De la bonne utilisation des nouvelles molécules en oncologie : comment concilier des soins de qualité et le contrôle des coûts?

Résumé Les récents progrès thérapeutiques en oncologie se traduisent par des augmentations importantes des coûts des médicaments en oncologie. Le département d’oncologie du Centre hospitalier de St. Mary, situé à Montréal, a développé une méthode de contrôle des coûts qui, fondée sur une approche consensuelle, fournit en même temps des soins de qualité.Cette méthode repose sur une politique d’utilisation des médicaments en oncologie acceptée par tous les oncologues et la pharmacienne en oncologie. Les médicaments sont classés en trois catégories et leur utilisation est régie par des règles précises, décrites en détail. L’évolution des coûts des médicaments d’oncologie au cours des cinq dernières années est présentée en parallèle avec celle du nombre de traitements.Jusqu’en 1999-2000, les dépassements budgétaires ont été limités en deçà de l’augmentation du nombre de traitements administrés. La hausse importante des dépenses en 2000-2001 et 2001-2002, amorcée en 1999-2000, s’explique par l’arrivée simultanée dans l’arsenal thérapeutique de plusieurs médicaments innovateurs extrêmement coûteux.Les facteurs expliquant ce succès sont exposés. Abstract Recent advances in cancer therapy have been accompanied by major increases in the costs of the medications used. The Oncology Department of St. Mary’s Hospital in Montreal has developed a method of cost control which, arrived at by consensus, ensures quality care. The method is based upon a policy on the use of medications in oncology that has been accepted by the oncologists as well as the pharmacist in oncology. Medications have been divided into three categories, and their use is governed by specific rules, which are described in detail. The evolution in the cost of oncology medication over the last five years is presented parallel to that of the number of treatments.Until 1999-2000, budgetary surpluses were kept below the level of increase in the number of treatments administered. The large increase in expenses in 2000-2001 and 2001-2002, begun in 1999-2000, is the result of the simultaneous arrival of several extremely costly new medications for cancer therapy. This article discusses the factors responsible for the success of cost control

Mutations of von Hippel-Lindau Tumor-Suppressor Gene and Congenital Polycythemia

The von Hippel-Lindau (pVHL) protein plays an important role in hypoxia sensing. It binds to the hydroxylated hypoxia-inducible factor 1α (HIF-1α) and serves as a recognition component of an E3-ubiquitin ligase complex. In hypoxia or secondary to a mutated VHL gene, the nondegraded HIF-1α forms a heterodimer with HIF-β and leads to increased transcription of hypoxia-inducible genes, including erythropoietin (EPO). The autosomal dominant cancer-predisposition von Hippel-Lindau (VHL) syndrome is due to inheritance of a single mutated allele of VHL. In contrast, we recently showed that homozygous germline 598C→T VHL mutation leads to Chuvash polycythemia (CP). We subsequently found VHL mutations in three unrelated individuals unaffected with CP, one of whom was compound heterozygous for the 598C→T mutation and another VHL mutation. We now report seven additional polycythemic patients with VHL mutations in both alleles. Two Danish siblings and another American boy were homozygous for the VHL 598C→T mutation. Three unrelated white Americans were compound heterozygotes for 598C→T and another VHL mutation, 562C→G in two and 574C→T in the third. Additionally, a Croatian boy was homozygous for a 571C→G VHL mutation, the first example of homozygous VHL germline mutation causing polycythemia, other than the VHL 598C→T mutation. We have not observed VHL syndrome–associated tumors in polycythemic subjects or their heterozygous relatives; however, this will need to be evaluated by longitudinal studies. Over all, we found that up to half of the consecutive patients with apparent congenital polycythemia and increased serum Epo we have examined have mutations of both VHL alleles. Those findings, along with reports of CP, underscore that VHL mutations are the most frequent cause of congenital polycythemia and define a new class of polycythemic disorder, polycythemias due to augmented hypoxia sensing

Novel germline JAK2 mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-Interferon.

Polycythemia vera (PV) is a clonal disorder arising from the acquired somatic mutations of the JAK2 gene, including JAK2 or several others in exon 12. A 38-year-old female had a stroke at age 32 and found to have elevated hemoglobin, normal leukocytes, normal platelets, and tested negative for JAK2 and exon 12 mutations. Next generation sequencing revealed a novel mutation: JAK2 in the pseudokinase domain (JH2) at 47.5%. Its presence in her nail DNA confirmed a germline origin. Her mother and her son similarly had erythrocytosis and a JAK2 mutation. Computer modeling indicated gain-of-function JAK2 activity. The propositus and her mother had polyclonal myelopoiesis, ruling out another somatic mutation-derived clonal hematopoiesis. Some erythroid progenitors of all three generations grew without erythropoietin, a hallmark of PV. The in vitro reporter assay confirmed increased activity of the JAK2 kinase. Similar to PV, the JAK2 native cells have increased STAT5 phosphorylation, augmented transcripts of prothrombotic and inflammatory genes, and decreased KLF2 transcripts. The propositus was not controlled by hydroxyurea, and JAK2 inhibitors were not tolerated; however, Ropeginterferon-alfa-2b (Ropeg-IFN-α) induced a remission. Ropeg-IFN-α treatment also reduced JAK2 activity in the propositus, her mother and JAK2 PV subjects. We report dominantly inherited erythrocytosis secondary to a novel germline JAK2 gain-of-function mutation with many but not all comparable molecular features to JAK2 PV. We also document a previously unreported inhibitory mechanism of JAK2 signaling by Ropeg-IFN-α