Reduced dose pentostatin for initial management of hairy cell leukemia patients who have active infection or risk of hemorrhage is safe and effective

Andritsos, Leslie A.; Dunavin, Neil; Lozanski, Gerard; Jones, Jeffrey A.; Blachly, James S.; Lucas, David M.; Byrd, John C.; Kraut, Eric H.

doi:10.3324/haematol.2014.113290

Cited by 12 publications

(9 citation statements)

References 14 publications

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“…This association is further reinforced by the reports of low neutrophil counts among patients treated with cladribine (2-chloro-29-deoxyadenosine) or pentostatin (29-deoxycoformycin), which are potent ADA inhibitors used for T-cell suppression and hairy cell leukemia. 6 Our study has several important clinical implications. ADA deficiency should be considered in infants presenting with SCID and neutropenia.…”

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confidence: 83%

“…Additional research-level genetic testing at a central laboratory (J. Puck, UCSF) is also available, as described in full elsewhere. 6 Unbiased, population-wide NBS for SCID in the United States has facilitated an improved understanding of the true incidence of SCID, which affects 1 in 58,000 (95% CI, 1 in 46,000-80,000) newborns, 3 though this may be much higher in certain populations, such as the Navajo (1 in 2000 newborns). 7 Based on approximately 4.4 million births per year in the United States and Canada (per www.nichd.nih.gov, www.statcan.gc.ca), approximately 76 (range, 55-96) infants will be born with SCID annually.…”

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confidence: 99%

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Neutropenia among patients with adenosine deaminase deficiency

Kim

Pham‐Huy

Grunebaum

2019

Journal of Allergy and Clinical Immunology

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(ADA) is a ubiquitous enzyme important for the degradation and salvage of adenosine (Ado) and deoxyAdo (dAdo). Autosomal-recessive defects that severely disrupt the function of ADA lead to accumulation of purine metabolites, which are toxic for rapidly proliferating cells, such as lymphocytes. 1 Most ADA-deficient patients present in the first year of life with profound T-and B-cell defects, leading to severe combined immunodeficiency (SCID). In addition, ADA-deficient patients frequently suffer from liver, lungs, bone, and other tissues abnormalities. 1 Management of ADA deficiency includes supportive care with antimicrobials such as trimethoprim/ sulfamethoxazole (TMP-SMZ) and immunoglobulins. Enzyme replacement therapy (ERT) with polyethylene-glycol-conjugated ADA can improve purine homeostasis and may serve as a ''bridge'' until patients undergo allogeneic hematopoietic stem cell transplantation (HSCT) or gene therapy (GT). HSCT using healthy HLA-matched or mismatched family-related or unrelated donors can correct the immune and some of the systemic abnormalities. 2 Myelodysplasia has previously been reported among ADA-deficient patients; however, because most patients were after unsuccessful HSCT or GT, the role of the metabolic abnormality was not clear. 3 Here, we tested the hypothesis that ADA deficiency could be directly associated with myeloid abnormalities and neutropenia. We analyzed data from all 20 patients diagnosed at our center

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confidence: 83%

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confidence: 99%

Neutropenia among patients with adenosine deaminase deficiency

Kim

Pham‐Huy

Grunebaum

2019

Journal of Allergy and Clinical Immunology

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“…In the initial studies of this highly effective agent, patients with uncontrolled infection were excluded. 52,53 In contrast, pentostatin has been used effectively in patients with an active infection, 50,54 and reduced doses have been used in patients who are likely to have complications from prolonged myelosuppression. In the absence of infection, cladribine is probably the agent that is used most often.…”

Section: Treatmentmentioning

confidence: 99%

Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia

Grever

Abdel‐Wahab

Andritsos

et al. 2017

Blood

220

290

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Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients

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“…Nevirapine has also been revealed in various in-silico drug screening with the main protease 117,118 . Pentostatin is a purine analog that is widely used as a treatment for hairy cell leukemia 119 . Similar to pentostatin, cladribine is also a therapy for hairy cell leukemia.…”

Section: Resultsmentioning

confidence: 99%

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening and in vitro assays

Gupta

Maciorowski

Zak

et al. 2020

Preprint

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The emergence of SARS/MERS drug-resistant COVID-19 with high transmission and mortality has recently been declared a pandemic. Like all coronaviruses, SARS-CoV-2 is a relatively large virus consisting of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs by identifying potential drugs that are predicted to effectively inhibit critical enzymes. We targeted seven proteins with enzymatic activities known to be essential at different stages of the virus life cycle; PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2’-O-MT. For virtual screening, the energy minimization of a crystal structure of the modeled protein was carried out using the Protein Preparation Wizard1. Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs (n=5903) that are approved by worldwide regulatory bodies. The screening was performed against viral targets using three sequential docking modes (i.e. HTVS, SP, and XP). Our in-silico virtual screening identified ~290 potential drugs based on the criteria of energy, docking parameters, ligand, and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. Top lead from each target pool was further subjected to molecular dynamics simulation using the Desmond module. Herein we report the evaluation of in-vitro efficacy of selected hit drug molecules on SARS-CoV-2 virus inhibition. Among eight molecules included in our evaluation, we found the micromolar inhibitor of protein kinase C isoforms, Bisindolylmaleimide IX (BIM IX), as the most potent inhibitor of SARS-CoV-2 in-vitro. Further, in-silico predicted target validation through enzymatic assays confirmed its interaction with 3CLpro to be the target. Therefore, our data support advancing BIM IX for clinical evaluation as a potential treatment for COVID-19. This is the first study that has showcased the possibility of using bisindolylmaleimide IX to treat COVID-19 through this pipeline.

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Reduced dose pentostatin for initial management of hairy cell leukemia patients who have active infection or risk of hemorrhage is safe and effective

Cited by 12 publications

References 14 publications

Neutropenia among patients with adenosine deaminase deficiency

Neutropenia among patients with adenosine deaminase deficiency

Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening and in vitro assays

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