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British Journal of Haematology May 2017Patients with hairy cell leukaemia (HCL) have highly favourable outcomes after purine analogue therapy. However, most patients subsequently relapse and require... (Review)
Review
Patients with hairy cell leukaemia (HCL) have highly favourable outcomes after purine analogue therapy. However, most patients subsequently relapse and require re-treatment. A minority of patients develop purine analogue-refractory disease. Targeted therapies have improved outcomes for such patients. Recently, the BRAF V600E mutation was identified in most patients with classical HCL, resulting in constitutive mitogen-activated protein kinase pathway activation; impressive responses are achieved in heavily pre-treated patients with BRAF inhibition. The CD22-targeted immunoconjugate moxetumomab pasudotox and BTK inhibitor ibrutinib also achieve responses in relapsed and refractory patients. HCL variant and the IGHV4-34 molecular variant of HCL lack BRAF mutation and have inferior outcomes with standard purine analogue therapy. The addition of rituximab to purine analogues achieves very high rates of minimal residual disease-negative complete remission and improves outcomes for patients with HCL variant. Given the rarity of HCL, optimal integration of novel therapies into treatment algorithms will require well-designed, collaborative studies.
Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cladribine; Diagnosis, Differential; Humans; Immunologic Factors; Interferon-alpha; Leukemia, Hairy Cell; Mutation; Opportunistic Infections; Pentostatin; Proto-Oncogene Proteins B-raf; Purine Nucleosides; Rituximab; Social Support; Splenectomy; Treatment Outcome
PubMed: 28146266
DOI: 10.1111/bjh.14524 -
Oncology (Williston Park, N.Y.) Jun 2000Pentostatin (Nipent) has demonstrated significant activity as a single agent in patients with low-grade B- and T-cell lymphomas, but thus far, clinical experience with... (Review)
Review
Pentostatin (Nipent) has demonstrated significant activity as a single agent in patients with low-grade B- and T-cell lymphomas, but thus far, clinical experience with combinations of pentostatin and other agents is limited. A study of alternating administration of pentostatin and high-dose interferon-alfa-2a (Roferon A) in cutaneous T-cell lymphoma patients has been undertaken and has demonstrated a 41% response rate, with tolerable toxicity. Studies combining pentostatin with alkylating agents, including chlorambucil (Leukeran) and cyclophosphamide (Cytoxan, Neosar) in patients with chronic lymphocytic leukemia (CLL) have reported significant immunosuppression and have required dose modifications of one or both agents. Recently, a clinical trial was initiated to evaluate the combination of pentostatin and cordycepin, a novel purine analog, in patients with terminal deoxynucleotidyl transferase-positive acute lymphocytic leukemia, based on in vitro data demonstrating the significant synergy of this combination.
Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Deoxyadenosines; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Interferons; Lymphoma, B-Cell; Lymphoma, T-Cell; Male; Middle Aged; Pentostatin; Purine Nucleosides; Treatment Outcome; Vidarabine
PubMed: 10887642
DOI: No ID Found -
Current Opinion in Hematology Nov 2011This article summarizes recent reports on the risks, pathogenesis and treatment of chronic graft-versus-host disease (GVHD). (Review)
Review
PURPOSE OF REVIEW
This article summarizes recent reports on the risks, pathogenesis and treatment of chronic graft-versus-host disease (GVHD).
RECENT FINDINGS
Chronic GVHD remains an elusive disorder to characterize and to treat. Recent evidence on tolerance induction by regulatory T-cells and on B-cell involvement shed some insights into the pathogenesis of chronic GVHD. In a recent large comparative study, the overall risk profiles for acute and for chronic GVHD were similar, but risk factors were not changed after adjustment for prior acute GVHD, supporting the concept that chronic GVHD is not an end stage of acute GVHD. Glucocorticoids remain the standard initial treatment of chronic GVHD, but the outcomes are not satisfactory, particularly for patients with high-risk features. Many treatments for chronic GVHD including extracorporeal photopheresis, rituximab, sirolimus, mycofenolate mofetil, imatinib, pentostatin and infusion of mesenchymal stem cells have been reported in several retrospective and relatively small phase I/II studies with a wide range of overall responses.
SUMMARY
No current therapies used for chronic GVHD have been approved by the US Food and Drug Administration. Large well designed prospective studies are warranted to establish better treatments. Targeted therapies based on the pathogenesis of chronic GVHD may lead to better outcomes.
Topics: Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Immunosuppressive Agents; Photopheresis; Risk Factors
PubMed: 21912257
DOI: 10.1097/MOH.0b013e32834ba87d -
British Journal of Haematology May 2019In a prospective phase II trial, pentostatin combined with cyclophosphamide and rituximab (PCR) induced strong responses and was well-tolerated in previously untreated... (Randomized Controlled Trial)
Randomized Controlled Trial
In a prospective phase II trial, pentostatin combined with cyclophosphamide and rituximab (PCR) induced strong responses and was well-tolerated in previously untreated patients with advanced-stage, indolent non-Hodgkin lymphoma (iNHL). After a median patient follow-up of more than 108 months, we performed an intent-to-treat analysis of our 83 participants. Progression-free survival (PFS) rates at 108 months for follicular lymphoma (FL), marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL) were 71%, 67% and 15%, respectively, and were affected by clinicopathological characteristics. Ten-year PFS rates for those with beta-2-microglobulin levels <2·2 and ≥2·2 mg/l prior to treatment were 71% and 21%, respectively. Patients without bone marrow involvement had 10-year PFS rates of 72% vs. 29% for those with involvement. At time of analysis, the median overall survival (OS) had not been reached. The OS rate was 64% at 10 years and differed significantly based on histology: 94% for FL, 66% for MZL and 39% for SLL. Long-term toxicities included 18 (21·7%) patients with second malignancies and 2 (2·4%) who developed myelodysplastic syndrome after receiving additional lines of chemotherapy. Our 10-year follow-up analysis confirms that PCR is an effective, robust and tolerable treatment regimen for patients with iNHL.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Cyclophosphamide; Disease Progression; Disease-Free Survival; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasms, Second Primary; Pentostatin; Rituximab; Treatment Outcome
PubMed: 30820940
DOI: 10.1111/bjh.15814 -
Best Practice & Research. Clinical... Dec 2015This brief review highlights the sequence of therapeutic milestones and advances in our understanding of the biology of hairy cell leukemia (HCL) with a focus on recent... (Review)
Review
This brief review highlights the sequence of therapeutic milestones and advances in our understanding of the biology of hairy cell leukemia (HCL) with a focus on recent molecular findings and how these may be applied to improve disease outcomes in the future. Targeted therapy is discussed in the context of the recently identified BRAF mutation and other genetic findings.
Topics: Antineoplastic Agents; B-Lymphocytes; Cladribine; Disease Management; History, 20th Century; History, 21st Century; Humans; Immunotoxins; Indoles; Leukemia, Hairy Cell; Mutation; Pentostatin; Proto-Oncogene Proteins B-raf; Remission Induction; Rituximab; Splenectomy; Sulfonamides; Survival Analysis; Vemurafenib
PubMed: 26614906
DOI: 10.1016/j.beha.2015.10.015 -
Cancer Control : Journal of the Moffitt... Jan 1998BACKGROUND: T-cell prolymphocytic leukemia (T-PLL) is a post-thymic T-cell malignancy with aggressive clinical course. Although T-PLL has been referred to under...
BACKGROUND: T-cell prolymphocytic leukemia (T-PLL) is a post-thymic T-cell malignancy with aggressive clinical course. Although T-PLL has been referred to under different designations, it is a distinct clinico-biological entity and should be distinguished from other T-cell disorders. METHODS: The literature on T-PLL is reviewed. Experience on the clinical and laboratory features, differential diagnosis, and therapy on a large series of T-PLL patients is presented. RESULTS: T-PLL affects adults and occurs more frequently in men. The principal disease characteristics are organomegaly, skin lesions, and a raised lymphocyte count. Immunological markers show a post-thymic T-cell phenotype (TdT- CD2+ CD5+ CD3ñ) with strong expression of CD7. A CD4+ CD8- phenotype is seen in two thirds of cases. CD4 and CD8 are coexpressed in 25%, and a CD4- CD8+ phenotype is rare. Cytogenetics show a recurrent abnormality inv(14)(q11;q32) that is always associated to other aberrations (particularly iso8q or trisomy 8). Differential diagnosis between T-PLL and other T-cell malignancies is based on a constellation of clinical and laboratory features. Generally, T-PLL patients are refractory to the therapy used in lymphoid disorders. Median survival is short but is improving with the use of 2'-deoxycoformycin and the humanized monoclonal antibody, anti-CDw52 (Campath-1H). CONCLUSIONS: T-PLL is a distinct T-cell disorder with characteristic clinical and laboratory features and a poor prognosis. A precise diagnosis of this disease is important in determining patient management and treatment.
PubMed: 10761013
DOI: 10.1177/107327489800500102 -
Journal of Clinical Pathology Feb 1985This report summarises the current knowledge regarding the clinical utility of biochemical enzyme markers for both diagnostic and therapeutic purposes in acute... (Review)
Review
This report summarises the current knowledge regarding the clinical utility of biochemical enzyme markers for both diagnostic and therapeutic purposes in acute leukaemia. The enzymes studied most extensively in this field are terminal deoxynucleotidyl transferase, adenosine deaminase, 5'-nucleotidase, purine nucleoside phosphorylase, and acid phosphatase, esterase, hexosaminidase isoenzymes. For each enzyme, the quantitative and qualitative characteristics in various immunologically defined subclasses of acute leukaemia are described. The quantitative evaluation of enzyme activities represents an adjunctive classification technique which should be incorporated into the multivariate analysis, the "multiple marker analysis." By qualitative characterisation pronounced heterogeneity of leukaemia subsets is uncovered. The application of 2'-deoxycoformycin, a specific inhibitor of adenosine deaminase, and the potential usefulness of two other enzymes as targets for treatment with selective agents is discussed. The concept that gene products expressed at certain developmental stages of normal cells can similarly be detected in leukaemic cells (which therefore seem to be "frozen" or "arrested" at this particular maturation/differentiation stage) is supported by the results obtained in enzyme studies. Besides their practical clinical importance for classification and treatment of acute leukaemias, biochemical enzyme markers constitute a valuable research tool to disclose biological properties of leukaemic cells.
Topics: 5'-Nucleotidase; Acid Phosphatase; Acute Disease; Adenosine Deaminase; DNA Nucleotidylexotransferase; Enzyme Inhibitors; Esterases; Hexosaminidases; Humans; Leukemia; Leukocytes; Nucleotidases; Phenotype; Purine-Nucleoside Phosphorylase
PubMed: 2981904
DOI: 10.1136/jcp.38.2.117 -
Toxins Jun 2020Ascomycete fungi such as , , and have been mass produced on artificial media either as food supplements or health additives while the byproducts of culture substrates... (Review)
Review
Ascomycete fungi such as , , and have been mass produced on artificial media either as food supplements or health additives while the byproducts of culture substrates are largely used as animal feed. The safety concerns associated with the daily consumption of fungi or related products are still being debated. On the one hand, the known compounds from these fungi such as adenosine analogs cordycepin and pentostatin have demonstrated different beneficial or pharmaceutical activities but also dose-dependent cytotoxicities, neurological toxicities and or toxicological effects in humans and animals. On the other hand, the possibility of mycotoxin production by fungi has not been completely ruled out. In contrast to a few metabolites identified, an array of biosynthetic gene clusters (BGCs) are encoded in each genome of these fungi with the potential to produce a plethora of as yet unknown secondary metabolites. Conservation analysis of BGCs suggests that mycotoxin analogs of PR-toxin and trichothecenes might be produced by fungi. Future elucidation of the compounds produced by these functionally unknown BGCs, and in-depth assessments of metabolite bioactivity and chemical safety, will not only facilitate the safe use of fungi as human food or alternative medicine, but will also benefit the use of mass production byproducts as animal feed. To corroborate the long record of use as a traditional medicine, future efforts will also benefit the exploration of fungi for pharmaceutical purposes.
Topics: Animal Feed; Animals; Consumer Product Safety; Cordyceps; Dietary Supplements; Food Microbiology; Humans; Industrial Microbiology; Mycotoxins; Risk Assessment
PubMed: 32575649
DOI: 10.3390/toxins12060410 -
Journal of Pharmacological Sciences Jan 2015Cordyceps sinensis, a fungus that parasitizes on the larva of Lepidoptera, has been used as a valued traditional Chinese medicine. We investigated the effects of water... (Review)
Review
Cordyceps sinensis, a fungus that parasitizes on the larva of Lepidoptera, has been used as a valued traditional Chinese medicine. We investigated the effects of water extracts of Cordyceps sinensis (WECS), and particularly focused on its anticancer and antimetastatic actions. Based on in vitro studies, we report that WECS showed an anticancer action, and this action was antagonized by an adenosine A3 receptor antagonist. Moreover, this anticancer action of WECS was promoted by an adenosine deaminase inhibitor. These results suggest that one of the components of WECS with an anticancer action might be an adenosine or its derivatives. Therefore, we focused on cordycepin (3'-deoxyadenosine) as one of the active ingredients of WECS. According to our experiments, cordycepin showed an anticancer effect through the stimulation of adenosine A3 receptor, followed by glycogen synthase kinase (GSK)-3β activation and cyclin D1 suppression. Cordycepin also showed an antimetastatic action through inhibiting platelet aggregation induced by cancer cells and suppressing the invasiveness of cancer cells via inhibiting the activity of matrix metalloproteinase (MMP)-2 and MMP-9, and accelerating the secretion of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 from cancer cells. In conclusion, cordycepin, an active component of WECS, might be a candidate anticancer and antimetastatic agent.
Topics: Adenosine A3 Receptor Agonists; Adenosine A3 Receptor Antagonists; Animals; Antineoplastic Agents; Atherosclerosis; Cell Line, Tumor; Cordyceps; Deoxyadenosines; Drug Therapy, Combination; Humans; Kupffer Cells; Medicine, Chinese Traditional; Methotrexate; Models, Biological; Neoplasm Metastasis; Pentostatin; Phytotherapy; Plant Extracts; Receptor, Adenosine A3; Signal Transduction
PubMed: 25704018
DOI: 10.1016/j.jphs.2014.09.001 -
Current Treatment Options in Oncology Jun 2014Hairy cell leukemia (HCL) is an uncommon chronic leukemia of mature B cells. Leukemic B cells of HCL exhibit a characteristic morphology and immunophenotype and... (Review)
Review
Hairy cell leukemia (HCL) is an uncommon chronic leukemia of mature B cells. Leukemic B cells of HCL exhibit a characteristic morphology and immunophenotype and coexpress multiple clonally related immunoglobulin isotypes. Precise diagnosis and detailed workup is essential, because the clinical profile of HCL can closely mimic that of other chronic B-cell lymphoproliferative disorders that are treated differently. Variants of HCL, such as HCLv and VH4-34 molecular variant, vary in the immunophenotype and specific VH gene usage, and have been more resistant to available treatments. On the contrary, classic HCL is a highly curable disease. Most patients show an excellent long-term response to treatment with single-agent cladribine or pentostatin, with or without the addition of an anti-CD20 monoclonal antibody such as rituximab. However, approximately 30-40 % of patients with HCL relapse after therapy; this can be treated with the same purine analogue that was used for the initial treatment. Advanced molecular techniques have identified distinct molecular aberrations in the Raf/MEK-ERK pathway and BRAF (V600E) mutations that drive the proliferation and survival of HCL B cells. Currently, research in the field of HCL is focused on identifying novel therapeutic targets and potential agents that are safe and can universally cure the disease. Ongoing and planned clinical trials are assessing various treatment strategies, such as the combination of purine analogues and various anti-CD20 monoclonal antibodies, recombinant immunotoxins targeting CD22 (e.g., moxetumomab pasudotox), BRAF inhibitors, such as vemurafenib, and B-cell receptor signaling inhibitors, such as ibrutinib, which is a Bruton's tyrosine kinase inhibitor. This article provides an update of our current understanding of the pathophysiology of HCL and the treatment options available for patients with classic HCL. Discussion of variant forms of HCL is beyond the scope of this manuscript.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Agents; B-Lymphocytes; Cladribine; Disease-Free Survival; Humans; Immunophenotyping; Immunotoxins; Indoles; Leukemia, Hairy Cell; Mutation; Pentostatin; Proto-Oncogene Proteins B-raf; Recombinant Proteins; Recurrence; Rituximab; Sulfonamides; Vemurafenib
PubMed: 24652320
DOI: 10.1007/s11864-014-0285-5