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.
