As I shared with him my idea of turning off B cell receptor signaling using pills, he told me, “Jeff, it sounds like you are swinging for the fences, and for our Stanford fellows, we are happy if you just crowd the plate and get hit by a pitch…” Oh well, I suppose everything worked out fine, and I still don't really care much for baseball. I wanted to compile the history of home-runs in the field to highlight just where we are and point out where I think we are going.
If you look back over the last 60 years of advances cancer medicine, there are only a handful of clinical breakthroughs in low grade lymphoma (indolent) that fundamentally re-oriented our treatment strategies in the disease and upended the status quo of the time. It hasn’t necessarily been a story of slow and steady progress. Instead there are discrete episodes that shred through the treatment landscape and when the dust settles, the field has evolved into something new.
Cancer is a complex beast and many discoveries have only served to show us just how little we actually know. While the progress is now exponential, so too is the amount we realize we don’t know. Every so often something comes along that genuinely moves the needle and patients have longer and better lives. I am very excited about an emerging story in indolent NHL and I wanted to help put in context a story that I think we are going to hear about very soon.
Here is my short list – for the interested reader, I highly recommend the book The Emperor of All Maladies. It was written by one of my residency training classmates at MGH and has received the Pulitzer Prize. It is a fantastic read.
1) Way back in the 1940's local radiation therapy was the only treatment available. This really didn't work well in a disease that is typically "systemic." Since we didn't know much about radiation dosing, patients were burned and burned again until their disease became "radiation resistant" and they died of massive lymph node enlargement or complications from radiation.
2) In 1946 we had the introduction of "chemotherapy" which actually spun out of chemical warfare research during WWII. (The remarkable story of America’s “Second Pearl Harbor” and the birth of chemotherapy is one of the most amazing little known stories in medicine). Patients with lymphoma were the very first to be treated with modified versions of mustard gas. Responses were short-lived but merely 15 years after the introduction of penicillin the idea that “medicine” could treat cancer was born.
3) In the 1950's the drug Adriamycin was isolated from a soil sample of a 13th century Italian Castle and subsequently was shown to be effective in lymphoma. This drug became a "backbone" of many treatment strategies in lymphoma and is still commonly used today. It is the “big red” drug that makes many lymphoma patients lose their hair but is also commonly used in breast cancer, gastric cancer, sarcoma’s and other diseases.
4) For the next several decades, progress was built in many small steps. New drugs were found, developed, and tested one at a time. Vincristine was isolated from the Madagascar Periwinkle, Etoposide was isolated from the “mayapple” and so forth. Multiagent drug cocktails were assembled and tested. When you put as many drugs together as you possibly could, you got crazy names such as M-Bacod (6 drugs), Pro-Mace-Cytabomb (8 drugs), and CODOX-M-IVAC (7 drugs). While some of these were for more aggressive lymphomas, each had their loyal adherents and debates raged without much comparative data. That all ended however in 1993 CHOP (4 drugs) was declared the winner over several more "intensive" regimens.
5) In 1997 we saw the introduction of rituximab in lymphoma. This was the first time we used a therapeutic antibody (like the ones your body makes to fight the flu) to treat cancer. Rituximab administered alone has impressive single agent activity and has become increasingly utilized as monotherapy. It was also quickly added to CHOP to make the R-CHOP regimen. This was the first "chemo-immuno-therapy" regimen and led to substantial improvements in long term outcome of patients with both low grade and DLBCL. Until 2007, patterns of care data indicate that if you were going to get chemo for follicular lymphoma, 50% got R-CHOP, and another 25% got the same regimen without the Adriamycin which adds quite a punch in terms of side effects (R-CVP), and about 15% received rituximab alone.
6) In 2008, there was a US based study of a drug that had been floating around East Germany during the entire cold war yet remained unknown to western cancer doctors. This was the first that most US docs had heard of Bendamustine. The data was quite impressive for how effective the drug was compared to standard alternatives. In 2009, the German lymphoma study group initially presented data at ASH comparing bendamustine-rituximab to R-CHOP in follicular lymphoma. It was actually only published in Lancet last year. This showed improved efficacy with bendamustine, and far reduced side effects which led to the sweeping changes in patterns of care. Bendamustine with rituximab has upended practice patterns. In the last two years, US patterns of care data reveals approximately 1/3 of previously untreated follicular lymphoma patients needing treatment receive Bendamustine-Ritxuximab, 1/3 receive rituximab alone, and only about 1/5 receive R-CHOP in front line treatment and virtually nobody receives it following relapse. Fludarabine utilization is virtually gone (see attached slide presentation at the bottom of this post and my post on "How I treat follicular lymphoma).
7) As ASCO 2007, our lab at Stanford presented the first “pre-clinical” data showing that inhibition of B-Cell receptor signaling enzymes could have therapeutic effect in B cell malignancies. This theory was subsequently confirmed in a plenary session presention at ASH in 2008 utilizing the drug fostamatinib. The discussant at the time felt that the data met the criteria for “game-changing” and put it on his list of NHL history makers. While fostamatinib is no longer being actively developed, the proof of concept directly preceded / led to the exploration of ibrutinib and idelalisib in similar diseases. In heavily pretreated patients, both of these drugs have approximately 50% overall response rate (size criteria for response determination, many more actually shrink and benefit – just not enough to be considered “partial response”) and average a year of benefit for responding patients. Idelalisib was recently FDA approved in follicular lymphoma and we await data on ibrutinib in this population. While the impact in follicular lymphoma remains an evolving story, the impact in chronic lymphocytic leukemia and small lymphocytic lymphoma is nothing short of transformative.
8) I believe story 8 in indolent lymphoma will be “immunotherapy." Rarely a day goes by where I am not asked by a patient, “is there anything I can do to boost my immune system.” While my answer has always been, “not really” a number of very important new therapies are showing that harnessing the power of the immune system to attack cancer can be extremely powerful. Drugs have been either approved or are soon to be approved in melanoma, lung cancer, kidney cancer, and bladder cancer that help the immune system identify and destroy the cancer cells – without using chemotherapy. Some of these are antibodies that interfere with the “on/off” switches of the immune system. Others “re-program” T-cells using engineered viruses that can go absolutely crazy on B cells (see amazing video here). The most accessible and perhaps most exciting of these for patients with indolent lymphoma may very well be the combination of revlimid with rituximab. There are several very important studies that are poised to position this combination at the center of treatment pathways for patients with follicular lymphoma.
Nathan Fowler’s data from MD Anderson – link here
Nearly completed study in frontline follicular lymphoma Rev-Rituximab vs R-Chemo – link here
Open study of Rev-Ritux in relapsed follicular lymphoma – link here
I think of the combination of revlimid-rituximab (also called R2) as a road trip with a pot of coffee and a map. Rituximab helps orient the immune system to go after the cancerous b cells by coating the outside of them and serving as an alarm for the T cells (like a road map). Revlimid (lenalidomide) helps overcome what has been called T-Cell “pseudo-exhaustion” and get them to reactivate (ready for the road). B cell cancers have a remarkable ability to “put the t cells to sleep.” Whether though secretion of hormones, or actually manipulating the on/off switches of T cells, the cancerous B cells literally put the other half of the immune system into a post thanksgiving meal food coma. Revlimid acts like a cold splash of water to the face for the sleepy T cells. Not bad for a drug that really isn’t chemotherapy but is considered an “imid” for – immunomodulatory drug.
The combination has been explored in CLL. It can be so active at times that there can be problems with tumor lysis syndrome. The combination is not approved by the FDA in this setting and should be utilized very carefully due to the associated risks.
The combination has also been explored in follicular lymphoma with some pretty spectacular results… and that will be the subject of an upcoming post!
Thanks for reading
(Patterns of care data and a nice view of the Sisters volcanic range in Oregon from Mt Bachelor Ski area)