Wednesday, January 22, 2014

Idelalisib prolongs survival in CLL

At 2PM today, our article entitled "Idelalisib and Rituximab in Relapsed CLL" was posted to the New England Journal of Medicine webpage.  I blogged about "the race tightens" last October after a press release suggested this would be an important data set.  Press releases, abstracts, ASH presentations are important, but nothing matches the importance of the full manuscript.  The full article can be accessed here.

This study took patients who were considered inappropriate for traditional chemotherapy on the basis of bad kidney function (main way we get rid of fludarabine), poor marrow function, or lots of other medical conditions.  It then randomized patients to either rituximab or rituximab in combination with idelalisib - one of the new BCR signal inhibitors.

Critics have argued that rituximab is considered inappropriate care for patients with CLL.  In general I agree, but I think this study worked very hard to identify patients for whom this treatment might be appropriate.  NCCN guidelines list rituximab as an appropriate therapy for patients with lots of medical problems.  Patterns of care data sets indicate that it is commonly used in North America.  Ofatumumab is another CD20 antibody that is approved for single agent (and our rituximab control arm did almost as well as ofatumumab in the study that led to its approval).  You can argue this point endlessly but FDA standards point toward "commonly accepted standard" and I think you can make an argument that rituximab may be appropriate in selected circumstances and this trial worked hard to define when that might be.

Long story short - adding idelalisib to rituximab absolutely blows away rituximab alone.

The overall response rate >90% versus 4%, progression free survival and even OVERALL SURVIVAL favor the addition of idelalisib.  Very few studies in CLL have EVER shown improvement in overall survival.  In fact, we were not even trying to show that point in the study and were somewhat surprised the difference was so large.  The data set also shows the relative ineffectiveness of rituximab when administered alone in previously treated CLL patients (improves WBC for 4-6 months, nodes shrink a little, then disease takes off).

This study will hopefully pave the way for idelalisib to be approved in CLL sometime in 2014.  The drug has been granted "breakthrough" designation by the FDA for CLL and has a 9/11/14 decision date by the FDA in non hodgkins lymphoma

Thursday, January 16, 2014

Talking to friends and loved ones

Cancer can be an awful experience.  From the fear, the illness, the cost, the inconvenience, etc. cancer isn't something I would wish on anyone.

But there can be a silver lining....

Cancer can let you know just how much your community really loves you.  People rally when a loved one gets cancer.  Whether it is meals, rides to the clinic, sitting through chemotherapy, visits at the hospital etc, people will go the extra mile for a friend or loved on with cancer.

When people have a large enough community, keeping everyone up to date can be a real challenge.  Telling everyone about the victories (got through bone marrow biopsy, finished chemo, had a good scan) or sharing bad news (had to delay chemotherapy a week, hospitalized for antibiotics, cancer is back) can be really daunting when you feel like crap.

I've seen a number of patients make blogs of their experience (see here and here and here) as a way to let everyone stay up to speed with what is going on in their journey.  They can make entries of any length (short or long) that allows their support network to keep up to speed with what is going on.  Sometimes you just don't want to have to tell someone a part of your story that you've already told ten other people about, sometimes you want everyone to know your good news as soon as you can!

One of the reasons I am aware of these sites (and I deeply appreciate) is that patients have often linked their own blogs to mine for specific pages that make sense to link (ie. making sense of different types of lymphoma, what is R-CHOP or FCR chemotherapy, when to treat CLL etc).  I've heard several patients tell me my post on nutritional supplements was helpful getting a well intentioned but misguided friend to lay off.  Sometimes trying to tell people all the things you heard during your doctors visit can be quite difficult and linking to a nice summary is a lot easier than trying to explain it yourself.  If my blog can help in that way, I am delighted.

Quite frankly, those links from external sites help my blog rank higher in the google search results so I appreciate each and every one of them.

There are FANTASTIC blogging sites out there like carringbridge, wordpress, or even blogger that are extremely easy to start and maintain.  You really do not need to have any computer skills beyond what you would normally use to navigate the web.  If you are truly web-phobic, ask your kids, they can set it up for you.

There are a number of really great "chat groups" out there like cllforum or that are additional great venues but I would encourage anyone out there looking for a way to have their own "homepage" think about making their own blog.

Thanks for reading

Friday, January 10, 2014

Relapsed Diffuse Large B Cell Lymphoma

Taking care of patients with Diffuse Large B Cell lymphoma (DLBCL) can be very satisfying (see my posts on front line therapy for DLBCL and the different types of lymphoma) because you can cure a good number of patients.  By "cure" I mean real, legitimate cure.  The disease is gone.  It never comes back.

With standard R-CHOP chemotherapy, close to 60% of patients will never have their disease return.  We use the "International Prognostic Index" or "IPI" criteria to get a little more specific for likelihood of cure in different patients that looks at several clinical variables such as age, LDH, amount of disease, functional status of the patient etc. With these details we can be a little more precise about likelihood of a cure for an individual patient.  New features such as "cell of origin," "gene expression" or mutation data can add a dimension of precision to this.

Unfortunately, some patients will not be cured by their first line of treatment - for those patients, cure remains a possibility but the odds of getting that cure the second time around is a lot harder.  Back in the days prior to rituximab when patients with DLBCL were treated CHOP alone (no rituximab) a study was done that compared regular chemotherapy to stem cell transplant.  The results of the PARMA study showed that almost half of patients who got transplants were probably cured of their lymphoma.  This was a lot better than the patients who only got chemotherapy (no transplant) and 12% were without recurrence at five years.

I strongly encourage people to read my blog post about transplants because it deserves its own discussion.  It is generally restricted to patients less than 70 years old with good health aside from their lymphoma.  For the most part, we are talking about "autologous" or giving your own stem cells.

The PARMA trial still informs most oncologists approach for "transplant eligible" patients (ie. salvage chemotherapy such as R-ICE or R-DHAP followed by transplant if patient has response to chemotherapy).  Unfortunately, the PARMA trial took place when patients were treated with CHOP instead of R-CHOP and the landscape has changed more than most oncologists necessarily appreciate.

Along came the CORAL study which set out to compare the difference between R-ICE and R-DHAP chemotherapy in preparation for transplant.  This study took place after R-CHOP had mostly become the standard for front line therapy.  As a result, the many of the patients enrolled in the study experienced relapses following R-CHOP (although there were some who had recurred after CHOP alone). This study enabled us to look at the natural history of relapsed DLBCL and contrast the differences between those who relapsed following CHOP and those who relapsed following R-CHOP - in other words it gave us important insight into how Rituxan had changed the landscape.

Patients who get R-CHOP do better than patients who get CHOP for front line therapy of diffuse large B cell lymphoma.  Unfortunately, that probably "selects" for the bad actors because relapses after R-CHOP are a lot worse then relapses after CHOP alone.   In most cases R-CHOP is the standard of care today. The CORAL study shows us that there are really two separate groups of patients who relapse following initial R-CHOP therapy - those that we call "primary refractory" and those with late relapses.

For the 1/3 of patients with late relapses (greater than 12 months following start of R-CHOP) can still be "cured" with transplant (45% of the time).  Provided the patient is young enough and sturdy enough to go through transplant.  In essence, they have already proven that their lymphoma is "sensitive" to chemotherapy because their initial "remission" lasted "long enough."  For those patients, if they respond to a chemotherapy "test" (i.e. R-ICE / R-DHAP), then giving them mega doses of chemotherapy (i.e. autologous stem cell transplant) may be a good idea.

Unfortunately, for the 2/3 of patients who relapse within 12 months (of initial diagnosis) have "primary refractory" disease and most thought leaders acknowledge that the rules established in the original PARMA study (pre-rituxan) may need to be reconsidered in these patients.  In many cases these patients have what was called "double hit" DLBCL (subject for future post).  In other cases, they may have had a mutation in a gene called TP53.  In other cases, we simply do not know why they are "refractory" to initial therapy.

If a patient experiences early relapse, it is probably a sign that chemotherapy is less likely to be  effective.  In young / sturdy patients, we often still follow the "PARMA rules" and try to get the patient to transplant but unfortunately what we have learned from the "CORAL rules" is that only 1 in 5 such patients is likely to be alive and free of lymphoma at the three year mark.  Twenty percent is a tough number.  It is high enough to want to try for it but low enough that in many cases you may have wished you went a different direction.

So what are the options if the transplant route doesn't work out or the patient is either too old or not sturdy enough to even try a transplant?

There are a handful of chemotherapies that we call "salvage regimens."  These are designed to buy the patient some time but not necessarily aim for cure anymore.  These are often given in combinations of drugs with names like, DHAP, Gem-Ox, ICE, ESHAP, CEPP, and EPOCH.  Most of the time, we throw in some rituximab as well.  Sometimes these regimens may be a little too stiff for older "transplant ineligible patients" and you may take just about any of the individual drugs and give them alone or at reduced doses.

I think that there are a number of drugs that are either available or soon to be available that may improve the outcome of patients in such situations.

I've previously written about the different subtypes of DLBCL known as "germinal center (GCB)" or "activated B cell (ABC)" DLBCL.  Interestingly, some drugs have unique activity in the ABC subtype which is often more likely to cause problems after R-CHOP anyhow.  These drugs include ibrutinib, bortezomib, and lenalidomide (links go to data in relapsed DLBCL).  Another emerging technology is known as "antibody drug conjugates" which has been subject of prior posts as well.  These drugs do not appear to necessarily be restricted to ABC subtype and may possibly work in either setting.  This includes drugs like brentuximab, and others that target B cell markers like CD79 and CD19 (but only have incomprehensible names) that are only available in clinical trials.  There is the emerging technology of "chimeric antigen receptor T-cells" which most of my patients call "gene therapy" and has been the subject of intense media attention recently.  This technology holds out hope that we can cure some patients that we have previously considered incurable.  Finally, there are new genetic tests that can be run on DLBCL that may point toward therapies that are uniquely appropriate for a specific individual based upon their mutation profile.

At least for now, the goal of MOST of these is to slow the lymphoma down and maybe even get to a remission.  While I would love to think that we were aiming for a cure when relapsed DLBCL either can't make it to transplant or transplant would be inappropriate, that is infrequently the case.

Hopefully this gives a reasonable roadmap for patients whose DLBCL.  It is not meant to be exhaustive or substitute for individual discussions with your own doctor.

Thanks for reading.