Webinar: Understanding Hairy Cell Leukemia (HCL)
March 2026
This webinar was hosted by the Hairy Cell Leukemia Foundation (HCLF) with guest speaker Dr. Robert Kreitman from the National Cancer Institute, NIH. This presentation is part of the HCLF’s ‘Understanding Hairy Cell Leukemia’ webinar series. Each webinar features a presentation by an HCL expert and an overview of diagnosis, standard treatments, and new research.
Below, view a webinar recording and transcript of the presentation and Q&A.
Transcript of Dr. Kreitman’s presentation
Introduction
Thank you again for inviting me to give an update on understanding Hairy Cell Leukemia.
As many of you already know, Hairy Cell Leukemia is a B-cell malignancy. It represents about 2% of all leukemias and accounts for approximately 1,300 new cases per year.
Patients typically present with low blood counts, enlarged spleens, and characteristic cells with cytoplasmic projections that look like “hairs.” These cells are strongly positive for CD22 and CD20, and in classic Hairy Cell Leukemia they are also CD25 positive. The disease is driven in most cases by the BRAF V600E mutation.
The standard treatment still includes purine analogs, mainly cladribine and pentostatin. These treatments can induce long-term complete remissions, but they are not considered curative, and their effectiveness tends to decrease with repeated use.
Diagnosis is made by flow cytometry of the blood or bone marrow. This is important not only to confirm the disease but also to exclude other disorders and determine whether the patient has classic Hairy Cell Leukemia or a variant form.
What is the difference between Hairy Cell Leukemia and the HCL variant?
In the variant form, patients tend to have more severe spleen enlargement and may also have enlarged lymph nodes. Blood counts may appear more normal, but there are often higher levels of malignant cells circulating in the blood. Importantly, these cases are typically negative for CD25 and do not carry the BRAF V600E mutation. As a result, their response to cladribine and pentostatin is generally poor.
Our laboratory also described an overlap syndrome known as IGHV4-34 positive Hairy Cell Leukemia. This form resembles the variant, although it can sometimes be CD25 positive. Because of this, patients may initially be labeled as having Hairy Cell Leukemia. However, these cases are BRAF negative and also respond poorly to cladribine or pentostatin.
These variants are more commonly seen in patients with relapsed or refractory disease, which is why we frequently encounter them in clinical trials.
What defines remission?
A complete remission requires improvement in blood counts, reduction in spleen and lymph node size if they were enlarged, and a decrease in leukemia cells in the bone marrow.
Additionally, no hairy cells should be visible using standard staining methods, such as Wright stain or hematoxylin and eosin (H&E) staining. There should also be resolution of splenomegaly, lymphadenopathy, or high levels of malignant cells in the blood.
Blood counts should recover to at least the following levels: neutrophils above 1.5, hemoglobin above 11, and platelets above 100.
When is treatment needed?
Treatment is typically indicated when counts fall below certain thresholds: neutrophils below 1.0, hemoglobin below 10, or platelets below 100. This is often referred to as the “1–10–100 rule,” which has been used for decades.
What is Minimal Residual Disease, or MRD?
Minimal residual disease, or MRD, refers to small numbers of leukemia cells that remain detectable by sensitive methods such as immunohistochemistry or flow cytometry. MRD is important because it can eventually lead to relapse.
Many of our clinical trials over the past decade have focused on eliminating or minimizing MRD. These approaches include targeting CD20 with rituximab combined with cladribine, bendamustine, or pentostatin. Other strategies involve targeting the BRAF and MEK pathways with inhibitors, combining BRAF inhibitors with CD20 antibodies, and exploring additional targets such as BTK, BCL-2, and CD22.
We have also investigated CAR T-cell therapy targeting CD22.
The use of rituximab to eliminate MRD in first-line treatment
In previously untreated patients, rituximab given as eight weekly doses starting four weeks after cladribine was able to eliminate MRD at three to four months in 78% of patients in studies from MD Anderson.
However, laboratory studies have shown that rituximab can increase the sensitivity of lymphoma cells to cladribine, which has a short half-life. This suggests that giving the drugs together may be more effective than delaying rituximab.
To test this, we conducted a randomized trial comparing cladribine with immediate rituximab versus cladribine with rituximab delayed until MRD appeared.
The results showed that MRD-free complete remission rates were 94% with the combination given together, compared to only 32% with cladribine alone.
Even when looking at durability, most patients who achieved MRD-free remission with cladribine alone became MRD-positive relatively quickly, whereas those treated with the combination maintained deeper remissions.
Delayed rituximab did improve outcomes, with MRD-free remission rates reaching 67%, but these were still not as strong or durable as when rituximab was given concurrently.
At a median follow-up of 6.5 years, the need for additional treatment was only about 1.5% with either combination approach, compared to 28% historically with cladribine alone.
Cladribine plus rituximab given together
When comparing all approaches, the combination of cladribine and rituximab given together consistently produced the highest MRD-free remission rates. This is likely due to synergy between the drugs, as cladribine leaves the body within one to two days, and delayed rituximab cannot take full advantage of this effect.
Although rituximab can cause a temporary drop in platelet counts early in treatment, this is not associated with bleeding and is followed by improved blood counts within a few weeks.
Second-line treatment
In patients receiving cladribine as a second-line therapy, the complete remission rate is about 62%. In our randomized trial of patients who had relapsed after prior treatment, the combination of cladribine and rituximab resulted in higher complete remission rates and significantly higher MRD-free remission rates compared to cladribine alone.
Delayed rituximab was also able to improve outcomes in both groups.
Hairy Cell Leukemia variant (HCLv)
For HCLv, cladribine alone achieves very low complete remission rates, around 7% in historical data. In contrast, the combination of cladribine and rituximab achieved complete remission rates as high as 95%.
Therefore, purine analogs alone should not be used for the variant form.
Long-term follow-up shows that while many patients achieve MRD-free remission with the combination, some eventually become MRD-positive again. In those cases, delayed rituximab can often restore MRD-free remission for extended periods.
Patients with TP53 abnormalities or those who do not achieve MRD-free remission tend to have worse outcomes, highlighting the importance of molecular testing before treatment.
HCL with BRAF V600E negative
We have also identified non-V600E BRAF mutations in some patients with classic Hairy Cell Leukemia. These mutations are associated with shorter remission durations when treated with purine analogs alone.
However, overall survival does not appear to be worse. Importantly, these patients benefit from adding rituximab or obinutuzumab to their treatment.
Patients with multiple relapses
For patients with multiple relapses, combinations such as pentostatin plus rituximab or bendamustine plus rituximab have shown high response rates. In our studies, response rates exceeded 85% for both regimens, with pentostatin plus rituximab showing somewhat better long-term outcomes in certain analyses.
Targeted therapies
Turning to targeted therapy, the BRAF V600E mutation plays a central role in Hairy Cell Leukemia. Drugs such as vemurafenib and dabrafenib inhibit this pathway and can produce meaningful responses.
Combining BRAF inhibitors with MEK inhibitors improves both effectiveness and safety. In clinical trials, these combinations have achieved high complete remission rates and durable responses.
Adding CD20 antibodies, such as rituximab or obinutuzumab, can further improve outcomes and help eliminate MRD.
BTK inhibitors and CAR T-Cell
Other targeted therapies include BTK inhibitors like ibrutinib, which produce responses in about half of patients, although responses can take longer to develop. BCL-2 inhibitors such as venetoclax have also shown promising early results.
Targeting CD22 has also been effective. The drug moxetumomab pasudotox was approved in 2018 and showed strong activity, especially when combined with rituximab. Although it has been discontinued, there is interest in further development of similar therapies.
CAR T-cell therapy targeting CD22 is an emerging approach. Because CD22 is highly expressed in Hairy Cell Leukemia, this strategy may be particularly effective.
In one example, a patient with long-standing, treatment-resistant disease achieved a deep, MRD-free remission after CAR T-cell therapy that has remained ongoing for over a year and a half.
Conclusion
● Hairy Cell Leukemia is an indolent and highly treatable disease.
● First-line treatment now commonly includes cladribine combined with rituximab, which improves the depth and durability of remission.
● In relapsed disease, combination approaches remain more effective than single-agent therapy.
● Variant forms require different strategies and should not be treated with purine analogs alone.
● Targeted therapies, immunotherapies, and CAR T-cell approaches are expanding treatment options and improving outcomes.
● Clinical trials are strongly recommended, especially for patients with relapsed or variant disease.
Thank you very much. I would like to acknowledge our clinical team, laboratory team, and collaborators, and I look forward to answering your questions.
This transcript was edited for clarity.
Transcript of Q&A
1. What is the recommended follow-up schedule after treatment?
Dr. Kreitman:
You really have to focus first on resolving cytopenias, meaning the low blood counts. If counts are very low or getting worse, you may need to check blood counts every several days, even daily in some patients, especially those needing transfusions.
Once the cytopenias are resolved, we typically check CBCs every three months or so. We also like to check blood flow cytometry every six months until around two and a half years, and then half as often after that.
It is very important to check bone marrow at the six-month time point after treatment. Otherwise, you cannot really determine whether the patient has achieved a partial response or a complete remission, since those are based on bone marrow findings.
In our clinical trials, we check bone marrow yearly until about two and a half years, and then every other year. However, in routine practice, most physicians would only check at the six-month time point.
For patients not on trials, sometimes we just monitor with yearly blood flow cytometry instead of repeated bone marrow biopsies.
2. Should patients seek a second opinion if remission status is unclear?
Dr. Kreitman:
I think that would be reasonable.
We are often consulted to evaluate minimal residual disease (MRD). Looking for MRD can be very helpful. If patients do not have MRD in the blood, they are probably in a very good remission, although you really cannot be certain without a bone marrow.
We can also evaluate bone marrow samples to determine the response more definitively.
Regarding the spleen, it is an interesting organ. It can be very large before treatment, and even if you eliminate all hairy cells, the spleen can remain enlarged.
This is because enlargement is often due to fibrosis or scar tissue, which can persist for years after treatment. You should not expect the spleen to return to a completely normal size.
That enlarged spleen alone can still cause low platelet counts. Splenectomy should generally be avoided, except in very late palliative situations.
If needed, tumor markers like soluble CD22 or soluble CD25 can help assess disease activity. CD25 is more commonly used.
3. Why is TP53 mutation testing important, and should all patients be tested?
Dr. Kreitman:
We try to test all patients when possible, but it is much more common in the hairy cell variant.
If a patient has hairy cell variant, they really should be tested for TP53.
In our BRPR trial (bendamustine plus rituximab vs pentostatin plus rituximab), patients with poor-risk features, including TP53 mutation, have had no relapse for years.
It is possible that these regimens may even be better than cladribine plus rituximab in some of these higher-risk patients.
4. Why might combination therapies like cladribine plus rituximab be more effective, and how durable are the results?
Dr. Kreitman:
One reason could be synergy.
With regimens like cladribine plus rituximab, pentostatin plus rituximab, or bendamustine plus rituximab, there are more opportunities for synergy because the drugs are used simultaneously.
For first-line treatment, essentially no patients have relapsed.
Since we republished our data, only one patient has relapsed from MRD-free complete remission, and we have not seen additional relapses beyond that.
This is a really remarkable result. Some patients have been followed for more than 16 years.
5. Should some patients receive cladribine alone instead of combination therapy?
Dr. Kreitman:
Yes, there are rare circumstances.
For example, during COVID, we avoided rituximab because patients would not be able to mount an immune response to vaccines for several years after receiving it.
There was even a tragic case of a young patient who died after receiving rituximab following cladribine.
So, in certain situations, especially involving immune concerns, it may be appropriate to avoid rituximab.
6. Is 8 doses of rituximab better than 4 doses?
Dr. Kreitman:
No, they have not been directly compared.
There is not enough data with four doses to feel confident. I think eight doses are probably better to give an adequate chance of eliminating MRD, but there is no trial comparing the two.
7. Can non-chemotherapy options be used first?
Dr. Kreitman:
Yes, I think it is reasonable.
I like vemurafenib plus obinutuzumab for untreated patients who want to avoid chemotherapy. Although we do not yet have long-term data, it is a reasonable option.
If patients achieve MRD-free complete remission and it lasts, that is excellent. If not, they can still try cladribine or another regimen later.
Patients are probably most sensitive to their first treatment, but sequencing different treatments is possible.
8. How can patients access clinical trials, especially if they live far away?
Dr. Kreitman:
At the NIH, travel expenses are covered for U.S. patients, including those in Alaska and Hawaii. Patients need to get here initially, but once accepted, travel is paid.
Patients may receive stipends for lodging or be admitted to the hospital at no cost.
For international patients, travel for certain trials, such as CAR-T, can also be covered through grants.
Many treatments in trials are oral, which means patients can take them at home with minimal travel. In some cases, we can dispense up to six months of medication at a time.
Follow-up visits, especially for bone marrow evaluations, are often done at NIH, although sending samples from local providers can sometimes be arranged.
9. Why are clinical trials so important?
Dr. Kreitman:
Without patients willing to participate in clinical trials, we would not have any of the treatments we use today, including cladribine or targeted therapies.
Clinical trials are essential for advancing care and improving outcomes for future patients.
This transcript has been edited for clarity.