New Perspectives of Interferon-alpha2 and Inflammation in Treating Philadelphia-negative Chronic Myeloproliferative Neoplasms

Hasselbalch, Hans Carl; Silver, Richard T.

doi:10.1097/hs9.0000000000000645

Cited by 25 publications

(39 citation statements)

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“…In this context, MPNs have been described as “A Human Inflammation Model” and “A Human Inflammation Model for Cancer Development”, in which the malignant clone steadily expands in a vicious self-perpetuating cycle fueled by the malignant clone itself [ 14 , 15 ]. Accordingly, early initiation of treatment that directly targets the malignant clone-recombinant interferon-α2 (rIFN-α2) -and the concurrent chronic inflammatory state has been argued to be a prerequisite for a successful outcome of therapeutic intervention [ 22 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. It should be noted that this “Early Interferon Intervention Concept” should preferably be started as early as possible after the MPN diagnosis to prohibit clonal evolution due to inflammation-mediated genomic instability with subclone formation and additional mutations that might confer resistance to treatment, ultimately also mediating myelofibrotic and leukemic transformation.…”

Section: Introductionmentioning

confidence: 99%

“…During the last 30 years, recombinant interferon-α2 has been used in the treatment of MPNs, and its safety and efficacy have been convincingly demonstrated in several studies [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 …”

Section: Introductionmentioning

confidence: 99%

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Recombinant Interferon-β in the Treatment of Polycythemia Vera and Related Neoplasms: Rationales and Perspectives

Hasselbalch

Skov

Kjær

et al. 2022

Cancers

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About 30 years ago, the first clinical trials of the safety and efficacy of recombinant interferon-α2 (rIFN-α2) were performed. Since then, several single-arm studies have shown rIFN-α2 to be a highly potent anticancer agent against several cancer types. Unfortunately, however, a high toxicity profile in early studies with rIFN-α2 -among other reasons likely due to the high dosages being used-disqualified rIFN-α2, which was accordingly replaced with competitive drugs that might at first glance look more attractive to clinicians. Later, pegylated IFN-α2a (Pegasys) and pegylated IFN-α2b (PegIntron) were introduced, which have since been reported to be better tolerated due to reduced toxicity. Today, treatment with rIFN-α2 is virtually outdated in non-hematological cancers, where other immunotherapies—e.g., immune-checkpoint inhibitors—are routinely used in several cancer types and are being intensively investigated in others, either as monotherapy or in combination with immunomodulatory agents, although only rarely in combination with rIFN-α2. Within the hematological malignancies, rIFN-α2 has been used off-label for decades in patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs)—i.e., essential thrombocythemia, polycythemia vera, and myelofibrosis—and in recent years rIFN-α2 has been revived with the marketing of ropeginterferon-α2b (Besremi) for the treatment of polycythemia vera patients. Additionally, rIFN-α2 has been revived for the treatment of chronic myelogenous leukemia in combination with tyrosine kinase inhibitors. Another rIFN formulation-recombinant interferon-β (rIFN-β)—has been used for decades in the treatment of multiple sclerosis but has never been studied as a potential agent to be used in patients with MPNs, although several studies and reviews have repeatedly described rIFN-β as an effective anticancer agent as well. In this paper, we describe the rationales and perspectives for launching studies on the safety and efficacy of rIFN-β in patients with MPNs.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Recombinant Interferon-β in the Treatment of Polycythemia Vera and Related Neoplasms: Rationales and Perspectives

Hasselbalch

Skov

Kjær

et al. 2022

Cancers

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“…In recent years, several studies have substantiated that rIFNα is highly efficacious in the treatment of patients with ET, PV and early hyperproliferative myelofibrosis, implying a normalization of elevated blood cell counts within weeks, a decrease in the JAK2V617F allele burden within the first year in most patients [ 45 – 60 ], and in a subset of patients even induction of minimal residual disease as defined by low-burden JAK2V617F (< 1%) in concert with normalization of the bone marrow after long-term treatment (> 5 years) [ 63 – 67 ]. The mechanisms of action of rIFNα are pleitropic including upregulation of downregulated HLA-genes [ 68 ] and boosting of virtually all immune cells [ 69 – 71 ].…”

Section: Discussionmentioning

confidence: 99%

“…Interferon-alpha2 (rIFNα) is increasingly been recognized as a very efficacious and promising treatment modality in the treatment of MPNs [ 44 – 60 ]. Taken into account that chronic inflammation with ROS accumulation has a major role in the pathogenesis of MPNs [ 3 – 28 ], ultimately implying the induction of an altered redox balance of pivotal significance for stem cell mobilization [ 31 , 43 ], we herein report the first study containing novel information on the impact of rIFNα upon oxidative stress and antioxidative defense genes, showing that rIFNα downregulates several upregulated oxidative stress genes and upregulates downregulated antioxidative defense genes.…”

Section: Introductionmentioning

confidence: 99%

Interferon-alpha2 treatment of patients with polycythemia vera and related neoplasms favorably impacts deregulation of oxidative stress genes and antioxidative defense mechanisms

et al. 2022

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Chronic inflammation is considered a major driving force for clonal expansion and evolution in the Philadelphia-negative myeloproliferative neoplasms, which include essential thrombocythemia, polycythemia vera and primary myelofibrosis (MPNs). One of the key mutation drivers is the JAK2V617F mutation, which has been shown to induce the generation of reactive oxygen species (ROS). Using whole blood gene expression profiling, deregulation of several oxidative stress and anti-oxidative defense genes has been identified in MPNs, including significant downregulation of TP53, the NFE2L2 or NRF2 genes. These genes have a major role for maintaining genomic stability, regulation of the oxidative stress response and in modulating migration or retention of hematopoietic stem cells. Therefore, their deregulation might give rise to increasing genomic instability, increased chronic inflammation and disease progression with egress of hematopoietic stem cells from the bone marrow to seed in the spleen, liver and elsewhere. Interferon-alpha2 (rIFNα) is increasingly being recognized as the drug of choice for the treatment of patients with MPNs. Herein, we report the first gene expression profiling study on the impact of rIFNα upon oxidative stress and antioxidative defense genes in patients with MPNs (n = 33), showing that rIFNα downregulates several upregulated oxidative stress genes and upregulates downregulated antioxidative defense genes. Treatment with rIFNα induced upregulation of 19 genes in ET and 29 genes in PV including CXCR4 and TP53. In conclusion, this rIFNα- mediated dampening of genotoxic damage to hematopoietic cells may ultimately diminish the risk of additional mutations and accordingly clonal evolution and disease progression towards myelofibrotic and leukemic transformation.

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“…Myeloproliferative neoplasms (MPNs) are malignant clonal disorders of hematopoietic stem cells, clinically characterized by increased myeloid terminally differentiated cells [ 1 ]. It includes essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Analysis of the Clinical Significance and Safety of Interferon in the Treatment of Chronic Myeloproliferative Tumors

Yin

et al. 2022

Journal of Oncology

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Objective. To investigate the clinical significance and safety of interferon in the treatment of chronic myeloproliferative tumors (MPN). Methods. In this prospective study, a total of 120 patients with advanced chronic MPN admitted to our hospital between April 2016 and August 2020 were assessed for eligibility and recruited, including 62 patients with JAK2V617F mutation-positive ET (ET group) and 58 patients with JAK2V617F mutation-positive PV (PV group). 62 patients with JAK2V617F mutation-positive ET were assigned (1 : 1) to receive interferon-α (IFN-α) or hydroxyurea (HU). A similar subgrouping method for treatment of IFN-α and HU was introduced to patients with JAK2V617F mutation-positive PV. Outcome measures included efficacy and adverse reactions. Results. For patients with JAK2V617F mutation-positive ET and PV, there were no significant differences in the overall response rate between the groups treated with IFN-α or HU ( P > 0.05 ); however, the patients treated with IFN-α had a significantly higher 5-year progression-free survival (PFS) than those treated with HU ( P < 0.05 ). IFN-α was associated with a significantly lower incidence of disease progression, thrombotic events, splenomegaly, myelofibrosis, nausea, and vomiting and a higher incidence of hematological adverse reactions and flu-like symptoms versus HU ( P < 0.05 ). After six months of treatment, the PV group had 12 cases of hematological response both in the IFN-α subgroup and the HU subgroup and fewer PV patients treated with IFN-α required phlebotomy versus those treated with HU ( P < 0.05 ), in which 4 patients in the IFN-α subgroup had no hematological response and 6 patients in the HU subgroup had no hematological response. There was no significant difference in the number of cases with phlebotomy between the two subgroups of PV patients without hematological response ( P > 0.05 ). Conclusion. The use of IFN in the treatment of JAK2V617F mutation-positive ET and PV patients yields a prominent clinical effect by prolonging PFS and avoiding phlebotomy for JAK2V617F mutation-positive PV patients.

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New Perspectives of Interferon-alpha2 and Inflammation in Treating Philadelphia-negative Chronic Myeloproliferative Neoplasms

Cited by 25 publications

References 117 publications

Recombinant Interferon-β in the Treatment of Polycythemia Vera and Related Neoplasms: Rationales and Perspectives

Recombinant Interferon-β in the Treatment of Polycythemia Vera and Related Neoplasms: Rationales and Perspectives

Interferon-alpha2 treatment of patients with polycythemia vera and related neoplasms favorably impacts deregulation of oxidative stress genes and antioxidative defense mechanisms

Analysis of the Clinical Significance and Safety of Interferon in the Treatment of Chronic Myeloproliferative Tumors

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