Jae Park, MD: Another big question pertains to adding rituximab. We talked about this MRD [minimal residual disease] with deeper remission. Should it be a goal for everyone, or a particular patient population, that you would like to get a deeper remission?
Steven Coutre, MD: We all primarily use cladribine as frontline. I can’t remember the last time using pentostatin, for example, with hairy cell. Patients do exceedingly well for long periods of time, but for young patients of course, you anticipate having to treat them again and again, probably throughout their life. Now, what about rituximab? Seeing it work initially was intriguing, and what I’ve been really struck by is Bob Kreitman’s recent publication; it’s an interesting study design. If we’re doing a response assessment for hairy cell, and choose to do that with a bone marrow exam, you should wait at least 4 or 6 months because you could see ongoing responses later. In his study he randomized patients to cladribine plus up-front rituximab, starting on day 1, and then weekly for 8 weeks And then he looked at the 6-month response, including minimal residual disease versus patients getting standard cladribine and then doing the response at 6 months and then the delayed rituximab infusions. It wasn’t a direct randomized trial with or without rituximab, but it was effective. The striking finding to me is, not surprisingly, a much higher percentage of patients who are MRD undetectable, but with long-term follow-up, was maintained. The responses were maintained for a longer period of time. In that group the median response wasn’t even reached yet. It goes along with the theme we’ve seen in other diseases: Deeper responses give you longer response durations. We have to be critical and ask, “Well, does that matter?” Can you simply get that response, or do you do just as well even if you need to be treated earlier for a disease like this, which we can’t cure? Because of that, I would say that certainly for the younger patients and select older patients, I’ll use the combination now.
Farhad Ravandi-Kashani, MD: I am a big proponent of adding rituximab. Hairy cell leukemia has probably the highest expression of CD20 on its cell surface. Rituximab was developed in Southern California. We all know that rituximab is beneficial to virtually every other lymphoid malignancy when it was added to the classical or standard therapy for the other malignancies. For example, there have been studies in lymphoma and CLL and even in ALL. It was a randomized study from the French group that showed the rituximab addition to the classical treatment benefits patients in terms of most studies or even overall survival. Conceptually, for me it’s a no-brainer that we have a disease where there is a very high expression of CD20. There had been a number of studies that have used rituximab as a single agent in the relapse setting. Although it’s not as dramatic, highly effective agent as a single agent in the relapse setting, it does produce responses, so we know that it is active. For me, it has been a no-brainer to use the combination.
Originally when we designed the study that was mentioned, that was 15 years ago. Hairy cell leukemia was a disease that was thought to have been captured by cladribine. We didn’t want to make any mistakes or individual problems. We decided to do sequential, and we’ve kept up the same way, but I totally agree that if I want to combine the two drugs, I also would give it concomitantly as was described by my colleague, and he wrote a long-term follow-up of the combination of cladribine followed by Rituxan, which was published in the British Journal of Hematology on essentially a very long follow-up of over 10 or 12 years.
We have had 1 relapse, which wasn’t even a full-blown relapse. The physician decided that they wanted to treat the patient again. This is a very durable response. Now, Dr Saven will come back to me and say that I have had the hairy cell patient, received single agent cladribine in the nineties, and they’re still in remission. That’s obviously the core of this discussion. Are we going to treat the entire population of hairy cell leukemia patients with the addition of rituximab, where at least—Dr Saven will correct me—about 50% or 60% will have a very long response and will never relapse. I don’t even think it’s a medical discussion. That’s a socioeconomic discussion. Also just to discuss other frontline combinations, Dr Saven mentioned there is an interest in combining vemurafenib with CD20 antibodies. Jae has a vemurafenib plus obinutuzumab study. The Italian group presented data on vemurafenib plus rituximab. It seems that adding rituximab to vemurafenib also significantly improves the response rate, and likely will significantly improve the response duration. In a drug situation where you have an oral drug that you take daily, it is important to highlight a strategy that will improve your response duration that would obviate the need to continue to take an expensive oral daily for a long period of time.
Transcript Edited for Clarity