Curing “Incurable” Cancers

Follicular lymphoma is a subset of Non-Hodgkin’s lymphoma (NHL). Follicular lymphoma (FL) and CLL are both cancers of the B-cell compartment of our immune systems and both diseases are considered incurable by conventional chemotherapy approaches. While there are significant differences between CLL and FL, there are also many similarities. This makes it important for us to keep an eye out for developments in the FL arena.

Quoted below is a hot off the presses abstract in “Blood”, detailing the 8 year experience of M. D. Anderson doing mini-allo transplants for high risk FL patients. I have often been frustrated that research papers reporting mini-allo transplant statistics lump a whole list of cancers in their studies, including a lot of acute leukemias and myeloid cancers. CLL is truly “the good cancer” to have compared to some of these diseases. In other words, grim statistics from these much harder diseases may be drowning out the better outcomes when we split out CLL and other indolent lymphomas (such as FL) from the general mix of blood cancers. While the data below pertains to FL and not CLL, that is close enough to get us a sense of what to expect in CLL mini-allo transplants.

Blood First Edition Paper, prepublished online April 14, 2008

8-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide and rituximab

Issa F. Khouri*, Peter McLaughlin, Rima M. Saliba, Chitra Hosing, Martin Korbling, Ming S. Lee, L. Jeffrey Medeiros, Luis Fayad, Felipe Samaniego, Amin Alousi, Paolo Anderlini, Daniel Couriel, Marcos de Lima, Sergio Giralt, Sattva S. Neelapu, Naoto T. Ueno, Barry I. Samuels, Fredrick Hagemeister, Larry W. Kwak, and Richard E. Champlin

Nonmyeloablative stem cell transplantation in patients with follicular lymphoma has been designed to exploit the graft-versus-lymphoma immunity. The long-term effectiveness and toxicity of this strategy, however, is unknown. In this prospective study, we analyzed our 8-year experience. Patients received a conditioning regimen of fludarabine (30 mg/m2 daily for 3 days), cyclophosphamide (750 mg/m2 daily for 3 days),and rituximab (375 mg/m2 for 1 day plus 1000 mg/m2 for 3 days). They were then given an infusion of human leukocyte antigen-matched hematopoietic cells from related (n=45) or unrelated donors (n=2). Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Forty-seven patients were included. All patients experienced complete remission, with only 2 relapses. With a median follow-up time of 60 months (range, 19-94), the estimated survival and progression-free survival rates were 85% and 83%, respectively. All 18 patients who were tested and had evidence of JH/bcl-2 fusion transcripts in the bone marrow at study entry experienced continuous molecular remission. The incidence of grade II-IV acute GVHD was 11%. Only five patients were still undergoing immunosuppressive therapy at the time of last follow-up. We believe that the described results are a step forward toward developing a curative strategy for recurrent follicular lymphoma.

This is an important paper for two reasons. First, it gives us a better perspective of how mini-allo transplants work in B-cell cancers as opposed to a mix of all blood cancers. Second, it sets to rest (I hope) the concerns voiced on some of the Internet chat rooms that we don’t really know that mini-allo stem cell transplants actually CURE anyone. I beg to differ. The overall survival and disease free survival statistics quoted above are pretty impressive, 85% and 83% respectively. What is even more of an eye-opener is the graph below.

nhlminiallostats2008.gif

All you have to look is the very flat portion of the curves from around 20 months. True, the percentage of patients alive dropped by 15% from start of transplant, down to 85%. Also true, 2% of the patients relapsed with their original cancer over roughly the same time period. But it is wonderful to note that no more patients died after that point in time, no more patients relapsed either. After the initial 20 months (or thereabouts), folks were home free! The followup of 96 months is long enough to get an excellent fix on this important point. Bottom line, without this very important flattening of the survival curves, no therapy can claim to have cured anyone.

How does this compare with chemotherapy disease free survival curves? I am glad you asked! Also in the latest issue of “Blood” is a full length article detailing the results obtained at M. D. Anderson when chemo naive CLL patients were treated with their FCR combination therapy. As most of you know, MDA has obtained stellar response rates when chemo naive and relatively lower Rai stage patients were treated with the FCR combo. How long did these responses last? In other words, how did the disease free survival curves look? Take a look:

fcrresponsechemonaivepatients.gif

In this colorful graph MDA details how long remissions lasted for patients getting the various levels of response to FCR. Looking at the deep blue line (representing patients who got a clean CR response to FCR therapy), we can see that even 96 months out the curve continues to dip down inexorably. Roughly 60% of patients relapsed, even if they got a CR response immediately after finishing therapy. Looking at the shape of the curves, it is reasonable to think the curves will keep going down and eventually most if not all patients will relapse, sooner or later. While FCR is a potent chemoimmunotherapy combination, it seems this therapy does not CURE anyone.

How about overall survival, never mind the status of the remission? Below is the graph from the latest MDA paper that addresses this ultimate question.

fcrsurvivalstats.gif

The good news is that indeed FCR seems to be a better front line therapy (remember, these were chemo naive and rather early stage disease patients in the study) than single agent F or FC/M (fludarabine, cyclophosphamide with or without mitoxantrone chaser). People who got FCR lived longer, overall, than those that got the earlier generation “gold standards”. Rituxan seems to make all the difference, increasing the impact of F+C.

The disappointing news is that the blue curve (FCR patients) never pauses sufficiently in its downward slide, never flattens out. As time went on, patients died. At a slower pace than those treated with F or FC/M, but there is no hint of an actual CURE with any of these three therapy regimens. At the end of 8 years (the time horizon used in the follicular lymphoma mini-allo study), 60% of the patients treated with FCR were still alive. Remember too that these patients started out with relatively low Rai stage, and the FCR was their very first right-out-of-the-gate therapy. Compare that number with the 85% alive and kicking (83% in full remission /CURE) after their mini-allo transplants, especially when you remember these folks did not go into a transplant right off the bat, and you can see why I am excited.

While we are definitely doing a bit of an apples and oranges comparison (since the transplant stats are for late stage FL patients and the FCR stats are for early stage chemo naive CLL patients), it is clear that mini-allo transplant can actually CURE patients. Not all, but a goodly 83% of the patients are frankly cured of their “incurable” FL. I don’t know about you, but I will take that statistic any day of the week.

Will all institutions see similar stellar CURE rates for their mini-allo transplant programs, whether it is FL or CLL? I am not sure. As we discussed in prior articles, successful transplants depend on the status of the patient prior to transplants, the additional ‘baggage’ the patient is carrying in terms of comorbidities. MDA has the reputation for being willing to do transplants sooner than other centers. For example, as we discussed in the case of our “Catch-22″ patient “Richard”, the Hutchinson center in Seattle was reluctant to transplant him immediately after his first round of therapy. MDA, on the other hand, was willing to use this window of opportunity, transplant “Richard” as soon as he got himself his very first good remission. Will MDA have better transplant stats than the Hutch? I expect they would. Frankly, here is one case where I think MDA’s more aggressive stance on early treatment of patients is a good thing. For a change, we have an expert center that is willing to transplant high risk patients sooner rather than later, “elective” versus “salvage” transplants, and thereby give them a good shot of beating their otherwise incurable cancers.

I will be the first one to acknowledge that making the decision to go for a stem cell transplant (mini or full strength) is one of the hardest decisions patients and their families will ever make. Will you be in the lucky 83% above who sailed through the transplant and were disease free? Or will you be in the 15% that died within 20 months of initiating the transplant, or the 17% that were still stuck with the damn disease even after all the pain and suffering of going through a transplant? Would it be smarter to put off the transplant decision for as long as you can, get by on chemoimmunotherapy combinations and hope that you will be among the folks that get long, trouble free remissions for half a dozen or more years?

Any one has a good crystal ball?

Be well,

Chaya