Webinar: Hairy Cell Leukemia (HCL) Clinical Trial at Scripps Clinic
May 23, 2024
Speaker: Dr. David Hermel, Scripps
Hosted by the Hairy Cell Leukemia Foundation (HCLF) with guest speaker Dr. David Hermel, Scripps Clinic. Moderated by Anna Lambertson, HCLF Executive Director.
Webinar Materials
Transcript of Dr. David Hermel’s Presentation
Dr. David Hermel:
It's a pleasure to talk today about our clinical trial. If you look at that building in my slide, that was where Cladribine was first invented and trialed in patients. We've come a long way from Cladribine, although it's still standard of care in many cases.
Background
Our clinical trial came about in the COVID-19 era because of the risks of chemotherapy, with prolonged immunosuppression and weakening of the immune system, especially in vulnerable patients. We wanted to create a regimen or at least trial a regimen that was less immunosuppressive, had less myelosuppression and reduction in blood counts and fewer side effects overall. And so, in the COVID-19 era, we developed our protocol, which is a finite treatment with Rituximab and low dose Vemurafenib.
Brief history of HCL treatment, including introduction of BRAF inhibitors
The treatment of hairy cell leukemia has come a long way from initially just taking out the spleen to interferon-based therapies, to the 1990s with Cladribine-based therapies.
In 2001 there was an immunotoxin developed, which is now off the market. And then, the critical juncture was the identification that classic hairy cell leukemia has specific mutations in BRAF and the introduction of medications (BRAF inhibitors) that were inherited from melanoma patients.
Vemurafenib was a drug that was already very effective in patients with melanoma who had BRAF mutations. It adopted into the space for patients with hairy cell leukemia. With hairy cell leukemia, we only treat if we have to, because the disease itself, at least how we think of it currently, is not curable with conventional treatment.
So, the key is treating the HCL without causing undue harm. Typically, the requirements for treatment are hemoglobin less than 10, platelets greater than 100, or an absolute neutrophil count less than 1000. These are the accepted guidelines.
The identification of this BRAF mutation in classic HCL and the introduction of medications that were adopted from melanoma into this space were important. Vemurafenib was started at a dose of 960 milligrams twice daily; that dose had been adopted for melanoma patients. This dose was administered in HCL in a study in the US and Italy.
Vemurafenib showed efficacy as a single agent treatment. When you gave this treatment alone, it had efficacy. The unfortunate thing about using it alone was that the responses were less durable; patients who received this dose in the clinical trial would often have to dose reduce due to toxicity from the agent. If you looked at patients who had to dose reduce, the responses were similar to those who received the standard doses.
Low-dose Vemurafenib
We saw there were studies pointing to reduced dose efficacy, that reducing the dose of Vemurafenib would have potentially similar efficacy while reducing the side effects.
Link to article published in Blood in 2015, showing results of low-dose Vemurafenib. >>
The side effects of Vemurafenib are generally considered lower grades, grade one or two. In the trial, arthralgias or joint pains, rashes, pancreatitis, are notable as well as secondary malignancies, specifically skin cancers. Most of these toxicities were grade one or two, although there were some more severe toxicities.
A study trialed these lower doses of treatment and found similar efficacy in the treatment. There was no real difference in recovery of blood counts of patients who received low doses of Vemurafenib or higher doses of Vemurafenib. Patients who received a higher cumulative dose did not achieve a better response.
This was the initial seminal study published. In this study, they used Vemurafenib at 960 milligrams and administered it twice daily for eight weeks, and then used eight doses of Rituximab every other week.
In this seminal study, the complete response rate was 26; 26 out of 30 patients had a complete response. 18 patients had MRD negativity. So, the results were very encouraging.
Link to NEJM publication of Vemurafenib study in the US and Italy. >>
[There is also new data suggesting that you can use Vemurafenib and Obinutuzumab, which is similar to Rituximab.]
The point of our study is to do this, but with a reduced Vemurafenib dose and in both the front line and relapse refractory settings. This means if you've received Cladribine in the past, then you would be eligible to get this regimen, which you could get on study or off study.
Limiting therapy-related toxicity is extremely important. This became even more important during the COVID-91 era. Prolonged myelosuppression, which you can get from Cladribine, can potentially make you more susceptible to infection.
So, what we aim to do is use a targeted approach to treatment with Vemurafenib in combination with Rituximab. Instead of using the 960 milligram twice daily dose, we have attempted to use the 240 milligrams twice daily dose.
This is a phase two open label single arm study, here at Scripps. The study is eight weeks; you take the pill (Vemurafenib) twice daily and then you get eight intravenous infusions of Rituximab every two weeks. You start concomitantly.
To be eligible, you need to be diagnosed with hairy cell leukemia, and you have to have the BRAF v600e mutation, which is obviously very common in classical hairy cell leukemia. We use the standard treatment initiation criteria defined as an ANC less than one, hemoglobin less than 10, and platelets less than 100,000.
Link to Scripps clinical trial >>
Interim study results
This is some of the interim data that I presented most recently at the American Society of Hematology Conference.
Link to poster presentation at the 2023 ASH Conference >>
We had a total of seven patients. Median age was 60 and range was 49 to 69. All patients were male, three patients were previously untreated. The majority of patients were previously treated and the median number of treatment lines were two, ranging between one to five.
All the patients who had been previously treated had Rituximab and all had the nucleoside analog, Cladribine. One patient did have prior Vemurafenib.
All our patients had hematologic recovery. So, everybody had a complete hematologic response; everyone's blood counts improved. At the time of this data analysis, which was short, it was only 169 days, but the range was 85 to 533 days.
Relapse free survival rate was 100%. Obviously, it's a very short follow-up, so there are limitations.
The median time to improvement in blood counts was 29 days, although it could be up to 57 days until a resolution of the cytopenia or lowering of the blood count. We had bone marrow data for four of the patients, and in three of them, MRD was negative. In the fourth patient, he had residual disease but achieved a complete hematologic response.
Reassuringly in our study, there were no grade three or four events and no Vemurafenib dose limiting toxicity was observed. In terms of things that we saw in our study, infusion reactions related to Rituximab were fairly common in over half of the patients.
There were nausea, some elevations in bilirubin, arthralgias or joint pains. Rashes were common, although nothing was in the grade three or four category. One patient developed atrial fibrillation, although unclear if this was related to the treatment. Otherwise, generally tolerable toxicity profile.
Conclusion
So, in conclusion, the results suggest that taking Vemurafenib at a dose of 240 milligrams twice daily has high efficacy and safety. Our data is very early on, but we believe strongly in the dose of Vemurafenib that we're using in this study. And we think that a lower dose is generally what should become standard of care. Obviously, we would need a larger study, but we see good responses with a lower dose of Vemurafenib and Rituximab.
The absence of chemotherapy in a disorder, especially in the front line is important, particularly in a disease that is generally incurable where you really want to limit long-term toxicity, including toxicity for secondary malignancies, additional cancers down the road, and prolonged myelosuppression.
I want to thank Dr. Saven and Scripps and all the patients who've enrolled or are being treated and to the Hairy Cell Leukemia Foundation and Anna for inviting me.
This transcript has been edited for clarity.