Webinar: HCL Clinical Trials at the National Cancer Institute (NCI)-NIH
May 3, 2024
Speaker: Dr. Robert Kreitman, NCI-NIH
Hosted by the Hairy Cell Leukemia Foundation (HCLF) with guest speaker Dr. Robert Kreitman from the National Cancer Institute (NCI)-NIH. Moderated by HCLF Executive Director Anna Lambertson.
Webinar Materials
View a recording of Dr. Kreitman’s presentation.
Transcript of Dr. Robert Kreitman’s presentation
I want to thank everyone for tuning in, especially the Hairy Cell Leukemia Foundation, for inviting me to speak about our NCI-NIH clinical trials in classic and variant hairy cell leukemia. Hairy cell leukemia (HCL) is a B-cell malignancy, a B-cell cancer that comprises 2% of all leukemias. That 2% goes back to being measured by Dr. Bertha Bouroncle at the Ohio State University in 1958. I had the pleasure of working under Dr. Bertha Bouroncle in 1983.
Background: Classic HCL and HCL Variant
This 2% amounts to 1,300 new cases per year. Patients present with low blood counts, large spleens, and cytoplasmic projections on their cells. The classic HCL is typically CD25 positive and is driven by the BRAF V600E mutation. The HCL variant is CD25 negative; instead of BRAF V600E, there are multiple drivers of the disease.
The treatment of HCL has classically been cladribine and pentostatin, which can induce complete remissions. We call those CRs. However, cladribine and pentostatin are not known to be curative and have decreased efficacy with each repeated course.
There are variants of HCL that lack CD25. They might have CD25, but they express other things like unmutated IGHV4-34. These variants respond poorly to chemotherapy. Cladribine and rituximab, however, work well, are used for HCL variant and are increasingly used for classic HCL.
Diagnosis and Disease Presentation
The diagnosis is made by flow cytometry of the blood and bone marrow; it's important to do these tests to exclude other disorders and to determine if you're dealing with classic or variant HCL.
90% of patients have classic HCL. In classic HCL, the spleen size is mildly enlarged; it depends on how long patients go before they are diagnosed. HCL variant tends to have a more severe spleen size. The leukemic cells in the blood are higher than classic. HCL variants tend to be negative for CD25 and the BRAF mutation and response to chemotherapy are poor in HCL variant.
In the IGHV4-34 that my lab described back in 2009, the spleen size can be severe, blood counts can be poor, they can have high leukemic cells in the blood just like HCL variant, and they can be positive or negative for CD25. And they generally do not have the BRAF V600E mutation. You can only recognize that by molecular tests. Variant HCL tends to be more common among patients with relapsed or refractory HCL.
So what does complete remission (CR) mean?
CR means that you don't see hairy cells by standard morphologic stains. These can be hematoxylin/eosin or Wright's stains of the bone marrow and blood. There's also resolution in complete remission of the enlarged spleen, lymph nodes, and hairy cell counts. The normal blood counts have to achieve a neutrophil, hemoglobin, and a platelet count of at least 1.5 and 11 and a hundred. And to need treatment, you have to have a low blood count, either less than an ANC of one, hemoglobin of 10, or platelet count of a hundred. There are other indications for treatment as well, like painful spleens or growing lymph nodes and a variety of things depending on the protocol.
Minimal Residual Disease (MRD)
So then we talk about minimal residual disease (MRD). MRD refers to the traces of hairy cells seen by special stains of the bone marrow biopsy or flow cytometry of the blood and bone marrow. The bone marrow flow cytometry is the most sensitive standard tests that we have. We can do molecular studies like PCR or NGS (next-generation sequencing) if we get samples before treatment to characterize. The importance of MRD is that the CR can last longer if the MRD is negative.
Providing samples for study at the NCI-NIH
One of the clinical trials we have at the NCI-NIH is clinical trial number NCT01087333. This trial is for anyone who wants to send samples. It's best if patients who are untreated or have relapsed hairy cell or hairy cell-variant before retreatment can send the cells before chemotherapy partially or completely knocks them down. It's important to do this to establish the diagnosis, to rule out high-risk variants, determine the best treatment to start with, sequence the hairy cells and be able to detect them by molecular tests after treatment. You can detect down to one cell per million by molecular tests. You can't do that with flow cytometry. You can find this clinical trial here. >>
HCL Treatment
Treatment with HCL and HCL variant is rarely urgent and decisions for treatment should never be rushed. I find that oncologists want to treat tomorrow or within a week. It's good to establish the diagnosis and think about the options for treatment because once you start treatment, it's too late to go back.
The first-line treatment is often cladribine or pentostatin, or cladribine plus rituximab. This is called CDAR if the rituximab is started on the first day of the cladribine. CdA plus R is what we call it if the rituximab is started a month later.
A new chemo-free combination option is available, vemurafenib and obinutuzumab, for patients who have the BRAF mutation. And it's quite exciting. It doesn't have as much follow-up data, but it's gaining interest.
Patients can send samples after treatment to determine if MRD-free complete remission has been achieved, if and when the next treatment is needed, and if the patients are eligible for our protocols for relapsed HCL and HCL variants.
So, what are these protocols? Several of them deal with the BRAF pathway.
What is the BRAF pathway?
BRAF is a pathway where BRAF phosphorylates MEK, MEK phosphorylates ERK, leading to normal cell proliferation.
But in the BRAF V600E mutation, MEK over-phosphorylates ERK and that leads to a cancer phenotype, not just HCL, but also melanoma. If it happens in a melanocyte or a lung cancer cell, it can cause non-small cell lung cancer or colon cancer. So, we know a lot about this pathway from other cancers and how the inhibitors work.
The first inhibitor was vemurafenib; that inhibits V600E. It results in 35 to 45% complete remissions in HCL that were reported to be MRD-positive.
Dabrafenib also inhibits BRAF V600E. Trametinib is a drug that inhibits MEK.
The BRAF inhibitor dabrafenib alone gives 30% complete remissions in HCL. Dabrafenib and trametinib have been shown to be more effective and less toxic than vemurafenib alone in melanoma. And they were also effective in hairy cell giving a 66% complete remission rate in patients who were treated long-term for many years.
These agents can have significant side effects: skin rashes and skin cancers for vemurafenib, fevers and chills for dabrafenib and trametinib.
At the NCI-NIH, we’re testing the BRAF inhibitor encorafenib and MEK inhibitor binimetinib. Encorafenib has the advantage that it causes fever less often than dabrafenib. So, on the encorafenib-binimetinib protocol, the rituximab can be added later in order to convert an MRD-positive complete remission to an MRD-negative complete remission.
Why is it helpful to have a MEK inhibitor in addition to a BRAF inhibitor? When there's no inhibition, the BRAF normal pathway gives you normal cells. The BRAF V600E gives you cancer cells. When you use BRAF inhibition alone, like vemurafenib or dabrafenib, you block the BRAF V600E pathway, but then it overstimulates; it over-phosphorylates the normal BRAF pathway. This can lead to problems like fever and skin cancer, skin growth, and pancreatitis. But when you use a combination BRAF and MEK inhibitor, you get better blocking of their pathway, because MEK is inhibited in the tumor cells. That inhibition in normal cells damps down the increase in stimulation that the BRAF inhibitor causes.
So, the MEK inhibitor combines with the BRAF inhibitor to decrease toxicity.
In a study in animals: when you use BRAF inhibitor alone, there is thickening on the hand of the mice, which we call hyperkeratosis. When you use combined BRAF and MEK inhibition, you don't see that thickening. So, that is a good model for showing that the combined inhibition is less toxic.
Our study published last year in Blood looked at the BRAF inhibitor Dabrafenib and had complete remission rate of 66%. The duration of response at 24 months was 98%; every patient except for one, and the time to response was only 3.7 months. The time to complete remission was only six months. So it works very quickly and the overall survival and what we call progression-free survival were very high, partly because these patients were treated long-term, but also because of the combined treatment.
NCI-NIH Trials in Encorafenib plus binimetinib and Binimetinib alone
We're actively accruing to the encorafenib-binimetinib trial in BRAF V600E-positive HCL. In the trial where this combination for melanoma was FDA approved, it was found superior to vemurafenib; it had less fever than the dabrafenib-trametinib.
So, eligibility for this trial requires HCL being mutated at V600E, but patients with other mutations like V600D, V600K, they can also qualify. We could decrease a dose as needed for any toxicities. We like it if patients can get a dose without toxicity. And patients in an MRD-positive complete remission for one year can continue on the oral drugs while they're getting rituximab in order to get MRD-free. Or they could get any other antibody that their doctor wants to give them, such as obinutuzumab or Ruxience. Ruxience is a biosimilar to Rituxan. And then for patients who don't have this V600E mutated HCL, we can give binimetinib alone, which is the MEK inhibitor.
Generally, patients without the BRAF inhibitor have more aggressive disease. They have a poor survival without treatment. But we've seen complete remissions occur quickly with binimetinib, so I think this is a very valuable treatment. There's a strong need for better treatments in patients who don't have the V600E mutation.
Link to Binimetinib trial for people with relapsed/refractory BRAF Wild Type HCL and Variant. >>
CAR-T
I want to switch to CAR-T. CAR-T has been very successful in other B-cell malignancies like CLL. We target CD22; this is done by taking your T cells out through the blood through a procedure called apheresis where we remove lymphocytes and give you back your blood cells. Then, in the lab, we put CD22 on the T cells, grow them to be millions, and infuse them back into the patient. Then they go to the hairy cells and kill them.
The eligibility for this trial requires that patients have already had BRAF treatment or they're not eligible for that. If you have HCL variant, you can't be eligible for BRAF inhibitor and could be eligible for this trial. You have to need additional treatment and the cells have to be CD22 positive.
The design for the trial involves first getting the apheresis. Then we give chemotherapy at a low dose to decrease normal T cells that might compete with the CAR-T cells. We want the CAR-T cells to stay in the body and work and normal T cells might prevent them from doing that. That's handled with the lymphodepleting chemotherapy. On day zero, we infuse the CAR-T cells and follow you as an inpatient for a couple of weeks until the toxicity period is over. Toxicity is mainly inflammation which is treated with different drugs. This is a high-intensity trial. Any trial that would admit patients for several weeks is a more aggressive-type treatment, but it's one that can be highly effective.
Venetoclax
We have a new trial that's for the same group of patients who've had prior BRAF inhibitors. Venetoclax targets BCL-2; BCL-2 is seen in HCL. Dr. Enrico Tiacci in Italy published six patients treated with Venetoclax when their HCL progressed after vemurafenib plus rituximab. With Venetoclax, two of these six patients got complete remission. Patients with complete remission has been reported by Forconi, et al. Three of the patients that were treated by Venetoclax received rituximab and the responses were improved.
[Link to this trial is not yet available.]
There is a multi-center trial of Venetoclax that's going to be led by the NIH, and that's going to start soon, hopefully in the next couple of months. That trial is going to be sponsored by NCI and CTEP.
We start on day one with Venetoclax at a very low dose. And every week the dose is increased until on cycle two, day one after four weeks, you're getting the full dose at 400 milligram per day. It's an oral drug. Patients are seen before treatment at the beginning of cycle two and four and nine, other times as needed. Some virtual visits are allowed for convenience. Disease status is checked at the beginning of cycle four and the beginning of cycle nine, and the treatment completes at one-and-a-half years. The other participating sites are Ohio State University, Virginia Commonwealth University, New York University, University of Maryland, and Cornell.
In summary, our clinical trials for HCL are: 1.) encorafenib plus binimetinib for patients with BRAF positive classic HCL, 2.) binimetinib alone for HCL or HCL variant lacking BRAF V600E, and 3.) CAR-T protocol targeting CD22 in HCL and HCL variant, and 4.) Venetoclax for the same population.
This transcript has been edited for clarity.