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.

Stem Cell Transplant

Very few of the things we do to treat patients with lymphoma or CLL are more foreign than “transplant.”  When I bring it up as a treatment option, I often get more of a bland reaction than anything else. When it comes to transplant, I suspect the reason is that most patients don’t even know what they don’t know.

It is easy to be scared of the “boogey man” because we all grow up terrified of the mythical character – but transplant?  Few patients have had firsthand experience to understand what it means until they start down that path on their own. Furthermore, there is more misinformation and even fraud out there about “stem cells” than just about any other treatment available.  Even the entire medical community was duped by fraudulent science for a number of years.  Like many aspects of cancer care, an informed patient with good judgment will always be better off.

There are two main types of transplant – autologous (aka. auto – from yourself) and allogeneic (aka. allo – from someone else).

 Auto transplant is really the easiest to understand.  The best way to conceptualize an auto transplant is just “high dose chemotherapy.”  In an auto transplant, the patient donates his own stem cells (normally by a process called apheresis which is a lot like dialysis).  The cells get stored in the freezer for later use. The patient then goes into the hospital for a very high dose of chemotherapy that is enough to wipe out the bone marrow completely.  The doc thaws out the stem cells from the freezer, and infuses them into the patient (via the arm) a day or two later. 

The stem cells magically find their way back to the bone marrow where they set up shop and begin producing new cells.  About three weeks later those stem cells “engraft” and the blood counts start coming back.  It has the effect of exposing the cancer to a very high dose of chemotherapy while protecting the bone marrow by keeping it out of the fight.

During the period of time following the chemotherapy and before engraftment, the patient is pretty fragile medically.  Red blood cell and platelet transfusions are almost always necessary.  Since transfusing white blood cells doesn’t work that well and could even be dangerous the patient is at risk for infections. 

Fevers are the norm as gut bacteria take advantage of the absence of an immune system.  Infections that would often be quite unusual including fungal infections of the sinuses and lungs can become very dangerous.  Just about every patient will be on some powerful antibiotics to get them through those several weeks whether they are treating an infection or trying to prevent one.  The patient is often in the hospital for a considerable part of the time while their immune system is compromised.  A number of transplant centers are able to get the patient out of the hospital for some of the time but getting readmitted is quite common.

Much of the acute risk abates after the first 30 days, but for a nearly a year, there may be some dysfunction of the immune system.  Shingles infections and a weird pneumonia known as PCP (or whatever they have changed its name to this year) can happen during this longer period so preventative antibiotics are fairly common and work pretty well.  Overall, I would say that patients feel like a survivor who has regained their footing somewhere between 30-60 days but the lingering, vague, sense of wellbeing takes quite a bit longer.  I’ve heard patients say they didn’t feel back to “normal” for anywhere between 6-12 months.

Age makes a huge difference for patients going through this.  We always make a point of saying, “chronology does not equal physiology” but as individuals get older the process becomes much harder.  The balance between risk and benefits shifts for the worse somewhere between ages 65-75.  Many 65 year olds could get through this though they will definitely feel quite a bit older when they are done with it.  Other 65 year olds who have acquired lung, heart, or kidney disease along the way may not be eligible.  At the other end, few 75 year olds would be able to get through this.  Many transplant centers will have an age cutoff of around 70 years and may make exceptions for the 72 year old who still does recreational distance running.  Europe tends to be more conservative and age restrictions are more firmly set and may be as young as 60-65 in some cases.

Auto transplant is often employed for patients with Diffuse Large B Cell Lymphoma whose disease has reoccurred after initial therapy.  It is also commonly used in T cell NHL (sometimes in first remission, sometimes after relapse depending on the type and other variables).  It is less frequently used in Follicular Lymphoma (or other indolent NHL’s) for a variety of reasons and rarely (if ever) used in CLL.  Multiple Myeloma is one other blood cancer where it is quite common but I have not written extensively on this blog about that disease.

Allo transplants are an entirely different animal and need considerably more explanation.  The fundamental difference in an allo transplant is that the bulk of the anti-cancer activity comes from the transplanted immune system identifying the cancer and eliminating it.  The hope is that the immune system doesn’t also eliminate the patient at the same time.  Unfortunately it can be hard to control the outcome once the wheels are set in motion.

In allo transplant, there are two main questions.  The first is whether the process will be myeloablative (ie. use powerful chemotherapy to wipe out the bone marrow first) or non-myeloablative (just weaken the immune system enough to slip somebody else’s immune system in).  The second question is how well matched the donor is.  A donor can be a “matched related donor” (MRD), a “matched unrelated donor” (MUD), or a “mismatched unrelated donor.”  There are other significant questions (ie. tumor purging, T-cell depletion, half-match donors (ie. haplo) but I want to finish this post before my plane lands in three hours.

In a myeloablative transplant you pretty much start out with an auto transplant in terms of chemotherapy.  The most obvious difference though is that the stem cells don’t come from the patient – instead they come from somebody else.  In a non-myeloablative transplant you utilize drugs that profoundly weaken the immune system (without getting rid of it completely) enough so that it doesn’t quickly “reject” a bunch of new stem cells as though they were an invading hoard of bacteria.  Interestingly, the drugs utilized  may include campath and fludarabine (two drugs often used to treat CLL in the first place).

The type of donor also makes an enormous difference.  I need to go into a little depth about how the immune system works.  HLA genes are central to how an individual’s immune system interacts with the body and any infections.  When an infection gets into the body, the virus or bacteria gets swallowed by certain cells and chopped up into lots of tiny bits.  These bits then get loaded onto proteins on the surface of the cell encoded by HLA genes sort of like an ice cube in a cup.  This is a process known as “antigen presentation.”  How the little pieces of chopped up virus or bacteria (the ice) sit inthe HLA proteins (the cup) plays an enormous role in whether the immune system decides there is a problem or not.  The better your cup matches somebody else’s cup, the more likely the ice is going to fit the same way (this analogy would work a lot better if it was a really small cup or a really big ice cube so that it was a pretty snug fit)

The major HLA genes are on chromosome 6 and you have two different sets (one from mom and one from dad).  On each chromosome, there are three main sites (HLA-A, HLA-B, and HLA-DR) and each site could have quite a few possible variations (59, 118, 124 respectively).  So there are six different sites that need to match up perfectly and each site could have a multitude of different variations. Therefore there is a very small chance that two genetically unrelated individuals would be a perfect match.   Since half of your HLA genes come from mom and half from dad and in each case they are inherited in unison (ie you get one chromosome with three automatic matches), you have a one in four chance of matching a biologic sibling. 

By definition, you could NOT be a match with either a parent or a child (half match at best unless they were cloned).  I did have a memorable patient from an area where individuals were occasionally known to get married to a relative.  He told me, “Son, my family tree don’t branch.”  You should  know that donor searches sometimes turn up family surprises (albeit rarely).

Beyond the “major” HLA genes, there are a bunch of “minor” genes that are so numerous and so variable, that it is simply best if you have a sibling donor that is a match.  That will almost always be the best fit.  If you didn’t win the sibling lottery with the 1/4 chance of a match, then they look through the donor registries.  I’ve never understood why this can take so long – but it does.  North American Caucasians have a pretty darn good chance of finding several matches.  Once you start throwing in ethnic minorities into the gene pool though, the chance of finding a match gets lower (not impossible).  Often they may find multiple donors that match and then they can utilize additional techniques to figure out who is a “better match.”  Sometimes banked umbilical cord blood can serve as the donor tissue in certain centers. 

Once a match is found, and the “conditioning regimen” is given to the patient (whether that is myeloablative chemotherapy, or non-myeloablative therapy), the new stem cells are injected.  These can take a while to engraft just like in auto transplants above.

Once the cells are engrafted, a new challenge arises.  Since these immune system is from another person, it will start to attack the body it was put into in a process called “graft versus host disease” (aka. GVHD).  The physician therefore needs to “lower” the new immune system by giving drugs like methotrexate and cyclosporine.  These are not necessarily easy drugs to manage.

You might therefore ask, “if I am getting a new immune system to attack my cancer, why are you choosing to handicap it?”  GVHD can be a lot worse than the cancer at times.  GVHD is divided into early versus late depending on which side of 100 days it falls.  Acute GVHD can manifest with dangerous rash, diarrhea, and liver dysfunction.  Chronic GVHD can have just about any sort of problem you can imagine, but often includes skin and gastrointestinal side effects.  Acute GVHD can be life threatening if not managed correctly.  Simultaneously with a lowered immune system, infections can be an enormous problem.

The danger often subsides with time and the immune suppression can be lowered.  This enables the transplanted immune system to go after the cancer.  Since that can take a while though, it makes most sense for patients to have their disease under optimal control before going into transplant.  If you have a lot of CLL running around, chances are it will progress before the immune system can go after it.  Furthermore, the immune system may think the cancer is supposed to be there, then you are stuck with both the cancer and the GVHD…..aargh.

If everything goes well, the transplant center may let you return to your home community after about 100 days.  Yes – you may need to temporarily live near the hospital for several months.  Transplant programs often have arrangements to make this possible. 

If all goes well, you may indeed be cured of your disease.  For something like relapsed DLBCL or CLL, that can be a life you would not possible have any other way.  It makes it quite a high stakes gamble.  There is both high risk and potentially high reward.

Many have heard about the new “engineered T-cells.”  I am on my way back from the IWCLL meeting (international workshop on CLL) where we heard an update on this technology.  Looks like 1 out of four patients may be genuinely cured by this.  Another 1 out of 4 get a partial response.  For half of those it is brief and the other half it continues to improve over time.  2 out of 4 patients may not benefit from the procedure.

These are impressive statistics for a procedure that functions like an “allo transplant” but by definition does not have the risk of GVHD.  Numbers are still VERY small.  Something like 30 patients have been treated at Penn TOTAL.  I think in the long run, this will be done before allo transplants – but it is still early enough that it remains difficult to predict.

Hopefully that is a good orientation.  It is by no means complete but I think I’ve officially got a writers cramp. 

Thanks for reading