Hemophagocytic Lymphohistiocytosis Secondary to Peripheral T Cell Lymphoma with Rapid Onset and Fatal Progression in a Young Patient: A Case Report and Review of the Literature.

BACKGROUND Constant stimulation of lymphocytes and histiocytes can result in hemophagocytic lymphohistiocytosis (HLH), which can be primary or secondary (sHLH). The main causes of sHLH are infections and hematological malignancies, especially non-Hodgkin lymphoma. Despite new insights into the pathogenesis of HLH, the diagnosis and treatment of this immune disorder remain a great challenge. CASE REPORT We present a case of a young adult without comorbidities whose clinical course was nonspecific for several months and resulted in late diagnosis of HLH secondary to peripheral T cell lymphoma (PTCL). The etiological factor of recurring fever, hepatosplenomegaly, and deteriorating condition was unidentified for a long time before fatal sHLH was finally diagnosed. The patient was treated according to the HLH-2004 protocol; however, he did not achieve any response. Unfortunately, due to nonspecific symptoms, lack of lymphadenopathy for a long time, and negative positron emission tomography results, the diagnosis of PTCL was established only after the patient's death. CONCLUSIONS It should be emphasized that early diagnosis is crucial for better prognosis of patients with sHLH. Bone marrow biopsy is worth considering in patients with prolonged fever of unknown origin, hyperferritinemia, splenomegaly, and unexplained cytopenia of 2 or more lineages. Despite the existence of diagnostic and therapeutic protocols available in the literature, the prompt diagnosis and treatment of HLH remains a great challenge. More precise and specific diagnostic tools for HLH are needed.

Immunosuppression as a Hallmark of Critical COVID-19: Prospective Study.

The dysregulation of both the innate and adaptive responses to SARS-CoV-2 have an impact on the course of COVID-19, and play a role in the clinical outcome of the disease. Here, we performed a comprehensive analysis of peripheral blood lymphocyte subpopulations in 82 patients with COVID-19, including 31 patients with a critical course of the disease. In COVID-19 patients who required hospitalization we analyzed T cell subsets, including Treg cells, as well as TCRα/ß and γ/δ, NK cells, and B cells, during the first two weeks after admission to hospital due to the SARS-CoV-2 infection, with marked reductions in leukocytes subpopulations, especially in critically ill COVID-19 patients. We showed decreased levels of Th, Ts cells, Treg cells (both naïve and induced), TCRα/ß and γ/δ cells, as well as CD16+CD56+NK cells in ICU compared to non-ICU COVID-19 patients. We observed impaired function of T and NK cells in critically ill COVID-19 patients with extremely low levels of secreted cytokines. We found that the IL-2/INFγ ratio was the strongest indicator of a critical course of COVID-19, and was associated with fatal outcomes. Our findings showed markedly impaired innate and adaptive responses in critically ill COVID-19 patients, and suggest that the immunosuppressive state in the case of a critical course of SARS-CoV-2 infection might reflect subsequent clinical deterioration and predict a fatal outcome.

Co-occurrence of unclassified myeloproliferative neoplasm and giant cell arteritis in a patient treated with allogeneic hematopoietic stem cell transplantation: a case report and literature review.

Myeloproliferative neoplasms (MPNs) are a group of hematologic disorders characterized by clonal proliferation of myeloid lineage cells. The diagnostic criteria are based on morphological features of bone marrow and peripheral blood cells but also include specific genomic mutations. In some patients, co-occurrence of hematologic and rheumatic diseases could be observed. To date, most of the reported cases concerned patients with myelodysplastic syndrome (MDS) or essential thrombocythemia (ET). In this paper, we present a case of a patient with a complicated diagnostic process leading to the diagnosis of unclassified MPN and giant cell arteritis (GCA). Routine tests did not reveal any mutations typical for MPNs such as JAK-2, CALR, MPL or BCR-ABL. Targeted next-generation sequencing (NGS) helped to confirm the diagnosis by demonstrating the presence of heterozygous ASXL1, TET2, SRSF2, and CBL mutations. The second important issue was the overlapping of symptoms of MPN and seronegative rheumatic disease, which finally was diagnosed as GCA. Leukocytosis and musculoskeletal pain, which were present at the time of diagnosis, resolved after allogeneic hematopoietic stem cell transplantation but recurred after a few months along with decreasing donor cell chimerism. Differentiation of the causes of recurrence of the symptoms was an important issue. This case shows the diagnostic challenge posed by co-incidence of MPN and rheumatic disease, especially its atypical variants.

Infection and expression of Toll-like receptors in lymphoid malignancy patients after autologous stem cell transplantation.

INTRODUCTION: High-dose chemotherapy with autologous stem cell transplantation (ASCT) is one of the main strategies for the treatment of haematological neoplasms. Infections are the most common cause of morbidity and mortality from the ASCT procedure. However, it is challenging to predict when these complications are likely to arise. Toll-like receptors (TLRs) are present on various immune cells and play a broad role in immune surveillance. The aim of the study was to investigate the association between the expression of TLR genes and the occurrence of infections in patients treated with ASCT. MATERIAL AND METHODS: TLR expression was analysed in 60 patients who underwent ASCT. The median age was 54 years. Blood samples were taken before high-dose chemotherapy and at the time of haematopoietic recovery after ASCT. RESULTS: The expression of Toll-like receptor 4 (TLR4) was significantly higher in patients before ASCT than after transplantation. The expression of Toll-like receptor 9 (TLR9) was significantly higher in patients after ASCT than before transplantation. The expression of TLR9 and TLR4 at the start of the procedure was significantly lower in patients who went on to develop a bacterial infection after ASCT. Moreover, we also observed a significant positive correlation between the expression of TLR9 and neutrophil recovery time after ASCT. CONCLUSIONS: Our findings suggest that TLRs could be useful biomarkers to predict and monitor infections in patients treated with ASCT.

Lymphocyte subsets in haematological patients with COVID-19: Multicentre prospective study.

The role of immune dysregulation in the course and prognosis of COVID-19 is not clearly established. In particular, immune status in specific populations such as haematological patients, who have an impaired immunological system, has not been described so far. Here, we performed a comprehensive analysis of peripheral blood lymphocyte subsets in 27 SARS-CoV-2-infected patients, including 16 patients with haematological malignancies. We identified T cell subpopulations, B cells, NK cells and TCR α/ß and É£/ƍ-expressing T cells during COVID-19 infection, with significant changes observed in immune profiles during the course of disease, especially in haematological patients. We observed an increase in activated T lymphocytes (CD3+HLA-DR+ and CD3+CD8+HLA-DR+) in the early stages of SARS-CoV-2 infection with a concomitant decrease in the CD4/CD8 ratio in haematological patients compared to non-haematological patients affected by COVID-19. We also found a decrease in É£/ƍ T cells in both studied groups of patients, with lower numbers of CD25+ T cells and CD16+CD56+ NK cells in haematological patients compared to non-haematological patients with COVID-19. Our findings demonstrate, for the first time, impaired adaptive immunity in patients with haematological malignancies infected with COVID-19, resulting in impaired cellular immune responses to SARS-CoV-2. This warrants further investigation of this disease group in COVID-19 patient cohorts.

Nosocomial outbreak of SARS-CoV-2 infection in a haematological unit - High mortality rate in infected patients with haematologic malignancies.

BACKGROUND: Here we report nosocomial outbreak of COVID-19 among patients in a haematological unit. To our knowledge this is the first report from Central Europe comparing morbidity and mortality in infected and non-infected patients after exposure to SARS-CoV-2. METHODS: The outbreak involved 39 individuals: 19 patients and 20 health care workers. The SARS-CoV-2 test by nasopharyngeal swabs was performed by real-time RT-PCR. Exposed patients were divided into two groups: quarantine patients with and without COVID-19. All patients were prospectively examined at the following time points: 0, 7 days, 14 days, 21 days and 28 days after confirmation or exclusion of SARS-CoV-2. RESULTS: Infection was confirmed in a total of 5/20 health care workers and 10/19 patients. Among the patients positive for SARS-CoV-2 infection, the mortality rate was 36.8 %. The probability of death in patients infected with SARS-CoV-2 increased 8-fold (p = 0.03). Bacterial, fungal, and viral co-infection significantly decreased survival in these patients (p < 0.05). Additionally, the probability of death was much higher in patients older than 40 years of age (p = 0.032). CONCLUSION: This study showed significantly higher mortality rate in COVID-19 patients with haematologic diseases compared to the non-infected patient group. Haematologic patients with COVID-19 have 50 % less chance of survival.

Higher efficacy of intermediate dose cytarabine + G-CSF compared to cyclophosphamide + G-CSF in hematopoietic stem cell mobilization in patients with multiple myeloma.

BACKGROUND: There are several regimens used in hematopoietic stem cell (HSC) mobilization in multiple myeloma (MM). Cyclophosphamide (Cy) is one of the most commonly used agents, although it does not always result in collecting adequate number of CD34+ cells. Recently, cytarabine (Ara-C) has been proposed as potentially efficient and safe option. AIMS: Since the data regarding Ara-C in HSC mobilization is limited, the aim of our study was to compare retrospectively the efficiency and toxicity of G-CSF combined with either Ara-C or Cy in MM patients. MATERIALS & METHODS: Of a total of 89 patients, 43 received low or intermediate doses of Cy, and 46 were treated with 800 mg/m2 /day of Ara-C administered for two days. RESULTS: The mean peak of CD34+ cells/ul in peripheral blood was 132 (range, 84-202) in Ara-C and 51 (range, 29-69) in Cy cohort (p < 0.001). The median number of collected CD34+ cells (×106/kg) was 10.3 (range, 4.2-17.9) vs 4.5 (range, 2.7-8.9), respectively (p < 0.001). Mobilization failure was observed in one patient in Ara-C cohort (2%) and in 8 patients treated with Cy (19%) (p = 0.013). In the Ara-C group 98% of patients obtained more than 4×106 CD34+ cells/kg required for tandem transplantation. Moreover, we observed a trend toward increased paraprotein levels measured at transplant compared to before HSC mobilization in Ara-C cohort and significantly higher transfusion rates in that group. CONCLUSION: Our findings confirm higher HSC mobilization efficacy of Ara-C compared to Cy in MM patients. However, lower transfusions rate and better disease control of Cy may justify its use in some cases.

The Expression of Toll-Like Receptors in Patients with B-Cell Chronic Lymphocytic Leukemia.

B-cell chronic lymphocytic leukemia (B-CLL) presents with progressive accumulation of monoclonal B cells in the peripheral blood, bone marrow and lymphoid organs. B-CLL is characterized by heterogeneous clinical outcome. The expression of Toll-like receptors (TLRs) and their association with other prognostic factors in B-CLL patients remain unclear. The aim of our study was to evaluate the expression of TLR2, TLR4 and TLR9 genes and their significance as biological markers in patients with B-CLL. Sixty patients with newly diagnosed B-CLL were evaluated. The healthy control group included 20 age-matched individuals. Using quantitative reverse transcriptase PCR, the mRNA expression of genes TLR2, TLR4 and TLR9 was measured. TLR4 gene expression was lower in B-CLL patients as compared to the control group and TLR2 gene expression was higher in B-CLL patients than in healthy individuals. TLR9 gene expression was higher in the control group than in patients with B-CLL. TLR4 mRNA expression was lower in patients with advanced-stage CLL (Rai stages III and IV) than in patients with early stage disease (Rai stages 0-II). TLR2 gene expression was higher in patients with advanced-stage CLL (Rai stages III and IV) than in patients with early stage disease (Rai stages 0-II; p < 0.05). Our results suggest that TLRs could become potential biological markers for the clinical outcome in patients with B-CLL.

Azacitidine in outpatient treatment - single center experience.

AIM OF THE STUDY: Azacitidine is a hypomethylating agent which is used in the treatment of myelodysplastic syndromes, acute myeloid leukemia and chronic myelomonocytic leukemia. Because of good tolerance to the drug, azacitidine can be administered both during hospitalization and in an outpatient setting. The aim of our retrospective analysis was to assess the efficacy of azacitidine treatment in patients with a myelodysplastic syndrome and with acute myeloid leukemia who had received treatment in hospital and in an ambulatory care setting. Offsets in the course of azacitidine administration and discontinuations of treatment have a negative impact on patients' response to the therapy. MATERIAL AND METHODS: The study included 31 patients. Sixteen patients received azacitidine in an ambulatory care setting, 15 patients within their hospitalization. RESULTS: A hematologic response was achieved in 48% of the patients. Forty-one percent of the cycles were delayed. In an outpatient setting, 62% of the cycles were administered systematically, while during hospitalization the patients received 54% of cycles on time. Administrative problems caused the delay of 26% of the cycles. CONCLUSIONS: Azacitidine has a high tolerance level and a high safety profile which allows for its use in an outpatient care setting. Outpatient administration of azacitidine is feasible and safe without compromising efficacy.