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Background: Monomorphic epitheliotropic intestinal T cell lymphoma (MEITL) (formerly termed enteropathy-associated T cell lymphoma, type II) is an extremely rare peripheral T-cell lymphoma that involves the malignant proliferation of a T- lymphocyte in the gastrointestinal tract. Over time, these T cells commonly spread throughout the mucosal lining of a portion of the GI tract (particularly the jejunum and ileum of the small intestine), lead to GI tract nodules and ulcerations, and cause symptoms such as abdominal pain, weight loss, diarrhea, obstruction, bleeding, and/or perforation. Its clinical, morphologic, and immunophenotypic features distinguishing it from the more common Enteropathy Associated T-Lymphoma (previously EATL type I) made it a separate entity. Case report: We present a case of a rare extremely aggressive T cell lymphoma that originates from the gastrointestinal tract, spreads to surrounding organs and is refractory to surgery and chemotherapy. We describe а case report of 79 years old patient with clinical features of acute abdomen, ileus, treated with surgery two times. During the first surgery partial resection of jejunum was performed. Pathohistology and immunоhistochemistry findings of MEITL. PET/CT scan revealed infiltration of intestinum, uterus, ovarium. During the second operation partial resection of ileum and hysterectomy with adnexectomy was performed. The patient is treated with antracycline-based regimen CHOP21 (4 cycles). Re-evaluation with second PET/CT scan revealed residual tumor on the intestinum and bladder. The patient deteriorate with acute renal failure and multi-organ failure. Despite aggressive treatment with extensive surgery and aggressive anthracycline-based chemotherapy, in a short time the tumor spread to surrounding organs (sigma, bladder). The patient survived 11 months from the initial definitive diagnosis. Conclusion: MEITL is a challenging primary intestinal T cell lymphoma to treat as the outcome is frequently poor despite surgery and chemotherapy. Most patients are elderly with co-morbidities and they usually present late rendering any therapy ineffective. Young age, early Ann-Arbor/Lugano disease stage, good performance scale status, patients receiving autologous stem cell transplantation and less bulky disease are associated with an improved survival outcome. Further research is needed to incorporate new therapeutic modalities based on molecular research for successful treatment of this aggressive lymphoma.

Autologous stem cell transplantation (ASCT) is considered standard therapeutic approach for patients with relapsed and refractory (R/R) diffuse large B cell lymphoma (DLBCL) that are transplant eligible. For transplant ineligible patients there are few therapeutic options and novel targeted therapies and immunotherapy that are still in development. Treatment of such patients with poor prognosis is considered to be a challenge and there is constant need for new salvage treatment regimens. The aim of this study was to evaluate patients’ characteristics and treatment strategies and considerations for diffuse large B cell lymphoma in our department, and to promote new therapeutic possibilities for R/R patients with NHL DLBCL. A total of 308 patients with NHL were treated at University Clinic for hematology from 2008 until 2020 and 49% (151) of patients with NHL DLBCL were included in this study. Survival analysis of all analyzed relapsed/refractory NHL patients revealed statistically significant better survival in patients with low risk IPI score, disease stage I/II and patients with age

BACKGROUND: Allogeneic stem cell transplantation (ASCT) is a potentially curative therapeutic approach in patients with intermediate and high-risk myelodysplastic syndrome (MDS). If a family sibling or unrelated donor is not available mismatched donors are viable option for young patients with no comorbidities. The aim of this case presentation was to evaluate our first experience with haploidentical transplantation for this indication. CASE PRESENTATION: We present a case of 50 years male patient with myelodysplastic syndrome (MDS) diagnosed at University Clinic for hematology, Skopje, North Macedonia. Patient was scored in IPSS -R as high risk patient. He was referred for HLA DNA typing of family siblings and since he didn’t have identical sibling and unrelated donor, he was referred to continue treatment with haploidentical stem cell transplantation. He received Flu Bu conditioning and PTCY, cyclosporine and MMF for GVHD prophylaxis. Peripheral blood stem cells (PBSC) from his mismatched brother were infused in the amount of CD34=5.8x106/kg. He experienced prolonged engraftment, severe infective bacterial infections and CMV reactivation with clinical manifestation of CMV colitis. He was successfully treated with antiviral drug and completely resolved. His bone marrow analysis showed complete remission and chimerism evaluation revealed high donor engraftment. Patient is now +34 months post transplant in complete remission. CONCLUSION: The use of a mismatched donor increases the risk of NRM, but there is also evidence to suggest that an haploidentical donor is a valid choice, as general outcome appears to be at least similar to MUD.

Introduction: Since December 2019, multiple human cases of novel coronavirus infection were reported, representing with upper respiratory symptoms (influenza-like presentation). The virus was named the Severe acute respiratory system coronavirus 2 (SARS-COV-2). Studies have reported cases of patients with COVID-19 infection, including development of several autoimmune events that suggests that infection with SARS CoV-2 may be associated with initiation of autoimmune hematological autoimmune disorders. Aim: Review the hematological autoimmune phenomenon after infection with SARS-COV-2 in order to assist into the pathogenic mechanisms, clinical manifestations and treatment of this group of patients. Materials and methods: This is a retrospective study that includes 21 patients with autoimmune diseases like secondary immune thrombocytopenia (ITP), autoimmune hemolytic anemia( AIHA) and thrombotic thrombocytopenic purpura (TTP) that have emerged after COVID-19 infection. The patients were diagnosed and treated at the University Clinic of Hematology for a period of time from January 2020 to April 2021. Results: The most common hematologic autoimmune disorder was ITP in 13 cases (62%) followed by AIHA in 5 cases (24%) and TTP in 3 individuals (14%). The mean time of onset of the hematologic auto-immune presentations was 18,4 ± 10,3 days. The therapy of this conditions in patients with COVID-19 infection requires an individualized approach to achieve a precise balance between the risk of severe bleeding and of thromboembolic events. Conclusion: Causal relationship between COVID-19 infection and these autoimmune events still requires further studies. We should all have in mind the risk of development of hematologic autoimmune disorders in infected patients.

Gaucher disease (GD) is a rare inherited lysosomal storage disease characterized by multi-system impairment. One of its main features is the over-expressed chronic stimulation and activation of the immune system, which may play a crucial role in the development of some malignancies associated with GD.We describe a young woman diagnosed with GD type 1 in early adulthood who developed early-onset colorectal cancer shortly after GD diagnosis and the initiation of enzyme replacement therapy. She underwent radical surgical resection of the colon and adjuvant chemotherapy due to metastatic disease in the liver. She failed first-line therapy with capecitabine and is currently being treated with irinotecan plus the monoclonal antibody cetuximab.Although there is no evidence of an association between GD and colorectal cancer, this presentation in a young woman without a family history or risk factors may indicate a link. During anticancer treatment, only grade 3 anaemia was documented and no other haematological toxicities were observed. Enzyme replacement therapy at the recommended dose is regularly administered at scheduled intervals. The dosage may be increased in future if necessary to alleviate profound cytopenia.Anticancer treatment in patients with GD can be challenging due to the accompanying cytopenia. Optimal treatment of these patients with cancer requires greater understanding of the pathophysiology of GD and its impact on haematopoiesis.There may be a correlation between the hyperinflammatory background of untreated Gaucher disease and the development of neoplasia.Gaucher disease has rarely been described in association with colorectal cancer.Gaucher disease can be further worsened by chemotherapeutic agents.

Acute promyelocytic leukemia (APL) is a subtype of acute leukemia (AL) with distinct cytogenetics, clinical and biological characteristics. APL was considered as one of the most rapidly lethal forms of acute myeloblastic leukemia (AML), but recently, with the introduction of all-trans retinoic acid (ATRA) it has become the most curable subtype of AL. The main difficulty with APL is early death (ED), defined as death because of any cause within 30 days after diagnosis, and it has emerged as the most important cause of treatment failure. Our retrospective-prospective study was realized at the University Clinic for Hematology from January 2004 until December 2020. It included 46 patients with APL, according to FAB and WHO classification with confirmed molecular diagnosis. The following patients’ risk stratification factors were analyzed: age, Sanz risk score, WBC, PL, clinical presentation of the disease, levels of fibrinogen and D-dimers. During the study period, APL was diagnosed in 46 patients, 24 females (52.2%) and 22 males (47.8%), with mean age of 45 years. The overall survival showed that 24 patients (52.1%) were alive and 22 (47.8%) had lethal outcome. Regarding treatment, five patients (10.9%) died before starting the chemo-treatment. But, still, ED was observed in 13 patients (59%), and in 9 patients (40.9%) death occurred 30 days after establishing the diagnosis. The main reasons of mortality were also analyzed. To prevent ED prior to treatment, suspected APL patients should be immediately hospitalized and treated as medical emergency. Keywords: acute promyelocytic leukemia, early death, all-trans retinoic acid

The Multiple myeloma (MM) is a plasma cell malignancy in which monoclonal plasma cells proliferate in bone marrow, resulting in an overabundance of monoclonal paraprotein (M protein), destruction of bone, and displacement of other hematopoietic cell lines. This retrospective-prospective study was conducted at the University Clinic for Hematology in Skopje, North Macedonia, in the period between January 2009 and December 2019. Patients younger than 65 years, without comorbidities, fit for autologous peripheral blood stem cell transplantation (PBSCT), were treated with Cyclophosphamide-Thalidomide-Dexamethasone (CyThalDex) protocol divided into two daily doses which were maintained until complete remission. Patients over 65 years of age, unfit for more aggressive treatment options like peripheral blood stem cells (PBSCT) with comorbidities and renal failure, were treated with Melphalan-Prednisone-Thalidomide (MPT) protocol. The third group of patients was treated without new immunomodulators such as thalidomide, but instead a salvage therapy was given consisted of chemotherapy and corticosteroids. The use of thalidomide can lead to more undesirable effects such as deep vein thrombosis and renal neuropathy. The results obtained in our study showed no high percentage of these effects. However, a better survival rate was registered along with a longer period without progression of the underlying disease (PFS). Moreover, a higher percentage of complete remission (CR) was achieved and a very good partial response (VGPR) in general. Myeloma multiplex is still incurable disease with pattern of regression and remission followed by multiple relapses rising from the residual myeloma cells, but in the future still many unsolved questions has to be answered. Keywords: myeloma multiplex, autologous stem cell transplantation, thalidomide

The concept generated by biological expression profile divided patients with diffuse large B-cell lymphoma (DLBCL) into two subtypes. This concept has been presented in the recent editions of WHO classification and became a prognostic tool. Aim of the study was introduction of new three-marker model for immunohistochemical and prognostic subclasification of patients with DLBCL. Our retrospective study enrolled 200 adult patients with DLBCL diagnosed and treated in the period between January 2013 to January 2021. They were all treated with chemoimmunotherapy with R+/-CHOP regimen and the median follow-up of the patients was 48 months. We analysed the biopsy samples immunohistochemically with the markers of germinal (BCL6) and post-germinal centre (MUM1), and the marker of apoptosis (BCL2). Using the immunohistochemical three-marker model, which consisted of BCL-2, BCL-6, and MUM1, we distributed the patients with DLBCL into 2 subgroups: germinal centre – like (GCL) and activated centre-like lymphoma (ACL). The GCL and ACL patients were comparable regarding age, gender and all other already established prognostic parameters. Patients with GCL had overall survival of 140 months, and patients with ACL had overall survival of 88 months. ACL patients with BCL2 expression had a shorter survival compared to ACL patients without BCL2 expression. The difference in survival was statistically significant for p=0.01914. The study introduced the new three-marker model for immunohistochemical subclasification of patients with DLBCL treated with immunochemotherapy. Apoptotic marker BCL2 is a strong survival predictor. In the present study, we confirmed the prognostic importance of BCL2 protein expression, which showed a predictive capacity in ACL. Keywords: DLBCL, three - marker model, immunohistochemical, BCL2

Introduction: Minimal residual disease (MRD) assessment in acute myeloid leukemia (AML) cases is a complex, multi-modality process and, though much of its clinical implications at different points are extensively studied, it remains even now a challenging area. It is a disease the biology of which governs the modality of MRD assessment; in patients harboring specific molecular targets, high sensitivity techniques can be applied. On the other hand, relapse is considered as the leading cause of treatment failure in AML patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). Materials and methods: Since November 2018 until June 2020, 10 AML patients underwent matched unrelated donor (MUD) HSCT at the University Clinic of Hematology-Skopje, Republic of North Macedonia. Molecular markers were identified in a total of 4 patients; 3 patients expressed chimeric fusion transcripts; two RUNX-RUNX1T1 and one for CBFB-MYH11. One patient harbored mutation in the transcription factor CCAAT/enhancer binding protein α (CEBPA). Post-transplant MRD kinetics was evaluated by using quantitative polymerase chain reaction (RT-qPCR) or multiplex fluorescent-PCR every three months during the first two years after the transplantation. Results: MRD negativity was achieved in three pre-transplant MRD positive patients by the sixth month of HSCT. They sustained hematological and molecular remission for 19, 9 and 7 months, respectively. The fourth patient died due to transplant-related complications. Conclusion: According to our experience, when molecularly-defined AML patients undergo HSCT, regular MRD monitoring helps predict impending relapse and direct future treatment strategies.

With a scientific background from filoviruses, paramyxoviruses, SARS-CoV, and MERS-CoV, remdesivir entered into the COVID-19 battle to become one of the favorable therapeutic candidates with potential antiviral activity in the treatment of this disease. Globally, remdesivir was accessed and investigated through clinical research (clinical trials) and clinical practice (compassionate use, expanded access, early access scheme, and emergency use). Currently, remdesivir approval status differs between states. This paper aims to review and analyze regulatory approaches for accessing and investigating remdesivir, by communicating regulatory variability between countries in terms of terminology, modalities, and protocols.

The majority of Gaucher Disease (GD) cases result from pathologic mutations in the GBA1 gene. A rich mutational spectrum of about 500 identified variants has been recognized. The disease is characterized by phenotypic diversity. Data regarding the genotype-phenotype correlation are scanty and inconclusive. Here, we summarize the genetic and phenotypic "portraits" of 14 patients with GD type 1 in the Republic of North Macedonia, 4 of Macedonian and 10 of Albanian origin. Altogether, 6 variants were detected, compounding 6 different genotypes. All genotypes contained the N370S variant, which was detected with an overall prevalence of 60.7%. Other frequent variants included the 1263del55 deletion and the double mutant allele D409H;H255Q, each with a prevalence of 14.2%. We detected two rare mutations: W92* - a pathogenic nonsense mutation and D399N - a single nucleotide variant of uncertain pathogenicity. The most common genotypes were N370S/1263del55 and H255Q;D409H/N370S, both present in 4/14 patients, followed by N370S homozygosity (3/14). Splenomegaly was the most common clinical manifestation, identified in all patients. Hepatomegaly was less frequent and was present in 50% of cases. Thrombocytopenia was present in 9/14, while half of the patients had anemia. Bone pathology was demonstrated in 8 patients. Patients with different genotypes displayed a high degree of phenotypic heterogeneity, suggesting that the other allele determines the onset and severity of the disease in patients with the N370S mutation. Longer follow-up, bigger cohorts of patients and multicentric studies should be conducted to further define the association between the genotypic and phenotypic expression in GD.

Background One year after the declaration of the coronavirus disease 2019 (COVID-19) pandemic by the World Health Organization (WHO) and despite the implementation of mandatory physical barriers and social distancing, humanity remains challenged by a long-lasting and devastating public health crisis. Management Non-pharmacological interventions (NPIs) are efficient mitigation strategies. The success of these NPIs is dependent on the approval and commitment of the population. The launch of a mass vaccination program in many countries in late December 2020 with mRNA vaccines, adenovirus-based vaccines, and inactivated virus vaccines has generated hope for the end of the pandemic. Current Issues The continuous appearance of new pathogenic viral strains and the ability of vaccines to prevent infection and transmission raise important concerns as we try to achieve community immunity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and its variants. The need of a second and even third generation of vaccines has already been acknowledged by the WHO and governments. Perspectives There is a critical and urgent need for a balanced and integrated strategy for the management of the COVID-19 outbreaks organized on three axes: (1) Prevention of the SARS-CoV-2 infection, (2) Detection and early diagnosis of patients at risk of disease worsening, and (3) Anticipation of medical care (PDA). Conclusion The “PDA strategy” integrated into state policy for the support and expansion of health systems and introduction of digital organizations (i.e., telemedicine, e-Health, artificial intelligence, and machine-learning technology) is of major importance for the preservation of citizens' health and life world-wide.

The identification of the JAK2V617F mutation in several distinct myeloproliferative neoplasms (MPNs) raised the question how one single mutation incites expression of at least three different clinical phenotypes, i.e., polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). In order to further evaluate already published data on the correlation between mutant JAK2V617F allele burden and specific hematological and clinical parameters, we tested the level of the JAK2 mutation in 134 JAK2+ patients with different MPNs. The patients were diagnosed according to the 2008 WHO criteria and followed for a median of 48 months. The JAK2 V617F quantification was done with a real time polymerase chain reaction (real time-PCR) method. The median allele burden was lowest in ET (25.8%), followed by 34.6% in PV and 51.8% in PMF patients (pp50.0% compared to those with a mutational load of

BACKGROUND: Erdheim Chester disease (ECD) is a rare form of non-Langerhans histiocytosis that still presents a diagnostic and clinical dilemma. CASE PRESENTATION: We present a rare case of ECD, young 31 male with atypical localisation and soft tissue presentation and no bone involvement. He started clinical investigations due to subcutaneous tumour mass in the lumbar spine that caused severe back pain. Skin biopsy revealed ECD with Immunohistochemistry CD68+, CD10+, CD11c+, vimentin+, S100A4+. Activating BRAFV600E mutation was positive from the tumour tissue. The patient was referred to the haematology department. PET CT was performed for initial disease staging. Treatment was started with corticosteroids (methylprednisolone 0.5 mg/kg per day), and after 7 days, a significant clinical improvement was noticed in terms of pain disappearance with no need for pain killers. After two weeks, treatment with interferon Alfa (IFN-α) was started in a dose of 3 million units 3 times per week. After 4 months of interim treatment PET, CT revealed a significant reduction of the tumour mass. Therapy with IFN-α was continued, and the patient is still clinically in good condition. CONCLUSION: It can be concluded that shortening the time of diagnosis of ECD is essential in treatment outcome of this disease. Still, large studies have to confirm the best treatment of this rare condition.

Posterior reversible encephalopathy syndrome (PRES) is one of the most serious complication after allogeneic stem cell transplantation in paediatric setting. It is most commonly reported as adverse event of immunosuppressive strategies during transplantation. We present a case of a 7 years old girl with myelodysplastic syndrome (MDS) treated with allogeneic stem cell transplantation (ASCT) at our department. Diagnosis of PRES was confirmed by imaging techniques during the first month after transplant and it was very likely connected with cyclosporine neurotoxicity. The aim of this article is to present our first experience in diagnosing and treating PRES in paediatric stem cell transplantation. Our experience showed that PRES is one of the reasons for higher transplant related mortality in children. Early prediction of factors contributing to PRES and closely monitoring of patient’s vital signs, especially blood pressure, neurological status and vision are the main contributors for challenging the patient with another immunosuppressive agent that has less neurological toxicity. Still studies have to be initiated to confirm the influence of PRES on transplant outcome.

The outbreak of the COVID-19 pandemic has generated the largest global health crisis of the 21st century, evolving into accelerating socioeconomic disruption. In spite of all rapidly and widely emerging scientific data on epidemiology, diagnosis, prevention and treatment of the COVID-19 disease, severe acute respiratory coronavirus 2 (SARS-CoV-2) is continuing to propagate in lack of definitive and specific therapeutic agents. Current therapeutic strategies are mainly focused on viral inhibition by antiviral drugs and hampering the exuberant immune response of the host by immunomodulatory drugs. In this review, we have studied the reports of the largest clinical trials intended to COVID-19 treatment published during the first year of the pandemics. In general, these results concentrate on seven therapeutic options: remdesivir, chloroguine/hydroxychloroquine, lopinavir-ritonavir combination, corticosteroids, tocilizumab, convalescent plasma and monoclonal antibodies. In line with the reviewed data, as of January 2021, most of the evidence support the use of remdesivir in hospitalized patients with moderate and severe forms of the disease and provide reliable data on the substantial beneficial effect of corticosteroids in patients requiring supplemental oxygen. Moreover, preliminary RECOVERY trial results have demonstrated the efficacy of tociluzumab in the treatment of critically ill patients. The reports presenting the outcomes of the other immune-based therapies under investigation are enthusiastically awaited.

Context Autologous peripheral blood stem cell transplant (PBSCT) ideally should be performed in every myeloma patient, but in the elderly, the procedure might be risky because of comorbidities, and the possibility of the organism to fully compensate possible complications. Objective Our main goal was to show that the age limit for autologous PBSCT in myeloma patients can be safely shifted upwards. Design We used conditioning with melphalan, followed by autologous PBSCT for elderly patients with myeloma, using the age limit of 65 years. Setting All patients were transplanted in the bone marrow transplant unit in the University Clinic for Hematology Skopje. They underwent standard post-transplant preventive and prophylactic measures during the period of pancytopenia. Patients or Other Participants We have done a retrospective analysis of patients with MM where autologous SCT was done. The main inclusion criteria was the diagnosis, age over 65, acceptable comorbidity profile. Interventions Mobilizing and harvesting of stem cells, melphalan conditioning, and application of the graft via central venous catheter were standard for all patients. Main Outcomes Measures We evaluated the rates of transplant related mortality (TRM), post-transplant follow-up, complete remission (CR). Results Our analysis of data for 20 years shows that we performed autologous PBSCT on 25 patients with myeloma at the age of 65 or older. 17 males (68%) and 8 female (32%). Average age was 67 years (65-73). All patients received melphalan conditioning. In 23 of the patients, we used non-cryopreserved hematopoietic stem cells. In two patients we performed tandem autologous PBSCT with no major complications. 75% had HTA, 20% some level of cardiomyopathy, 48% diabetes, and 12% with inserted prosthetic aortic valves. Our oldest patient was 73 years old and was still alive 2 years posttransplant. Our transplant related mortality was 0%. Conclusions Autologous PBSCT in elderly myeloma patients can be safe and effective, with careful selection of patients, balancing the risk profile of the patient, and the benefit of the procedure. Affective supportive care, monitoring, and reducing the risk of complications is an imperative to a good result.

Minimal residual disease (MRD) in acute myeloid leukemia (AML) is a complex, multi-modality assessment and much as its clinical implications at different points are extensively studied, it remains even now a challenging area. It is the disease biology that governs the modality of MRD assessment; in patients harboring specific molecular targets, high sensitivity techniques can be applied. In AML patients undergoing allogenic hematopoietic stem cell transplantation (alloHSCT), relapse in considered as leading cause for treatment failure. In post-transplant setting, regular MRD status assessment enables to identify patients at risk of impending relapse when early therapeutic intervention may be beneficent. We analyzed data of AML patients who underwent matched unrelated donor (MUD) HSCT since the introduction of this procedure in the Republic of North Macedonia. Chimeric fusion transcripts were identified in three patients; two of them positive for RUNX-RUNX1T1 transcript and one for CBFB-MYH11. One patient harbored mutation in the transcription factor CCAAT/enhancer binding protein α (CEBPA). Post-transplant MRD kinetics was measured by quantitative polymerase chain or multiplex fluorescent-PCR every three months after the transplantation during the first two years after the transplant. MRD negativity was achieved in three patients by the sixth month of HSCT, who were pre-transplant MRD positive. They sustained hematological and molecular remission for 19, 9 and 7 months, respectively. The forth patient died due to transplant-related complication. Our experience suggests, when molecularly-defined AML patients undergo HSCT, regular MRD monitoring helps predict impending relapse and direct future treatment strategies.

Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. This study was designed to determine the clinical, biological features and outcomes among children with ALL treated at the only pediatric hematology-oncology center in North Macedonia. Patients and methods: Seventy four consecutive children age 1 to 14 years, diagnosed with ALL between January 1, 2010 and October 31, 2017 and treated according to ALL IC BFM 2002 protocol were retrospectively evaluated. Results: The median age at diagnosis was 5 years and males were predominant (60.8%). Precursor B-cell ALL was diagnosed in 81.1% of patients, while 18.9% had T cell ALL. CNS involvement at the time of diagnoses was present in 6.8% of patients. Complete remission was achieved in 93.2% of patients. The induction death rate was 5.4%. The rate of death during first complete remission was 4.1%. Relapse occurred in 13.5% of patients. After a median observation time of 44 months, the 5-year overall survival (OS) and event-free survival (EFS) rates (± standard error) were 79.4% ± 5.2% and 74% ± 5.7%, respectively. The 5-year EFS rate for patients categorized as standard risk by NCI criteria was significantly higher than for high risk patients (83.3% versus 46.7%; P Conclusion: Our study demonstrated that the treatment results of childhood ALL in North Macedonia are comparable to those obtained in the ALL IC BFM 2002 trial.

This commentary aims to elaborate challenges in the regulatory approaches for accessing and investigating COVID-19 potential therapies either with off-label use, compassionate use, emergency use or for clinical trials. Since no therapies have been formally approved and completely effective and safe to date, the best clinical choice is acquired only after consistent and fair communication and collaboration between licensed clinicians, researchers, regulatory authorities, manufacturers and patients.

Herein synchronous occurrence of Hodgkin lymphoma and secondary myelodysplastic syndrome in a 60 year old male patient with small cell lung cancer treated with combined chemotherapy (carboplatin and paclitaxel) and radiotherapy is presented. The objective of this report is to stress the importance of documenting and monitoring adverse drug reactions that arise from chemotherapy. After four years of treatment with the combined chemotherapy, the patient presented inguinal lymphadenopathy and enlarged lymph nodes and histopathology rapport was suggestive for plasmacytoid variant of Castleman disease. Three years later, biopsy of lymph node was performed and diagnosis of Hodgkin lymphoma – mixed cellularity has been established. Molecular analyses revealed presence of dominant monoclonal population of the immunoglobulin genes in the oligo/monoclonal background. Bone marrow biopsy findings suggested secondary myelodysplasia and revealed signs of hematopoietic cells dismaturation with signs of megaloblastic maturation of the erytropoetic lineage, appearance of ALIP (abnormal localization of immature precursors) in the myeloid lineage and dysplastic megakaryocytes. In addition, an increased level of polyclonal plasmacytes (lambda vs kappa was 60%:40%) was found. Hodgkin lymphoma and MDS occurring after 4 years of carboplatin/paclitaxel therapy might be contributed to the accumulation of alkylator-related DNA damage. This emphasize the need of outlining a monitoring plan regarding development of secondary leukemia and other malignant hematological proliferations should be outlined in the protocols.

Introduction: Since the first months of the COVID-19 pandemic, efforts have been made to understand the importance of broadly neutralising natural antibodies in determining the response to SARS-CoV-2. Previous studies have shown that allelic variants of the IGHV1-69 gene play a dominant role in protective natural antibody responses to several other viral pathogens, including influenza virus, hepatitis C virus, human immunodeficiency virus and, most notably, the SARS-CoV-2-related viruses SARS-CoV and MERS-CoV. These allelic variants are commonly known as 51p1-related and differ from the other IGHV1-69 alleles (known as hv1263-related) in the presence of a Phe54 residue in the CDR2 region. Importantly, crystallographic studies have shown that the Phe54 residue is critical for the binding of IGHV1-69 antibodies to the SARS-CoV and MERS-CoV spike proteins. In this study, we evaluated the prevalence of 51p1 and hv1263 alleles and the clonality of 51p1- and hv1263-expressing B cells in a large cohort of healthy individuals and COVID-19 patients and correlated the findings with the severity of the disease. Мaterials and methods: A total of 419 samples were included in the study, of which 78 asymptomatic/mildly symptomatic individuals, 200 hospitalized patients with severe disease, 94 critically ill patients and 47 healthy donors. Peripheral blood was collected 8-20 days after the onset of symptoms and total cellular RNA was extracted from whole blood using an automated procedure. Аllelle-specific Ig-gene fingerprinting of IgM heavy chain transcripts was used to simultaneously analyse the clonality of the IgM+ B-cell population and the clonality of the 51p1- and hv1263-expressing B cell populations. The significance of the differences in the prevalence of clonal B-cell populations between healthy donors and patients and between patients with different severity of the disease was calculated with the Chi-Square test. Results: Analysis of the clonality of the IgM+ B-cell population showed a polyclonal pattern in most of the investigated healthy individuals (33/47, 70%) but in only 20% of all SARS-CoV-2 infected individuals (75/372, p0,01), while hv1263 transcripts were not detected in 155/289 (53,6%) and in 27/47 (68,6%) tasted patients and controls, respectively (p>0,05). We did not find a statistically significant difference in the prevalence of 51p1 and hv1263 alleles between patients with different disease severity. However, a significantly higher number of patients displayed clonal expansions of 51p1- or hv1263-expressing B cells (219/372(58.9%) and 118/244 (48,4%), respectively in comparison to healthy donors [5/47(10.6%) and 7/47(14.9%), respectively]. There was no statistically significant difference between mildly affected and severely/critically ill patients in the clonallity status of 51p1- 38/61 (62,3%) and 182/237 (76,7%) respectively or between hv1263- expressing B cells in the same two groups of patients [20/25 (80%) and 98/109 (89,9%), p>0.05]. Conclusions: Our results show that SARS-CoV-2 infection stimulates clonal expansions of IGHV1-69 -expressing B-cells, but this is independent of the severity of the disease. In addition, no difference in the prevalence of IGHV1-69 alleles was observed between patients at different stages of the disease, indicating that natural neutralizing antibodies encoded by this gene are not an important determinant of COVID-19 severity and progression. Disclosures No relevant conflicts of interest to declare.

Context: Early-stage patients with chronic lymphocytic leukemia (CLL) are diagnosed without need for treatment, managed with following. The distinct course of the disease is diverse, and planning treatment is barely projected at diagnosis. Objective: The aim of the study was first-time evaluation of International Prognostic Score to predict time to first treatment (TFT) in Macedonian patients with early stage CLL (International Prognostic Score for early-stage CLL IPS-E). Design: Retrospective study of asymptomatic patients with CLL at early stage of disease in a period of time from January 2011 to January 2021. The median follow-up was 60 months (1-120 months). Setting: Individual patient data from 120 treatment-naive CLL patients with Binet A stage were analyzed to composed International Prognostic Score for Early-stage CLL and correlated with time to treatment failure (TTF). Interventions: We presented IPS-E using three covariates: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TFT. Results: Our evaluation has shown that 55% patients were male and 45% were female. Average age was 64 years. Using IPS-E patients were distributed in three groups: low risk with 7, 5%, intermediate risk with 44, 1% and high-risk patients 48, 3%. Average TFS was 29, 3 months for low-risk group; 28, 6 months for intermediate-risk group and 27; 1 months for high-risk group. Using prognostic nomogram, we calculated 5 years probability of survival for low, intermediate, and high-risk group: 73%, 72% and 70% respectively with projected median survival of 9, 1 year for low-risk group and 9, 0 year, 8, 9 years for intermediate and high-risk groups. Conclusions: The IPS-E is a simple prognostic model that predicts the probability of treatment necessity in patients with early-stage CLL.

Context The diagnosis of classic Hodgkin Lymphoma (cHL) appears quite straightforward, as it is built upon extended histological and immunophenotypic assessment. Hodgkin and Reed-Sternberg cells reflect monoclonal cell proliferation, presumably originating from germinal center B-cells. In general, these cells lose the B-cell phenotype, yet one-third of cHL cases express at least one B-cell marker, which in some instances leads to diagnostic difficulties in distinguishing cHL from B-Cell Lymphomas (BCL). Objective We present a diagnostically complex case of cHL CD30+/CD15+ in a 21-year-old male. Immunohistochemistry demonstrated unusual, strong expression of markers of B-cell differentiation and positivity for Epstein-Barr Virus (EBV), which brought out serious constraints in the differential diagnosis of an EBV-positive Diffuse Large BCL. Patient Case Report A previously healthy 21-year-old male presented at our institution with neck lymphadenopathy. He experienced no B-symptoms. Except for a slightly elevated sedimentation rate, blood analyses were within normal ranges. Initial PET-CT scan identified stage II disease involving supradiaphragmatic lymph nodes. Fine needle aspiration of the lymph node was suggestive of HL. However, histological examination of the surgically extirpated lymph node was puzzling. The atypical lymphoid cells expressed classical Hodgkin phenotype CD30+/CD15+, but they showed strong CD20+ co-expression. The tumor cells were strongly positive for EBV, and a diagnosis of EBV-associated BCL was assumed. In addition, high EBV loads in blood were confirmed. PCR studies for B- and T-cell gene rearrangements were negative. The tumor tissue was sent for consultative opinion in three centers independently. Immunostains were consistent; lymphoma cells were strongly positive for CD30, CD15, EBV, and EBV receptor CD21, as well as the B-cell markers CD20, Bcl-6, and MUM1. Finally, next-generation sequencing for B-cell rearrangement was negative. In absence of sufficient diagnostic criteria for EBV-positive BCL and all things considered, the diagnosis of classic HL was concluded. Conclusions In consensus with reported literature, treatment was initiated with R-ABVD regimen. Complete regression of tumor masses became evident after the first cycle. An interim PET scan is planned for further evaluation.

Context: Plasmacytoid Dendritic Cells (pDCs) are hematopoietic, type 1 interferon-producing cells. Neoplastic expansion of these cells is very rare and is classified into two different malignancies: Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) and mature pDC proliferation associated with myeloid neoplasia. Objective: We present here a diagnostically challenging case of pDC proliferation associated with AML, with an unusual occurrence in a young 26-year-old male. This patient achieved complete remission with an ALL-based chemotherapy regimen in combination with a Bcl-2 inhibitor. Patient Case Report: A 26-year-old man presented to our clinic with a 1-month history of weakness, malaise and myalgia. Blood counts and peripheral blood smear showed normocytic anemia (Hb 103 g/L) and leukopenia (WBC 2.4 x 103 μ/L) with dominant lymphocytosis, which progressed to severe leukopenia (WBC 0.8 x103 μ/L) and thrombocytopenia (PLT 18 x 103 μ/L) in two weeks. Bone marrow biopsy was performed, indicating metastatic nasopharyngeal carcinoma. He underwent detailed ORL examination, and except for nodular lymphoid tissue in the epipharynx, no other abnormalities were observed. Additionally, MRI of the neck showed normal findings. We did a second bone marrow biopsy with bone marrow aspiration. Immunophenotyping by flow cytometry showed 50% infiltration with cells with weak expression of CD45, no expression of CD34, co-expression of CD4/CD56, presence of HLADR/CD123, and expression of CD33, CD117, and cytoplasmic nTDT, suggesting BDPCN. The histological examination of the bone marrow confirmed the diagnosis, and the immunohistochemical staining excluded neoplasia of ectodermal origin. Still, the patient had no evident cutaneous lesions, organomegaly, nor lymphadenopathy. The bone marrow sample was sent for consultative opinion in a referent center, and based on the negativity of TCL1, the diagnosis of pDCS associated with AML was established. RUNX-1 mutation and other prognostic markers for AML, however, were not detected. The patient achieved complete remission with 2 cycles of Hyper-CVAD plus venetoclax and underwent stem cell transplantation. Conclusions: pDC-myeloid neoplasm should be considered as a differential diagnosis of BPDCN, and more extended immunohistochemical analysis is required for correct diagnosis.