How I approach follicular lymphoma (part 2) - patients with higher risk disease

In the last follicular lymphoma post, we talked about what to do with our patients with lower risk or less extensive disease.  I wanted to talk about patients with more extensive disease or higher risk features.

If we go back to the lymphocare study as a starting point, back in 2004-2009 timeframe the main rituxan containing chemotherapy regimen choices were R-CHOP > R-CVP > R-Fludarabine.

With the genius of drug regimen naming, I should point out that R-CVP and R-CHOP are essentially the same drugs (vincristine is also called oncovin) with the latter having the addition of hydroxydoxorubicin which we call adriamycin - aargh.  R-CVP is mild but the addition of adriamycin is a pretty big deal for most patients.  It causes you to lose your hair, it can possibly weaken your heart muscle, and it can increase the likelihood of long term damage to your bone marrow.  These regimens were built out of the early chemotherapy days when "combination chemo" was all the rage.  The idea was that if one drug was good, four must be better.

To my knowledge there was never a CVP vs CHOP study sans rituxan (though if an reader knows of one, I will be happy to update my post).  In the pre-rituximab era CVP became the regimen you used when you had less extensive disease or you were worried about someone being too frail for CHOP.  CHOP was the "big guns" and used quite extensively to maximize remission duration.

CVP and CHOP both got a good "facelift" with the addition of rituxan which joined the picture in the very late 1990's.  Rituxan was the perfect drug to add to these combinations since it had essentially no toxicity on the bone marrow, was very effective on it's own, and seemed to make chemo work better.  There were several studies in which the design was chemo +/- rituxan - I highlight two:

Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up.

Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma.

This year at ASCO was the first time I have seen a direct comparison between R-CVP and R-CHOP (ignore the fludarabine-mitoxantrone combo because it is infrequently used in the US).  I don't think this study could have been done in the US because a study in which you are randomized to adriamycin or not is a tough sell to patients - thank goodness for the Italians!

R-CVP versus R-CHOP versus R-FM as first-line therapy for advanced-stage follicular lymphoma: Final results of FOLL05 trial from the Fondazione Italiana Linfomi (FIL).

This study showed that at three years 2/3 of patients who got R-CHOP were still disease free while < 1/2 of patients who got R-CVP were controlled.

The biggest change in treatment compared to the lymphocare study was the introduction of Bendamustine.  This drug has a wild history.  If you are looking for a cure for insomnia, watch my video on history of cancer treatment which starts with the bombing of Bari Italy and the startling birthplace of chemotherapy.  Bendamustine was hanging around East Germany for many years.  It wasn't until the fall of the Berlin Wall that folks in the West discovered what the East Germans had been using for decades.  I don't think it is an exaggeration to say that this drug has turned FL on it's head.

The change began with impressive results seen in smaller studies of patients with relapsed disease.  Even after patients had had multiple prior regimens, bendamustine came in and demonstrated pretty impressive results.

The biggest change though was the head to head matchup of BR vs R-CHOP done by the German group lead by Rummel.

Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study.

This turned a lot of heads when it was initially presented at ASH in 2009 because it showed that BR was at least equivalent to R-CHOP.  Since BR is considerably easier on the patient (no hair loss, no cardiac risk, perhaps less heme side effects) - it would be the equivalent of a mid weight boxer taking a heavy weight boxer into the late rounds for a tie match.

Perhaps more shocking however was the updated ASCO presentation this last June when it captured the plenary session for demonstrating a convincingly superior "progression free survival" (time that patient is alive without recurrence of lymphoma).  By a wide margin (average 3 years vs 6 years) BR kept patients disease away for longer with less side effects.

I have heard an interesting criticism of the study that the R-CHOP arm performed far worse in this study than virtually all other studies in FL.  Perhaps the magnitude of the difference is smaller than what is reported, but in a randomized study, you would expect BR to end up underperforming as well so I am not sure how to interpret that observation.

So where are we now?

If you go back to the lymphocare study that was pre-bendamustine, you had R-CHOP =50%, RCVP =25%, fludarabine-R at around 15% of front line therapy.

I think R-CVP is virtually gone at this point.  If BR > R-CHOP > R-CVP in terms of efficacy, I think BR = R-CVP in terms of tolerability.  At this point, I do not envision recommending R-CVP except in pretty unusual circumstances.  I think BR has also captured a significant portion of the R-CHOP and even the fludarabine based regimens.

I would wager if lymphocare was repeated today it would be BR = 60%, R-CHOP = 30%.  You may appropriately read my bias for BR in this post.  It is totally fair to ask when would you ever give R-CHOP.  I would not disagree strongly with anyone who were to recommend R-CHOP.  I still want to see Rummel's paper and I also want to see the initial results of the "Bright" study which was a US version of the same study (ASH 2012?).  If that one shows BR to be so much better - then R-CHOP has an even steeper hill to climb.

Occasionally (20-30% at 10 years) follicular lymphoma takes on a bad attitude and "transforms" into Diffuse Large B Cell Lymphoma (DLBCL).  Sometimes you have a biopsy in one place, but you suspect based on scans there is a transformation elsewhere.  In these cases R-CHOP is completely appropriate as we think the adriamycin is completely appropriate for the transformed disease.  Some other researchers are still sticking by R-CHOP since it has such a long track record and perhaps there will be some long term issues with bendamustine that we don't know about yet.  This is definitely possible.

I could probably switch gears now and talk about the PRIMA study for rituximab maintenance but I've spent too long on this post already and I would rather get it out there and leave that topic for another day.