative leukemias (8/154 (5.2%)). Disease course significantly differed between disease subsets (P=0.004) as shown in Figure. Patients with CLL and indolent lymphomas experienced more favorable disease course comparable to matched control groups of COVID-19 patients without malignancies, whereas other subsets of patients experienced more rapid deterioration. Recent treatment (actual or in 3 months prior to admission) did not affect survival outcomes (P=0.402), as well as active disease status (P=0.076) but where tendency for worse survival was evident. Patients previously receiving autologous or allogeneic stem cell transplantation also did not significantly differ in survival in comparison to non-transplanted patients (P=0.425). In a multivariate survival analysis, acute leukemias (HR 5.88; P<0.001), MDS (HR 2.91; P=0.006), plasma cell dyscrasias (HR 4.68; P<0.001) and aggressive lymphomas (HR 2.53; P<0.001) were associated with worse survival in comparison to matched control patients independently of age (HR 1.04; P<0.001), modified Charlson comorbidity index (HR 1.1; P=0.017), and COVID-19 severity on admission (HR 5.98; P=0.003 for severe and HR 11.06; P<0.001 for critical vs mild disease). Image:Summary/Conclusion: Hospitalized COVID-19 patients with acute leukemias, MDS, plasma cell dyscrasias and aggressive lymphomas experience higher mortality irrespectively of age, comorbidity burden and COVID-19 severity on admission.

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.

Background: Follicular lymphoma (FL) is a systemic neoplasm of the lymphoid tissue arising from B cell proliferation. The novel monoclonal anti-CD20 antibody obinutuzumab in combination with chemotherapy has been widely accepted as the first choice in front line treatment of FL. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), responsible for coronavirus disease 2019 (COVID-19) is causing increased mortality among patients with lymphoproliferative disorders compared with the general population. Furthermore, there are some concerns in terms of morbidity and mortality for patients with FL because of their immunocompromised status induced by recent exposure to cytotoxic chemotherapy, especially bendamustine and anti-CD20. Aims: To investigate efficacy and safety of immunochemotherapy protocols for patients with newly diagnosed FL during COVID-19 pandemic. Methods: We retrospectively investigated medical data of all patients with newly diagnosed FL grade 1, 2 or 3A from Croatian hematologic registry in period from April 2019 to March 2021. Only patients which required systemic treatment were included in the analysis. All patients received obinutuzumab (G) in combination with either CHOP, bendamustine (B) or CVP chemotherapy protocol. Treatment response was evaluated using international lymphoma response criteria. Results: We analyzed a total of 114 FL patients treated with G-chemotherapy. Mean age was 62.4 ±10.5 years. Majority of patients were female (71/114 (62.3%)). FL grade I was present in 45/114 (39.5%), grade II in 28/114 (24.6%), grade III in 27/114 (23.7%) and not specified (but not IIIB) in 14/114 (12.3%) patients. A total of 61/114 (53.5%) patients were treated with G-B, 49/114 (43%) with G-CHOP and 4/114 (3.5%) with G-CVP immunochemotherapy. Similar rates of adverse events were observed in patients treated with G-CHOP and G-B Median follow up was 17 months. Overall response rate was 94%, complete remission (CR) in 68% and partial remission (PR) in 25% of patients. Median overall survival (OS) and progression free survival (PFS) were not reached with 12-months rates of 94% and 92%, respectively. Patients treated with G-CHOP had statistically significantly superior OS and PFS compared to patients treated with G-B (P=0.002 and P=0.006, respectively, Fig. 1). More favorable survival course associated with G-CHOP in comparison to G-B persisted in multivariate analysis (P=0,026, HR=15,12) after adjustment for age, sex, FLIPI grade and SARS-CoV-2 infection. Total of 12 patients died during the follow up and COVID-19 was cause of death in 5 patients. During the follow-up SARS-CoV-2 infection was diagnosed in 20/114 (17,5%) patients with overall mortality rate of 25%. All of the 7 patients treated with G-CHOP recovered from SARS-CoV-2 infection and mortality rate in infected group of patients treated with G-B was 33% (4/12 patients). Image:Summary/Conclusion: Increased COVID-19 mortality in patients with lymphoproliferative disorders was observed in this study. Our group of patients had reduced OS and PFS compared to the GALLIUM trial and SARS‐CoV‐2 infection was the most pronounced risk factor for death. Even though in some studies bendamustine has shown to be less toxic and more effective than CHOP in FL, there are some important pandemic aspects that must be considered. Bendamustine exposure seems to be associated with worse outcome in case of the infection with SARS-CoV-2. These intriguing differences could play important role in treatment approach in COVID-19 pandemic. Future studies investigating hematological malignancies in COVID-19 pandemic are warranted.

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.

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.

Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of B-cell lymphoid malignancies and the most common subset of aggressive non-Hodgkin lymphomas (NHL). The current standard of care is R...