Advances in targeting programmed cell death 1/programmed cell death-ligand 1 therapy for hematological malignancies

Programmed cell death 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) are important immune checkpoints, and their interactions can mediate immune suppression in the tumor microenvironment. Targeting PD-1 and PD-L1 are immune checkpoint inhibitors that bind to PD-1 and PD-L1, respectively, to block the signal pathway between the two and increase the immune response. They are widely used in tumor treatment and have good efficacies for malignant melanoma, renal cell carcinoma, and non-small cell lung cancer, among others. In addition, for hematological malignancies, studies targeting PD-1 and PD-L1 have achieved gratifying results. This article briefly reviews the mechanisms of action and clinical and hematological malignancy applications of targeting PD-1 and PD-L1. Keywords: PD-1, PD-L1, mechanism of action, hematological malignancy

First Report of an Invasive Infection by Cephalotrichum gorgonifer in a Neutropenic Patient with Hematological Malignancy under Chemotherapy

The etiological agents of infrequent invasive fungal infections (IFI) are difficult to identify on the species level using classic morphological examination. We describe the first case of an IFI caused by Cephalotrichum gorgonifer in a neutropenic patient with a hematological malignancy and put it on the map as a new causative agent of IFI. Case report, microbiological findings and description of the etiological agent. A 60-year-old man was diagnosed with mantle cell lymphoma. A CT scan confirmed the presence of lung infiltrates located at the right upper lobe. Histological examination of one of the nodules showed a large number of narrow septate hyphae with acute-angle branching and irregular round cell morphology; vessels walls appeared infiltrated, proving an angioinvasive pulmonary IFI. Sample culture resulted positive and molecular identification proved the presence of Cephalotrichum gorgonifer. Voriconazole was used for 12 months and the patient did not report any complications or side effects. Complete remission of lymphoma was achieved later by the time chemotherapy, radiotherapy, and radioimmunotherapy consolidation were completed. We recommend the inclusion of Cephalotrichum gorgonifer in the list of opportunistic pathogens causing mycoses in neutropenic hematological patients with suspected mould-related IFI.

Hematological malignancies in the Northwest Ethiopia

Background The effect of malignant diseases is increasing globally, particularly in developing countries as shown by recent cancer statistics from the world health organization reports. It is anticipated that with an increase in life expectancy consequent upon the improved standard of living and increasing urbanization, the burden of hematological malignancies in sub-Saharan Africa particularly in Ethiopia is likely to increase recently. Therefore, this study was aimed to determine the incidence and trend of hematological malignancy in Northwest Ethiopia. Methods A facility-based retrospective study was conducted from 2015 to 2019 at the University of Gondar and Bahir-Dar Felegehiwot comprehensive specialized hospitals. Hematological malignancy data were collected by using a data collection sheet that was consisted of patients’ socio-demography, clinical, and laboratory data. Then, data were entered into Epi-info 3.5.1 and exported to SPSS version 20 for analysis. Skewness and kurtosis were used to check data distribution. Descriptive statistics were summarized as percentages, means, and standard deviations of background variables, and the trend were analyzed. Results In this study, a total of 1,342 study participants were included. The mean age of study participants was 41.49 ± 16.3 years with a range of 1 to 92 years. About 58.3%, 52.2%, and 80% of the cases were observed among males, 18–45 age group, and urban residences, respectively. Of the total cases, 92.9% and 7.1% were lymphoma and leukemia, respectively. On the other hand, from lymphoma cases, 72.3% and 27.7% were HL and NHL, respectively while from leukemic cases, 61.1%, 23.2, 6.3%, 4.2%, and 5.3% were CLL, ALL, CML, AML, and other HM types, respectively. In this study, there was no trend. Conclusion We concluded that lymphoma was the dominant type of hematological malignancy observed in northwest Ethiopia. The study indicated that the majority of cases were observed among male, urban residents, and adult populations aged 18–45 years. Therefore, special focus should be given to the highly affected population. Further, a prospective cohort study should be conducted for a better understanding of the prevalence and associated factors to it.

Identification of TCR repertoires in functionally competent cytotoxic T cells cross-reactive to SARS-CoV-2

SARS-CoV-2-specific CD8+ T cells are scarce but detectable in unexposed healthy donors (UHDs). It remains unclear whether pre-existing human coronavirus (HCoV)-specific CD8+ T cells are converted to functionally competent T cells cross-reactive to SARS-CoV-2. Here, we identified the HLA-A24-high binding, immunodominant epitopes in SARS-CoV-2 spike region that can be recognized by seasonal coronavirus-specific CD8+ T cells from HLA-A24+ UHDs. Cross-reactive CD8+ T cells were clearly reduced in patients with hematological malignancy, who are usually immunosuppressed, compared to those in UHDs. Furthermore, we showed that CD8+ T cells in response to a selected dominant epitope display multifunctionality and cross-functionality across HCoVs in HLA-A24+ donors. Cross-reactivity of T-cell receptors isolated from them exhibited selective diversity at the single-cell level. Taken together, when stimulated well by immunodominant epitopes, selective pre-existing CD8+ T cells with high functional avidity may be cross-reactive against SARS-CoV-2.

Outcomes and Risk Factors of Critically Ill Patients with Hematological Malignancy. Prospective Single-Centre Observational Study

Background and Objectives: Oncohematological patients have a high risk of mortality when they need treatment in an intensive care unit (ICU). The aim of our study is to analyze the outcomes of oncohemathological patients admitted to the ICU and their risk factors. Materials and Methods: A prospective single-center observational study was performed with 114 patients from July 2017 to December 2019. Inclusion criteria were transfer to an ICU, hematological malignancy, age >18 years, a central line or arterial line inserted or planned to be inserted, and a signed informed consent form. Univariate and multivariable logistic regression models were used to evaluate the potential risk factors for ICU mortality. Results: ICU mortality was 44.74%. Invasive mechanical ventilation in ICU was used for 55.26% of the patients, and vasoactive drugs were used for 77.19% of patients. Factors independently associated with it were qSOFA score ≥2, increase of SOFA score over the first 48 h, mechanical ventilation on the first day in ICU, need for colistin therapy, lower arterial pH on arrival to ICU. Cut-off value of the noradrenaline dose associated with ICU mortality was 0.21 μg/kg/min with a ROC of 0.9686 (95%CI 0.93–1.00, p < 0.0001). Conclusions: Mortality of oncohematological patients in the ICU is high and it is associated with progression of organ dysfunction over the first 48 h in ICU, invasive mechanical ventilation and need for relatively low dose of noradrenaline. Despite our findings, we do not recommend making decisions regarding treatment limitations for patients who have reached cut-off dose of noradrenaline.

Premaxillary and maxillary sinus mucormycosis post COVID: a rare case report

<p>Mucormycosis, previously termed as zygomycosis, is an opportunistic infection and is caused by fungi belonging to the order Mucorales. It is found in patients with predisposing conditions such as diabetic ketoacidosis, chronic kidney disease malignancy long-term steroid use and immunosuppressant drugs. Mucormycosis involving paranasal sinuses is a rare life-threatening opportunistic infection in a covid positive patient. The unprescribed use of corticosteroid in covid positive patient, the lymphopenia in severe covid 19 cases, preexisting diseases like uncontrolled diabetes mellitus, hematological malignancy, stem cell transplant causing weak immune system are the factors which are responsible for mucor infection in covid positive patients. We herein report the case of maxillary and premaxillary mucormycosis infection in the uncontrolled diabetic patient with post covid status in recovering phase of acute respiratory distress syndrome.</p>

Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy

We conducted population pharmacokinetic (PPK) analysis and Monte Carlo simulations to determine the appropriate prophylactic dose of fluconazole to prevent invasive candidiasis in patients with hematological malignancies. Patients receiving chemotherapy or hematopoietic stem cell transplantation at Yokohama City University Hospital between November 2018 and March 2020 were included. Additionally, patients receiving oral fluconazole for prophylaxis were recruited. We set the free area under the curve/minimum inhibitory concentration (MIC) = 50 as the target and determined the largest MIC (breakpoint MIC) that could achieve more than 90% probability of target attainment. The blood fluconazole concentration of 54 patients (119 points) was used for PPK analysis. The optimal model was the one-compartment model with first-order administration and first-order elimination incorporating creatinine clearance (CLcr) as a covariate of clearance and body weight as a covariate of distribution volume. We conducted Monte Carlo simulation with fluconazole at 200 mg/day or 400 mg/day dosing schedules and patient body weight and CLcr ranging from 40 to 70 kg and 40–140 mL/min, respectively. The breakpoint MICs on the first dosing day and at steady state were 0.5–1.0 μg/mL and 1.0–2.0 μg/mL for 200 mg/day and 1.0–2.0 μg/mL and 2.0–4.0 μg/mL for 400 mg/day, respectively. The recommended dose was 400–700 mg/day for the loading dose and 200–400 mg/day for the maintenance dose. Our findings suggest that the optimal prophylactic dose of fluconazole in hematological malignancy patients depends on CLcr and body weight, and a sufficient loading and maintenance dose may be needed to completely prevent invasive candidiasis.

Role of Extracorporeal Photopheresis in Prevention of Graft-Versus-Host Disease in Patients Treated with Allogeneic Hematopoietic Stem Cell Transplantation: A Randomized Controlled Trial

Introduction In many patients diagnosed with a hematological malignancy, the disease cannot be totally eradicated by conventional therapeutic approaches, and for them allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option. A major complication of allo-HSCT is graft-versus-host disease (GvHD), affecting about 50% of transplant recipients. In addition to increased risk of death and long-lasting debilitating conditions, severe GvHD also impairs health-related quality of life. High-dose systemic steroids is the first line treatment for GvHD, but treatment failure is common, and steroid-refractoriness is a major cause of non-relapse mortality after allo-HSCT. While there is no established second line GvHD-treatment, extracorporeal photophoresis (ECP) has emerged as an attractive and increasingly applied alternative, partly due to its favourable safety profile. However, the use of ECP in preventing GvHD is sparse and data are inconclusive due to lack of randomized controlled trials (RCT). We therefore conducted a RCT to study if ECP given post transplantation could prevent the development of GvHD. Methods Between June 2017 and February 2020, we enrolled 157 patients (&gt; 18 years) diagnosed with a hematological malignancy and treated with an allo-HSCT in first remission into an intention-to-treat open RCT. Ethical and IRB approvals were granted, and the RCT was registered with Clinical Trials (ID NCT03204721). The sample size (76 in intervention group and 81 controls) was calculated based on a reduction of 25% in the total number of patients diagnosed with any form of GvHD within the first year of allo-HCST (primary end-point) as clinically relevant. The patients were stratified according to whether they received myeloablative or reduced intensity conditioning (Table 1), and they were given GvHD prophylaxis as shown in Table 1. ECP (Therakos Cellex ®, Mallinckrodt Pharm., NJ) was initiated when patients had engrafted (i.e. leukocytes &gt; 1 x 10 9/L and platelets &gt; 20 x 10 9/L), and, according to the study protocol, we planned for ECP on two consecutive days/week for two weeks, then weekly for four weeks to a total eight treatments for each patient in the intervention group. Chi-square test was used to test differences between the two study groups. Results Table 1 shows that patient characteristics were well balanced among the two study groups. Four patients did not receive ECP while 39 received all the eight treatments. One year after allo-HCST, the proportion of GvHD was 45/76 (59%) in the intervention group and 52/81 (64%) in the controls (p=0.52). There were no significant differences between the intervention and control group regarding development of acute (45% vs. 48%) or chronic (39% vs. 40%) GvHD. Neither did we detect any statistical differences between the two study groups regarding organ involvement or severity of the GvHD manifestations (data not shown). During the one-year observation period, 16/76 (21%) and 10/81 (12%) relapsed in the intervention and control group, respectively (p=0.14). The corresponding numbers of deaths were 12/76 (16%) and 16/81 (20%), respectively (p=0.52). Six patients in the intervention group experienced mild to moderate temporary, adverse events that could possibly be related to the ECP-procedure. Conclusion In this first RCT addressing ECP as GvHD prophylaxis in allo-HSCT for hematological malignancy, we found no significant difference in the numbers, types, organ involvement, or severity of GvHD between the intervention and the control group. Thus, our study does not support the use of ECP as an adjunct to GvHD-prophylaxis based on cyclosporine and methotrexate, mycophenolate mofetil, or sirolimus. However, ECP did not seem to be harmful in this setting. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.