Showing papers in "Hematology in 2020"

Managing toxicities of Bruton tyrosine kinase inhibitors

Abstract: Inhibition of Bruton's tyrosine kinase (BTK) has revolutionized the treatment landscape for patients with chronic lymphocytic leukemia (CLL). By targeting this critical kinase in proximal B-cell receptor signaling, BTK inhibitors (BTKis) impair cell proliferation, migration, and activation of NF-κB. Clinically, because indefinite inhibition is a mainstay of therapy, there is an extended period of exposure in which adverse effects can develop. Given the impressive efficacy and activity of BTKis in the treatment of patients with CLL, appropriate management of treatment-emergent adverse events (AEs) is of paramount importance. Here we review the BTKi landscape and present the available toxicity and safety data for each agent. The long-term toxicity profile of ibrutinib, a first-in-class inhibitor, is well characterized and includes a clinically significant incidence of cardiac arrhythmias, bleeding, infection, diarrhea, arthralgias, and hypertension. Acalabrutinib, the initial second-generation BTKi to earn approval from the US Food and Drug Administration, demonstrates improved kinase selectivity for BTK, with commonly observed adverse reactions including infection, headache, and diarrhea. Mediated by both on-target inhibition of BTK and variable off-target inhibition of other kinases including interleukin-2-inducible T-cell kinase (ITK), tyrosine-protein kinase (TEC), and endothelial growth factor receptor (EGFR), the toxicity profile of BTKis is closely linked to their pattern of kinase binding. Other emerging BTKis include second-generation agents with variable degrees of kinase selectivity and third-generation agents that exhibit reversible noncovalent binding to BTK. We also highlight critical considerations for the prevention and monitoring of AEs and offer practical management strategies for treatment-emergent toxicities.

Therapeutic development and current uses of BCL-2 inhibition

Abstract: B-cell lymphoma 2 (BCL2) is a key protein regulator of apoptosis. It is variably highly expressed in many hematological malignancies, providing protection from cell death induced by oncogenic and external stresses. Venetoclax is the first selective BCL2 inhibitor, and the first of a new class of anticancer drug (BH3-mimetics) to be approved for routine clinical practice, currently in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). To help understand the potential and limitations of this therapy, this brief review will touch on the history of development of venetoclax, dissect its mechanism of action, and summarize critical evidence for its approved use in the management of patients with CLL and AML. It will also consider recent data on mechanisms of resistance and explore concepts pertinent to its future development based on key lessons learned to date.

Hematologic predictors of mortality in hospitalized patients with COVID-19: a comparative study.

Abstract: Background: The first cases of proved COVID-19 in Iran were reported in February 2020 and has since rapidly spread worldwide. We aimed to clarify the clinical significance of hematologic parameters alteration in COVID-19. Methods: Different hematologic parameters were measured in 225 hospitalized COVID-19 patients in a tertiary care university hospital, during the peak of COVID-19 outbreak and their association with duration of hospitalization, ICU admission and especially mortality was analyzed. Results: Among a total of 225 patients, 24.4% did not survive after admission. Lymphopenia and neutrophilia were observed in 52.7% and 21.4% of the patients, respectively. The mean count of neutrophils was significantly higher in non-survived patients (P = .032). Elevated neutrophil-to-lymphocyte ratio (NLR) was significantly associated with mortality (P < .001). Low hemoglobin (Hb) concentration significantly correlated with mortality (P = .004) and ICU admission (P = .04). Platelet (Plt) count was significantly lower in the non-survived patients (P = .023). Non-survivors had significantly lower nadir Hb and Plt counts than survivors (P < .001 in both parameters). Platelet-to-lymphocyte ratio (PLR) also correlated with mortality and was significantly higher in non-survivors (P = .034). Conclusions: Hematologic laboratory parameters have always been a crucial component of diagnostic and therapeutic strategies in infectious disease. Hematologic predictors of a fatal outcome in COVID19 hospitalized patients in our series include elevated NLR and PLR, lower than normal Hb and Plt, elevated d-dimer and prolonged prothrombin time (PT), together with elevated inflammatory indicators in the blood.

Bispecifics, trispecifics, and other novel immune treatments in myeloma.

Abstract: Despite recent advances in treatment, relapses in multiple myeloma (MM) are inevitable. Off-the-shelf immunotherapeutics represent a promising avenue for research, with various classes of agents under development and several demonstrating deep and durable responses in patients who have exhausted all available therapies. Antibody-drug conjugates (ADCs) seek to improve on naked monoclonal antibodies by delivering a cytotoxic payload directly to tumor cells while largely limiting systemic effects. Belantamab mafodotin, a B-cell maturation antigen (BCMA)-targeted ADC, has shown response rates >30% in a phase 2 trial of highly refractory patients and is being investigated in a variety of settings and combinations. Several other ADCs are in earlier stages of development that target cell surface antigens that are internalized, including BCMA, CD38, CD46, CD56, CD74, and CD138. Bispecifics are designed to bring cytotoxic immune effector cells into proximity with tumor cells, and several agents have shown high response rates in early trials. Current targets include BCMA, CD38, GPRC5d, and FCRH5, and all of these seek to engage T cells through CD3. Bispecifics targeting natural killer (NK) cells through CD16 are still in preclinical development. Trispecific antibodies may represent an advance over bispecifics by providing a T-cell costimulatory signal such as CD28, or alternatively, dual MM antigens to increase specificity of NK or T-cell targeting. This is an area of active preclinical research at this time. Lastly, designed ankyrin repeat proteins, which are small antibody-mimetic proteins with high target-binding affinity, have the potential to block multiple pathways at once and provide stimulatory signals to the immune system.

Platelet transfusion refractoriness: how do I diagnose and manage?

Abstract: Platelet refractoriness continues to be a problem for thrombocytopenic patients because the risk of a major spontaneous or life-threatening bleed significantly increases when platelet counts drop below 10 × 109/L. The majority of patients have nonimmune causes driving the refractoriness, such as bleeding, medications, or diffuse intravascular coagulation; however, this article is dedicated to the diagnosis and support of patients with immune-based platelet refractoriness. Antibodies to class I HLA molecules (A and B alleles) are responsible for most immune-based refractory cases, with antibodies to platelet antigens seen much less frequently. Patients may be supported with either crossmatch-compatible or HLA-matched/compatible platelet units. When trying to select HLA units it can be difficult to find a perfect "4 of 4" match for the patient's class IA and IB alleles. In these cases, it is better to use the antibody specificity prediction method, which identifies compatible units that lack antigens recognized by the patient's anti-HLA antibodies. For an algorithmic approach to the patient with platelet refractoriness, see Visual Abstract.

Preventing infections in children and adults with asplenia.

Abstract: An estimated 1 million people in the United States have functional or anatomic asplenia or hyposplenia. Infectious complications due to encapsulated organisms such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae can lead to fulminant sepsis and death, particularly in young children, in the period shortly after splenectomy, and in immunocompromised patients. Patients with asplenia are also at risk for less common infections due to Capnocytophaga, Babesia, and malaria. Antibiotic prophylaxis, vaccines, and patient and family education are the mainstays of prevention in these at-risk patients. Recommendations for antibiotic prophylaxis typically target high-risk periods, such as 1 to 3 years after splenectomy, children ≤5 years of age, or patients with concomitant immunocompromise. However, the risk for sepsis is lifelong, with infections occurring as late as 40 years after splenectomy. Currently available vaccines recommended for patients with asplenia include pneumococcal vaccines (13-valent pneumococcal conjugate vaccine followed by the 23-valent pneumococcal polysaccharide vaccine), meningococcal vaccines (meningococcal conjugate vaccines for serogroups A, C, Y and W-135 and serogroup B meningococcal vaccines), H. influenzae type b vaccines, and inactivated influenza vaccines. Ongoing booster doses are also recommended for pneumococcal and meningococcal vaccines to maintain protection. Despite the availability of prevention tools, adherence is often a challenge. Dedicated teams or clinics focused on patient education and monitoring have demonstrated substantial improvements in vaccine coverage rates for individuals with asplenia and reduced risk of infection. Future efforts to monitor the quality of care in patients with asplenia may be important to bridge the know-do gap in this high-risk population.

Managing toxicities of phosphatidylinositol-3-kinase (PI3K) inhibitors

Abstract: Despite the proven effective approach to targeting the phosphatidylinositol-3-kinase (PI3K) pathway in B-cell malignancies, the approved PI3K inhibitors idelalisib and duvelisib have been less commonly selected for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), given the availability of other more tolerable agents. However, patients with CLL/SLL can experience a disease course that is multiply relapsed, refractory, or intolerant to treatment, and PI3K inhibitors can achieve meaningful responses. This article reviews the common early- and late-onset (considered immune-mediated) toxicities with PI3K inhibitors, including infections, hepatotoxicity, diarrhea and/or colitis, and pneumonitis. Data on pretreatment considerations, toxicity management, and drug rechallenge are presented. In addition, next-generation PI3K inhibitors and novel treatment approaches with PI3K inhibitors, including combinations, time-limited treatments, and intermittent dosing, are highlighted.

Updates in infection risk and management in acute leukemia.

Abstract: Patients with hematologic malignancies are at increased risk of infection, with associated morbidity and mortality. Patients with acute myeloid leukemia (AML) have qualitative and quantitative deficits in granulocytes predisposing to bacterial and fungal infections. Acute lymphoblastic leukemia results in qualitative deficits in lymphocytes, resulting in hypogammaglobulinemia and reduced cell-mediated immunity predisposing to certain bacterial and viral as well as fungal infections. Chemotherapeutic regimens often compound these deficits, result in prolonged periods of severe neutropenia, and disrupt mucosal barriers, further elevating infection risk. Despite advances in antimicrobial therapies and prophylaxis, acute leukemia patients with disease- and treatment-related immunosuppression remain at risk for life-threatening infection, including with resistant organisms, antimicrobial-related adverse events, and higher treatment costs. Additionally, our knowledge of infection risk and drug-drug interactions with new immune-targeted cancer therapeutics is evolving. Here, we review 3 areas in which standard practice is evolving as challenges arise and new experience is gained, including antibiotic use in febrile neutropenia, fungal prophylaxis, and use of targeted therapies.

Monoclonal gammopathies of clinical significance

Abstract: "Monoclonal gammopathy of clinical significance" (MGCS) is the term used to describe nonmalignant monoclonal gammopathies causing important disease. MGCS is the differential diagnosis for any patient presenting with what appears to be a monoclonal gammopathy of undetermined significance but is also experiencing other unexplained symptoms. Broadly, these conditions can be separated into symptoms and signs referable to the nerves, the kidneys, and the skin. The first step in making these diagnoses is to consider them. With a particular condition in mind, the next step is to order those tests that can help confirm or dismiss a particular diagnosis. Nearly all of the renal and dermatologic conditions are diagnosed by renal and skin biopsies, respectively. The importance of a highly competent renal pathologist and dermatopathologist cannot be underestimated. Biopsy is less specific for the neuropathic conditions. Because several of the MGCSs are syndromes, recognizing other manifestations is also key. Treatment recommendations for many of these conditions are anecdotal because of their rarity, but for several of the conditions, IV immunoglobulin, rituximab, and plasma cell-directed therapy are the best options.

Therapy for lower-risk MDS.

Abstract: Lower-risk myelodysplastic syndromes (MDS) are characterized by the presence of dysplasia, low bone marrow blast percentage, low number and depth of cytopenia(s), and relatively good-risk karyotpic and molecular abnormalities. A score of ≤3.5 on the Revised International Prognostic Scoring System classifies patients as lower-risk MDS. Information from a mutational profile of the MDS at time of diagnosis (and over serial time points) can be reassuring for predicted behavior of lower-risk MDS compared with one expected to progress more rapidly (higher-risk MDS). Supportive care continues to be the crux of treatment, although the options to reduce transfusion needs have improved in 2020. Erythropoiesis stimulating agents, lenalidomide, and luspatercept address the most frequent (and symptomatic) cytopenia (anemia) and are started only when patients are transfusion dependent. Patients can derive long-term benefits (years) from these approaches but will often progress to higher-risk MDS. Interestingly, some patients with lower-risk MDS can present with an isolated thrombocytopenia for which thrombopoietin receptor analogs such as romiplostim and eltrombopag are options (as long as blast counts are low). The presence of pancytopenia and or intensifying and unremitting clinical symptoms are often treated with hypomethylating agents or (anti-thymocyte globulin if hypocellular MDS is of concern). Targeted therapies are emerging for small subsets of MDS patients with specific somatic mutations (ie, TP53, IDH1/2, FLT3), although currently, there are no approved, mutation-directed medications to treat MDS.

Genomics of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes

Abstract: Myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes are uniquely classified neoplasms occurring in both children and adults. This category consists of 5 neoplastic subtypes: chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), BCR-ABL1-negative atypical chronic myeloid leukemia (aCML), MDS/MPN-ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), and MDS/MPN-unclassifiable (U). Cytogenetic abnormalities and somatic copy number variations are uncommon; however, >90% patients harbor gene mutations. Although no single gene mutation is specific to a disease subtype, certain mutational signatures in the context of appropriate clinical and morphological features can be used to establish a diagnosis. In CMML, mutated coexpression of TET2 and SRSF2 results in clonal hematopoiesis skewed toward monocytosis, and the ensuing acquisition of driver mutations including ASXL1, NRAS, and CBL results in overt disease. MDS/MPN-RS-T demonstrates features of SF3B1-mutant MDS with ring sideroblasts (MDS-RS), with the development of thrombocytosis secondary to the acquisition of signaling mutations, most commonly JAK2V617F. JMML, the only pediatric entity, is a bona fide RASopathy, with germline and somatic mutations occurring in the oncogenic RAS pathway giving rise to disease. BCR-ABL1-negative aCML is characterized by dysplastic neutrophilia and is enriched in SETBP1 and ETNK1 mutations, whereas MDS/MPN-U is the least defined and lacks a characteristic mutational signature. Molecular profiling also provides prognostic information, with truncating ASXL1 mutations being universally detrimental and germline CBL mutations in JMML showing spontaneous regression. Sequencing information in certain cases can help identify potential targeted therapies (IDH1, IDH2, and splicing mutations) and should be a mainstay in the diagnosis and management of these neoplasms.

Management of AL amyloidosis in 2020.

Abstract: In amyloid light chain (AL) amyloidosis, a small B-cell clone, most commonly a plasma cell clone, produces monoclonal light chains that exert organ toxicity and deposit in tissue in the form of amyloid fibrils. Organ involvement determines the clinical manifestations, but symptoms are usually recognized late. Patients with disease diagnosed at advanced stages, particularly when heart involvement is present, are at high risk of death within a few months. However, symptoms are always preceded by a detectable monoclonal gammopathy and by elevated biomarkers of organ involvement, and hematologists can screen subjects who have known monoclonal gammopathy for amyloid organ dysfunction and damage, allowing for a presymptomatic diagnosis. Discriminating patients with other forms of amyloidosis is difficult but necessary, and tissue typing with adequate technology available at referral centers, is mandatory to confirm AL amyloidosis. Treatment targets the underlying clone and should be risk adapted to rapidly administer the most effective therapy patients can safely tolerate. In approximately one-fifth of patients, autologous stem cell transplantation can be considered up front or after bortezomib-based conditioning. Bortezomib can improve the depth of response after transplantation and is the backbone of treatment of patients who are not eligible for transplantation. The daratumumab+bortezomib combination is emerging as a novel standard of care in AL amyloidosis. Treatment should be aimed at achieving early and profound hematologic response and organ response in the long term. Close monitoring of hematologic response is vital to shifting nonresponders to rescue treatments. Patients with relapsed/refractory disease are generally treated with immune-modulatory drugs, but daratumumab is also an effective option.

Does ABO and RhD matching matter for platelet transfusion

Abstract: Platelets express ABO antigens and are collected in plasma, which contains ABO antibodies as would be consistent with the donor ABO group. Platelet ABO antigens that are incompatible with recipient ABO antibodies may have accelerated clearance from circulation and result in lower count increments. ABO antibodies that are passively transferred from donor plasma may result in hemolysis of recipient red blood cells. Although platelets do not express Rh antigens, they contain small numbers of intact red blood cells or fragments, which can lead to alloimmunization in the recipient. Alloimmunization to the RhD antigen may occur when platelets obtained from RhD-positive donors are transfused to RhD-negative recipients. All of these compatibility considerations must be balanced against the available supply, which may be limited due to the 5- to 7-day shelf life of platelets. This articles describes considerations for platelet ABO and RhD selection for platelet transfusions, including the impact of major ABO incompatibility on count increments, the risks of hemolysis associated with minor ABO incompatibility, and the risk of RhD alloimmunization when RhD-negative patients receive platelets obtained from RhD-positive donors.

Preventing and monitoring for tumor lysis syndrome and other toxicities of venetoclax during treatment of chronic lymphocytic leukemia.

Abstract: Recent developments in the management of chronic lymphocytic leukemia (CLL) have moved the standard of care away from chemoimmunotherapy to targeted agents such as oral kinase inhibitors or BCL-2 antagonists, alone or in combination with anti-CD20 antibodies. Two different treatment approaches have evolved: continuous, indefinite treatment and, more recently, fixed-duration combination treatment. With venetoclax-based treatment, there is a requirement to follow the established guidelines for close monitoring during initiation and ramp up, to reduce the risk of tumor lysis syndrome. The patient's risk should be assessed before the initiation of venetoclax. Appropriate management strategies should be used, including uricosuric agents, hydration, and routine laboratory monitoring, per guidelines. With early identification, immediate management, and dose adjustments, we suggest that tumor lysis syndrome and other toxicities, such as neutropenia and infections, with venetoclax-based treatment can be dealt with successfully.

Management of Waldenström macroglobulinemia in 2020.

Abstract: The management of Waldenstrom macroglobulinemia (WM) has evolved tremendously with recent genomic discoveries that correlate with clinical presentation and could help to tailor treatment approaches. The current diagnosis of WM requires clinicopathological criteria, including bone marrow involvement by lymphoplasmacytic lymphoma cells, a serum immunoglobulin M (IgM) monoclonal paraprotein, and presence of the MYD88 L265P mutation. Once the diagnosis is established, the relationship between the patient's symptoms and WM should be carefully investigated, because therapy should be reserved for symptomatic patients. Bone marrow involvement and serum levels of IgM, albumin, and β2-microglobulin can be used to estimate the time until treatment initiation. The treatment of WM patients should be highly personalized, and the patient's clinical presentation, comorbidities, genomic profile, and preferences, as well as toxicity of the treatment regimens, should be taken into account. Alkylating agents (bendamustine, cyclophosphamide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), anti-CD20 monoclonal antibodies (rituximab, ofatumumab), and Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) are safe and highly effective treatment options in patients with WM. Because novel covalent and noncovalent BTK inhibitors (tirabrutinib, vecabrutinib, LOXO-305, ARQ-531), BCL2 antagonists (venetoclax), and CXCR4-targeting agents (ulocuplumab, mavorixafor) are undergoing clinical development in WM, the future of WM therapy certainly appears bright and hopeful.

Outpatient transfusions for myelodysplastic syndromes.

Abstract: Patients with myelodysplastic syndromes (MDS) often need extended periods of red blood cell or platelet transfusion support, with the goal to manage symptoms of anemia and thrombocytopenia, respectively, and improve quality of life. Many questions about the optimal approach to transfusion management in MDS, especially in the outpatient setting, remain unanswered, including hemoglobin and platelet thresholds for transfusion. Restrictive transfusion approaches are often practised, but whether these are appropriate for outpatients with MDS, who are often older and may be frail, is not known. Current schedules for transfusion-dependent patients are burdensome, necessitating frequent visits to hospitals for sample collection and blood administration. Questions of optimal schedule and dosage are being explored in clinical trials, including the recently completed REDDS study. Patient-reported outcomes and functional assessments are increasingly being incorporated into research in this area so that we can better understand and improve transfusion support for patients with MDS.

“TEG talk”: expanding clinical roles for thromboelastography and rotational thromboelastometry

Abstract: Viscoelastic assays (VEAs) that include thromboelastography and rotational thromboelastometry add value to the investigation of coagulopathies and goal-directed management of bleeding by providing a complete picture of clot formation, strength, and lysis in whole blood that includes the contribution of platelets, fibrinogen, and coagulation factors. Conventional coagulation assays have several limitations, such as their lack of correlation with bleeding and hypercoagulability; their inability to reflect the contribution of platelets, factor XIII, and plasmin during clot formation and lysis; and their slow turnaround times. VEA-guided transfusion algorithms may reduce allogeneic blood exposure during and after cardiac surgery and in the emergency management of trauma-induced coagulopathy and hemorrhage. However, the popularity of VEAs for other indications is driven largely by extrapolation of evidence from cardiac surgery, by the drawbacks of conventional coagulation assays, and by institution-specific preferences. Robust diagnostic studies validating and standardizing diagnostic cutoffs for VEA parameters and randomized trials comparing VEA-guided algorithms with standard care on clinical outcomes are urgently needed. Lack of such studies represents the biggest barrier to defining the role and impact of VEA in clinical care.

Future of CAR T cells in multiple myeloma.

Abstract: Despite the significant improvement in survival outcomes of multiple myeloma (MM) over the past decade, it remains an incurable disease. Patients with triple-class refractory MM have limited treatment options and a dismal prognosis. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen has transformed the treatment armamentarium of relapsed/refractory MM (RRMM), with unprecedented overall response rates in this difficult-to-treat patient population. However, a significant proportion of patients ultimately relapse despite achieving deep remission. Several innovative approaches, including alternative/dual-antigen-specific CAR T-cell constructs, genetically engineered "off-the-shelf" CAR T cells, and strategies to counteract an immunosuppressive microenvironment, may dramatically reshape the field of CAR T-cell therapy in the future. These strategies are being actively investigated in preclinical and early clinical trial settings with the hopes of enhancing the durability of responses and, thereby, improving the overall survival of RRMM patients after CAR T-cell therapy.

Inferior vena cava filters: a framework for evidence-based use.

Abstract: Venous thromboembolism (VTE) is a common cause of morbidity and mortality. Although most patients can be managed safely with anticoagulation, inferior vena cava filters (IVCFs) represent an important alternative to anticoagulation in a small subset of patients. IVCF use has expanded exponentially with the advent of retrievable filters. Indications for IVCFs have liberalized despite limited evidence supporting this practice. Because indiscriminate use of IVCFs can be associated with net patient harm, knowledge of the risks and benefits of these devices is essential to optimal evidence-based practice. Patients with acute VTE and absolute contraindications to anticoagulation or major complications from anticoagulation are universally agreed indications for IVCFs. However, the reliance on IVCFs for primary VTE prophylaxis in high-risk patients is not substantiated by the available literature. This review examines trends in IVCF use, practice-based recommendations on IVCF use in various clinical scenarios, complications associated with indwelling IVCFs, and indications for IVCF retrieval.

Distribution of sickle cell disease and assessment of risk factors based on transcranial Doppler values in the Gulf region.

Abstract: Background/Objective: Stroke is a potentially fatal complication of sickle cell disease (SCD). Transcranial Doppler (TCD) is useful at identifying increased risk of stroke in children with SCD and ...

Epidemiology of aplastic anemia: a study of 1324 cases

Abstract: Objective: Prevalence of aplastic anemia (AA) is high in the Asian population. This study was done to explore the etiology and association of AA with various socio-economic and environmental factor...

Combining antiplatelet and anticoagulant therapy in cardiovascular disease

Abstract: Up to 10% of the >3 million Americans with atrial fibrillation will experience an acute coronary syndrome or undergo percutaneous coronary intervention. Therefore, concurrent indications for multiple antithrombotic agents is a common clinical scenario. Although each helps reduce thrombotic risk, their combined use significantly increases the risk of major bleeding events, which can be life threatening. In the past 5 years, a number of randomized clinical trials have explored different combinations of anticoagulation plus antiplatelet agents aimed at minimizing bleeding risk while preserving low thrombotic event rates. In general, shorter courses with fewer antithrombotic agents have been found to be effective, particularly when direct oral anticoagulants are combined with clopidogrel. Combined use of very low-dose rivaroxaban plus aspirin has also demonstrated benefit in atherosclerotic diseases, including coronary and peripheral artery disease. Use of proton pump inhibitor therapy while patients are taking multiple antithrombotic agents has the potential to further reduce upper gastrointestinal bleeding risk in select populations. Applying this evidence to patients with multiple thrombotic conditions will help to avoid costly and life-threatening adverse medication events.

Does aspirin prevent venous thromboembolism

Abstract: Venous thromboembolism (VTE; deep vein thrombosis and/or pulmonary embolism) is a well-established cause of morbidity and mortality in the medical and surgical patient populations. Clinical research in the prevention and treatment of VTE has been a dynamic field of study, with investigations into various treatment modalities ranging from mechanical prophylaxis to the direct oral anticoagulants. Aspirin has long been an inexpensive cornerstone of arterial vascular disease therapy, but its role in the primary or secondary prophylaxis of VTE has been debated. Risk-benefit tradeoffs between aspirin and anticoagulants have changed, in part due to advances in surgical technique and postoperative care, and in part due to the development of safe, easy-to-use oral anticoagulants. We review the proposed mechanisms in which aspirin may act on venous thrombosis, the evidence for aspirin use in the primary and secondary prophylaxis of VTE, and the risk of bleeding with aspirin as compared with anticoagulation.

First-generation vs second-generation tyrosine kinase inhibitors: which is best at diagnosis of chronic phase chronic myeloid leukemia?

Abstract: In 2020, for the great majority of patients with chronic phase chronic myeloid leukemia (CML), life expectancy is unaffected by a diagnosis of CML because of the unparalleled efficacy of ABL-targeted tyrosine kinase inhibitors (TKIs) in halting disease progression. A wealth of choices exist for first-line treatment selection, including the first-generation TKI imatinib and the second-generation TKIs bosutinib, dasatinib, and nilotinib. How I select first-line therapy between first-generation and second-generation TKIs is discussed in the context of patient-specific CML disease risk, therapy-related risks, and treatment goals. Although rare, identifying patients with CML at higher risk for disease progression or resistance is important and influences first-line TKI selection. I review the impact of first-generation vs second-generation TKI selection on treatment response and outcomes; the ability to achieve, as well as the timing of, treatment-free remission; and the impact of specific TKIs on longer-term health.

LncRNA SNHG4 regulates miR-10a/PTEN to inhibit the proliferation of acute myeloid leukemia cells.

Abstract: Objectives: Long non-coding RNA (lncRNA) small nucleolar RNA host gene 4 (SNHG4) is a characterized oncogenic lncRNA in osteosarcoma. The analysis of the TCGA dataset suggested the downregulation of SNHG4 in acute myeloid leukemia (AML), indicating its possible involvement in this disease. Therefore, this study was performed to analyze the interaction between SNHG4 and miR-10a in AML.Methods: We included 60 patients with AML and 60 healthy participants. Transient transfections, luciferase activity assay, RT-qPCR, CCK-8, and Western blot were used to carry out the research.Results: In this study, we found that SNHG4 was downregulated in AML patients compared to healthy participants. SNHG4 and miR-10a can interact with each other. However, overexpression of SNHG4 and miR-10a failed to affect the expression of each other. Instead, SNHG4 overexpression led to upregulated PTEN, a downstream target of miR-10a. Cell proliferation analysis showed that SNHG4 and PTEN overexpression led to decreased proliferation rates of AML cells and attenuated the enhancing effects of miR-10a on cell proliferation.Conclusion: In conclusion, SNHG4 may regulate miR-10a/PTEN to inhibit the proliferation of AML cells.

Practical approach to monitoring and prevention of infectious complications associated with systemic corticosteroids, antimetabolites, cyclosporine, and cyclophosphamide in nonmalignant hematologic diseases.

Abstract: Corticosteroids constitute a first-line therapy for adults and children suffering from nonmalignant immune-mediated hematologic diseases. However, high disease relapse rates during the tapering period or upon drug discontinuation result in long-term corticosteroid use that increases the risk of infection. This same concept applies to other immunosuppressive agents, such as antimetabolites, calcineurin inhibitors, and cyclophosphamide. Corticosteroids are associated with a length-of-treatment and dose-dependent risk for infection. Screening and antimicrobial prophylaxis against tuberculosis, hepatitis B, Strongyloides stercoralis, and Pneumocystis jirovecii pneumonia (PJP) might be indicated in patients who are scheduled to be on high-dose corticosteroids for >4 weeks (>30 mg of prednisone-equivalent dose [PEQ]) or in patients chronically treated (≥8 weeks of continuous or intermittent corticosteroid use) with moderate doses (≥15 to <30 mg PEQ). Antimetabolites (azathioprine, mycophenolate) increase the risk of progressive multifocal leukoencephalopathy (PML); however, other opportunistic infections and viral reactivation have also been reported. In case of new onset of neurological symptoms, PML needs to be considered, and an urgent neurology consultation should be obtained. Cyclophosphamide-induced myelosuppression can lead to serious infections related to neutropenia. PJP prophylaxis should be considered with combination therapy of cyclophosphamide and corticosteroids until a PEQ dose ≤ 5 mg/d is reached. Data on infectious risk when cyclosporine is used in patients with nonmalignant hematologic diseases are lacking. Discontinuation of any immunosuppressive agent during an episode of infection is recommended. In all patients, adherence to an age-based immunization schedule is appropriate.

The efficacy and adverse events of venetoclax in combination with hypomethylating agents treatment for patients with acute myeloid leukemia and myelodysplastic syndrome: a systematic review and meta-analysis

Abstract: To evaluate the efficacy and adverse effects of venetoclax(VEN) in combination with hypomethylating agents(HMAs) in acute myeloid leukemia(AML) or myelodysplastic syndrome(MDS). Clinical studies we...

Special pre- and posttransplant considerations in inherited bone marrow failure and hematopoietic malignancy predisposition syndromes.

Abstract: Advances in the diagnosis and treatment of inherited bone marrow failure syndromes (IBMFS) have provided insight into the complexity of these diseases. The diseases are heterogeneous and characterized by developmental abnormalities, progressive marrow failure, and predisposition to cancer. A correct diagnosis allows for appropriate treatment, genetic counseling, and cancer surveillance. The common IBMFSs are Fanconi anemia, dyskeratosis congenita, and Diamond-Blackfan anemia. Hematopoietic cell transplantation (HCT) offers curative treatment of the hematologic complications of IBMFS. Because of the systemic nature of these diseases, transplant strategies are modified to decrease immediate and late toxicities. HCT from HLA-matched related or unrelated donors offers excellent survival for young patients in aplasia. Challenges include the treatment of adults with marrow aplasia, presentation with myeloid malignancy regardless of age, and early detection or treatment of cancer. In this article, I will describe our approach and evaluation of patients transplanted with IBMFS and review most frequent complications before and after transplant.

Direct oral anticoagulants for thromboprophylaxis in ambulatory patients with cancer.

Abstract: Background: Venous thromboembolism (VTE) is a common complication in cancer patients. We aim to evaluate the effect and safety of direct oral anticoagulants (DOACs) as primary prophylaxis i...

Donor CMV-specific cytotoxic T lymphocytes successfully treated drug-resistant cytomegalovirus encephalitis after allogeneic hematopoietic stem cell transplantation.

Abstract: Background: Cytomegalovirus (CMV) infection of the central nervous system (CNS) is a rare but life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Cases presentation: Two patients with drug-resistant CMV encephalitis after allo-HSCT were successfully treated with donor CMV-specific cytotoxic T lymphocytes (CTLs). In the first case, a 27-year-old male who received haploidentical transplantation to treat T-cell acute lymphoblastic leukemia (T-ALL), developed CMV encephalitis during the time of the ganciclovir maintenance treatment. After intravenous foscarnet and donor CMV-specific CTLs, CMV-DNA of CSF became undetectable and the abnormal signs of brain magnetic resonance imaging (MRI) were limited. Another case, a 57-year-old female with acute myeloid leukemia (AML) who underwent haploidentical transplantation, also developed CMV encephalitis during the maintenance treatment of the ganciclovir. After administering donor CMV-specific CTLs intrathecally, the CMV load of the CSF decreased.Conclusions: The intravenous/intratheca administration of donor CMV-specific CTLs may be a safe and effective treatment for CMV encephalitis, especially for patients who suffered from drug-resistant CMV infection.