Ongoing Trial Demonstrates Promising PFS With Ibrutinib in Hairy Cell Leukemia

Kerry Rogers, MD

Patients with hairy cell leukemia have limited options. Purine nucleoside analogues (PNA) have provided benefit and promising responses to many patients with hairy cell leukemia, but more options are required for those patients who relapse. Data from an ongoing trial demonstrating promising results with ibrutinib (Imbruvica) were presented at the 2019 Hairy Cell Leukemia Foundation Annual Conference.

The phase II trial of ibrutinib (NCT01841723) began enrolling patients with hairy cell leukemia of both the classic and variant subtype in 2013, and 39 patients have been enrolled to date, with 38 having started treatment with ibrutinib. However, the data presented are from a smaller group of these patients as it has taken 6 years to fully accrue the trial due to the rarity of this disease.

The overall response rate (ORR) in this patient population is 50%, and while the principal investigator on the study, Kerry Rogers, MD, notes that this may not be an outstanding response, she says it is promising for such a rare type of leukemia. Additionally, the progression-free survival (PFS) rate at 3 years was nearly 75%, which Rogers says is impressive, given that these patients were, for the most part, not responding to standard treatments.

In an interview with OncLive, Rogers, assistant professor at The Ohio State University Comprehensive Cancer Center, discussed the potential of ibrutinib in hairy cell leukemia, emerging treatment options such as moxetumomab pasudotox (Lumoxiti), and next steps and challenges in the field.

What was the rationale for evaluating ibrutinib in patients with hairy cell leukemia?

As most people know, ibrutinib is an oral targeted inhibitor of BTK. This has been a really important target, and it has been FDA-approved in 4 different B-cell malignancies. There’s an unmet need for new therapies for the subset of hairy cell leukemia patients who don’t respond to PNA or don’t benefit from them anymore or as much as we want. Therapies that work in chronic lymphocytic leukemia (CLL) and other B-cell cancers frequently do work in hairy cell leukemia; in particular, CLL and hairy cell leukemia have some overlap for therapies that work. Since ibrutinib is available and potentially effective (especially for patients who might not benefit from chemotherapy), we decided to evaluate [the BTK inhibitor] in hairy cell leukemia.

How was this study designed?

It’s a single-agent study, and it is a phase II study. In this study, everyone receives treatment with ibrutinib once daily. The ibrutinib dose is administered continuously until either patients progress, don’t tolerate ibrutinib, or decide to stop therapy. That is the way it is given in other diseases.

The study was opened in 2013 and designed before that. At the time the study was designed, not as much was known about ibrutinib compared to what we know now. There were 2 different dose levels used in the study, 420 mg and 840 mg. Ultimately, the 420-mg dose was the dose we decided to move forward with. There was no difference in response or toxicity that we could discern between the 420 mg and 840 mg doses. However, the sample size was pretty small, so it was hard to tell, but since the 420 mg dose was effective and used in other diseases, such as being the approved dose in CLL, that is what we have been treating people with who are enrolled in the study more recently.

What were the results from this study?

We have enrolled 39 patients now, and 38 have started on treatment. This is substantial for a hairy cell leukemia study, but as the study has accrued over 6 years, due to the rarity of this patient population, the longest follow-up we have is from a smaller group of patients who were enrolled earlier.

We found that the ORR for best response, meaning the best response that patients achieved at any time, is just over 50%. That may not seem like an outstanding response rate, but that’s really because of the rigor of response criteria. A lot of patients who didn’t meet criteria for response did have a very substantial clinical benefit. The estimated 3-year PFS is just under 75%. Even though you only have just half of the patients responding, at 3 years, just under 3-quarters had not had disease progression and are alive. Really, the PFS has been very good with this study, and I think that’s the major benefit of this drug.

What else is significant about the study findings?

The other important thing to know is who we enrolled in this study. It was open to both classic and variant hairy cell leukemia patients…We enrolled variant patients who had either been treated before or had never taken a treatment before, and we enrolled classic hairy cell leukemia patients who were previously treated.

The median time that patients had been living with hairy cell leukemia before enrolling on this study was just over 10 years. This is a relatively experienced cohort of hairy cell leukemia patients, and the median number of prior therapies was 4.5. This is a heavily pretreated population, so this is not so much the population of patients who took a single dose of cladribine or a single course and were still in remission 2 decades later. This is the group of hairy cell leukemia patients that we wanted to capture, which are those not really benefiting from cladribine or pentostatin. Really, the significance is that in this difficult-to-treat population, we have a PFS estimated at 3 years of just under 75%. It is showing that patients who weren’t benefiting from standard therapies like pentostatin or cladribine are able to benefit from ibrutinib in terms of stable disease control for a good duration.

I will also mention that the adverse events we found were very similar to what has been seen with ibrutinib in other diseases, so we didn’t have any surprises in terms of the tolerability. Any clinician familiar with the use of ibrutinib for other diseases could feel comfortable using it in hairy cell leukemia.

Like in other diseases, responses tended to improve over time, so we had built in a 32-week and 48-week response assessment. Since the study opened in 2013, it was before we knew that ibrutinib, in many other diseases, has responses that occur after a year or longer and that the responses deepen over time. We did allow for repeat response assessment later at the investigator’s discretion, and that is how our response rate ended up being so good. A lot of those responses happened later than 48 weeks, so anyone attempting to use this drug should realize that recovery of blood counts from cytopenias is slow and that the optimal response can usually occur after 48 weeks. Again, 50% might not seem really good for a response rate, but the PFS is good, and this is a group of patients who really aren’t benefiting from other therapies.

What are the next steps for this research?

We are still actually enrolling patients, so we have reported these results because this study has been going on for 6 years, and it is important to get the information about this drug into the hands of people treating patients with hairy cell leukemia. We are still treated patients in the study, and we will be publishing our results short of accrual because we think it is very important to get this information out there, and we do have some relatively mature study results.

The next thing I would like to see happen is combination studies including ibrutinib and another targeted agent in hairy cell leukemia. Ibrutinib combination studies have been utilized in other diseases successfully, and I think that might improve the response rate. Again, the response rate was relatively modest, but the PFS was good. That is the next thing I would like to do.

What are the unmet needs that still exist in this patient population?

There are a couple unmet needs here. Again, it’s important to realize that a lot of people with hairy cell leukemia take a single dose of pentostatin or cladribine or a single course and are alive without leukemia recurrence 8 to 10 years later. For those patients, things are relatively good, but there are other complications of this that can still happen.

Hairy cell leukemia, in many cases, doesn’t shorten people’s natural life spans, but the few things that do affect patients greatly are [things such as] infection, which is actually very high on the list. Many people, when diagnosed, are diagnosed at the time of having a severe or life-threatening infection, or they develop infection after treatment, especially treatment with PNA. Looking at therapies for patients with uncontrolled or inactive infections and better supportive care and management surrounding that is really important.

The other unmet need is this group of patients that aren’t expected or who haven’t gotten many years out of a PNA like pentostatin or cladribine, so people who are getting cladribine every 2 years, that is not a good strategy. It’s really damaging to the immune system, and it’s difficult on the patients. We do have some other targeted agents, such as vemurafenib (Zelboraf), which is a BRAF inhibitor that has been very successful. We also have moxetumomab pasudotox, which was approved by the FDA very recently, which is an anti-body drug conjugate that has been successful, but we have a group of patients that sometimes don’t get very good or very long remissions from those [treatments], and [developing] therapies for this population is important.

People with hairy cell leukemia variant really don’t benefit from the therapies, particularly PNA, in the same way that classic patients do. That is an even rarer population of hairy cell leukemia, but there is a very big unmet medical need for patients with variant hairy cell leukemia.

How do you see the treatment landscape evolving in the coming years?

What I think we are going to see is that patients who are newly diagnosed with classic hairy cell leukemia and are fit to take PNA will keep taking those; they’ll get a course of cladribine or pentostatin. I think there is a question now of whether or not that should be combined initially with an anti-CD20 monoclonal antibody, such as rituximab (Rituxan). I think that standard is not going to change for patients who can receive that, especially when I have seen patients who have taken a course of treatment 20 years ago and are still alive without leukemia relapse.

I think supportive care has improved a lot, and that will continue, but I think we will see some better utilization of the targeted agents, such as vemurafenib. There is an ongoing study of vemurafenib and obinutuzumab (Gazyva; NCT03410875), which is going to be exciting. We have also used vemurafenib in patients with classic hairy cell leukemia when they have a BRAF mutation. However, I want to be clear that without the BRAF mutation, that drug does not work.

I really look forward to seeing how things play out with other targeted therapies that are being developed in other diseases that can be used in hairy cell leukemia. I’m also looking forward to seeing how moxetumomab pasudotox changes the treatment landscape. That’s going to be really exciting, I think. Hopefully, there will be safer, more effective, and less toxic therapies with better utilization of them based on selection from patient factors.

Any final thoughts on the current treatment paradigm?

I would just like to say that some people think hairy cell leukemia is easy to manage because you can give cladribine for 5 to 7 days and get people into remission, but really, there are a lot of things that affect the lives of patients with hairy cell leukemia, like prolonged cytopenias and infections. Those things require expert management, and I am just really excited to see different forms of targeted therapies are really going to be benefiting people with hairy cell leukemia more and more. It’s nice to know that even in this rare disease, while many people feel it doesn’t require the attention we have devoted to it, it is getting this attention. I think it is extremely important for people with hairy cell leukemia to get the same benefits as people with more common diseases.

<<< View more from the 2019 Hairy Cell Leukemia Foundation Annual Conference