Figure 1: PFS (Kaplan-Meier curves): The outcome of EU and AS patients - 5-y PFS 95% vs. 98%, respectively. Full-length vs. shorter steroid courses - 5 y PFS 98% vs. 95%, respectively. Background: eBEACOPP is the most effective chemotherapy regimen for younger patients with early unfavourable (EU) and advanced stage (AS) Hodgkin lymphoma (HL), but is burdened with early and late toxicities. The original 14 days of steroids contributes to side effects, including severe osteoarticular events, like avascular bone necrosis (AVN). We have been using eBEACOPP since 2009 for AS and since 2014 also for EU patients. We started reducing the length of steroid treatment to 8–10 days in 2016, primarily to reduce the risk of AVN. Methods: We analysed outcomes of our patients, focusing on the comparison of EU and AS patients and those receiving full length and shorter steroid courses. Data was obtained retrospectively, from the hospital database. Results: 162 patients received eBEACOPP as front-line treatment, 130 with AS and 32 with EU HL. Median age was 31 y, range 19–59; 88 (54%) were male. After a median follow-up of 58 mo, 5-y PFS of the whole cohort was 97% and OS 98%. The outcome of EU and AS patients was indistinguishable with a 5-y PFS of 95% vs. 98%, respectively (Fig). Outcome of patients receiving full-length or shorter steroid courses was also indistinguishable, with a 5 y PFS of 98% vs. 95% respectively (Fig). The incidence of AVN was numerically, but statistically insignificantly lower in patients receiving 6 cycles of eBEACOPP with a shorter steroid course (1/42 vs. 4/72, p=0.65). There were no differences in emergency hospital admissions and episodes of febrile neutropenia between the two cohorts. Conclusion: eBEACOPP provides excellent and durable first line disease control. Our data confirms the findings of GHSG of lack of outcome differences between different prognostic groups if eBEACOPP is used as primary treatment. Reducing the duration of steroid treatment to 8 days per cycle is safe, but longer follow-up and more patients are needed to confirm that it reduces serious acute and chronic toxicities.

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.

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 twoyear 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.

Due to age and comorbidities many patients with CLL receive chlorambucil as front-line treatment. Doses and schedules of this drug vary widely but it is not clear whether this affects outcomes. We performed this retrospective analysis to compare the efficacy and toxicity of continuous high-dose chlorambucil (12-20 mg daily until response or toxicity) (cHD-Clb-R) and intermittent high dose chlorambucil (8-10 mg/m2 daily for 7 days q 4 wk) (iClb-R) in combination with rituximab (375 mg/m2/cycle for 8 cycles) in previously untreated CLL patients. Thirtysix patients received cHD-Clb-R and 32 iClb-R. Median age was 66 years (range 41-80); 24 were women and 44 men; 24 had Binet stage A, 27 B and 17 C; 5 had del(17p). Most common severe adverse events were granulocytopenia, occurring in 14; and infections in 7 patients, one of whom died. One patient stopped treatment due to hepatotoxicity. Both schedules resulted in similar toxicity and efficacy (cHD-Clb-R vs. iClb-R overall survival, progression-free survival and survival without next treatment at 30 mo. 70% vs. 83%, 49% vs. 55% and 67% vs. 75% respectively). Combinations of rituximab and chlorambucil are well tolerated and effective treatments for patients ineligible for fludarabine-based regimens. Outcomes seem to be related more to total drug doses than schedules.

Currently, there is no consensus regarding optimal front-line treatment for younger high-risk patients with large B cell lymphoma. American recommendations list only R-CHOP as standard, while European also include R-ACVBP and R-CHOEP14. We have been routinely using the latter regimen at our institution since 2011 and performed this retrospective real-life single-center study to analyze outcomes. Between September 2011 and April 2019, 66 newly diagnosed patients aged 18 to 60 years with B-large cell lymphoma and high-risk age-adjusted International Prognostic Index score were scheduled to receive 6 or 8 cycles of bi-weekly chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, etoposide, steroids, and rituximab (R-CHOEP14). After a median follow-up of 4.7 years, the estimated 3-year progression-free survival was 87% (95% CI 80–96%) and 3-year overall survival 90% (95% CI 83–98%). Grade ≥ 3 hematological side effects occurred in 83% and infectious in 41% of patients; one patient died of toxicity. Grade ≥ 2 cardiac toxicity occurred in 21% of patients, more frequently than previously reported. The cumulative 5-year risk of congestive heart failure with all-cause mortality as the competing risk was 17%. R-CHOEP14 is a very effective and manageable regimen for younger high-risk patients with B-large cell lymphoma, but the risk of cardiotoxicity warrants further investigations.

A 40-year-old female patient was admitted to the Department of Oral Medicine due to oral ulcerations. Oral ulcerations were present on vestibular mucosa above teeth 21, 22, 25 and 26 and were 1 cm in diameter, and also around teeth 45 and 46. The patient had prolonged neutropenia due to therapy-related myelodysplastic syndrome that progressed to therapy-related acute myeloid leukemia. Initially, the patient was successfully treated with polychemotherapy for non-Hodgkin lymphoma. Unfortunately, many toxic complications ensued, such as peripheral neuropathy, dilated cardiomyopathy and therapy-related myelodysplastic syndrome/therapy-related acute myeloid leukemia. The onset of therapy-related myelodysplastic syndrome was less than six months after initiation of chemotherapy treatment, which was rather early, but cytogenetic changes (monosomy 5 and 7) were consistent with the diagnosis. Upon admission to our Department, microbiological swabs were obtained and were all negative, while x-ray finding showed that ulcerations did not have dental cause. Biopsy was not obtained as the patient had severe neutropenia and thrombocytopenia. While viral and fungal swabs were negative, Stenotrophomonas maltophilia was cultured from the oral cavity. Thus, differential diagnoses are listed in this report. Neutropenic ulcerations did not heal albeit extensive medicamentous oral and systemic treatments were applied and the patient died.

Background:Maintenance therapy after autologous hematopoietic stem cell transplantation (AHSCT) in multiple myeloma (MM) patients was a matter of debate until recently, when lenalidomide in this setting proved to increase overall survival (OS). Before lenalidomide interferon alpha (IFN) was standard maintenance therapy.Aims:The aim of this analysis was to determine the impact of maintenance therapy after AHSCT on progression free survival (PFS) and OS in MM patients treated at our institution between 1993 and 2014.MethodsWe performed a retrospective analysis of outcomes of MM patients autografted at our institution between 1993 and 2014. We identified 274 pts. who had PFS at least 6 months posttransplant; median age was 57, range 28‐71, 48% were male. 124 of them received tandem and 150 single AHSCT. Median follow‐up was 62 mo. Posttransplant 200 patients received IFN, 44 thalidomide and 30 no maintenance according to physicians’ choice.Results:Patients receiving IFN had longer 5‐year PFS compared to patients receiving thalidomide or no maintenance (52% vs. 34% vs. 31%, respectively, p < 0.001). OS was best in the IFN group, intermediate in the thalidomide and worst in the no maintenance group (67% vs. 59% vs. 32%, respectively, p < 0.001). The difference was limited to patients receiving tandem transplants. In this group 5‐year PFS was 61% vs. 35% vs 0% (p < 0.001) and OS 85% vs. 67% vs. 65% (p = 0.003) in the IFN, thalidomide and no maintenance group respectively. In patients that received a single transplant 5‐year PFS was 43% vs. 33% vs 36% (p = 0.157) and 5‐year OS 70% vs. 75% vs. 54% (p = 0.06) in the IFN, thalidomide and no maintenance group respectively.Summary/Conclusion:Our results indicate that maintenance therapy has beneficial effects on OS and PFS in MM patients treated with tandem, but not single AHSCT. IFN is superior in this setting to thalidomide and could be considered as a treatment option when lenalidomide is not available.

Background:Due to availability and pricing problems recently many transplant centers substituted carmustine in the BEAM regimen (carmustine, etoposide, cytarabine, melphalan), used for conditioning of lymphoma patients undergoing autologous stem cell transplantation (ASCT), with bendamustine (BeEAM). Very few comparisons of the toxicity and efficacy of these two conditioning regimens have been reported.Aims:Describe the toxicity and efficacy of BeEAM and compare it to that of BEAM.Methods:We analyzed outcomes of 35 patients with frequent lymphoma types (B‐large cell, follicular, Hodgkin (HL), T‐cell and mantle‐cell) conditioned with BeEAM in 2016 and 2017 and compared them to 37 patients conditioned with BEAM between 2011 and 2015 matched by age, sex, diagnosis and risk according to standard prognostic indices. Bendamustine was administered at a total dose of 160 mg/m2 divided over two days. Etoposide, cytarabine and melphalan were given as usual.Results:Median follow‐up of BeEAM conditioned patients was 18 mo and BEAM conditioned 46 mo. Number of reinfused CD34+ cells/kg body weight was similar between the groups (median 5.87 vs. 5.56 × 106, p = 0,412). One of the BeEAM conditioned patients died of cardiac shock and one progressed before hematologic recovery, no such events occurred in those conditioned with BEAM. There was a trend towards lower incidence of infections and febrile neutropenia (80% vs. 95%, p = 0.0719) and significantly less mucositis in the former group (11% vs. 51%, p = 0,0002). Neutrophil recovery was similar (median 11 days, range 8‐16 vs. median 10 days, range 7‐18; p = 0,215), but platelet recovery was slower after BeEAM (median 16 days, range 8‐29 vs. median 12, range 8‐27; p = 0.00132). Hospitalization duration was similar (median 16 days, range 12‐32 vs. median 17 days, range 12‐24; p = 0.215). OS was almost identical (85% vs. 86% at 2 years, p = 0.781). There was a non‐significant difference in EFS in the whole cohort in favor of BEAM (Fig) (66% vs. 76% at 2 years, p = 0.39), but this was limited to HL (2‐year EFS 61% vs. 82%, p = 0.257). 2‐year EFS of NHL patients was 70% vs. 73%, p = 0.808.Summary/Conclusion:Substituting carmustine in BEAM with bendamustine, at least in the dose of 160 mg/m2, results in somewhat delayed platelet recovery but less mucositis and possibly infectious complications. Efficacy in NHL seems maintained. However, reduced efficacy of the BeEAM conditioning regimen in HL cannot be excluded and additional studies, preferably multicenter, in a larger patient population are needed.image

INTRODUCTION:For over a decade, imatinib has been the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML). Doubts on the bioequivalence and bioavailability of emerging generic compounds have been expressed. Adequate imatinib plasma concentration ([IPC] ≥1000 μmol/L) is associated with a better chance of optimal treatment response in patients with CML. In this study, we compared the achieved IPCs between the branded compound and its 2 generic forms. PATIENTS AND METHODS:IPCs were compared in 24 consecutive patients with CML in the first chronic phase who changed from branded to generic imatinib. The median age was 49 years (range, 22-76 years). Fifteen of them were male. Six patients were switched to Neopax, 13 to Imakrebin, and 5 patients received both generics consecutively. All compounds were used in an equivalent dose of 400 mg orally once daily for at least 1 month before plasma concentrations were measured. High-performance liquid chromatography was used to determine imatinib plasma concentration from a specimen collected 21 to 24 hours after the last dose. RESULTS:The median IPC achieved with branded imatinib was 1454 μmol/L (range, 485-2707 μmol/L) with 18 patients (75%) having IPC ≥ 1000 μmol/L. For Neopax and Imakrebin, median IPCs were 1717 μmol/L (range, 1249-3630 μmol/L) and 1458 μmol/L (range, 707-880 μmol/L), respectively, with 11 of 11 (100%) and 16 of 18 (89%) patients having IPC ≥ 1000 μmol/L. No significant difference in measured IPCs between all 3 compounds was found (P > .257). CONCLUSION:When taken at equivalent doses, imatinib generics are bioequivalent and comparable in clinical efficacy and have the potential for substantial savings in the treatment cost for CML.