The treatment landscape for BCR/ABL-negative myeloproliferative neoplasms (MPNs), driven by
and
mutations, has evolved significantly over the last decade. Recent regulatory approvals in polycythemia ...vera (PV) include the JAK inhibitor ruxolitinib, and more recently, a novel recombinant interferon alfa-2 (IFN-α) therapeutic agent. Many clinical trials have documented the safety and efficacy of IFN-α therapy in PV and essential thrombocythemia, the classical BCR/ABL-negative MPNs. Used off-label for more than 30 years as a cytoreductive agent, IFN-α therapy promotes significant clinical, hematologic, and molecular responses. In some IFN-α-treated patients, partial or complete reduction of the mutant
allele burden may lead to a durable measurable residual disease state, owing to the ability of long-term IFN-α therapy to selectively deplete mutant
-harboring hematopoietic stem cells. Pegylated IFN-α forms were developed to improve the drug stability and tolerability of first-generation IFN-α therapeutics. More recently, a novel pegylated IFN-α, ropeginterferon alfa-2b, received approval for PV by the European Medicines Agency and the US Food and Drug Administration in 2019 and 2021, respectively. This article reviews the clinical research and recent advances that led to the first regulatory approval of IFN-α in a BCR/ABL-negative MPN and its future promise as a disease-modifying therapeutic agent.
The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) ...are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.
•Rates of thrombosis and progression were low in patients with ET/PV treated with either HU or IFN in this randomized study.•PEG was more effective in normalizing counts and reducing JAK2V617F VAF in PV whereas HU induced more HPRs in ET.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Erythrocytosis is frequently encountered as an incidental abnormality on laboratory testing that reveals persistent elevation of the hematocrit level (> 52% in men and > 48% in women). In ...many cases, erythrocytosis is the manifestation of an underlying cardiopulmonary process, drug-induced due to androgens, or secondary to smoking, rather than a primary bone marrow disorder such as polycythemia vera. A systematic approach to the clinical and laboratory evaluation of each patient is indicated to consider diverse differential diagnosis possibilities and to identify the underlying etiology of erythrocytosis in order to formulate appropriate subspecialist referral and management plans. A thorough medical history and meticulous physical examination supplemented by a focused initial laboratory evaluation will enable the general practitioner to ascertain the etiology of erythrocytosis in the majority of cases. Patients with clinical and laboratory features suggestive of polycythemia vera and those patients without an apparent underlying condition known to cause erythrocytosis benefit from early referral to a hematologist for further specialized diagnostic evaluation and therapy considerations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The induction of tumor angiogenesis, a pathologic process critical for tumor progression, is mediated by multiple regulatory factors released by tumor and host cells. We investigated the role of the ...hematopoietic cytokine erythropoietin as an angiogenic factor that modulates tumor progression.
Fluorescently-labeled rodent mammary carcinoma cells were injected into dorsal skin-fold window chambers in mice, an angiogenesis model that allows direct, non-invasive, serial visualization and real-time assessment of tumor cells and neovascularization simultaneously using intravital microscopy and computerized image analysis during the initial stages of tumorigenesis. Erythropoietin or its antagonist proteins were co-injected with tumor cells into window chambers. In vivo growth of cells engineered to stably express a constitutively active erythropoietin receptor EPOR-R129C or the erythropoietin antagonist R103A-EPO were analyzed in window chambers and in the mammary fat pads of athymic nude mice. Co-injection of erythropoietin with tumor cells or expression of EPOR-R129C in tumor cells significantly stimulated tumor neovascularization and growth in window chambers. Co-injection of erythropoietin antagonist proteins (soluble EPOR or anti-EPO antibody) with tumor cells or stable expression of antagonist R103A-EPO protein secreted from tumor cells inhibited angiogenesis and impaired tumor growth. In orthotopic tumor xenograft studies, EPOR-R129C expression significantly promoted tumor growth associated with increased expression of Ki67 proliferation antigen, enhanced microvessel density, decreased tumor hypoxia, and increased phosphorylation of extracellular-regulated kinases ERK1/2. R103A-EPO antagonist expression in mammary carcinoma cells was associated with near-complete disruption of primary tumor formation in the mammary fat pad.
These data indicate that erythropoietin is an important angiogenic factor that regulates the induction of tumor cell-induced neovascularization and growth during the initial stages of tumorigenesis. The suppression of tumor angiogenesis and progression by erythropoietin blockade suggests that erythropoietin may constitute a potential target for the therapeutic modulation of angiogenesis in cancer.
Erythropoietin Biology in Cancer HARDEE, Matthew E; ARCASOY, Murat O; BLACKWELL, Kimberly L ...
Clinical cancer research,
01/2006, Volume:
12, Issue:
2
Journal Article
Peer reviewed
Open access
Erythropoietin (Epo) has long been known to be the principal hematopoietic growth factor that regulates cellular proliferation
and differentiation along the erythroid lineage. Recent studies have ...shown that Epo is a pleiotropic cytokine that is proangiogenic
and exerts broad tissue-protective effects in diverse nonhematopoietic organs. Recombinant Epo (rEpo) has been widely used
in the clinic to prevent or treat malignancy-associated anemia. A series of clinical trials have documented the efficacy of
rEpo in reducing RBC transfusion requirements and improving quality of life in cancer patients, and a recent meta-analysis
suggested a positive effect on survival. However, two randomized trials reported negative outcomes with rEpo, as patients
in the rEpo arm fared worse than their placebo-treated counterparts with respect to progression-free survival. The expression
of Epo receptor (EpoR) in cancer cells has raised the possibility that exogenous rEpo may exert direct effects on tumor cells
associated with the potential for stimulation of proliferation, inhibition of apoptosis, or modulation of sensitivity to chemoradiation
therapy. The presence of an autocrine-paracrine Epo-EpoR system in tumors and potential effects of Epo on tumor microenvironment
and angiogenesis are consistent with a complex biology for Epo-EpoR signaling in cancer that requires further research. This
review describes Epo and EpoR biology, focusing on the pleiotropic effects of Epo on nonhematopoietic tissues as well as the
expression and function of EpoR in cancer cells.
Erythropoiesis-stimulating agents (ESA) used for the treatment of chemotherapy-induced anemia in cancer patients have been
associated with adverse outcomes of enhanced tumor progression and impaired ...survival in a series of recent clinical trials.
As clinical practice guidelines for ESA administration in cancer patients have evolved to improve safety, the mechanisms underlying
the adverse outcomes and whether ESAs exert direct and/or indirect effects in primary tumors to modulate tumor cell growth,
survival, and chemoradiotherapy responses remain uncertain. Erythropoietin receptor (EpoR) expression in tumor cells has raised
the simplistic possibility that Epo signaling mediated via a functional cellular receptor may contribute to tumor progression
in a direct manner. However, Epo biology in cancer is likely to be complex and an interplay of multiple factors is potentially
involved in the overall tumor response to exogenous Epo. Optimization of ESA use as an important supportive therapy modality
in cancer patients, and further investigation of the role of Epo-EpoR in cancer biology will require a combination of carefully
designed preclinical and clinical studies designed to ascertain not only the effect of ESA therapy on clinical outcomes such
as tumor response, progression-free, and overall survival but also to investigate the potential effects of Epo on biomarkers
of EpoR activation and factors related to tumor biology and chemoradiation responsiveness.
Purpose: To update American Society of Hematology/American Society of Clinical Oncology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. Methods: An Update ...Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. Results: The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews. Recommendations: For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration–approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
Clozapine is the favoured antipsychotic for treatment‐refractory schizophrenia, but has a 1%‐2% incidence of agranulocytosis. Patients who require chemotherapy therefore pose a unique ...management dilemma for haematologists, oncologists and psychiatrists.
Methods
The Ovid MEDLINE and EMBASE databases were searched to identify reports describing use of clozapine concurrent with chemotherapy until 31 March 2019. The following terms (with variations) were used: neoplasm, cancer, tumour, malignancy, chemotherapy, antineoplastic and clozapine.
Results
Twenty‐seven cases were included after reviewing titles and s for relevance. Fifteen patients had solid organ tumours, and 12 had haematological malignancies, including three who underwent autologous haematopoietic stem cell transplantation (AutoHSCT). Clozapine was continued in 14 cases (albeit dose reduced in 2), with a reported median neutropaenic nadir of 0.29 × 109/L (range 2.2 to <0.0 × 109/L). Clozapine was discontinued or substituted for another antipsychotic in the remaining 13 cases, all except one of whom experienced marked psychiatric deterioration. The only neutropenia‐related complication was one case of bacteraemia with high‐dose melphalan conditioning for AutoHSCT.
Conclusions
These findings argue in favour of clozapine continuation during chemotherapy. Further research is needed to develop guidance to minimise the risk of neutropenia‐related complications from concurrent treatment.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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