Immunotherapy for Metastatic Melanoma

The big news out of ASCO 2013 was not about CLL, but about metastatic melanoma.

ASCO is well known to be more of a solid tumor meeting and it lived up to its reputation.

The big buzz is that now oncologists are using a new class of immune therapies that takes the brakes off the immune system so that it can aggressively attack the cancer.

Harnessing the immune system has long been an elusive goal in cancer therapy.

Until recently the best durable response rate in advanced melanoma was about 5% with a very difficult interleukin 2 protocol that made patients feel just awful.

Now it is over 70% and quite durable with simple combination of two separate immune therapy. And with a manageable side effect profile.

Moreover, the breakthrough PD- L1 antibody drugs discussed may have potential in a broad range of cancers, including blood cancers. It is important that those of us with CLL follow the developments in other tumor therapy so that we can be aware of any possible application or parallel research for our particular malignancy.

Exciting and hopeful times for those of us with cancer.

I am grateful to Andrew Schorr and the dedicated professional team at Patient Power for providing the support to do these fun interviews with these pioneering doctors. Please check out Patient Power over the next few weeks for more interviews from ASCO 2013.

Here's a link to Patient Power for the the first part of this same interview on the tremendous parallel progress in targeted therapy for advanced melanoma with a specific mutation that until recently had been well known as a fast working assassin for most victims.

Targeted therapy.

Immunotherapy.

Logical and complementary drug combinations.

This is the future not just for the treatment of melanoma, but for all of oncology.

Soon I will be posting my interviews with several CLL experts done in partnership with Patient Power.

Dr. Lynn Mara Schuchter on the Latest News on Immunotherapy for Advanced Melanoma from ASCO 2013

More News on Ibrutinib

The New England Journal of Medicine (NEJM) is arguably the most prestigious medical journal in the world. It is not easy to get your research into its pages and when you do, it is usually because you have moved the needle of medical science in an important way.

My daughter, when she was eleven years old, had a letter published in its pages that was picked up in the national news.

Check out  http://www.nejm.org/doi/full/10.1056/NEJM199204163261612

Dad has been published in CMAJ (Canadian Medical Assoc. Journal) and AFP (American Family Physician), but never in the NEJM.

The article on the ibrutinib where my doctor at OSU, Dr. John Byrd, is the lead author is considered groundbreaking news.

But for those of us who are living and breathing CLL everyday, this is hardly anything new.

However the rest of the world and the rest of the medical community doesn't think that much about CLL.

That is of course until it shows up in the NEJM.

Once it did, CNN and Time and Dr. Gupta were all over this CLL breakthrough.

Those of us who regularly read the updates here on my blog or in the CLLSLL Yahoo group or ACOR or at PatientPower long knew the broad outlines of this "breaking story".

But now it is vetted. Now we have the details. Now it is peer reviewed.

Now it is out in the world.

And it is pretty amazing. Please note that these great responses are independent of the usual bad risk factors.

This is an unprecedented improvement in the response rate for us who are the most difficult to treat CLL patients.

There was also an extremely important ibrutinib article on Mantle Cell Lymphoma and a thoughtful editorial on these changes in the same journal.

More on all this content and other news soon.

I have a presentation to give at UCSD to their local CLL support group on July 3 (Please join me at the Commons on the second floor of the Moore Cancer Center at 4 PM if you are interested), and then I am done with travel until my next trip to Columbus in mid July.

What that means is some free time to read, write, and edit the videos from ASCO to post here.

Here is the NEJM abstract on monotherapy. Exciting times. Enjoy.

Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia 

John C. Byrd, M.D., Richard R. Furman, M.D., Steven E. Coutre, M.D., Ian W. Flinn, M.D., Ph.D., Jan A. Burger, M.D., Ph.D., Kristie A. Blum, M.D., Barbara Grant, M.D., Jeff P. Sharman, M.D., Morton Coleman, M.D., William G. Wierda, M.D., Ph.D., Jeffrey A. Jones, M.D., M.P.H., Weiqiang Zhao, M.D., Ph.D., Nyla A. Heerema, Ph.D., Amy J. Johnson, Ph.D., Juthamas Sukbuntherng, Ph.D., Betty Y. Chang, Ph.D., Fong Clow, Sc.D., Eric Hedrick, M.D., Joseph J. Buggy, Ph.D., Danelle F. James, M.D.,
and Susan O’Brien, M.D. 

Background
The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton’s tyrosine kinase (BTK), an essential component of B-cell–receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells.
Methods
We conducted a phase 1b–2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg.
Results
Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%.
Conclusions
Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.)
n engl j med nejm.org 

The Biggest Mistake Patients Make

The Biggest Mistake Patients Make

This is a link to an interesting post.

Even doctors are not immune to thinking anecdotally. Our personal mistakes and successes inform our future decisions and the advice we offer more than we might admit. It can be easier to remember a particular patient than a bunch of statistics.

One caveat: statistics are always blended data. Rare indeed is the CLL study on 57 year old females with exactly two prior chemo-immunotherpies who now needs treatment for enlarged nodes, but whose counts are good.

More likely we will see a study that takes all comers whatever the age or gender or indication for therapy. Maybe the trial only accepted those who have relapsed or who are under 65, but whether is a statistic or an individual, we need to assess carefully how similar their situation is to ours, and then discount or value the information accordingly.

We are always making decisions with imperfect knowledge. Knowing how to weight the value of what we do and don't know can help.

Delays

OK, it is not about CLL or cancer survivorship, but I am delayed again for hours at an airport. Second time to or from Chicago in two weeks. Hours of sitting around.

Hours in planes, hours in airports, waits at train stations and subway stations, days in hotels, long cab and bus and tram and not so express train trips to and from. More security lines and custom checks, though with my Global Entry and TSA Pre-Check, the process is pretty short and sweet.

I am tired, but at least I am not sick and tired.

Can't wait to be back in California. Only one more cross country trip in June, and then I am done until I fly back to Columbus in July.

Turns out even my landing today was delayed because Air Force Two (with the VP) was on the tarmac at SFO.

IVIG: FDA Demands More Prominent Notification of the Risk of Blood Clots

I get IVIG for my ITP. It used to be every three weeks, but now I have been able to stretch it out to every six and my counts are still great. No one is really sure how it works for ITP, but there are theories that it coats my platelets and protects them from premature destruction. I also enjoy the added benefit of protection against infections.

But it comes with risks. I have discussed some before including infusion reactions and allergies, and renal disease. It is an expensive pooled blood product, so there is always the theoretical risk of an occult infection, but there is such extensive safety measures in place that I don't worry much about that one.

Now the FDA is highlighting the risk of blood clots (thrombosis) in a boxed warning.

Ironically those of us with ITP already have a simultaneously higher risk of both bleeding and clotting. How lucky can you be?

I don't plan to stop getting the infusions, though there is a good chance my ITP is no longer active, but why take the chance. Instead I will try to avoid hopping on a plane the day after an infusion as has been in the case many times in the past. Hydration, being active, and my omega 3 rich diet might also help mitigate risk. So would aspirin, but that's not for me with all my platelet problems in the past.

This is the communication directly from the FDA:

Vaccines, Blood & Biologics FDA Safety Communication: New boxed warning for thrombosis related to human immune globulin products. Date: June 10, 2013 Purpose: FDA has analyzed recent data that has strengthened the association between the use of intravenous, subcutaneous and intramuscular human immune globulin products and the risk of thrombosis. Additional caution regarding the use of these products is warranted. Summary of Safety Issue 1 Recommendations for Patients 2 Recommendations for Health Professionals 3 Summary of Safety Issue The U.S. Food and Drug Administration (FDA) is requiring manufacturers to add information on thrombosis to th current boxed warning in the labels of all intravenous human immune globulin products and to add a boxed warning to the labels of all subcutaneous and intramuscular human immune globulin products to highlight the risk of thrombosis and to add information on its mitigation. A retrospective analysis of data from a large health claims-related database, as well as continued postmarketing adverse event reports of thrombosis have strengthened the evidence for an association between the use of intravenous, subcutaneous, and intramuscular human immune globulin products and the risk of thrombosis. This information necessitates a boxed warning for the entire class of products. Human immune globulin products are used in a variety of conditions, both on and off-label, by healthcare professionals who may not be aware of the thrombosis risk and measures that could be taken to mitigate this risk. Although all human immune globulin products already contain some information related to the risk of thrombosi in the current WARNINGS and PRECAUTIONS sections of their labels, FDA recognizes that the communication of this risk and its mitigation are not standardized. FDA proposes that for thrombosis a more prominent placement of risk information and a uniform approach for communicating the risk and its possible mitigation will help to reduce the occurrence of these serious adverse events. The information on thrombosis in the boxed warning states: Thrombosis may occur regardless of the route of administration. Risk factors include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. For patients at risk of thrombosis, administer at the minimum concentration available and at the minimum rate of infusion practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Recommendations for Patients Patients should be aware of this risk and discuss this risk with their healthcare professionals. Be aware that thrombosis is associated with human immune globulin products. Talk to your healthcare professional about any risk factors or concerns you may have with human immune globulin products. Contact your healthcare professional if you develop any signs or symptoms of thrombosis during or after receiving human immune globulin. Signs or symptoms of thrombosis may include: pain and/or swelling of an arm or leg with warmth over the affected area discoloration of an arm or leg unexplained shortness of breath

chest pain or discomfort that worsens on deep breathing unexplained rapid pulse
chest pain
numbness or weakness on one side of the body

Recommendations for Healthcare Professionals

Healthcare professionals should be aware of the risk for thrombosis with human immune globulin products and ensure appropriate patient selection and monitoring.
Discuss with your patients the risk of thrombosis associated with these products.
Carefully consider risk factors when selecting patients for treatment with human immune globulin products
Monitor patients carefully for signs and symptoms of thrombosis both at the time of infusion and after infusion and encourage patients to report any signs or symptoms.
Report adverse events involving human immune globulin products to the FDA MedWatch program.

New Adverse Event for Ibrutinib: Brittle Nails

The Registration Trials that are ongoing are purposed not only to find out if the strong response rates seen in the earlier phase 1 and 2 trials hold up with larger and different populations of patients, but also to look for early signals of unanticipated side effects of adverse events.

But problems with medications can show up very late in the game.

Who would have guessed that pregnant mothers who received DES (Diethylstilbestrol) in what turned out to be a futile attempt to reduce the risk of miscarriage would see a problem a generation later when it was realized that their daughters exposed in utero had an increased risk of a rare vaginal and cervical cancer.

And while a good number of the brave first patients out of the handful that entered the phase 1 trial of ibrutinib are still doing well on drug, at the time of this writing I don’t believe that anyone has been on the medicine for even four years, and most of us for much shorter times.

Therefore we should not be surprised as our experience grows with the new generation of treatments heading rapidly for FDA approval when new possible concerns pop up.

I didn’t get a chance to ask Dr. Byrd when he spoke on the early results with ibrutinib in Stockholm at the same meeting where I too lectured (I gave a patient’s perspective on having CLL and how my life was impacted by both the disease and by my dramatic response to the new medicine) about the incidence or statistical significance of what to me was an unknown adverse event: brittle fingernails.

That explains why my career as a hand model will never get off the ground. My fingernails break easily and I must keep then very short at all times to avoid them tearing. Reaching in and out of my carry-on bag with its computer sleeve and tight pockets where I stuff my papers and medications is like a dance in a minefield for my fingertips, and they are often the worse for wear after my travels.

I also am certain just as we all know that when someone asks us if our nose is itchy, our noses are more likely to itch, awareness of the possibility of any problem increases the incidence of the problem. I will now join the ranks of those ibrutinib subjects reporting brittle nails, though for me the fashion consequences are much less significant compare to the women who enjoy growing and painting their nails and who, I bet, were much more astute and observant than me in pointing out this problem early on.

I just thought it was a consequence of my vegan way. Maybe it is.

In the big scheme of things, jagged fingernails are not a biggie. Sure beats pneumonia or neutropenia. Still could it be a marker of a bigger problem?

What’s next? Split ends? This isn’t so crazy. Many chemo drugs not only cause your hair to fall out, but when it grows back, it grows in curlier due to the broken bisulfide bonds.

Will our future doctors be able to walk into our exam room, check our fingernails, and assess if we have been compliant with taking our medications?

Time will tell, but I am pleased that so far, so few nasty signals are popping up.

ASCO 2013: The increasing numbers with Ibrutinib

As many of you know I have done very well on ibrutinib for the last year. When I started on PCI-32765 on May 7, 2012, there had been just a little more than a hundred patients who had been on the exciting new oral drug. Many of those early adapters are well known members of the CLL online community. Many are friends.

Personally, I am continuing to do great with near normal counts and no palpable nodes. CT next month in Ohio. All good. Off to Stockholm next week before EHA and just home from ASCO.

Now the community of ibrutinib users including those taking it for other B cell cancers including MCL, WM, and others now exceeds 1500 brave volunteers. Remember that the first trials were only begun in 2009. Many of those phase 1 trial patients are still on drug that tells us something about the durability of the responses, albeit in very small numbers. Still that makes the longest experience with ibrutinib something short of 4 years.

And as with many other biological treatments, the longer we stay on ibrutinib, the more responses, the more complete responses.

One of the nice problems is that when over 200 patients from the early trials were consolidated to look for those who had relapsed after more than a year on therapy, there was only a handful patients to study in more depth. Leaving aside the expected number of Richter's Transformation, about  only 1 out of 20 patients had relapsed with CLL. Most were 17p deleted but one was 11q deleted with a history of nasty auto-immune hemolytic anemia. I refer you to Dr. Sharman's nice review of the subject.

Whenever ibrutinib is approved (and hopefully that will be soon), the number of patients taking the medicine will swell. Other oral drugs may quickly follow. We will need to remain vigilant to see if rarer side effects become apparent post approval. And watch for long term surprises.

Many questions unanswered, but we have come so far in so few years.

And this is just the beginning of a new wave of targeted therapy. Ibrutinib and idelalisib and ABT-199 and GA101 are just the beginning of new wave of game changing therapies. Second and third generations of mAB and TKIs are following on their heels. We patients are needed for the trials to maintain the forward progress.

But let's celebrate the progress that we have made.

These are good times.