Friday, March 30, 2012
Wednesday, March 28, 2012
Update on the trial of ofatumumab and Ibrutinib
Monday, March 26, 2012
PCI-32765 or Ibrutininb and why the great responses in CLL
I almost never just have a strictly medical post, but I thought this was such a clear and concise explanation of how ibrutinib (I better get used to PCI-32765's new name) and GS-1101 (another new name, this time for for CAL-101) that it needed to be shared by those considering one of these new agents for treating their CLL.
Dr. Rai has more experience than anyone in treating CLL and he has no time or tolerance for bogus claims or hype, so I deeply respect his opinion.
That doesn't stop me from questioning his argument in favor of combination therapy.
First. it is too early to know what is best. Dr. Wiestner at the NIH is looking at a single agent therapy and others including Dr Byrd at OSU and Dr. O'Brien at MDACC at combinations.
Second, I worry about powerful chemo selecting out the most refractory clone.
And third and most importantly, I believe that these new small molecules portent a sea change in how we treat CLL with the depth of remission not being the measure of success, but rather the duration of the response.
Let me know what you think.
The original article in Blood can be found here:BLOOD article on ibrutinib.
It is an exciting time in the world of CLL.
9 0Posted March 25, 2012
BTK inhibitor linked to CLL regression
de Rooij MF. Blood. 2012;doi:10.1182/blood-2011-11-390989.
The Bruton’s tyrosine kinase inhibitor PCI-32765 demonstrated inhibitive properties in primary chronic
lymphocytic leukemia, according to recent results.
The researchers based their hypothesis on the premise that small molecule drugs that target the B-cell antigen receptor (BCR) signalosome demonstrate efficacy in B-cell non-Hodgkin’s lymphoma. One such drug, the Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765, also demonstrates a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis in CLL. This reduction is reversible upon temporary drug deprivation, according to the researchers↓ The researchers hypothesized that the clinical response induced by PCI-32765 reflects impaired integrin- mediated adhesion and/or migration.
In the current study, it is demonstrated that the drug strongly inhibits BCR-controlled signaling and integrin alpha-4 beta-1–mediated adhesion to fibronectin and vascular cell adhesion molecule-1 of lymphoma cell lines and primary CLL cells, according to the results.
It also has been shown that the drug is an inhibitor to CXCL12-, CXCL13- and CCL19-induced signaling, adhesion and migration of primary CLL cells.
“Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of the malignant B cells in their growth- and survival-supporting lymph node and bone marrow microenvironment, resulting in the clinically evident CLL regression,” the researchers concluded.
Two important new drugs have attracted the attention of colleagues all over the world who treat patients with CLL. Both PCI-32765 and GS-1101 demonstrated an extraordinary level of activity when each was used as a single agent in previously treated CLL patients who had bulky lymphadenopathy, and had relapsed or refractory disease. PCI-32765 is an inhibitor of BTK, while GS-1101 is an inhibitor of PI-3 kinase delta isoform. These kinases are considered to be highly active inhibitors of BCR signalling and chemokine networks. The paper by de Rooij and colleagues provides clear and convincing evidence as to how PCI-32765 actually works. These researchers,by meticulous and disciplined work, demonstrate that this drug acts on the micro- environment of lymph nodes and bone marrow where the leukemic cells can live safely and proliferate, an important mechanism for maintenance and progression of the disease. When exposed to PCI-32765, the leukemic cells can no longer hide in their safe harbors of lymph nodes and bone marrow, and they also can no longer continue to proliferate. Being deprived of adhesion-capabilities, these leukemic cells must, therefore, migrate into the circulating blood. That explains why the bulky lymph nodes shrink in size dramatically and rapidly when the patient starts taking this oral medication. This paper also makes it clear as to why the numbers of lymphocytes in the circulating blood increase equally dramatically,at least initially, while the lymph nodes are shrinking. Finally, this paper explains why it will be important to move from using PCI-32765 as a single agent and toward combining it with a monoclonal antibody or chemotherapy, if a lasting and good-quality remission is the desired objective. The leukemic cells pushed out from the lymph nodes and other tissues are eminently killable by cytocidal agents while they are in the blood circulation, where they no longer have the protective chemokines that allowed them to resist while they resided in the lymph nodes. In my view, this is an important contribution that explains the mechanism of action of the exciting and promising new drugs in the treatment of CLL.
– Kanti Rai, MD
HemOnc Today Editorial Board member Disclosure: Dr. Rai reports no relevant financial disclosures.
Copyright © 2012 HemOnc Today. All rights reserved.
Thursday, March 22, 2012
Spiritual Teaching about Food
When Swami Vidyatmananda, a westerner that had joined the Ramakrishna order was a probationer, he went to India to visit the headquarters of the Order. One day, he decided to leave the ashram in the outskirts of Calcutta and go into the city for the day to do some shopping. When he told his superiors his plans, one of the swamis inquired as to what he would do for food while he was there. He told the swami that he would simply go to a hotel to eat (thinking to himself that he could get a good western-style meal that way). The swami responded to his idea by suggesting that it would be better if he went to the order’s ashram in the city for his meals and offered to phone them for him. The swami then went on to explain that the members of the Order avoided eating in hotels and restaurants because of the low spiritual vibration of the food there.
“Food not prepared with devotion, not prepared with the idea that it is to be offered [to God] in the shrine – but just devised impersonally for making money by people with their minds full of gross thoughts – can adversely influence your spiritual growth.”
In one of his teachings, the Baal Shem Tov asks the question: the body receives nourishment from the food we eat but from where does the soul receive its nourishment? The answer that he gives is that the soul receives its nourishment from the Divine spark that is in everything; for everything in the world has been made by God and therefore is filled with His Spirit.
When we eat, it is our bodies that take up the physical nourishment that is in the food. However, if we recite a blessing with intention before eating, and turn our minds towards God, then it is our soul that receives nourishment from the Divine spark that is enrobed in the material form of the food.
Tuesday, March 20, 2012
Dealing with "this mental roller coaster"
The transitions between high alert stages and the low alert stages take too much mental energy. I need to find a middle ground to function in.
Monday, March 19, 2012
Death in the PCI-32765 trial
Sunday, March 18, 2012
Tornado Warnings, sore hips, and my broken internal clock
Tuesday, March 13, 2012
WIRED AND TIRED, GEESE AND BEAVERS
After a mostly sleepless night and a wasted day (sounds like back in college, but not nearly as much fun), I am quickly crashing from my "roids" driven high. Patty and I did manage a lovely short walk at the wetlands a mile from here where we saw beavers and Canada geese and a million other birds before the floor dropped out from under me and I stumbled home. The scene made me long for my birth land, O, Canada, the true north strong and free. Thanks for the tip, Wayne. Much appreciated.
The winter seems to have vanished in Columbus, which is just fine with me. What a difference a week makes. Last week it was snow flurries and howling winds. This weeks it's golf and biking weather.
But I am getting dreamy and have work to do tomorrow, so I forced myself to not nap today so I can sleep tonight.
Just because I teach others about sleep disorders, doesn't mean I have to demonstrate them.
Monday, March 12, 2012
Don't do anything RASH
Thursday, March 8, 2012
Virtual Cancer Buddy
I have been dreaming.
Actually at the urging of a forward thinking doctor friend, I have been wondering what might be in the best interest of all cancer survivors in a high tech approach to managing what is increasingly being understood as a chronic disease. That is certainly the case with CLL as the new therapies evolve.
I am envisioning something much more than a simple excel sheet that tracks labs. What I want is some kind of virtual helper that electronically nudges me to take my meds on time and do my aerobics. I don't think this is a fantasy. Hospitals are already exploring using patient portals to help manage heart failure and diabetes after discharge. Cancer care has a more distant and broader horizon, but I still think it can work.
What would you want included in this virtual cancer buddy?
Here are some thoughts I had in no particular order.
Contact info for providers?
Personal reminders of meds, exercise, appointments, lab?
A patient portal to ask questions or review labs?
Annotated interactive med lists that highlight possible risks, adverse events, and interactions?
Lab flow sheets with graphs and alerts?
Vital sign flow sheets?
Diet and exercise charts and advice?
Stress reduction techniques?
Glossary of terms?
Information for family and other caregivers?
Help with the decision process?
"Red flags" and what to do if you have one?
A "Siri" that answers your questions?
Please email me or post your thoughts and suggestions. Do you agree with my list? What would you add or delete? Dream big. Forget being practical. What do you really want? I will organize them and present them here and to my contacts in the hospitals systems and see if I can get some traction. At least I can make sure someone is hearing us.
I have posted this identical request on CLL at ACOR and the CLL Yahoo group and got very valuable responses that I am trying to tie together, but my blog reaches different readers and I want to hear what you have to say.
We are all in this together.
Labels: Virtual Cancer Buddy