CAL-101 in CLL chronic lymphocytic leukemia

TARGETED AGENT SHOWS PROMISE FOR CHRONIC LYMPHOID LEUKEMIA

For more information:
CLL: http://www.leukemia-lymphoma.org/all_page?item_id=7059

An abstract of the study: http://www.ncbi.nlm.nih.gov/pubmed/20522708

Researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James) have identified an experimental agent that targets chronic lymphocytic leukemia and perhaps other proliferative disorders of lymphocytes.

Their study shows that the small-molecule inhibitor CAL-101 directly promotes cell death by apoptosis in chronic lymphocytic leukemia (CLL) cells and disrupts several external survival pathways needed for CLL cell viability and proliferation.

The agent blocks a molecule called PI3K-delta, an isomer of the PI3K (phosphatidylinositol-3 kinase) pathway, which is activated mainly in blood-forming, or hematopoietic, cells.

The research was posted recently in the journal Blood.

"Overall, our findings provide a rationale for the development of CAL-101 as the first in a new class of targeted therapies for CLL," says principal investigator Amy J. Johnson, assistant professor of hematology and medicinal chemistry, and a CLL researcher in the OSUCCC-James.

"A PI3K inhibitor hasn't been developed yet because this pathway is required for many essential cellular functions, but the identification of PI3K-delta, which is hematopoietic-selective, unlocks a potential new therapy for B-cell malignancies," Johnson says.

CLL is the most common from of adult leukemia in the United States, with about 15,000 new cases and 4,500 deaths annually. An estimated 100,760 people in the United States are living with or are in remission from CLL.

People with the asymptomatic phase of CLL can live many years, even without treatment. But once the disease progresses to its symptomatic phase, treatment is required. This is usually a chemotherapy-based regimen that often induces remission. But current therapies are not curative and nearly all patients relapse.

The PI3K pathway is essential for survival of cells generally. This made it an unsuitable target for small molecule inhibitors until recently when research showed that PI3K-delta expression occurs mainly in hematopoietic cell types. Preclinical studies suggest that blocking this molecule may kill B cells with little toxicity to other hematopoietic cells.

The present study, which used CLL cells from patients, found the following:
• CLL cells show high PI3K pathway activity and PI3K-delta expression;

• CAL-101 preferentially kills CLL cells compared to normal B-cells;

• CAL-101 selectively inhibits PI3K-delta and directly promotes apoptosis in primary CLL cells, and it disrupts multiple external survival pathways;

• CAL-101 cell killing is caspase dependent and not diminished by the presence of stromal cells;

• CAL-101 does not kill normal T-cells or NK cells or reduce antibody-dependent cellular cytotoxicity, but it does lower production of inflammatory and anti-apoptotic cytokines by activated T-cells.

Note: A phase I clinical trial (NCT00710528) of CAL-101 is currently under way in select relapsed or refractory hematologic malignancies at Ohio State and other centers. For more information on this phase I trial: http://clinicaltrials.gov/ct2/show/NCT00710528?term=cal-101&rank=2

Category:

Science & Technology

Tags:

• CLL
• CAL-101
• chronic
• lymphocytic
• leukemia
• lymphoma
• society
• james
• cancer
• ohio
• state

[tyme4mike]

It would be nice if all the 'experts' on YouTube who are talking about CLL would get together and speak ENGLISH to people like me because I have CLL and it's KILLING ME! But there are so many opinions from so many different people that I don't know my ass from a hole in the ground anymore because everyone has the answers while I sit here waiting to die. That's why I leave my life and fate in God's hands. He's the only one who knows what he's doing.

[osumedicalcenter]

@tyme4mike would you like us to connect you with someone here at Ohio State to discuss?

[heym3may3]

I have CLL and been on the Cal101 trial at Stanford since April of 2011. I had severe adenopathy (very large lymph nodes in my abdomen, the size of a basketball), white blood level around 100,000 and over 80% of my bone marrow filled with leukocytes. I have had very good success with this trial, and my adenopathy is almost gone, my blood levels are around 6,000 and bone marrow is reversing. After being admitted to the hospital three times in 2011, I have higher almost normal blood levels

[happinesson]

this is a good news for CLL patients..

[rhauentein1]

If you haven't heard, this is more than likely changing the way CLL will be treated in the fairly near future. Trials are underway and have shown great promise. Not a cure, but will probably extend lives quite a few years.

[tyme4mike]

@osumedicalcenter Thank you, no. Millions sit and wait for a glimmer of hope, and hear "new and promising", "recent trials", and "testing is about to begin". I've spent 40 years being a lab rat and I have no more to give. I'm fine with the idea of death and embrace the Bible's viewpoint. Don't you feel it's time that all these "great promises and new ideas" become "one big idea" rather than a thousand individual ones? Work for the whole cure and lose the individualism within cancer research.