American journal of blood research最新文献

Objectives: Lenalidomide is an active agent in acute myeloid leukemia (AML); response rates are about 15-30%. There are no well-defined predictive factors for benefit from lenalidomide in AML. One of the mechanisms of lenalidomide is natural killer (NK) cell activation; hence human leukocyte antigen (HLA) class I alleles (serving as killer immunoglobulin-like receptor ligands) could play a predictive role. We here evaluate the same when lenalidomide was used as a bridge to transplant.

Methods: Consecutive AML patients started on lenalidomide as bridge to transplant between Aug-2013 to Aug-2018 were included in this single centre retrospective analysis. The starting dose and schedule of lenalidomide were at the discretion of the treating clinician. Lenalidomide was scheduled to be stopped about 2-4 weeks prior to planned transplant admission (or was stopped earlier if there was intolerance). For this study, event was defined as progression/relapse while on lenalidomide or within 4 weeks of stopping the drug. The primary endpoint was event free survival (EFS). Those who underwent transplant without an event were censored on the day of transplant. Toxicities and post-transplant outcomes were secondary endpoints.

Results: Twelve patients (8 males, median age 29 years) were included. At start of lenalidomide, 7 had complete remission (CR)-1 (measurable residual disease or MRD by flow cytometry was positive in 3, negative in 3, and 1 unknown), 4 CR-2 (all MRD negative) and 1 active disease. In the whole cohort, median EFS was not reached with projected 3 year EFS being 80%. There was a significantly reduced risk of event with HLA A*24 (0% vs 75%, P=0.018) or with HLA B*40 (0% vs 60%, P=0.045). Only 1 patient needed discontinuation due to toxicities (cytopenias). Among patients who underwent transplant, grade II-IV acute graft versus host disease (GVHD) was seen in 83%.

Conclusions: This is first study to show that HLA alleles may have a bearing on the effect of lenalidomide in AML and could serve as predictive biomarkers. These findings need to be confirmed in larger prospective studies.

Acute myeloid leukemia (AML), although genetically and morphologically distinct from other B and T cell ALL subtypes, has one of the most rapidly progressing course and worse outcomes. The current diagnostic classification of AML offers best curative intent, the outcomes are not usually those that are expected at the start of therapy. This is partly attributed to the complex mechanism of leukemogenesis and resistance to chemotherapy. The underlying genetic mechanism of resistance is as complex as is the disease etiopathogenesis. Recent advances in therapy of drug resistant AML highlight the role of epigenetic targets. New FDA approved targeted therapy has also provided some evidence at improving outcomes in clinical trials. This review provides a detailed review of FDA approved targets and ongoing clinical trials for targeting CRISPER, CAR-T and other intestinal modalities for approach to epigenetictargets. However, this group of epigenetic targeted therapy needs more validation to prove its clinical efficacy. A systematic review of all published research on these targets, investigational agents and FDA approved targeted therapy summarizes this evidence. It also takes us through a brief review of mechanism of action and targets for therapy.

Background: Fanconi anemia is an inherited bone marrow failure syndrome characterized by somatic abnormalities and an increased predisposition to malignancies.

Objective: To determine the clinical spectrum and evaluate the hematological parameters as well as highlight diagnosis by chromosomal breakage analysis of Fanconi anemia patients.

Material and methods: A total of 124 patients were diagnosed as having Fanconi anemia from August 2014 to May 2020 at Armed Forces Institute of Pathology, Rawalpindi, Pakistan. Clinical details, somatic abnormalities, radiological findings, lab parameters and result of chromosomal breakage analysis were noted and analyzed.

Results: One hundred and twenty four (14.29%) were diagnosed as having Fanconi anemia (FA) on chromosomal breakage test. Median age was 09 years 06 months. Male to female ratio was 1.9:1. Six of these patients exhibited mosaicism and were classified as FA mosaic. Somatic abnormalities were detected in 74 (59.7%) patients; the most common being skeletal abnormalities and short stature.

Conclusion: Chromosomal breakage analysis is a cost-effective method for diagnosis of Fanconi anemia. Early diagnosis is pertinent for proper treatment and long term prognosis.

The prognosis of patients with relapsed Early Thymic Precursor acute lymphoblastic leukemia (ETP-ALL) remains poor. Unlike B cell Precursor-ALL (BCP-ALL), there are no approved targeted therapies for ETP-ALL. Recent studies have identified a consistent expression of CD38 on the blasts of patients with T-ALL (both ETP-ALL and non ETP-ALL). Pre-clinical studies indicate that CD38 expression persists on the blasts of T-ALL even after receipt of conventional chemotherapy. These findings make CD38 an attractive targetable surface protein for patients with relapsed refractory T-ALL. We were the first to describe the clinical use of daratumumab in a patient of ETP-ALL, with relapsed disease post allogeneic transplant. We describe here the long term outcome of this patient more than 3 years after starting single agent daratumumab.

Acute myeloid leukemia (AML) is a complex, aggressive myeloid neoplasm characterized by frequent somatic mutations that influence different functional categories' genes, resulting in maturational arrest and clonal expansion. AML can arise de novo (dn-AML) or can be secondary AML (s-AML) refers to a leukemic process which may arise from an antecedent hematologic disorder (AHD-AML), mostly from a myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) or can be the result of an antecedent cytotoxic chemotherapy or radiation therapy (therapy-related AML, t-AML). Clinical and biological features in secondary and therapy-related AML are distinct from de novo AML. Secondary and therapy-related AML occurs mainly in the elderly population and responds worse to therapy with higher relapse rates due to resistance to cytotoxic chemotherapy. Over the last decade, advances in molecular genetics have disclosed the sub-clonal architecture of secondary and therapy-related AML. Recent investigations have revealed that cytogenetic abnormalities and underlying genetic aberrations (mutations) are likely to be significant factors dictating prognosis and critical impacts on treatment outcome. Secondary and therapy-related AML have a poorer outcome with adverse cytogenetic abnormalities and higher recurrences of unfavorable mutations compared to de novo AML. In this review, we present an overview of the clinical features of secondary and therapy-related AML and address the function of genetic mutations implicated in the pathogenesis of secondary leukemia. Detailed knowledge of the pathogenetic mechanisms gives an overview of new prognostic markers, including targetable mutations that will presumably lead to the designing and developing novel molecular targeted therapies for secondary and therapy-related AML. Despite significant advances in knowing the genetic aspect of secondary and therapy-related AML, its influence on the disease's pathophysiology, standard treatment prospects have not significantly evolved during the past three decades. Thus, we conclude this review by summarizing the modern and developing treatment strategies in secondary and therapy-related acute myeloid leukemia.

Introduction: Hemophilia A (HA) is an inherited deficiency in blood coagulation factors. Starting the treatment based merely on patients' hemorrhage feelings results in more than 63.6% mistakes in joint bleeding diagnosis. This study aimed to design a useful ambulatory service model for Patients With Severe Hemophilia A (PWSHA).

Methods: This study was done in 3 steps. In step-I, the current service model to PWSHA in Tehran was evaluated. In step II, an ambulatory service model was proposed according to the existed gaps and their requirement. In step III, the model's acceptability was assessed from the perspective of clinicians, PWSHA, and healthcare policymakers.

Results: There were 1660 PWSHA in Tehran in 2018. The average use of Factor VIII (FVIII) was 44814 IU in Iran. The yearly budget of FVIII in Tehran was 10,627,320 US$ in 2018. We proposed a home care model with five care centers in Tehran. Ten caregivers and three hematologists for each care center were suggested to cover all services per day. The extracted data indicated that the total service demand would be 39 for each center per day. The results of the questionnaires in all groups were supportive and cooperative.

Conclusion: The current service delivery model to PWSHA has significant economic and clinical defects. Implementing our model can significantly improve the efficiency of bleeding management in PWSHA. Most of the PWSHA, healthcare managers, and clinicians were satisfied with the proposed model.

Granulocyte colony-stimulating factors (G-CSFs) have been used post hematopoietic stem cell transplant (HSCT) for earlier neutrophil engraftment. The use of G-CSFs, and their effect on other post-HSCT outcomes remains debatable. In this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane library, Google Scholar, and IndMed using a predefined search strategy. We included randomized controlled trials (RCTs) and non-randomized studies (NRSs) reporting data on G-CSF administration post-HSCT, published in the English language from their inception until Jan 31, 2021. The primary outcome of this systematic review and meta-analysis was to evaluate the time to neutrophil engraftment (NE). The secondary outcomes were probability of NE, time to platelet engraftment (PE), the incidence of graft-versus-host disease (GVHD), duration of hospital stay (HS), and overall survival (OS). The review is registered with PROSPERO (CRD42020206989). Fourteen studies were extracted (n=9850), of which five were RCTs, and nine were NRSs. As per Egger's test, publication bias was not present for any outcome. After meta-analysis, we found that the duration of NE favouring G-CSF arm from RCTs was -0.94 days (SMD) [(95% CI: -1.38, -0.51); I²=35%], and from NRSs -1.2 days (SMD) [(95% CI: -1.43, -0.96); I²=74%]. For the outcome of GVHD, the relative risks (RR) of incidence for chronic GVHD and overall GVHD were not significant for the RCTs, and these were 1.11 (RR) [(95% CI: 1.00, 1.22); I²=43%] and 1.10 (RR) [(95% CI: 1.03, 1.18); I²=48%], respectively for NRSs. There was no difference in the incidence of GVHD (acute or chronic) in both arms. No significant difference was found between the two arms for the outcomes of PE, HS, and OS. For NE, there was a marginal benefit of around one day with the use of G-CSF. The use of G-CSF did not alter time to PE, the incidence of GVHD, HS, and OS in both arms.

Purpose: The role of platelets in the pathogenesis of hypertension is not well known. The aim of this study was to ascertain if patients with immune thrombocytopenia (ITP) had different rates of hypertension.

Materials and methods: Using the Nationwide Inpatient Sample (NIS) database, we analyzed the correlation between hypertension and ITP from the years 2002-2011.

Results: We found no significant differences in the rate of hypertension between ITP and Non-ITP patients. For instance, in 2002, 25.90% of patients with ITP had a concurrent diagnosis of hypertension, compared with 26.53% of Non-ITP patients. Then in 2011, 31.95% of patients with ITP had a concurrent diagnosis of hypertension, compared with 32.31% of Non-ITP patients.

Conclusion: Based on our large database, the presence of ITP does not appear to be associated with an increased or decreased risk of hypertension.

TP53 gene mutations are common in Myelodysplastic Syndromes (MDS) with del5q and have a clinical and prognostic significance. Next Generation Sequencing (NGS) is an accurate, but expensive, technique, and not commonly available. Immunohistochemistry (IHC) for TP53 expression has been recently used as a surrogate to assess TP53 mutations. To compare the concordance between TP53 expression in IHC and TP53 mutations by NGS, 30 cases with MDS harbouring a del5q abnormality were evaluated. Overall, 10/30 patients (33.3%) had TP53 mutations by NGS, while 16/29 (55.1%) had TP53 overexpression in IHC. TP53 expression by IHC had a 70% sensitivity to identify patients with TP53 mutation by NGS, but its specificity was low (52.6%, kappa = 0.198; P = 0.24). In addition, ROC curve analyses showed that the overall diagnostic value (accuracy) of TP53 expression in IHC to identify patients with TP53 mutation by NGS was 68% in the whole study sample and 67% in patients with isolated del5q-. In both cases, the areas under the curves did not attain the statistical significance (P = 0.11 and P = 0.29, respectively). Based on the ROC curve, the cut-off of 2.3% TP53 expression in IHC was shown to be the best cut-off to identify TP53 mutations: using this cut-off, the agreement between TP53 expression and TP53 mutation by NGS reached statistical significance (kappa = 0.42; P = 0.023). In conclusion, the agreement between TP53 expression in IHC and TP53 mutation analysis by NGS is rather unsatisfactory in MDS patients with del5q at the standard cut-off. Thus, the IHC technique cannot be considered a valid alternative to NGS evaluation of TP53 mutational status in these patients.

Introduction: PCSK9 inhibitors (PCSK9i) are often used in statin-intolerant patients, aiming to reduce low-density lipoprotein cholesterol (LDL-C). Along with the growing experience with their use, there is a lack of evidence regarding the safety, tolerability, and clinical utility of PCSK9i in patients with markedly elevated creatine phosphokinase (CPK) levels.

Methods: We screened a comprehensive HMO database for patients treated with PCSK9i (Jan 2016-Dec 2019), in whom elevated CPK levels (>1,000 U/L) were documented prior to the initiation of therapy. Treatment plans, adherence, and the levels of CPK and LDL-C were analyzed.

Results: Of the 1,600 patients initiating treatment with PCSK9i, 26 had prior CPK values >1,000 U/L [median (IQR): 3,687 (1,876-8,344) U/L]. All 26 patients were previously treated with statins, which presumably resulted in adverse effects (myalgia in 24, and rhabdomyolysis in 5 patients) therefore mandating their discontinuation. Concomitant secondary factors for CPK elevation were present in 11 patients, and included renal failure, rheumatoid disorders, hypothyroidism, intensive exercise, proteinuria and genetic muscular disease. Of the 26 patients treated with PCSK9i, alirocumab was administered to 12 patients, and evolocumab to 14. Following the initiation of treatment with either drug, 24 patients (92%) demonstrated a reduction in CPK of >50%, and in 12 (46%) CPK levels have returned to normal values. With regard to treatment goals, 17 patients (65%) have achieved an LDL-C level of <70 mg/dL, and 12 (46%) have reached a level of <55 mg/dL. No serious adverse reactions were documented, and only 2 patients discontinued the treatment (not due to muscle symptoms or CPK elevation).

Conclusions: PCSK9i constitute a safe, tolerable, and effective treatment for hyperlipidemia in patients with markedly elevated CPK. While statin intolerance is a major cause for CPK elevation, concomitant etiologies for increased CPK values were rather common.