scholarly journals LC-Q-TOF-MS driven identification of potential degradation impurities of venetoclax, mechanistic explanation on degradation pathway and establishment of a quantitative analytical assay method

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Dhruvisha Pokar ◽  
Amit Kumar Sahu ◽  
Pinaki Sengupta
Keyword(s):  
Drug Product ◽  
Mass Measurement ◽  
Mechanistic Explanation ◽  
Degradation Pathway ◽  
Stability Study ◽  
Lymphocytic Leukemia ◽  
Assay Method ◽  
Increased Risk ◽  
Analytical Assay ◽  
Tof Ms

AbstractVenetoclax is a selective orally active Bcl-2 protein inhibitor very recently approved by USFDA to treat chronic lymphocytic leukemia and other hematological malignancies. Postmarketing surveillance of any drug depends on its acceptability based on risk to benefit ratio. When risk outweighs the benefits, withdrawal of an already marketed drug is warranted. Presence of impurity is the primary cause of increased risk in a drug substance or drug product. With the discovery of newer molecules, it is of great importance to establish advanced analytical techniques for quantification of the drugs as well as their related impurities to address the prospective regulatory queries even if it is already in the market. In this study, a quantitative analytical assay method has been developed and validated for quantification of venetoclax in presence of its degradation impurities. A stress study was performed to examine the stability of the drug in hydrolytic, oxidative, thermolytic and photolytic environments. Venetoclax was found to be prone to degradation in acidic hydrolytic and oxidative stress conditions. Three new degradation impurities have been identified and characterized with the help of LC-Q-TOF-MS with accurate mass measurement and their putative structures have been proposed. Furthermore, for the first time, a possible degradation pathway has been established with mechanistic explanation. Moreover, the analytical method developed in this study will be of immense help for routine analysis of quality control and stability study samples of venetoclax in industry and research laboratories.

scholarly journals Validation of an HPLC Assay Method for Routine QC Testing and Stability Study of Compounded Low-Dose Capsules of Acetylsalicylic Acid

2018 ◽  
Vol 3 (4) ◽  
pp. 199-206
Author(s):  
Nelly Lonca ◽  
Fabienne Maillard ◽  
Géraldine Leguelinel ◽  
Tahmer Sharkawi ◽  
Ian Soulairol
Keyword(s):  
Acetylsalicylic Acid ◽  
Orthophosphoric Acid ◽  
Low Dose ◽  
Stability Study ◽  
Assay Method ◽  
Stability Studies ◽  
Physicochemical Stability ◽  
Hospital Pharmacies ◽  
Provocation Testing ◽  
Low Dosage

Abstract Background The intolerance to Acetylsalicylic Acid (ASA) can be detected by conducting oral provocation testing (OPT), which is to gradually introduce low doses of ASA. To perform this test, hospital pharmacies compound small batches of different low-dosage ASA capsules. This work aims to validate a method for fast HPLC-UV assay that allows routine quality control and physicochemical stability studies of capsules. Methods The chromatographic separation is performed using a C18 column Kinetex (100 A, 50×4.6 mm, 2.6 µm) equipped with a precolumn C18. Separation is achieved using a mobile phase composed of water-acetonitrile-orthophosphoric acid (68:32:0.2 v/v/v) at a flow rate of 0.8 mL/min and UV detection at 237 nm. Results Validation shows that the method was suitable for routine analysis and could be used to perform stability studies. Conclusions The 5, 25, 100 and 250 mg dosed capsules show acceptable stability over 12 months, while the 1 mg dosed capsule show an unacceptable degradation of more than 15 % after 3 months. Therefore, hospital pharmacy can plan the manufacture of capsules and anticipate the requests of doctors.

scholarly journals Could the candidate causal gene (LZTFL1) identified by Oxford University scientists, which doubles the risk of COVID-19-related respiratory failure, be used to boost the Weak immunogenicity of COVID-19 mRNA vaccines in patients with B-cell chronic lymphocytic leukemia (CLL)???. A double edged sward

2021 ◽  
Author(s):  
Mahmoud Ramadan Elkazzaz ◽  
Yousry Esam-Eldin Abo-Amer ◽  
Amr Ahmed ◽  
Tamer Haydara
Keyword(s):  
Respiratory Failure ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Risk Allele ◽  
Lymphocytic Leukemia ◽  
Causal Gene ◽  
Oxford University ◽  
Increased Risk ◽  
University Scientists ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Patients with B-cell chronic lymphocytic leukemia (CLL) have an increased risk of severe infections due to disease- and treatment-related immunodeficiency. As a result, patients with hematologic malignancies have been given priority for primary COVID-19 vaccination. Unfortunately, many studies have suggested that patients with B-cell chronic lymphocytic leukemia (CLL) who have been fully vaccinated can develop severe and often fatal complications. Therefore, adjuvants that can induce mRNA vaccine efficacy are desperately needed for this category of patients with haematological malignancies. A recent, study by Oxford University scientists showed that leucine zipper transcription factor-like 1(LZTFL1), as a candidate causal gene and its enhancer the rs17713054 A risk allele was significantly responsible for the twofold increased risk of respiratory failure from COVID-19 associated with 3p21.31.By using sequence analysis, the risk allele generates a second CCAAT/enhancer binding protein beta (CEBPB) motif in the enhancer. Moreover, neither LZTFL1 variants found in T cells nor B cells are responsible for increasing death risk from COVID-19 infection according to oxford study. Here, we propose attestable hypothesis that trans retinoic acid could enhance the immune response in vaccinated patients with B-cell chronic lymphocytic leukemia (CLL) according to the recent findings of Oxford scientists by inducing the casual gene(LZTFL1) in CD4 T cells and inhibiting (CEBPB) motif.

scholarly journals Concurrent Squamous Cell Carcinoma and Chronic Lymphocytic Leukemia Presenting as an Enlarging Neck Mass

2019 ◽  
Vol 7 ◽  
pp. 232470961984290
Author(s):  
Prabhjot Bhinder ◽  
Michael Chahin ◽  
Lara Zuberi
Keyword(s):  
Squamous Cell Carcinoma ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Neck Mass ◽  
Lymphocytic Leukemia ◽  
Secondary Malignancies ◽  
Increased Risk ◽  
History Of ◽  
Tonsillar Squamous Cell Carcinoma

Chronic lymphocytic leukemia (CLL) patients are at an increased risk for developing more aggressive lymphomas via Richter’s transformation and of developing secondary malignancies. Despite the known association for secondary cancers, oropharyngeal cancers occur rarely. We present a case of a woman with a history of CLL who presented to our facility via transfer for impending airway compromise. Her initial workup was consistent with CLL; however, biopsies were taken of the neck mass because of its aggressive nature. She was treated with rituximab with good response. Final pathology showed evidence of CLL and tonsillar squamous cell carcinoma (SCC). Direct laryngoscopy and further biopsies yielded a diagnosis of unresectable oropharyngeal SCC. She was to be treated with chemotherapy and radiation for her SCC while holding treatment for CLL. This case demonstrates a rare and unexpected concurrent diagnosis.

scholarly journals AIHA and Pancytopenia as Complications of Pembrolizumab Therapy for Metastatic Melanoma: A Case Report

2019 ◽  
Vol 12 (2) ◽  
pp. 456-465 ◽  
Author(s):  
Dan Ni ◽  
Fatmah AlZahrani ◽  
Michael Smylie
Keyword(s):  
Case Report ◽  
Adverse Effects ◽  
Metastatic Melanoma ◽  
Death Receptor ◽  
Tumour Response ◽  
Lymphocytic Leukemia ◽  
Immune Checkpoints ◽  
Immune Mediated ◽  
Successful Recovery ◽  
Increased Risk

Immunotherapy has been an emerging treatment for metastatic melanoma and several other malignancies since 2015. Hematological immune-mediated adverse effects from immunotherapy are rarely reported but they can cause serious harm to patients. Antibodies such as ipilimumab, nivolumab and pembrolizumab target different immune checkpoints to promote T cell anti-tumour response. In particular, pembrolizumab is an antibody that inhibits programmed cell death receptor 1 (PD-1) to upregulate tumour suppression. In this report, we present a case of pembrolizumab-induced autoimmune hemolytic anemia and pancytopenia in a patient who was receiving pembrolizumab treatment for metastatic melanoma. This patient has a history of chronic lymphocytic leukemia and was diagnosed with metastatic melanoma in 2017. He developed symptomatic AIHA and pancytopenia after receiving 8 cycles of pembrolizumab in 2018. Pembrolizumab treatment was discontinued and he was treated with blood transfusion and prednisone. After 5 months of tapering prednisone treatment, his anemia and pancytopenia have improved toward successful recovery. Cancer patients already face an increased risk of immunosuppression with conventional chemotherapy. This case report also summarized all reported cases of PD-1 inhibitor hematological adverse effects in the treatment of oncological diseases. These incidents reflect the risk of immune-mediated hematologic adverse effects, which should be considered in all patients using immunotherapy.

scholarly journals Prognostic Significance of PET/CT in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Frontline Chemoimmunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1773 ◽  
Author(s):  
Marika Porrazzo ◽  
Emanuele Nicolai ◽  
Mara Riminucci ◽  
Candida Vitale ◽  
Marta Coscia ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Chronic Lymphocytic Leukemia ◽  
Negative Impact ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Independent Effect ◽  
Proliferating Cells ◽  
Richter Syndrome ◽  
Increased Risk ◽  
Pet Ct

The role of positron emission tomography/computed tomography (PET/CT) in identifying Richter Syndrome (RS) is well established, while its impact on the survival of patients with chronic lymphocytic leukemia (CLL) has been less explored. The clinical characteristics and PET/CT data of 40 patients with a biopsy-proven CLL who required frontline chemoimmunotherapy, FCR (fludarabine, cyclophosphamide, rituximab) in 20 patients, BR (bendamustine, rituximab) in 20, were retrospectively analyzed. Standardized uptake volume (SUVmax) values ≥ 5 were observed more frequently in patients with deletion 11q (p = 0.006) and biopsies characterized by a rate of Ki67 positive cells ≥ 30% (p = 0.02). In the multivariate analysis, the presence of large and confluent PCs emerged as the only factor with a negative impact on progression-free survival (PFS), and overall survival (OS). Deletion 11q also revealed a significant and independent effect on PFS. SUVmax values ≥ 5 showed no statistical impact on PFS while in multivariate analysis, they revealed a significant adverse impact on OS (median survival probability not reached vs. 56 months; p = 0.002). Moreover, patients with higher SUVmax values more frequently developed Richter Syndrome (p = 0.015). Our results show that higher SUVmax values identify CLL patients with a pronounced rate of proliferating cells in the lymph-node compartment, inferior survival, and an increased risk of developing RS.

scholarly journals Determination of Rosuvastatin in the Presence of Its Degradation Products by a Stability-Indicating LC Method

2005 ◽  
Vol 88 (4) ◽  
pp. 1142-1147 ◽  
Author(s):  
Tushar N Mehta ◽  
Atul K Patel ◽  
Gopal M Kulkarni ◽  
Gunta Suubbaiah
Keyword(s):  
Degradation Products ◽  
Stability Study ◽  
Tablet Formulation ◽  
Assay Method ◽  
Forced Degradation ◽  
Degradation Study ◽  
Stability Indicating ◽  
Degraded Samples ◽  
Accelerated Stability

Abstract A forced degradation study was successfully applied for the development of a stability-indicating assay method for determination of rosuvastatin Ca in the presence of its degradation products. The method was developed and optimized by analyzing the forcefully degraded samples. Degradation of the drug was done at various pH values. Moreover, the drug was degraded under oxidative, photolytic, and thermal stress conditions. Mass balance between assay values of degraded samples and generated impurities was found to be satisfactory. The proposed method was able to resolve all of the possible degradation products formed during the stress study. The developed method was successfully applied for an accelerated stability study of the tablet formulation. The major impurities generated during the accelerated stability study of the tablet formulation were matches with those of the forced degradation study. The developed method was validated for determination of rosuvastatin Ca, and the method was found to be equally applicable to study the impurities formed during routine and forced degradation of rosuvastatin Ca.

scholarly journals Chronic lymphocytic leukemia (CLL) risk is mediated by multiple enhancer variants within CLL risk loci

2020 ◽  
Vol 29 (16) ◽  
pp. 2761-2774
Author(s):  
Huihuang Yan ◽  
Shulan Tian ◽  
Geffen Kleinstern ◽  
Zhiquan Wang ◽  
Jeong-Heon Lee ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Immune Cell ◽  
Association Studies ◽  
Cell Types ◽  
Lymphocytic Leukemia ◽  
Type I ◽  
Genome Wide Association Studies ◽  
Gene Promoters ◽  
Functional Variants ◽  
Increased Risk

Abstract Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. It has a strong genetic basis, showing a ~ 8-fold increased risk of CLL in first-degree relatives. Genome-wide association studies (GWAS) have identified 41 risk variants across 41 loci. However, for a majority of the loci, the functional variants and the mechanisms underlying their causal roles remain undefined. Here, we examined the genetic and epigenetic features associated with 12 index variants, along with any correlated (r2 ≥ 0.5) variants, at the CLL risk loci located outside of gene promoters. Based on publicly available ChIP-seq and chromatin accessibility data as well as our own ChIP-seq data from CLL patients, we identified six candidate functional variants at six loci and at least two candidate functional variants at each of the remaining six loci. The functional variants are predominantly located within enhancers or super-enhancers, including bi-directionally transcribed enhancers, which are often restricted to immune cell types. Furthermore, we found that, at 78% of the functional variants, the alternative alleles altered the transcription factor binding motifs or histone modifications, indicating the involvement of these variants in the change of local chromatin state. Finally, the enhancers carrying functional variants physically interacted with genes enriched in the type I interferon signaling pathway, apoptosis, or TP53 network that are known to play key roles in CLL. These results support the regulatory roles for inherited noncoding variants in the pathogenesis of CLL.

Treatment with Fludarabine and Rituximab Produces Extended Overall Survival (OS) and Progression-Free Survival (PFS) in Chronic Lymphocytic Leukemia (CLL) without Increased Risk of Second Malignancy: Long-Term Follow up of CALGB Study 9712.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 539-539 ◽  
Author(s):  
Jennifer A Woyach ◽  
Amy S Ruppert ◽  
Nyla A. Heerema ◽  
Bercedis Peterson ◽  
John G. Gribben ◽  
...  
Keyword(s):  
Single Agent ◽  
Progression Free Survival ◽  
Large Cell ◽  
Lymphocytic Leukemia ◽  
Published Data ◽  
Increased Risk ◽  
Long Term Follow Up ◽  
Sequential Group

Abstract Abstract 539 Introduction: The addition of rituximab to fludarabine-based regimens in CLL has been shown to produce high response rates with extended remissions. The long-term follow-up of these regimens with respect to progression, survival, and development of secondary malignancies has been limited. Patients and Methods: We report the long-term follow up of the chemoimmunotherapy trial CALGB 9712 (Blood 2003;101:6-14). This trial randomized 104 untreated, symptomatic patients to receive either 6 monthly cycles of fludarabine plus rituximab (FR) followed 2 months later by 4 weekly doses of rituximab (concurrent arm) or 6 monthly cycles of single agent fludarabine followed by rituximab consolidation using 4 weekly doses (sequential arm). With a median follow up of 92 months (range: 60-107), we analyzed the updated CALGB database and flow sheets submitted by treating physicians. Results: The overall response rate (ORR) was 84% (95% CI: 77%-91%), with a 90% ORR in the concurrent group (95% CI: 82%-98%) and a 77% ORR in the sequential group (95% CI: 66%-89%). Complete response (CR) was seen in 38% of patients (95% CI: 30%-45%), and partial response (PR) in 46% (95% CI: 38%-54%). The median OS was 85 months (95% CI: 71-95), with 71% of patients alive at 5 years (95% CI: 61%-79%). The median PFS was 37 months (95% CI: 27-45), with 27% progression-free at 5 years (95% CI: 19%-36%). With long-term follow up, the estimated median OS and PFS for the concurrent group were 84 months (95% CI: 57-100) and 32 months (95% CI: 23-55), respectively; the median OS and PFS for the sequential group were 91 months (95% CI: 71-110) and 40 months (95% CI: 23-50), respectively. Patients with del(17p13.1)/del(11q22.3)(18 patients) and unmutated IgVH(43 patients) continue to have an inferior OS (P=0.01 and P=0.04, respectively) and PFS (P=0.03 and P=0.04, respectively) compared to those without these abnormalities. We next assessed the frequency of therapy-related myeloid neoplasms (t-MN) and other cancers occurring after this chemoimmunotherapy regimen. No patient has developed MDS or AML prior to relapse. One patient (1%) developed t-MDS following relapse and receipt of FCR 41 months after completing trial therapy; t-MDS was diagnosed 9 months later. Richter's transformation was noted in three (3%) of the CALGB 9712 patients with large cell (n=2) or Hodgkin lymphoma (n=1). Second malignancies have included localized basal cell or squamous cell skin cancer in 12 (12%) patients whereas 11 (11%) have developed other epithelial malignancies including 4 GI, 3 lung, 3 melanomas, and 1 prostate cancer. Conclusions: Long-term follow up of patients enrolled on CALGB 9712 demonstrates extended OS and PFS with fludarabine plus rituximab, given either concurrently or sequentially, with an estimated 17%(95% CI: 9%-27%) of responders still in remission 8 years later. Looking at other published data, patients treated with FR administered concurrently or sequentially do not appear to have an increased risk of t-MN or second cancers. These long-term data reaffirm that FR is one of several acceptable frontline treatments for symptomatic patients with CLL. Disclosures: Morrison: Genentech: Speakers Bureau.

Acute Lymphocytic Leukemia and Down Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-8-SCI-8
Author(s):  
Shai Izraeli
Keyword(s):  
Down Syndrome ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Mtor Inhibitors ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Aberrant Expression ◽  
Childhood All ◽  
Increased Risk ◽  
The Common

Abstract SCI-8 Children with Down syndrome are at a markedly increased risk for acute lymphoblastic leukemia (DS-ALL). These leukemias are exclusively of the B lymphoid precursor phenotype and occur in a similar age to “common” sporadic ALLs with the striking absence of infant ALL. Recent studies reveal that DS-ALLs are heterogeneous and differ from sporadic ALLs. Only about a fifth of DS-ALLs carry the common cytogenetic aberrations typical to childhood ALL. Genomic rearrangements leading to the expression of a cytokine receptor, CRLF2, are detected in 60% of DS-ALL in comparison with up to 10% of sporadic ALLs. CRLF2 heterodimerizes with Interleukin 7 receptor-α (IL7R) to form the receptor to thymic stromal lymphopoietin (TSLP). This receptor is usually present in macrophages, dendritic cells, and some T lymphocytes and participates in allergic and inflammatory processes. The aberrant expression of the TSLP receptor is DS-ALL (and sporadic ALL) is often associated with additional mutations that cause constitutive activation of the downstream JAK-STAT and mTOR growth signaling pathways. These are either lymphoid specific activating mutations of JAK2 or JAK1 or mutations in CRLF2 or IL7R that cause ligand-independent receptor dimerization. The role of the trisomy in selecting these somatic abnormalities is presently unknown. Clinically, the prognosis of DS-ALL is inferior to sporadic ALL mainly because of increased treatment toxicity. However, recent data suggest that the inferior outcome may also be related to the genetic properties of the leukemic cells and that excessive chemotherapy dose reduction may not be appropriate for these patients. Therefore increased vigilance for infectious complications and optimal supportive care are required during periods of intensive chemotherapy. The common activation of the TSLP signaling pathway in DS-ALLs suggests a future for targeted therapy with JAK and/or mTOR inhibitors. Importantly, research of DS-ALL has proven relevant for the general patient population with ALL, as somatic mutations in the TSLP pathway have been discovered in children and adults with sporadic ALL. A major research challenge is the elucidation of the roles of constitutional and somatic trisomy 21 in leukemogenesis. Disclosures: No relevant conflicts of interest to declare.

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