Showing papers in "Annals of Hematology in 2020"

Mechanism of thrombocytopenia in COVID-19 patients.

Abstract: Since December 2019, a novel coronavirus has spread throughout China and across the world, causing a continuous increase in confirmed cases within a short period of time. Some studies reported cases of thrombocytopenia, but hardly any studies mentioned how the virus causes thrombocytopenia. We propose several mechanisms by which coronavirus disease 2019 causes thrombocytopenia to better understand this disease and provide more clinical treatment options.

Blood type and outcomes in patients with COVID-19.

Abstract: This study aimed to determine if there is an association between ABO blood type and severity of COVID-19 defined by intubation or death as well as ascertain if there is variability in testing positive for COVID-19 between blood types. In a multi-institutional study, all adult patients who tested positive for COVID-19 across five hospitals were identified and included from March 6th to April 16th, 2020. Hospitalization, intubation, and death were evaluated for association with blood type. Univariate analysis was conducted using standard techniques and logistic regression was used to determine the independent effect of blood type on intubation and/or death and positive testing. During the study period, there were 7648 patients who received COVID-19 testing throughout the institutions. Of these, 1289 tested positive with a known blood type. A total of 484 (37.5%) were admitted to hospital, 123 (9.5%) were admitted to the ICU, 108 (8.4%) were intubated, 3 (0.2%) required ECMO, and 89 (6.9%) died. Of the 1289 patients who tested positive, 440 (34.2%) were blood type A, 201 (15.6%) were blood type B, 61 (4.7%) were blood type AB, and 587 (45.5%) were blood type O. On univariate analysis, there was no association between blood type and any of the peak inflammatory markers (peak WBC, p = 0.25; peak LDH, p = 0.40; peak ESR, p = 0.16; peak CRP, p = 0.14) nor between blood type and any of the clinical outcomes of severity (admission p = 0.20, ICU admission p = 0.94, intubation p = 0.93, proning while intubated p = 0.58, ECMO p = 0.09, and death p = 0.49). After multivariable analysis, blood type was not independently associated with risk of intubation or death (referent blood type A; blood type B: AOR: 0.72, 95% CI: 0.42-1.26, blood type AB: AOR: 0.78, CI: 0.33-1.87, blood type O: AOR: 0.77, CI: 0.51-1.16), rhesus factor positive (Rh+): AOR: 1.03, CI: 0.93-1.86. Blood type A had no correlation with positive testing (AOR: 1.00, CI: 0.88-1.13), blood type B was associated with higher odds of testing positive for disease (AOR: 1.28, CI: 1.08-1.52), AB was also associated with higher odds of testing positive (AOR: 1.37, CI: 1.02-1.83), and O was associated with a lower risk of testing positive (AOR: 0.84, CI: 0.75-0.95). Rh+ status was associated with higher odds of testing positive (AOR: 1.23, CI: 1.003-1.50). Blood type was not associated with risk of intubation or death in patients with COVID-19. Patients with blood types B and AB who received a test were more likely to test positive and blood type O was less likely to test positive. Rh+ patients were more likely to test positive.

Hematological findings in coronavirus disease 2019: indications of progression of disease.

Abstract: Coronavirus disease 2019 (COVID-19) is a new human infectious disease. The etiology for this outbreak is a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus far, related research on COVID-19 is still in preliminary stage. This paper summarized the latest outcomes of corresponding study from Chinese centers and clarified the hematopoietic abnormality caused by SARS-CoV-2 and potential mechanism. Lymphopenia was common in the early stage after the onset of COVID-19. A significant decrease was observed in peripheral CD4+ and CD8+ T lymphocytes. As the illness progressed, neutrophilia emerged in several cases, and patients with severe critical pulmonary conditions showed higher neutrophils than common type. Thrombocytopenia was resulting from the consumption and/or the reduced production of platelets in damaged lungs. Anemia was not observed notably, but the decrease in hemoglobin was frequent. The activation of monocyte-macrophage system aggravates the immune damage of lung and other tissues, which leads to the increase of D-dimer, prothrombin time, and platelet consumption.

COVID-19-driven endothelial damage: complement, HIF-1, and ABL2 are potential pathways of damage and targets for cure.

Abstract: COVID-19 pandemia is a major health emergency causing hundreds of deaths worldwide The high reported morbidity has been related to hypoxia and inflammation leading to endothelial dysfunction and aberrant coagulation in small and large vessels This review addresses some of the pathways leading to endothelial derangement, such as complement, HIF-1α, and ABL tyrosine kinases This review also highlights potential targets for prevention and therapy of COVID-19-related organ damage and discusses the role of marketed drugs, such as eculizumab and imatinib, as suitable candidates for clinical trials

Signals of T h 2 immune response from COVID-19 patients requiring intensive care.

Abstract: Dear Editor, Naїve T-helper cells (Th0) can respond to novel pathogens that the immune system has never encountered before, as is the specific case of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the positivesense single-stranded RNA virus responsible for the ongoing pandemic named coronavirus disease 2019 (COVID19). Depending on the infectious agent, Th0 polarize the immune response into T-helper type 1 (Th1), the default response in immunocompetent subjects to intracellular or phagocytosable pathogens (e.g. viruses, bacteria, protozoa, fungi) and mediated by macrophages and Tcytotoxic (Tc) cells (cell-mediated immunity), or into Thelper type 2 (Th2), classically directed against extracellular non-phagocytosable pathogens, for instance helminths, and whose main effectors are eosinophils, basophils and mastocytes, as well as B cells (humoral immunity) [1]. Eosinophils play a direct role in fighting RNA viruses, as demonstrated by the presence of RNases inside their granules [1]; however, they have been negatively associated with the pathophysiology of the respiratory virus infections, since they trigger bronchoconstriction and dyspnea, besides virus-induced exacerbations of allergic airways diseases, by releasing a large amount of cationic proteins and cytokines, among which interleukin-6 (IL6), a key mediator also for the development of the “cytokine storm” in COVID-19 fatal cases [2, 3]. At some extent, the smooth muscle cells in the tunica media of blood vessels can produce IL-6, too [4]. It belongs to Th2 cytokines class together with IL-4, IL-5, IL-9, IL-10, IL-13 and IL-25; contrariwise, IL-2, IL-12, interferon-γ and tumor necrosis factor-α are the main Th1 cytokines, able to stimulate the inducible form of the nitric oxide (NO) synthase to produce NO free radicals endowed with virucidal activity [1]. To minimize the contagion risk in healthcare personnel, we have prepared and examined a limited number of 15 peripheral blood smears from a wider series of hospitalized COVID-19 patients, just admitted to intensive care and monitored through blood tests; in all the cases, we have found cytological signals of Th2 immune response, represented by eosinophilia plus basophilia, degranulated eosinophils, Türk cells or plasma cells, together with rouleaux and Tc lymphopenia (Fig. 1). On the basis of our findings, for reasons still unclear, maybe related to the viral load, Th1 and Tc breakdown, antigenic cross-reactivity or the type of antigen-presenting cell stimulating Th0, the immune system mounts a Th2 response against SARS-CoV-2 in patients requiring intensive care, rather than a Th1 response, which would keep the infection under control by means of macrophages and Tc cells. This event is more likely in patients affected by cancer, immunodeficiency, autoimmune disorders, congestive heart failure, chronic obstructive pulmonary disease and hepatic cirrhosis, or in those who have suffered major surgery and traumatic injury, or who are on glucocorticoid therapy and total parenteral nutrition, all known conditions suppressive to Th1 immunity [1]. The mounting of a Th2 immune response allows to explain well the concurrent

Management of myelofibrosis after ruxolitinib failure

Abstract: Myelofibrosis is a BCR-ABL1–negative myeloproliferative neoplasm characterized by anemia, progressive splenomegaly, extramedullary hematopoiesis, bone marrow fibrosis, constitutional symptoms, leukemic progression, and shortened survival. Constitutive activation of the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, and other cellular pathways downstream, leads to myeloproliferation, proinflammatory cytokine expression, and bone marrow remodeling. Transplant is the only curative option for myelofibrosis, but high rates of morbidity and mortality limit eligibility. Several prognostic models have been developed to facilitate treatment decisions. Until the recent approval of fedratinib, a JAK2 inhibitor, ruxolitinib was the only available JAK inhibitor for treatment of intermediate- or high-risk myelofibrosis. Ruxolitinib reduces splenomegaly to some degree in almost all treated patients; however, many patients cannot tolerate ruxolitinib due to dose-dependent drug-related cytopenias, and even patients with a good initial response often develop resistance to ruxolitinib after 2–3 years of therapy. Currently, there is no consensus definition of ruxolitinib failure. Until fedratinib approval, strategies to overcome ruxolitinib resistance or intolerance were mainly different approaches to continued ruxolitinib therapy, including dosing modifications and ruxolitinib rechallenge. Fedratinib and two other JAK2 inhibitors in later stages of clinical development, pacritinib and momelotinib, have been shown to induce clinical responses and improve symptoms in patients previously treated with ruxolitinib. Fedratinib induces robust spleen responses, and pacritinib and momelotinib may have preferential activity in patients with severe cytopenias. Reviewed here are strategies to ameliorate ruxolitinib resistance or intolerance, and outcomes of clinical trials in patients with myelofibrosis receiving second-line JAK inhibitors after ruxolitinib treatment.

Autoimmune thrombotic thrombocytopenic purpura (TTP) associated with COVID-19.

Abstract: Dear Editor: A 57-year-old woman with a history of hypertension and breast cancer in complete remission was seen in lateMarch 2020 at the emergency ward in a private clinic with dry cough, anosmia, and dysgeusia. Physical examination found a low grade fever (37.8 °C) but was otherwise normal. A thoracic computerized tomography was normal, and a single nasopharyngeal swab (NPS) was reported as negative for severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) by a polymerase chain reaction (PCR)–based test. A complete blood work-up was normal except for mild lymphopenia (Day 1 on Table 1). Because of the pandemic state of SARS-CoV-2 and associated symptoms [1], the treating physicians considered the patient to have coronavirus disease 2019 (COVID-19) but with a false-negative result of the PCR NPS test. The patient was treated with lopinavir/ritonavir, hydroxychloroquine, and azithromycin. On the fifth day of treatment (Day 6 on Table 1) routine blood tests showed severe thrombocytopenia, moderate anemia with a normal reticulocyte count, and high serum lactate dehydrogenase (LDH) and bilirubin (Table 1). Treatment with methylprednisolone 1 mg/kg/ 24 h and intravenous immunoglobulin was added, but after no improvement in laboratory findings (Day 8 on Table 1), the patient was transferred to our institution for further management. After initial clinical and laboratory work-up at our institution (Day 9 on Table 1), a diagnosis of autoimmune thrombotic thrombocytopenic purpura (TTP) was rapidly established, based on the presence of microangiopathic hemolytic anemia, severe thrombocytopenia, and very low activity (2%) of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in combination with the presence of an ADAMTS-13 inhibitor, which is an autoantibody to ADAMTS-13 [2, 3]. A NPS sample was retested in our center on admission and was negative for SARS-CoV-2, but serological tests were positive for SARS-CoV-2 IgG, thus confirming the past COVID-19 [4]. Treatment with plasma infusion on admission led to a rapid rise in the patient’s platelet count (Day 10 on Table 1). After placement of a central venous catheter, therapeutic plasma exchange was begun, with a favorable clinical and laboratory course over the next week (Day 17 on Table 1). We present a case of acquired autoimmune TTP whose onset occurred immediately after COVID-19, since the patient was admitted for this latter infection with normal laboratory values. Of course, this could be a mere coincidence rather than a causal relationship, owing to the very high incidence of SARS-CoV-2 infection [5]. As with other hematological disorders, the COVID-19 pandemic may change the way in which the approach to and management of patients may vary from the standard of care, as highlighted by the American Society of Hematology COVID-19 Resources Center (specific information on TTP can be found at https://www.hematology.org/covid-19/ covid-19-and-ttp).

Coagulopathy and thromboembolic events in patients with SARS-CoV-2 infection: pathogenesis and management strategies.

Abstract: In October 2019, a viral infectious disease appeared in the city of Wuhan in China. A new betacoronavirus, SARS-CoV-2, has been recognized as the responsible pathogen in this infection. Although coronavirus disease is principally expressed as a pulmonary infection, critical SARS-CoV-2 infection is frequently complicated with coagulopathy, and thromboembolic events are recognizable in several patients. Dehydration, acute inflammatory condition, protracted immobilization during disease, existence of multiple cardiovascular risk factors such as diabetes, obesity or hypertension, previous coronary artery disease, ischemic stroke, peripheral artery disease are frequent comorbidities in SARS-CoV-2 hospitalized subjects, which possibly augment thrombo-embolic risk. However, other causal factors can still be identified such as unrestricted angiotensin II action, the use of immunoglobulins, an increased production of adhesion molecules able to induce vascular inflammation and endothelial activation, complement stimulation, excessive production of neutrophil extracellular traps (NETs), and increased platelet count. Low-molecular-weight heparin should be chosen as early treatment because of its anti-inflammatory action and its ability to antagonize histones and so defend the endothelium. However, several therapeutic possibilities have also been proposed such as fibrinolytic treatment, drugs that target NETs, and complement inhibition. Nevertheless, although the violence of the pandemic may suggest the use of heroic treatments to reduce the frightening mortality that accompanies SARS-CoV-2 infection, we believe that experimental treatments should only be used within approved and controlled protocols, the only ones that can provide useful and specify information on the validity of the treatments.

COVID-19 infection associated with autoimmune hemolytic anemia.

Abstract: Dear Editor, A 62-year-old man with a medical past history of arterial hypertension and heavy smokingwas ongoing radiochemotherapy for an oropharyngeal squamous cell carcinoma (cT3N0M0). Three days after the first cisplatin injection, the patient started a dry cough without fever. A nasopharyngeal swab was positive for Covid-19 (tested by PCR). A week later, he presented a marked asthenia and was referred to the emergency room. Physical examination showed fever and mild dyspnea, with a low oxygen saturation on room air. The patient was perfectly conscious, and there was no evidence of motor deficit. Chest X-ray showed bilateral lung infiltrates. The laboratory examination results were as follows: white blood cell count (WBC) 6620/μL, lymphocyte count 500/μL (Nl, 800– 5000), normal neutrophil count, platelet count 101, 000/μL (Nl, 150,000–450,000), hemoglobin 12 g/dL (Nl, 13.3–16.7), CRP 45mg/L (Nl, < 5), normal serum creatinine, LDH 307 IU/L (Nl, < 250), and bilirubin 0.7 mg/dL (Nl, < 1.2). Fourteen days after the first respiratory symptoms, he was transferred to the intensive care unit (ICU), and orotracheal intubation was required soon after admission. Anemia also deteriorated progressively with a rise of LDH level. On day 16, the patient developed acrocyanosis. Laboratory tests showed lymphocyte count 120/μL, normal neutrophil count, platelet count 145,000/μL, hemoglobin 6.9 g/dl, LDH 726 IU/L, reticulocyte count 40,000/μL (Nl, 30,000–100,000) raising to 231,000/μL 10 days later, potassium 6.78 mmol/L (Nl, 3.5–5), haptoglobin 0.13 g/L (Nl, 0.3–2), CRP 335 mg/L, normal creatinine, and bilirubin 1.3 mg/dL. Blood smear showed numerous red blood cell agglutination, schizocytes < 1%. Direct Coombs test was positive for C3b and negative for IgG. Cold agglutinins were positive (titer 1/16384) and anti-I (titer 1/1024). Antinuclear antibodies were positive (titer 1/160), ENA screening negative, and antiphospholipid negative. A multiplex PCR testing performed on tracheal aspiration was negative for Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia pneumoniae, Adenovirus, and Influenza. Serology testing was negative for HBV, HCV, and HIV, while IgG antibodies were found for EBV and CMV and IgM and IgG antibodies for Mycoplasma pneumoniae. Leucocytes immunophenotyping performed on peripheral blood showed lymphopenia without evidence of clonality. There was an oligoclonal pattern of gammaglobulins at serum protein electrophoresis; light chains kappa/lambda ratio was normal. The patient received 8 units of red packet cells over 1 week. At 6-week follow-up, the patient is slowly recovering from respiratory failure. While the main target of Covid-19 remains the lung, with respiratory failure and acute respiratory distress syndrome for the most severe cases, extra-pulmonary complications are now increasingly reported. Among autoimmune manifestations, autoimmune hemolytic anemia (AIHA) is an unusual finding. Autoimmune hemolytic anemia (with warm or cold antibodies) was recently described in 7 patients with Covid-19 disease [1, 2]. The delay between Covid-19 and hemolytic manifestations ranged from 4 to 13 days. Four patients had indolent B lymphoid malignancy either already known or discovered at the time of hemolytic episode. The chronological sequence in our case suggests that Covid-19 was the causal factor for AIHA. Temporal events and exclusion of other potential causes support this hypothesis. Indeed, our patient had a history of oropharyngeal carcinoma which is not usually considered as a triggering factor for autoimmune hemolytic anemia. The interpretation of Mycoplasma pneumonia serology should also be extremely careful, as IgM antibodies do not mandatory indicate a recent infection [3]. In our case, PCR testing was negative on the sputum, and there was no significant increase in IgG antibody titer over time. Among other hematological complications of Covid-19 infection, autoimmune thrombocytopenia and antiphospholipid syndromewere also described, but not present in our observation [1, 4, 5]. * Philippe Hantson philippe.hantson@uclouvain.be

Thrombotic complications and anticoagulation in COVID-19 pneumonia: a New York City hospital experience.

Abstract: Infection with SARS-CoV-2 (COVID-19) can cause prothrombotic complications. We aim to study the frequency of thrombotic complications and impact of anticoagulation on outcomes in hospitalized patients. We conducted a retrospective chart review of 921 consecutive patients admitted to our hospital with COVID-19. Patients were divided into four groups depending on whether they were on anticoagulation prior to admission, started anticoagulation during the admission, received prophylactic anticoagulation, or did not receive any anticoagulation. At the time of analysis, 325 patients (35.3%) had died, while 544 patients (59%) had been discharged resulting in inpatient mortality of 37.3%. Male sex, age > 65 years, and high D-dimer at admission were associated with higher mortality. Sixteen patients (1.7%) had venous thromboembolism confirmed with imaging, 11 patients had a stroke, and 2 patients developed limb ischemia. Treatment with therapeutic anticoagulation was associated with improved inpatient mortality compared with prophylactic anticoagulation alone (63% vs 86.2%, p < 0.0001) in patients requiring mechanical ventilation. Other outcomes such as rates of liberation from mechanical ventilation and duration of mechanical ventilation were not significantly impacted by the type of anticoagulation.

Baseline clinical characteristics and disease burden in patients with paroxysmal nocturnal hemoglobinuria (PNH): updated analysis from the International PNH Registry

Abstract: The International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry (NCT01374360) was initiated to optimize patient management by collecting data regarding disease burden, progression, and clinical outcomes. Herein, we report updated baseline demographics, clinical characteristics, disease burden data, and observed trends regarding clone size in the largest cohort of Registry patients. Patients with available data as of July 2017 were stratified by glycosylphosphatidylinositol (GPI)-deficient granulocyte clone size (< 10%, ≥ 10%-< 50%, and ≥ 50%). All patients were untreated with eculizumab at baseline, defined as date of eculizumab initiation or date of Registry enrollment (if never treated with eculizumab). Outcomes assessed in the current analysis included proportions of patients with high disease activity (HDA), history of major adverse vascular events (MAVEs; including thrombotic events [TEs]), bone marrow failure (BMF), red blood cell (RBC) transfusions, and PNH-related symptoms. A total of 4439 patients were included, of whom 2701 (60.8%) had available GPI-deficient granulocyte clone size data. Among these, median clone size was 31.8% (1002 had < 10%; 526 had ≥ 10%-< 50%; 1173 had ≥ 50%). There were high proportions of patients with HDA (51.6%), history of MAVEs (18.8%), BMF (62.6%), RBC transfusion (61.3%), and impaired renal function (42.8%). All measures except RBC transfusion history significantly correlated with GPI-deficient granulocyte clone size. A large proportion of patients with GPI-deficient granulocyte clone size < 10% had hemolysis (9.7%), MAVEs (10.2%), HDA (9.1%), and/or PNH-related symptoms. Although larger GPI-deficient granulocyte clone sizes were associated with higher disease burden, a substantial proportion of patients with smaller clone sizes had history of MAVEs/TEs.

Cytogenetics and mutations could predict outcome in relapsed and refractory acute myeloid leukemia patients receiving BCL-2 inhibitor venetoclax

Abstract: Venetoclax, a selective B cell leukemia/lymphoma-2 (BCL2) inhibitor, has recently shown activity in relapsed or refractory (R/R) acute myeloid leukemia (AML). Effective biomarkers for identifying patients most likely to respond to venetoclax-based treatment are of clinical utility. In this study, we aimed to evaluate the efficacy and safety profiles of venetoclax-based therapy in a total 40 R/R AML patients and identify the potentially predictive factors for response. Overall response rate was 50%, including 9 (22.5%) complete response (CR) or CR with incomplete hematologic recovery of either neutrophil or platelet counts (CRi). Median time to best response was 1.4 months and the median overall survival (OS) was 6.6 months. Presence of intermediate-risk cytogenetics predicted better OS compared to unfavorable-risk cytogenetics. Patients harboring NPM1, RUNX1, or SRSF2 mutations seemed to have higher CR/CRi rates and median OS was significantly longer in RUNX1-mutated patients. On the contrary, patients with FLT3-ITD, TP53, or DNMT3A mutations did not reach any objective response and had worse OS. No laboratory or clinical tumor lysis syndrome was observed and the most common adverse events were prolonged cytopenias which resulted in 67.5% of febrile neutropenia. Patients with concurrent use of azole antifungals had similar incidence of cytopenias compared with those without azole antifungals. In summary, we demonstrate that venetoclax is an effective and well-tolerated salvage option for R/R AML patients. Survival benefits were particularly remarkable in patients with intermediate-risk cytogenetics or RUNX1 mutations. In contrast, TP53, NRAS, and DNMT3A mutations as well as FLT3-ITD conferred negative impact on survival.

Clozapine-induced agranulocytosis.

Abstract: Wider use of clozapine, one of the most effective antipshychotic drugs, is precluded by its propensity to cause agranulocytosis. Currently, clozapine is used for treatment-resistant schizophrenia, with mandatory blood count monitoring for the duration of treatment. Agranulocytosis occurs in up to 0.8% of patients and presents a significant medical challenge, despite decreasing mortality rates. In this paper, we review the epidemiology of clozapine-induced agranulocytosis (CLIA), advances in identifying genetic risk factors, and the preventive measures to reduce the risk of CLIA. We discuss the pathogenesis of CLIA, which, despite receiving considerable scientific attention, has not been fully elucidated. Finally, we address the clinical management and suggest the approach to clozapine re-challenge in patients with a previous episode of neutropenia. With a significant proportion of clozapine recipients in Western hemisphere being Black, we comment on the importance of recognizing benign ethnic neutropenia as a potential impediment to clozapine administration. This review aims to aid haematologists and psychiatrists to jointly manage neutropenia and agranulocytosis caused by clozapine.

Antifungal prophylaxis and novel drugs in acute myeloid leukemia: the midostaurin and posaconazole dilemma.

Abstract: With the advent of new targeted drugs in hematology and oncology patient prognosis is improved. Combination with antifungal prophylaxis challenges clinicians due to pharmacological profiles prone to drug–drug interactions (DDI). Midostaurin is a novel agent for FLT3-TKD/-ITDmut-acute myeloid leukemia (AML) and metabolized via cytochrome P450 3A4 (CYP3A4). Posaconazole is a standard of care antifungal agent used for prophylaxis during induction treatment of AML and a strong CYP3A4 inhibitor. Concomitant administration of both drugs leads to elevated midostaurin exposure. Both drugs improve overall survival at low numbers needed to treat. The impact of CYP3A4-related DDI remains to be determined. Severe adverse events have been observed; however, it remains unclear if they can be directly linked to DDI. The lack of prospective clinical studies assessing incidence of invasive fungal infections and clinical impact of DDI contributes to neglecting live-saving antifungal prophylaxis. Management strategies to combine both drugs have been proposed, but evidence on which approach to use is scarce. In this review, we discuss several approaches in the specific clinical setting of concomitant administration of midostaurin and posaconazole and give examples from everyday clinical practice. Therapeutic drug monitoring will become increasingly important to individualize and personalize antineoplastic concomitant and antifungal treatment in the context of DDI. Pharmaceutical companies addressing the issue in clinical trials may take a pioneer role in this field. Other recently developed and approved drugs for the treatment of AML likely inhere potential of DDI marking a foreseeable issue in future treatment of this life-threatening disease.

Real-world effectiveness and safety of ixazomib-lenalidomide-dexamethasone in relapsed/refractory multiple myeloma

Abstract: Real-world data on regimens for relapsed/refractory multiple myeloma (RRMM) represent an important component of therapeutic decision-making. This multi-centric, retrospective, observational study conducted by the treating physicians evaluated the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in 155 patients who received ixazomib via early access programs in Greece, the UK, and the Czech Republic. Median age was 68 years; 17% had an Eastern Cooperative Oncology Group performance status ≥ 2; median number of prior therapies was 1 (range 1–7); 91%, 47%, and 17% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Median duration of exposure to ixazomib was 9.6 months. Overall response rate was 74%, including 35% very good partial response or better (16% complete response). Median progression-free survival (PFS) was 27.6 months (27.6 and 19.9 months in patients with 1 or > 1 prior lines, respectively). IRd treatment for ≥ 6 months was associated with longer PFS (hazard ratio 0.06). Fourteen patients (9%) discontinued IRd due to adverse events/toxicity in the absence of disease progression. Peripheral neuropathy was reported in 35% of patients (3% grades 3–4). These findings support the results of the phase III TOURMALINE-MM1 trial in a broader real-world RRMM population.

Prognostic role of baseline 18F-FDG PET/CT metabolic parameters in elderly HL: a two-center experience in 123 patients

Abstract: Elderly Hodgkin lymphoma (HL) is an aggressive lymphoma subgroup with high 18F-FDG avidity at 18F-FDG-PET/CT but no shared criteria for PET/CT in treatment evaluation and prediction of outcome are available. The aim of our bicentric study was to investigate whether the metabolic baseline PET/CT parameters can predict treatment response and prognosis in elderly HL. We retrospectively included 123 patients who underwent baseline 18F-FDG-PET/CT and end of treatment PET/CT scans. The PET images were analyzed visually and semi-quantitatively by measuring the lesion to liver SUVmax ratio (L-L SUV R), lesion to blood-pool SUVmax ratio (L-BP SUV R), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Survival curves were plotted according to the Kaplan-Meier method. At a median follow-up of 40 months, the median PFS and OS were 29 and 37 months. L-BP SUV R, L-L SUV R, MTV, and TLG were significantly higher in patients with no complete response compared with complete response group at end of treatment. Moreover, these parameters were demonstrated to be independent prognostic factors for PFS together with tumor stage, while only L-L SUV R and L-BP SUV R for OS. End of treatment PET/CT results using Deauville criteria were significantly correlated with outcome survival. End of treatment PET/CT results (using Deauville criteria) and semiquantitative baseline PET/CT parameters were significantly correlated with response to treatment and long-term outcome.

M2-like polarization of THP-1 monocyte-derived macrophages under chronic iron overload.

Abstract: Macrophages are characterized by phenotypical and functional heterogeneity. In different microenvironments, macrophages can polarize into two types: classically activated macrophages (M1) or alternatively activated macrophages (M2). M1 macrophages are a well-known bacteriostatic macrophage, and conversely, M2 macrophages may play an important role in tumor growth and tissue remodeling. M1 macrophages have been reported to have high intracellular iron stores, while M2 macrophages contain lower intracellular iron. It has been well-described that disturbances of iron homeostasis are associated with altered immune function. Thus, it is important to investigate if chronic iron overload is capable of polarizing macrophages. Human monocytic leukemia THP-1 cells were maintained in culture medium that contained 100 μM ferrous sulfate heptahydrate (FeSO4) (I-THP-1) and differentiated into THP-1-derived macrophages (I-TDMs) by induction with phorbol 12-myristate 13-acetate (PMA). We characterized that I-TDMs not only enhanced the surface expression of CD163 and CD206 but also increased arginase and decreased iNOS protein expression. I-TDMs enhanced pSTAT6 expression and decreased pSTAT1 and NF-κB expressions. Furthermore, the gene expression profile of I-TDMs was comparable with M2 macrophages by performing human oligonucleotide DNA microarray analysis. Finally, functional assays demonstrated I-TDMs secreted higher levels of IL-10 but not M1 cytokines. Additionally, the conditional medium of I-TDMs had enhanced migration and increased invasion of A375 melanoma cells which was similar to the characteristics of tumor-associated macrophages. Taken together, we demonstrated that THP-1-derived macrophages polarized to a phenotype of M2-like characteristics when subjected to chronic iron overload.

Progression of disease within 2 years (POD24) is a clinically relevant endpoint to identify high-risk follicular lymphoma patients in real life.

Abstract: Follicular lymphoma (FL) is an indolent non-Hodgkin’s lymphoma with heterogeneous outcomes. Progression or relapse of FL within 2 years (so-called POD24) after diagnosis is associated with a poor outcome for patients treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) in clinical trials. POD24 needs further validation before it can be used as a relevant endpoint to assess treatment efficacy. In the present retrospective monocentric study, we investigated the predictive value of POD24 in a cohort of grade 1, 2, or 3a FL patients treated in our institution (Nantes Medical University, France) and registered in our local database. We investigated the nature of treatment lines, patients’ outcomes, and the prognostic value of POD24. Between 2007 and 2016, 317 patients were included. After first-line therapy, 60 patients relapsed within 2 years (POD24-pos cohort), and 254 patients did not relapse within 2 years (PO24-neg cohort). Thirty-three patients died, and 34 patients had an aggressive transformation. The median follow-up is 59.9 months (1.6–395.5). The median PFS is 59.9 months. Overall survival (OS) at 1 year, 3 years, and 5 years is 98.4% [97.0–99.8], 95.1% [92.6–97.6], and 92.5% [89.3–95.9], respectively. The 5-year OS was statistically lower for POD24-pos patients (82% [71.9–93.5]) than for POD24-neg patients (93.3% [88.98–97.8]) (p = 10−5). In multivariate analyses, transformation was predictive of OS, and PS (≥ 1) was predictive of POD24. POD24 is predictive of a worse OS and may be recommended as a relevant endpoint in clinical trials and in real life in particular for patients with advanced disease.

Clinical impact of the CONUT score in patients with multiple myeloma

Abstract: Novel anti-myeloma drugs have significantly improved the overall survival (OS) of patients with multiple myeloma (MM). However, not all MM patients treated with these drugs show survival benefits, and biologic and genetic prognostic factors are insufficient to predict the response to treatment. Decreasing treatment-related complications is important to improve the efficacy of treatment in patients with MM. The Controlling Nutritional Status (CONUT) score is a screening method for poor nutritional status, which is associated with poor prognosis in several cancers because it increases the rate of treatment-related complications. We retrospectively analyzed the OS of 64 patients with symptomatic MM and evaluated the correlation between the CONUT score and patient prognosis in MM. The median age at diagnosis was 66 years, and multivariate analysis showed that a high CONUT score (≥ 5; hazard ratio, 3.937; 95% confidence interval, 1.214-12.658; P = 0.022) was an independent prognostic risk factor. Subgroup analysis was performed according to patient age because the choice of treatment strategy, particularly autologous peripheral blood stem cell transplantation (auto-PBSCT), can vary depending on age in MM patients. Younger patients (< 65 years old) who received auto-PBSCT and had a lower CONUT score (0-3) showed a significantly better survival outcome than those with a higher CONUT score (≥ 4) (median OS, not reached vs. 64.1 months; P = 0.011). The CONUT score is simple to calculate and provides a useful prognostic indicator in patients with MM, especially transplant-eligible patients.

Randomized controlled trial of twice-daily versus alternate-day oral iron therapy in the treatment of iron-deficiency anemia

Abstract: Recent studies in iron-depleted women have challenged the current approach of treating iron-deficiency anemia (IDA) with oral iron in divided daily doses. Alternate day dosing leads to more fractional absorption of iron. In this randomized controlled trial, we looked at the efficacy and safety of alternate-day (AD) versus twice-daily (BD) oral iron in all severity of IDA. Total of 62 patients were randomized, 31 patients in BD arm received 60 mg elemental iron twice daily while 31 patients in AD arm received 120 mg iron on alternate days. The primary endpoint of 2 g/dl rise in hemoglobin was met in significantly more patients in the BD arm at 3 weeks (32.3% vs. 6.5%, p < 0.0001) and 6 weeks (58% vs. 35.5%, p = 0.001). There was a significant rise in the median hemoglobin at 3 (1.6 vs. 1.1, p = 0.02) and 6 weeks (2.9 vs. 2.0 g/dl, p = 0.03) in the BD arm. However, the median hemoglobin rise in the AD arm at 6 weeks was not significantly different than the BD arm at 3 weeks. Alternate-day dosing for 6 weeks and twice-daily dosing for 3 weeks resulted in the provision of the same total amount of iron. There were more reports of nausea in the BD arm (p = 0.03). In conclusion, the choice of twice-daily or alternate-day oral iron therapy should depend on the severity of anemia, the rapidity of response desired, and patient preference to either regimen due to adverse events. Trial Registration: CTRI reg. no. CTRI/2018/07/015106 http://ctri.nic.in/Clinicaltrials/login.php.

Monitoring oral iron therapy in children with iron deficiency anemia: an observational, prospective, multicenter study of AIEOP patients (Associazione Italiana Emato-Oncologia Pediatrica)

Abstract: Oral ferrous salts are standard treatment for children with iron deficiency anemia (IDA). The objective of our study was to monitor oral iron therapy in children, aged 3 months–12 years, with IDA. We prospectively collected clinical and hematological data of children with IDA, from 15 AIEOP (Associazione Italiana di Ematologia ed. Oncologia Pediatrica) centers. Response was measured by the increase of Hb from baseline. Of the 107 analyzed patients, 18 received ferrous gluconate/sulfate 2 mg/kg (ferrous 2), 7 ferrous gluconate/sulfate 4 mg/kg (ferrous 4), 7 ferric iron salts 2 mg/kg (ferric), 62 bis-glycinate iron 0.45 mg/kg (glycinate), and 13 liposomal iron 0.7–1.4 mg/kg (liposomal). Increase in reticulocytes was evident at 3 days, while Hb increase appeared at 2 weeks. Gain of Hb at 2 and 8 weeks revealed a higher median increase in both ferrous 2 and ferrous 4 groups. Gastro-intestinal side effects were reported in 16% (ferrous 2), 14% (ferrous 4), 6% (glycinate), and 0 (ferric and liposomal) patients. The reticulocyte counts significantly increased after 3 days from the start of oral iron supplementation. Bis-glycinate iron formulation had a good efficacy/safety profile and offers an acceptable alternative to ferrous iron preparations.

Mosaicism in Fanconi anemia: concise review and evaluation of published cases with focus on clinical course of blood count normalization

Abstract: Fanconi anemia (FA) is a DNA repair disorder resulting from mutations in genes encoding for FA DNA repair complex components and is characterized by variable congenital abnormalities, bone marrow failure (BMF), and high incidences of malignancies. FA mosaicism arises from reversion or other compensatory mutations in hematopoietic cells and may be associated with BMF reversal and decreased blood cell sensitivity to DNA-damaging agents (clastogens); this sensitivity is a phenotypic and diagnostic hallmark of FA. Uncertainty regarding the clinical significance of FA mosaicism persists; in some cases, patients have survived multiple decades without BMF or hematologic malignancy, and in others hematologic failure occurred despite the presence of clastogen-resistant cell populations. Assessment of mosaicism is further complicated because clinical evaluation is frequently based on clastogen resistance in lymphocytes, which may arise from reversion events both in lymphoid-specific lineages and in more pluripotent hematopoietic stem/progenitor cells (HSPCs). In this review, we describe diagnostic methods and outcomes in published mosaicism series, including the substantial intervals (1–6 years) over which blood counts normalized, and the relatively favorable clinical course in cases where clastogen resistance was demonstrated in bone marrow progenitors. We also analyzed published FA mosaic cases with emphasis on long-term clinical outcomes when blood count normalization was identified. Blood count normalization in FA mosaicism likely arises from reversion events in long-term primitive HSPCs and is associated with low incidences of BMF or hematologic malignancy. These observations have ramifications for current investigational therapeutic programs in FA intended to enable gene correction in long-term repopulating HSPCs.

Germinotropic lymphoproliferative disorder: a systematic review

Abstract: Germinotropic lymphoproliferative disorder is a rare and rather enigmatic novel entity with distinctive clinicopathological features, one of which is the typical co-infection by Human herpesvirus 8 and Epstein-Barr virus. Human herpesvirus 8 is a lymphotropic virus detected in Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, Human herpesvirus 8-positive diffuse large B cell lymphoma not otherwise specified, and germinotropic lymphoproliferative disorder. Co-infection by Human herpesvirus 8 and Epstein-Barr virus is identified only in two lymphoproliferative diseases: germinotropic lymphoproliferative disorder and primary effusion lymphoma, which are otherwise diseases with totally different clinical presentations and outcomes. Unlike primary effusion lymphoma mostly occurring in immunocompromised individuals and following an aggressive course, germinotropic lymphoproliferative disorder usually presents with single or multiple lymphadenopathy affecting mainly immunocompetent individuals and mostly follows an indolent course. Based on the PRISMA guidelines, we carried out a systematic search on PubMed/MEDLINE, Web of Science, Scopus, EMBASE, and Cochrane Library using the search terms “germinotropic” and “lymphoproliferative disorder.” Current scientific literature reports just 19 cases of germinotropic lymphoproliferative disorder. The purpose of our systematic review is to improve our understanding of the disease, focusing on epidemiology, clinical presentation, pathological features, treatment, and outcome. In addition, we discuss the differential diagnosis with the other Human herpesvirus 8-related lymphoproliferative diseases as currently recognized in the World Health Organization classification, adding a focus on lymphoproliferative disorders showing overlapping features.

High levels of proinflammatory cytokines IL-6 and IL-8 are associated with a poor clinical outcome in sickle cell anemia.

Abstract: Sickle cell anemia (SCA) pathophysiology is characterized by the activation of sickle red blood cells, reticulocytes, leukocytes, platelets, and endothelial cells, and with the expression of several inflammatory molecules. Therefore, it is conceivable that variations in levels of proinflammatory cytokines may act as a signaling of differential clinical course in SCA. Here, we evaluated the clinical impact of proinflammatory cytokines interleukin 1-β (IL-1β), interleukin 6 (IL-6), and interleukin 8 (IL-8) in 79 patients with SCA, followed in a single reference center from northeastern Brazil. The main clinical/laboratory data were obtained from patient interview and medical records. The proinflammatory markers IL-1β, IL-6, and IL-8 were evaluated by using commercially available enzyme-linked immunosorbent assay kits. According to levels of the proinflammatory markers, we observed that patients who had a higher frequency of VOC per year (P = 0.0236), acute chest syndrome (P = 0.01), leg ulcers (P = 0.0001), osteonecrosis (P = 0.0006), stroke (P = 0.0486), and priapism (P = 0.0347) had higher IL-6 levels compared with patients without these clinical complications. Furthermore, increased levels of IL-8 were found in patients who presented leg ulcers (P = 0.0184). No significant difference was found for IL-1β levels (P > 0.05). In summary, the present study emphasizes the role of inflammation in SCA pathophysiology, reveals an association of IL-8 levels and leg ulcer occurrence, and indicates that IL-6 levels can be used as a useful predictor for poor outcomes in SCA.

Evaluation of dsDNA from extracellular vesicles (EVs) in pediatric AML diagnostics.

Abstract: Acute myeloid leukemia (AML) is a heterogeneous malignant disease characterized by a collection of genetic and epigenetic changes. As a consequence, AML can evolve towards more aggressive subtypes during treatment, which require additional therapies to prevent future relapse. As we have previously detected double-stranded DNA (dsDNA) in tumor-derived extracellular vesicles (EVs), in this current study we attempted to evaluate the potential diagnostic applications of AML EV-dsDNA derived from primary bone marrow and peripheral blood plasma samples. EVs from plasma of 29 pediatric AML patients (at initial diagnosis or during treatment) were isolated by ultracentrifugation, after which dsDNA was extracted from obtained EVs and analyzed for leukemia-specific mutations using next generation sequencing (NGS) and GeneScan-based fragment-length analysis. In 18 out of 20 patients, dsDNA harvested from EVs mirrored the (leukemia-specific) mutations found in the genomic DNA obtained from primary leukemia cells. In the nanoparticle tracking analysis (NTA), a decrease in EV numbers was observed in patients after treatment compared with initial diagnosis. Following treatment, in 75 samples out of the 79, these mutations were no longer detectable in EV-dsDNA. In light of our results, we propose the use of leukemia-derived EV-dsDNA as an additional measure for mutational status and, potentially, treatment response in pediatric AML.

Concepts in immuno-oncology: tackling B cell malignancies with CD19-directed bispecific T cell engager therapies

Abstract: The B cell surface antigen CD19 is a target for treating B cell malignancies, such as B cell precursor acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma. The BiTE® immuno-oncology platform includes blinatumomab, which is approved for relapsed/refractory B cell precursor acute lymphoblastic leukemia and B cell precursor acute lymphoblastic leukemia with minimal residual disease. Blinatumomab is also being evaluated in combination with other agents (tyrosine kinase inhibitors, checkpoint inhibitors, and chemotherapy) in various treatment settings, including frontline protocols. An extended half-life BiTE molecule is also under investigation. Patients receiving blinatumomab may experience cytokine release syndrome and neurotoxicity; however, these events may be less frequent and severe than in patients receiving other CD19-targeted immunotherapies, such as chimeric antigen receptor T cell therapy. We review BiTE technology for treating malignancies that express CD19, analyzing the benefits and limitations of this bispecific T cell engager platform from clinical experience with blinatumomab.

De-escalation of empiric broad spectrum antibiotics in hematopoietic stem cell transplant recipients with febrile neutropenia

Abstract: Febrile neutropenia (FN) is a common serious complication in patients undergoing hematopoietic stem cell transplantation (HSCT) requiring urgent evaluation and initiation of empiric broad spectrum antibiotics (BSA). The appropriate duration of BSA for FN in patients with negative cultures and no identifiable infection remains undefined. We retrospectively analyzed allogenic and autologous HSCT patients with FN and negative infectious work-up at our facility from 2012 to 2018. The early de-escalation group (EDG) included those who had BSA de-escalation to fluoroquinolone prophylaxis at least 24 h prior to absolute neutrophil count (ANC) recovery after the patient was fever-free for at least 48 h. Among 297 patients undergoing their first HSCT who experienced FN with negative infectious work-up, 83 patients were de-escalated early with the remaining 214 in the standard of care group (SCG) whose BSA were continued until ANC was > 500. Duration of broad-spectrum antibiotics was shorter in EDG compared to SCG (3.86 days vs. 4.62 days, p = 0.03). Rates of mortality, new infections, and clinical decompensation requiring intensive care unit transfer and/or pressor use within 30 days were all similar between the two groups (0% vs. 0.4% p = 1.00, 0% vs. 1.4% p = 0.56, 13.2% vs. 8.4% p = 0.27). This indicates that it is safe to de-escalate antibiotics prior to ANC recovery, leading to less BSA exposure.

Validation and comparison of prognostic values of GNRI, PNI, and CONUT in newly diagnosed diffuse large B cell lymphoma.

Abstract: Diffuse large B cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin lymphoma. Emerging evidence indicates that poor nutritional status determined with nutritional indices such as geriatric nutritional risk index (GNRI), prognostic nutritional index (PNI), and controlling nutritional status score (CONUT) was associated with poor prognosis of DLBCL. We conducted this multicenter retrospective study to validate and compare prognostic values of the three indices in 615 newly diagnosed DLBCL patients. The overall survival (OS) in patients with poor nutritional status determined with each of these nutritional indices were significantly inferior compared with that in those without nutritional risks (5-year OS in patients with GNRI 4 and CONUT ≤ 4 were 53.1% and 77.1%, P 4, HR 1.53, 95% CI 1.05-2.23, P = 0.028) after multivariate analyses. Nutritional status determined with GNRI affected OS more strongly in the patients with nongerminal center B cell-like (nonGCB) DLBCL compared with that in those with GCB-type DLBCL. In conclusion, baseline poor nutritional status determined based on GNRI or CONUT was an independent risk factor of newly diagnosed DLBCL, and GNRI was also useful as an independent prognostic factor for patients with nonGCB-type DLBCL.

SARS-CoV-2-associated cold agglutinin disease: a report of two cases.

Abstract: Dear Editor, Hematological manifestations reported in SARS-CoV-2 infection mainly include lymphocytopenia as a poor prognosis factor [1]. Thrombocytopenia can be associated with disseminated intravascular coagulation [2] or immune process [3]. Data regarding anemia are scarce and in line with a recent report on six patients with heterogeneous hemolytic anemia [4], we herein report on two patients with SARS-CoV-2related cold agglutinin disease (CAD).

A study of the geographic distribution and associated risk factors of leg ulcers within an international cohort of sickle cell disease patients: the CASiRe group analysis.

Abstract: Vasculopathy is a hallmark of sickle cell disease ultimately resulting in chronic end organ damage. Leg ulcer is one of its sequelae, occurring in ~ 5–10% of adult sickle cell patients. The majority of leg ulcer publications to date have emanated from single center cohort studies. As such, there are limited studies on the geographic distribution of leg ulcers and associated risk factors worldwide. The Consortium for the Advancement of Sickle Cell Research (CASiRe) was formed to improve the understanding of the different phenotypes of sickle cell disease patients living in different geographic locations around the world (USA, UK, Italy, Ghana). This cross-sectional cohort sub-study of 659 sickle cell patients aimed to determine the geographic distribution and risk factors associated with leg ulcers. The prevalence of leg ulcers was 10.3% and was associated with older age, SS genotype, male gender, and Ghanaian origin. In fact, the highest prevalence (18.6%) was observed in Ghana. Albuminuria, proteinuria, increased markers of hemolysis (lower hemoglobin, higher total bilirubin), lower oxygen saturation, and lower body mass index were also associated with leg ulceration. Overall, our study identified a predominance of leg ulcers within male hemoglobin SS patients living in sub-Saharan Africa with renal dysfunction and increased hemolysis.