Historical Treatment for Relapsed/Refractory HCL

Jae Park, MD: Let’s discuss the relapsed and the refractory patients with the hairy cell leukemia after they get treated with their first-line therapy of choice. Andrea, what defines a relapse? At which point should we consider treating the patients again?

Andrea Sitlinger, MD: Various papers have looked at the rates of relapse. It’s usually 30% to 50%, depending on what you’re looking at. Technically, true laps are not someone who has disease that still had a PR [partial response] to initial therapy, but at least a clinical CR [complete response] by counts. A true relapse does not need to be re-treated again until they meet the criteria for treatment. They’re at treatment-naïve hairy cell leukemia because of pan cytopenias or other symptoms. That’s because, while absolutely treatable, it’s not curable in the long run. So you don’t need it if the patient is doing well and has some mild cytopenias, and you detect that it is present, treating them doesn’t necessarily change their course, and you’re exposing them to treatment that they may not need and all those adverse effects. Additionally, this is where the MRD [minimal residual disease] debate comes in, we do know that with each subsequent treatment at least with the pairing analogs, your remissions are likely to get shorter in between. Exposing to treatments when they don’t need them may end up using up treatments faster.

For all those reasons, we do not need to treat them until they’re showing symptoms that would require treatment as outlined before. One thing that’s really important is the timing. If you relapse with less than 2 years versus relapsing after 2 years, and part of that is basically because if you’re relapsing in a longer response to appearing analog, you may respond and often do respond with a long period of duration. If it was 10 years ago and it relapses again, then you certainly can get another long duration with rechallenging versus a patient who is relapsing less than 2 years. The likelihood of having a durable response when they didn’t initially is much shorter. Those are important keys to think about when you’re picking what you do next and when to treat.

Jae Park, MD: Dr Coutre, what are the options, with the second- or third line therapy, for relapsed or refractory hairy cell leukemia? What are some of the guidelines? I know NCCN has listed some of the drugs, and Dr Sitlinger also mentioned retrying cladribine or pentostatin, especially to late relapsed patients. How has the landscape changed over the last several years with research that’s been done in this area?

Steven Coutre, MD: Similar to Andrea, for somebody who’s had a long, durable response, I would re-treat with cladribine or cladribine with rituximab. I would not advocate changing nucleoside analogs. I don’t see the point for a patient like that. Then of course there are our clinical trial options that we’ve touched on. Ibrutinib is in trials. The BRAF inhibitor mentioned and other BRAFinhibitors are in trials. Those can be perfectly appropriate options for patients too. We’re always trying to develop new and more effective therapies. Then we have approved drugs, but I believe that’s for second-relapse patients in their first few months. As with many very uncommon hematologic diseases, we have a wealth of options, which is always nice.

Jae Park, MD: Dr Saven, if the patient has received a cladribine or pentostatin as their first-line therapy and they relapsed, when you re-treat them with cladribine, for example, would you add rituximab the second time if they didn’t receive it the first time?

Alan Saven, MD: I add the combination to patients when they’ve relapsed unless there’s some reason why I wouldn’t add the rituximab. I do combination therapy for patients who’ve relapsed. If a person’s first remission is 12 years, it could be debated. But if the patient’s remission is 3 or 4 years, and they didn’t do as well as they were supposed to do, then I’d be inclined to add the rituximab. Andrea does quote that 2-year interval, which I always found a little humorous because I was once asked to write a review, and I came up with a No. 2. Then I noticed it was added to all consensus and it came into NCCN Guidelines. I’m not sure that 2½ is less than 1.8 years. If the patient doesn’t do like everybody else and has a brief remission, whether it’s 2 years or 2½ years, you’re told that he’s not that sensitive to purine nucleoside analogs. I don’t think the 2 years is on the Ten Commandments. You can use your clinical judgment about the advisability of reintroducing the purine nucleoside analog. It was also thought that pentostatin and cladribine were almost exactly the same drug, but they aren’t. When I was a filler, I wrote a paper in Annals of Internal Medicine. There were 5 patients who were refractory to pentostatin a number of times, so they were clearly refractory. When we introduced cladribine, they actually responded. Then the papers from the United Kingdom in which patients got cladribine first and later got pentostatin and then responded. There are mechanistic dissimilarities between the purine nucleoside analogs. They’re not exactly the same drug, although they’re very similar. What is concerning is the repeated use of a purine nucleoside analog and damage to the bone marrow in and of itself. Subsequently, you make clear that hairy cell may induce hyperplastic changes in the bone marrow. Also, there is the cumulative effect of profound immunosuppression. They’re not the same drug, but they have similar long-term consequences.

Transcript Edited for Clarity