Clonal analysis of erythroid progenitors suggests that pegylated interferon α-2a treatment targets JAK2V617F clones without affecting TET2 mutant cells

Kiladjian, J-J; Massé, Aline; Cassinat, Bruno; Mokrani, Hayat; Teyssandier, Irène; Couedic, JP Le; Cambier, Nathalie; Almire, Carole; Pronier, Elodie; Casadevall, Nicole; Vainchenker, William; Chomienne, Christine; Delhommeau, François

doi:10.1038/leu.2010.120

Cited by 81 publications

(57 citation statements)

References 9 publications

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“…Interferon preferentially targets JAK2V617F-mutated cells, 65 causing progressive decrease of mutated allele burden and eventually its complete disappearance 63,66 ; however, founder clones harboring TET2 mutations are not targeted by interferon. 67 The usual maintenance dose is 3 3 10 6 /MU 3 times a week (conventional) or 90 to 180 mg weekly (pegylated), but it is titrated individually based on efficacy and toxicity. Side effects (autoimmune disorders, flu-like manifestations, depression, heart, and ocular disease) lead to permanent discontinuation in 20% to 40% on conventional and 20% to 25% on pegylated interferon.…”

Section: Therapy Goals and Therapy Optionsmentioning

confidence: 99%

How I treat polycythemia vera

Vannucchi

2014

Blood

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Polycythemia vera (PV) is a chronic myeloproliferative neoplasm associated with JAK2 mutations (V617F or exon 12) in almost all cases. The World Health Organization has defined the criteria for diagnosis, but it is still unclear which parameter (hemoglobin or hematocrit) is the most reliable for demonstrating increased red cell volume and for monitoring response to therapy; also, the role of bone marrow biopsy is being revisited. PV is associated with reduced survival because of cardiovascular complications and progression to post-PV myelofibrosis or leukemia. Criteria for risk-adapted treatment rely on the likelihood of thrombosis. Controlled trials have demonstrated that incidence of cardiovascular events is reduced by sustained control of hematocrit with phlebotomies (low-risk patients) and/or cytotoxic agents (high-risk patients) and antiplatelet therapy with aspirin. Hydroxyurea and interferon may be used as first-line treatments, whereas busulfan is reserved for patients that are refractory or resistant to first-line agents. However, there is no evidence that therapy improves survival, and the significance of reduction of JAK2 mutated allele burden produced by interferon is unknown. PV is also associated with a plethora of symptoms that are poorly controlled by conventional therapy. This article summarizes my approach to the management of PV in daily clinical practice.

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Section: Therapy Goals and Therapy Optionsmentioning

confidence: 99%

How I treat polycythemia vera

Vannucchi

2014

Blood

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“…21,24,25 Interestingly, particular combinations of mutations could better define subgroups of patients with different outcomes. 26 Such molecular complexity could also affect the response to treatment. For example, we found that a TET2-mutated clone could persist after IFNa therapy, whereas JAK2-mutated cells were eradicated in the same patient.…”

Section: Introductionmentioning

confidence: 99%

Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations

Verger

Cassinat

Chauveau

et al. 2015

Blood

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“…A similar decrease in the JAK2-V617F singlepositive clone was reported in a biclonal TET2 positive MPN patient treated with pegylated interferon ␣. 4 However, our patient was treated with 5-hydroxyurea only and did not receive interferon. The proportion of colonies single-positive for the heterozygous TET2 mutation increased from 16% to 40% in our patient, suggesting that the presence of the heterozygous TET2 mutation alone may provide a growth advantage.…”

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confidence: 82%