Une découverte pour contrôler la leucémie B-CLL

Led by Mayo Clinic, researchers found that ibrutinib and chemotherapy (bendamustine and rituximab, known as BR) reduced the risk of death or cancer progression by almost 80 percent in patients with previously treated CLL or SLL, compared to use of BR alone.

The announcement was made at a press briefing at the 2015 meeting of the American Society of Clinical Oncology by HELIOS' senior investigator Asher Chanan-Khan, M.D., professor of medicine and chair of Hematology & Oncology, Mayo Clinic Cancer Center in Jacksonville, Florida.

"This finding represents a significant advancement in the management and treatment of this leukemia," says Dr. Chanan-Khan. "Although CLL remains incurable, this new regimen offers longer disease control and a decreased risk of relapse for our patients."

The HELIOS study -- which enrolled 578 patients from centers around the world -- was the first to compare, head-to-head, chemo immunotherapy alone to chemo immunotherapy plus a targeted drug in patients with CLL.

CLL, the most common adult leukemia in the U.S., is a B-cell cancer that is present in blood and lymph nodes. SLL is a B-cell cancer found only in lymph nodes.

Ibrutinib is an oral pill that blocks Bruton's tyrosine kinase (BTR), making the cancer vulnerable to death. "This BTR inhibitor interrupts the cellular signaling path that drives B-cell growth and survival," says Dr. Chanan-Khan.

Ibrutinib was approved by the U.S. Food and Drug Administration (FDA) for use in November 2013 for the treatment of mantle cell lymphoma, a subset of B-cell lymphoma. It was also approved in February 2014 for use in CLL, following a study of the agent alone in patients with very advanced disease who had been through multiple treatments.

The HELIOS trial was designed to test the two therapies in less heavily treated patients whose cancer had returned.

In the randomized study, 289 patients received ibrutinib plus BR, and the other 289 were treated with BR plus a placebo pill. At a median follow-up of 17.2 months, progression- free survival was significantly longer in the group who received the ibrutinib combination compared to those who did not.

Overall response rate in the BR/ibrutinib group was 83 percent versus 68 percent in the group treated with BR alone. At the time of analysis (18 months) 79 percent of the patients receiving ibrutinib remained in remission vs. only 24 percent who did not. Additional findings will be presented at the ASCO press briefing.

"We cannot say the very positive findings from this study were surprising, because we saw how effective ibrutinib can be when used alone in advanced patients," says Dr. Chanan-Khan. "But we are pleased to see the great value ibrutinib offers even in the setting of chemotherapy. We are gratified to have multiple options for our patients."

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Dirigée par la Mayo Clinic, les chercheurs ont constaté que Ibrutinib et la chimiothérapie (bendamustine et rituximab, connu sous le nom BR) réduit le risque de mort ou de la progression du cancer de près de 80 pour cent chez les patients atteints de LLC traités auparavant ou SLL, par rapport à l'utilisation de BR seul.

L'annonce a été faite lors d'une conférence de presse lors de la réunion 2015 de l'American Society of Clinical Oncology par l'enquêteur principal HELIOS 'Asher Chanan-Khan, MD, professeur de médecine et président d'hématologie et d'oncologie, de la Mayo Clinic Cancer Center à Jacksonville, en Floride.

"Cette découverte représente une avancée significative dans la gestion et le traitement de cette leucémie," explique le Dr Chanan-Khan. "Bien que CLL reste incurable, ce nouveau régime offre plus de contrôle de la maladie et une diminution du risque de rechute pour nos patients."

L'étude HELIOS - qui ont recruté 578 patients provenant de centres à travers le monde - était la première à comparer, en tête-à-tête, chimio immunothérapie seule à la chimio immunothérapie plus un médicament ciblé chez les patients atteints de LLC.

CLL, leucémie chez l'adulte le plus commun aux États-Unis, est un cancer des cellules B qui est présent dans le sang et les ganglions lymphatiques. SLL est un cancer des cellules B trouvé uniquement dans les ganglions lymphatiques.

Ibrutinib est une pilule que la tyrosine kinase de Bruton blocs (BTR), rendant le cancer vulnérables à la mort. "Cet inhibiteur BTR interrompt la voie de signalisation cellulaire qui stimule la croissance des cellules B et la survie», explique le Dr Chanan-Khan.

Ibrutinib a été approuvé par la US Food and Drug Administration (FDA) pour une utilisation en Novembre 2013 pour le traitement du lymphome à cellules du manteau, un sous-ensemble de B-cell lymphoma. Il a également été approuvé en Février 2014 pour une utilisation dans la LLC, suite à une étude de l'agent seul chez les patients avec une maladie très avancé qui avait été à travers de multiples traitements.

Le procès HELIOS a été conçu pour tester les deux thérapies chez les patients moins lourdement traités dont le cancer était revenu.

Dans l'étude randomisée, 289 patients ont reçu Ibrutinib ainsi que BR, et l'autre 289 ont été traités avec BR plus une pilule placebo. Après un suivi médian de 17,2 mois, la survie sans progression était significativement plus longue dans le groupe ayant reçu la combinaison de Ibrutinib rapport à ceux qui ne l'a pas.

Taux de réponse global dans le groupe BR / Ibrutinib était de 83 pour cent contre 68 pour cent dans le groupe traité avec BR seul. Au moment de l'analyse (18 mois) 79 pour cent des patients recevant Ibrutinib sont resté en rémission contre seulement 24 pour cent qui ne le sont pas restés. D'autres constatations seront présentés lors de la conférence de presse ASCO.

"Nous ne pouvons pas dire que les résultats très positifs de cette étude ont été surprenants, parce que nous avons vu comment l'Ibrutinib peut être efficace lorsqu'il est utilisé seul chez les patients avancés," déclare le Dr Chanan-Khan. "Mais nous sommes heureux de voir la grande  valeur offette même dans le cadre de la chimiothérapie. Nous sommes heureux d'avoir plusieurs options pour nos patients."

(Dec. 11, 2011) — A new, targeted approach to treating chronic lymphocytic leukemia has produced durable remissions in a Phase I/II clinical trial for patients with relapsed or resistant disease, investigators report at the 53rd Annual Meeting of the American Society of Hematology.

Une nouvelle approche de traitement ciblé a produit des rémissions durable dans la phase I et II d'une étude clinique pour les patients avec des maladies résistantes ou en rechutes de la leucémie chronique lymphatique.

"PCI-32765, one of a new class of experimental drugs called B cell receptor inhibitors, has shown impressive potential in this clinical trial for its effectiveness and particularly for its relatively minimal toxicity," said lead investigator Susan O'Brien, M.D., professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center.

Le pci-32765, un médicament d'une nouvelle classe appelé inhibiteur de récepteur de classe B, a montré un potentiel impressionnant quant à l'efficacité et à sa toxicité minimale.

According to the National Cancer Institute's Surveillance Epidemiology and End Results database, an estimated 14,570 people will receive a diagnosis of CLL in 2011 and about 4,380 patients will die of the disease.

Six-month progression free survival of 90-92 percent

Of 27 CLL patients treated at a dose of 420 milligrams daily, 70 percent had complete or partial remission at 10.2 months of median follow-up. Six-month progression-free survival was 92 percent. Patients received a median three prior treatments before entering the clinical trial.

At a higher dose of 840 mg, 44 percent of 34 patients achieved complete or partial remission at 6.5 months median follow-up, similar to the response rate of the lower-dose cohort at 6.2 months. Progression free survival at 6 months was 90 percent. Study participants had received a median of five prior treatments.

Overall, five patients (8 percent) of the 61 from both arms had progressive disease and 50 (82 percent) remained on the therapy.

Drug does not suppress blood cell production

CLL presently is treated with combination chemotherapies that can cause myelosuppression -- inhibited bone marrow function leading to decreased production of blood cells. The resulting susceptibility to infection can be a problem for patients, O'Brien said.

"PCI-32765 is not myelosuppressive. The main side effect is mild diarrhea that is usually self-limiting," O'Brien said.

Chronic lymphocytic leukemia is caused by overproduction of defective B cell lymphocytes, white blood cells that fight infection by producing antibodies.

PCI-32765 is orally administered and inhibits the Burton's tyrosine kinas (BT) enzyme, which is central to B cell receptor signaling. The drug causes programmed cell death and hinders cell migration and adhesion in malignant B cells.

A Phase III clinical trial is planned. The clinical trial was funded by Pharmacyclics, Inc., the drug's developer.

Pair Of MicroRNA Molecules Controls Major Oncogene In Most Common Leukemia

Une paire de molécules microARN contrôle un oncogène majeur dans la forme la plus courante de la leucémie.

Researchers at Ohio State University have discovered that two microRNA (miRNA) molecules help control the oncogene responsible for a dangerous form of B-cell chronic lymphocytic leukemia (B-CLL), the most common human leukemia in the world.

Les chercheurs de l'université de Ohio ont découvert que deux microARN (miARN) aide au contrôle de l'oncogène responsable pour une dangereuse forme de la leucémie (B-CLL), la leucémie la plus courante de part le mode.

Their findings, published in the December 15 issue of Cancer Research, demonstrate that miRNAs are emerging as powerful regulators of gene expression in cancer development, and could offer new targets for drug treatment, the investigators say.

Leurs découvertes, publiées dans le numéro du 15 décembre de "Cancer Research" démontre que les miARN deviennent de puissants régulateurs de l'expression des gènes dans le développement du cancer et pourraient offrir de nouvelles cibles pour des traitements par médicaments.

In this case, high levels of two miRNAs known as miR-29 and miR-181 seem to suppress expression of the TCL1 oncogene that drives the most aggressive forms of the leukemia, said the study's lead author, Yuri Pekarsky, Ph.D., assistant professor in the Department of Molecular Virology, Immunology and Medical Genetics at Ohio State University's Comprehensive Cancer Center.

Dans ce cas, de hauts niveaux de miARN connus comme miR-29 et miR-181 semblent supprimer l'expression de l'oncogène TCL1 qui dirige la forme la plus agressive de leucémie

"We have found a direct inverse association between expression of miR-29 and miR-181 and that of the TCL1 oncogene," he said. "It works in both directions. High expression of these miRNAs correlates with low expression of TCL1, in the indolent form of cancer that is less likely to progress. A low level of miR-29 and miR-181 is associated with a much more aggressive cancer."

"Nous avons trouvé une association directe entre l'expression de miR-29, miR-181 et cet oncogène TCL1" dit-il "Cela marche dans les deux directions, quand l'expression des miARN est basse l'expression de TCL1 est haute et inversement quand l'expresions des miARN est haute celle de TCL1 est basse.

Drugs that boost production of these two natural TCL1 inhibitors might work as a future treatment for B-cell chronic lymphocytic leukemia, he said. These molecules could also be combined with 12 other miRNAs known to be associated with B-CLL to provide a test that may help determine prognosis and treatment, he said.

Les médicaments qui boostent la production de ces deux inhibiteurs naturels pourraient être une future thérapie pour la B-CLL. Ces molécules pourraient aussi être associé avec 12 autres miARN pour faire un test pour aider à déterminer le pronostic et le traitement.

Researchers at Ohio State have been leaders in characterizing the role of miRNAs in cancer development. These small molecules are single-stranded RNA molecules that can act either as tumor suppressors or oncogenes. They can block transcription of genes by stopping them from producing messenger RNA or can inhibit translation of the genes by blocking production of proteins from messenger RNA, according to Pekarsky. Earlier this year the investigators provided the first direct evidence that over-expression of an miRNA molecule could result in development of cancer have since identified a number of miRNAs associated with B-cell chronic lymphocytic leukemia that appear to promote tumor development. But the protective miR-29 and miR-181 molecules are emerging as the most important miRNAs discovered to date, Pekarsky said. "MicroRNAs such as these could prove to be as powerful as the protein transcription factors that we know can turn genes on and off," he said.

The researchers studied TCL1 expression and miRNA expression in 23 samples of indolent B-CLL, 25 samples of aggressive B-CLL, and 32 samples of B-CLL exhibiting a chromosomal deletion, which makes it the most difficult type to treat. They found that TCL1 over-expression correlated with the two most aggressive forms of the cancer. To determine which miRNAs targeted TCL1, they used microRNA-microchips and elaborate computer programs to identify miR-29 and miR-181.

Regulation of TCL1 expression by these two miRNAs is relevant to all the three groups of cells studied, Pekarsky said. "You can look at the miRNA profile and say whether the cancer is aggressive or indolent," he said. And of the two miRNAs, miR-29 offers the most predictive power, Pekarsky added.

"We have a lot of work to do to characterize these miRNAs because we don't even know whether they work on transcriptional or translational level," he said. "But finding that they control this cancer's major risk factor is a very helpful advance."

The study was funded by the National Institutes of Health, among other grants. Researchers from the University of California at San Diego also contributed to the stud