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Patients with lymphoid malignancies are at increased risk of death or prolonged infection due to COVID-19. Data on the influence of different antineoplastic treatment modalities on outcomes are conflicting. Anti-CD20 monoclonal antibodies increase the risk of prolonged infection. It is unclear whether this risk is affected by the choice of the antibody (rituximab vs. obinutuzumab). To elucidate the role of antineoplastic therapy on COVID-19 outcomes, KroHem collected data on patients with lymphoid malignancies diagnosed with COVID-19 between October 2020 and April 2021. A total of 314 patients were identified, 75 untreated, 61 off treatment and 178 on treatment. The mortality rate in untreated and off-treatment patients was 15% and 16%; 9% and 10% had prolonged infection. In the on-treatment group, 3% were still prolonged positive at time of data collection, 62% recovered and 35% died; 42% had prolonged infection. Disease type, use of anti-CD20 monoclonal antibodies, prior autologous stem-cell transplantation (ASCT) and line of treatment did not significantly affect mortality. Mortality was higher in older patients ( p = 0.0078) and those treated with purine analogues ( p = 0.012). Prolonged COVID-19 was significantly more frequent in patients treated with anti-CD20 monoclonal antibodies ( p = 0.012), especially obinutuzumab, and purine analogues ( p = 0.012). Age, prior ASCT and treatment line did not significantly affect risk of prolonged infection. These data suggest that increased age and use of purine analogues are main risk factors for increased mortality of COVID-19 in patients with lymphoid malignancies. Obinutuzumab further increases the risk of prolonged disease, but not of death, in comparison to rituximab. Epidemiological considerations should be taken into account when choosing the appropriate antineoplastic therapy for patients with lymphoid malignancies.

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.

Follicular lymphoma is the second most frequent non-Hodgkin's lymphoma, accounting for around 20 % of all lymphomas in Western countries. Initially, it behaves indolently, but in time becomes more aggressive and less susceptible to chemotherapy. Multiple features correlate with the survival of the patients and the progression of the disease, such as therapy with rituximab, tumour microenvironment and the intrafollicular proliferation index. Our research was focused on the association of specific components of tumour microenvironment and the tumour behaviour. The presence and the relative percentage of T lymphocytes, follicular dendritic cells, dendritic cells and macrophages was detected by immunohistochemical staining of the antigens specific for certain cell populations. Our results show that T lymphocytes and dendritic cells affect tumour growth, possibly through interactions with tumour cells. Higher patients' ECOG score and the outcome of the disease are associated with the presence of CD14+ dendritic cells in tumour tissue, while the worse overall survival of patients is associated with the increased number of activated helper T lymphocytes that express marker of exhaustion CD57. Taken together, our results suggest that the efficiency of the immune response against follicular lymphoma depends on more than one type of immune cells. Also, we found that the phenotype of these cells, rather than just their number, affects the tumour behaviour and in consequence survival of the patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Hodgkin lymphoma (HL) is a biologically diverse group of lymphoid tumors, which accounts for 1% of all de novo neoplasms in the world's population. It is divided into two main groups: the more common classic Hodgkin lymphoma (cHL) and the less common nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). cHL is further divided into four subtypes, which differ in morphology and the contents of tumor microenvironment. Macrophages are one of the components of tumor microenvironment known to contribute to creating an immunosuppressive microenvironment, which inhibits the activity of cells expressing granzyme B against tumor cells, even when tumor cells are infected with Epstein-Barr virus (EBV). Our research aimed to explore the association between the specific contents of tumor microenvironment and the genetic anomalies in tumor cells. The presence and the relative percentage of cytotoxic T lymphocytes and macrophages was detected by immunohistochemical staining of the antigens specific for certain cell populations. Fluorescent in situ hybridization was used to detect anomalies in the genome of tumor cells and in situ hybridization was used to detect the presence of EBV. Our results show an association between the number of CD163+ macrophages and the number of TP53 copies or BCL6 gene translocation. Patients who had a higher number of CD163+ macrophages infiltrating tumor tissue and three or higher number of copies of TP53 showed poorer survival. We conclude that the presence of macrophages may contribute to genetic instability in cHL, which drives the progression of cHL and decreases survival of the patients.

Introduction: Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries occurring typically in elderly patients. These patients often present with comorbidities limiting treatment options. During the last decade, the treatment paradigm has rapidly changed with the introduction of novel oral targeted agents and monoclonal antibodies., Areas Covered: The review focuses on the combination of type II antiCD20 antibody obinutuzumab in combination with chemotherapy or oral targeted agents in patients not suited for fludarabine-based therapy because of comorbidities or age. The main focus of the review is whether classical immunochemotherapy with obinutuzumab-chlorambucil is still a valid therapeutic option or whether the combination of obinutuzumab and ibrutinib or venetoclax presents novel standard of care., Expert Opinion: Both pivotal and registrational studies iLLLUMINATE study testing the combination of ibrutinib and obinutuzumab and CLL14 study testing the fixed combination of venetoclax and obinutuzumab have shown major benefit over chemoimmunotherapy approach in this population. Furthermore, they have excellent activity in high-risk subgroups of CLL paving the road toward a chemo-free immunotherapy approach in this setting. However, there are some pitfalls in these strategies warranting further research.

ECHELON-1 study is a randomized open-labeled controlled trial investigating whether addition of brentuximab vedotin to chemotherapy offers benefit over the standard chemotherapy regimen in advanced Hodgkin lymphoma. After a median follow-up of 24.6 months, it has met its primary endpoint the reduction of modified progression-free survival being 23 percent. However, the beneficial effects have not been seen across all subgroups leading to further questions. The main aim of this review is to tackle these questions to provide the reader with in-depth insight of pros and cons of this novel, promising but ultimately controversial regimen., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

- The aim of this review is to present data on bendamustine, a non-cross resistant alkylating agent, alone or in combination for treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Bendamustine is currently approved for rituximab-resistant indolent NHL and CLL in patients not fit for conventional chemotherapy. Recent studies have shown superiority of bendamustine combination with rituximab (B-R) in first line treatment of indolent NHLs and mantle cell lymphoma, suggesting a shift of the standard of care in this setting. B-R regimen has also shown efficacy in relapsed setting suggesting the possible treatment option for patients failing conventional chemotherapy. In rituximab-resistant NHL, the recent GADOLIN study exploring the addition of obinutuzumab to bendamustine has yielded impressive result changing the standard of care in this hard-to-treat population. Concerning CLL, despite inferiority to the standard of care in young fit patients, as defined in CLL10 study, B-R has yielded a more beneficial toxicity profile and its use in first line treatment should be decided individually. In relapsed setting, the addition of ibrutinib to B-R has shown superior results compared to B-R alone, possibly changing the paradigm of treatment of relapsed CLL. In conclusion, bendamustine as a single agent or in combinations has shown activity with acceptable toxic profile in the treatment of patients with indolent NHLs or CLL without del(17p) mutation.

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.

Rituximab is a chimeric monoclonal CD20 antibody used in the treatment of CD20 positive non-Hodgkin lymphomas and has revolutionized treatment approach to these hematologic malignancies in the last decade. The main aim of this review is to present data on the use of rituximab in the treatment of follicular lymphoma (FL). We will focus on rituximab maintenance strategies in the first and second line treatment. This approach has improved the outcome in FL patients with better progression-free survival in all patients and better overall survival in relapsed setting. Regardless of good results, this strategy has generated controversies in medical community in the range from the lack of overall survival benefit in first line setting, adverse effects of possible overtreatment and toxicities to its unknown role in the era of novel agents. The existing data suggest that rituximab maintenance should be a rational therapeutic option for all patients with FL responding to fi rst line therapy and transplant-ineligible patients responding to reinduction.

New, extended and modernized recommendations for diagnostics and treatment of lymphomas were accepted at a meeting held in March 2012 with the participation of major Croatian experts. They encompass morphological, radiological and nuclear diagnostics, systemic treatment, radiotherapy and follow-up of most tumors of lymphoid tissues occurring in adults. The recommendations were agreed upon by consensus. Reporters presented data and suggested recommendations which had been first discussed in working groups and then agreed upon on the plenary session.

Myeloid sarcoma is a tumor mass with extramedullary growth pattern, composed of myeloblasts or immature myeloid cells. The development of myeloid sarcoma may precede or concur with acute or chronic myeloid leukemia (AML or CML) or other myeloproliferative diseases or myelodysplastic syndromes (MDS). Isolated myeloid sarcoma of the breast is very rare. A case is presented of a 25-year-old, previously healthy woman that presented to our department for a palpable node, 5 x 2 cm in size, in the upper medial quadrant of her left breast. Fine needle aspiration (FNA) produced a sample consisting of medium sized blasts. Additional work-up revealed anemia, thrombocytopenia and leukocytosis, along with atypical blasts detected in peripheral blood and bone marrow smear. Based on the morphology, cytochemical characteristics and immature cell immunophenotype, it was considered a case of acute myeloid leukemia without maturation. In spite of intensive chemotherapy, the patient died within a year of diagnosis. In cases of isolated breast myeloid sarcoma, the diagnosis can be missed if the possibility of myeloid sarcoma is not remembered on differential diagnosis of a breast neoplasm.

The exciting story about Hodgkin's lymphoma is 170 years old. Today, we know a lot about biology of this B cell neoplasma (derived from the germinative center), and the diagnostic standard criteria are clearly defined and accepted. Although the definition of prognostic factors for early disease varies between different study groups as well as the definition of advanced disease therapeutic aim is same for all clinicans: preserving the high cure rates while reducing the acute and long-term toxicities. Today, with adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy followed by radiotherapy in some patients' group, more than 85% patients can be cured. Maybe, the recently published results of the latest researches in Hodgkin's lymphoma (evidence for the cancer stem cell; the role of T cells in tumour microenvironment in survival of lymphomas cells; the role of galectin-1 in tumor escape in Hodgkin's lymphoma) will help us to reach our therapeutic goal: cure for all patients with Hodgkin's lymphoma!

Aim: The aim of the study was to identify the clinical and laboratory (hematologic, biochemical and morphological) prognostic parameters of chronic leukemic lymphoproliferative diseases (CLLPD)., Methods: The study included 155 CLLPD patients. Analysis was performed in the overall CLLPD population and separately in a subgroup of patients with B chronic lymphocytic leukemia with variants (B-CLL+V) including typical B chronic lymphocytic leukemia (B-CLL), mixed chronic lymphocytic leukemia and prolymphocytic leukemia (CLL/PLL), and a variant of chronic lymphocytic leukemia with lymphoplasmocytoid differentiation (CLL/IMC). Kaplan-Meier method (Statistica 7.1) was used on survival analysis., Results: Male patients older than 62 (p=0.03991), female patients (p=0.02871), patients not receiving antitumor therapy on study entry (p=0.01902) and patients not treated for CLLPB upon study entry (p=0.04076) showed better survival rate. Older patient predominated in the group requiring no antitumor therapy (p=0.019247). Analyis of sex distribution yielded an equal male to female ratio in the overall CLLPD population and B-CLL+V subgroup. Mann-Whitney U-test was used to assess the clinical significance of quantitative parameters related to patient age and sex. The level of bilirubin, the size of cervical lymph nodes and doubling of peripheral blood lymphocytosis (DTL) were lower in the group of older patients (>60 years). Men had higher levels of hemoglobin, bilirubin, SGOT and creatinine, and larger spleen and liver. Statistically significant survival differences were recorded for 16 of 20 clinical parameters. Patients older than 60, female patients and patients receiving no antitumor therapy showed better survival. Lower clinical stage according to Rai and Binet and total tumor mass (TTM) lower than 9 indicated better prognosis, whereas patients with spleen enlargement and multiple regions involved with lymph node enlargement showed poorer survival. B-CLL+V patients and patients free from doubling of total tumor (DTM) or of absolute lymphocyte count (DTL) within 12 months had better survival than the overall CLLPD patient population. A statistically significant survival difference was recorded for 5 of 15 bone marrow (BM) parameters tested: normal and less cellular BM puncture specimen, >70% of all lymphatic cells, >16% of atypical lymphatic cells, and >18% of granulocytes in myelogram indicated better prognosis. Poorer disease outcome was associated with interstitial and nodular infiltration found on bone biopsy. Ten of 20 hematologic parameters were found to be statistically significant. Poorer prognosis was associated with red blood cell count <2.5 x 10(12)/L, leukocyte count >100 x 10(9)/L, reticulocyte count >5/10(3) E, hemoglobin <100 g/L and iron <15 mol/L. Better survival was associated with absolute count of total lymphatic cells <100 x 10(9)/L and absolute count of atypical lymphatic cells <5 x 10(9)/L in peripheral blood; <10% of all atypical lymphatic cells, >5.1% monocytes and >10.1% granulocytes in differential blood count. Statistically significant survival differences were found for 10 of 20 biochemical parameters tested. Poorer survival was recorded in patients with LDH >300 U/L, SGOT >24 U/L, calcium <2.3 mmol/L, total protein <66.1 g/L, albumin <40 g/L, alpha2 globulin<5.9 g/L, beta globulin <7.3 g/L, y globulin <9 g/L and IgG <10 g/L. Better prognosis was only indicated by lower levels of IgM (<0.91 g/L)., Conclusion: Careful clinical examination is an important step on assessing the extent and progression of the disease, and a major chain on tailoring individualized therapeutic approach, along with clinical stages according to Rai and Binet, CLLPD subtype and progression factors (DTM and DTL). Laboratory parameters (hematologic and biochemical) as objective quantitative parameters obtained by simple venipuncture, in contrast to the 'researcher-dependent' ones, increase the utilization of some of these parameters as risk factors in CLL.

Radioimmunotherapy is a new antineoplastic treatment modality combining the effects of irradiation and monoclonal antibodies. 90Y-ibritumomab tiuxetan is a monoclonal antibody directed against the CD20 antigen to which a radioactive isotope of yttrium is attached, used for treating follicular lymphomas (FL). Using this compound we treated 8 patients with FL relapsing or refractory to combinations of rituximab and chemotherapy. Severe neutropenia developed in 5, and severe thrombocytopenia and anemia in 3 patients. Serious infections developed in 2 patients, one died. Six patients responded to treatment, 4 are still in remission after a median follow-up of 15 months, 2 died of lymphoma. Best response was achieved in low-risk patients with a low tumor burden. 90Y-ibritumomab tiuxetan is an effective treatment for FL with significant hematological toxicity and a high price.