Updated Consensus Guidelines for Hairy Cell Leukemia (HCL) and Hairy Cell Leukemia Variant (HCLv)
Webinar Presentation and Discussion with Dr. Michael Grever, The Ohio State University and Dr. Clive Zent, University of Rochester; Hosted by the Hairy Cell Leukemia Foundation in June 2026 with Anna Lambertson, HCLF, as moderator.
During this program, Drs. Grever and Zent discussed the newly updated expert guidelines for HCL and HCLv.
TRANSCRIPT OF THE WEBINAR PRESENTATION
Welcome and Introduction
Anna Lambertson
Today's webinar is about the process and what's new in the guidelines for Hairy Cell Leukemia and Hairy Cell Leukemia Variant. We are really looking forward to hearing from our speakers today.
Our first speaker, Dr. Michael Grever, is a hematologist at The Ohio State University in Columbus, Ohio. He specializes in treating leukemia and other blood cancers. He leads a group of Hairy Cell Leukemia experts at The Ohio State University and is also Chair of the Hairy Cell Leukemia Foundation's Scientific Advisory Committee.
Dr. Clive Zent is a hematologist at the University of Rochester Wilmot Cancer Center and is a very important member of the Hairy Cell Leukemia Foundation's Scientific Advisory Committee.
Both of these physicians are leading experts in Hairy Cell Leukemia, and their institutions are designated Hairy Cell Leukemia Centers of Excellence. They were both co-authors of the original guidelines published in 2017 and, together with more than 40 other experts in Hairy Cell Leukemia, co-authored these updated guidelines, which were published in April 2026.
Without further ado, I am delighted to turn the presentation over to our speakers. Dr. Grever will be kicking off the discussion.
The Importance of the Updated Guidelines
Dr. Michael Grever
I look forward to having this discussion with you, particularly with Dr. Zent, who is an outstanding hematologist and a highly productive member of the Hairy Cell Leukemia research team.
We are very grateful to the Hairy Cell Leukemia Foundation for providing an opportunity for international experts in this disease to convene yearly to discuss research findings and provide guidance for physicians caring for patients with this disease.
We've been meeting as experts for over 15 years with the support of the Hairy Cell Leukemia Foundation. During these meetings, we discuss advances and remaining challenges to improve the management of patients with this rare disease.
Through these discussions, we have developed guidelines. Initially, we published them in 2017. However, an updated version was needed, and the 2026 guidelines have already been accepted by Blood and are currently in print.
Our colleagues have had adequate time to contribute to these guidelines, review them, make suggestions, and ultimately endorse this most recent version.
The goal is to provide guidance regarding the diagnosis and management of these rare forms of adult leukemia.
We have made tremendous progress, and we need to continue working toward improving outcomes and, hopefully one day, curing this group of diseases.
A Message of Hope for Patients
Dr. Michael Grever
Hairy Cell Leukemia is one of the more treatable lymphoid malignancies. With treatment, most patients can expect to live nearly a normal lifespan.
This is in contrast to my early experience working with Dr. Bertha Bouroncle in the 1970s, when patients were often told that after about four years, the disease would become more challenging.
Today, we can reassure patients that they can expect to live as long as they might have lived without leukemia. They may require treatment for relapse, but the growing number of available therapies has greatly improved outcomes.
Current therapies are not considered curative, but targeted treatments and cellular therapies are bringing us closer to that goal.
If you have recently been diagnosed, you should be hopeful and encouraged.
Standard First-Line Treatment: Purine Analogs
Dr. Michael Grever
The traditional treatment for Hairy Cell Leukemia has been chemotherapy with drugs known as purine analogs. The two most commonly used are cladribine and pentostatin.
These treatments are highly effective, with complete remission rates of 70% to 90%, and remissions often last a long time—sometimes more than ten years.
Cladribine must be used carefully in patients with impaired kidney function because it is cleared through the kidneys. The same is true for pentostatin.
Cladribine should also be avoided in patients with active, uncontrolled infections. These treatment decisions must be made carefully by your hematologist.
Combining Cladribine and Rituximab
Dr. Michael Grever
The 2026 guidelines show strong evidence that combining cladribine with rituximab, either concurrently or sequentially, can produce better outcomes.
Rituximab is an immunotherapy, and it has significantly improved the duration of response when combined with cladribine.
In one study of 108 patients, 98% achieved a complete remission, and only 3% relapsed after nearly eight years.
In another trial, patients who received both cladribine and rituximab achieved complete remissions, and after 6.5 years, only one of 68 patients had relapsed.
By comparison, when purine analogs are used alone, without rituximab, relapse rates can exceed 28%.
Importantly, effective therapies remain available for patients who do relapse.
Why BRAF Testing Matters
Dr. Michael Grever
Another important recommendation is that the BRAF V600E mutation should be assessed in every patient as part of the initial diagnostic workup.
More than 95% of patients with classic Hairy Cell Leukemia carry this mutation.
The 2026 guidelines emphasize that testing for this mutation is now standard practice and is no longer simply a research tool.
A positive result helps confirm the diagnosis of classic Hairy Cell Leukemia because this mutation is not found in Hairy Cell Leukemia Variant.
It also helps guide treatment decisions because targeted therapies such as vemurafenib can specifically inhibit BRAF-mutated cells.
Patients who do not have this mutation may harbor other genetic abnormalities that could influence treatment planning.
The Growing Role of BRAF Inhibitors
Dr. Michael Grever
Although vemurafenib remains an off-label treatment for Hairy Cell Leukemia, the 2026 guidelines recommend it in several situations, including:
● Refractory disease that no longer responds to purine analogs
● Relapse within two years after initial therapy
● Relapse within five years after treatment with a purine analog plus rituximab
● Two or more relapses at any time
● Serious active infections where chemotherapy may be too risky
● Frail patients or those who wish to avoid chemotherapy
Unlike chemotherapy, vemurafenib does not suppress the immune system and does not interfere with vaccine responses.
Patients taking vemurafenib can still receive vaccines, including COVID-19 vaccines.
Vemurafenib is often combined with rituximab for improved results.
Managing Relapsed Hairy Cell Leukemia
Dr. Michael Grever
Approximately 30% to 40% of patients, and up to 58% of younger patients, will eventually relapse after their first treatment.
Fortunately, effective therapies are available to achieve additional remissions.
The 2026 guidelines offer a roadmap based on the duration of the first remission.
If the first remission lasts more than two years, treatment with a purine analog plus rituximab is recommended.
This approach leads to complete remissions in up to 70% of patients.
If remission lasts less than two years, or if the disease is refractory, options include:
● Vemurafenib plus rituximab
● Switching to a different purine analog (for example, cladribine to pentostatin) plus rituximab
For later relapses, additional options include:
● Dabrafenib plus trametinib
● Ibrutinib
● Zanubrutinib
● Venetoclax
The key message is that relapse is manageable, and more treatment options are available today than ever before.
Emerging Therapies and Clinical Trials
Dr. Michael Grever
There are also promising therapies on the horizon.
CAR T-cell therapy is being investigated for patients who have experienced multiple relapses and no longer respond to standard treatments.
The 2026 guidelines also discuss:
● Venetoclax, a BCL-2 inhibitor
● BTK inhibitors such as ibrutinib and zanubrutinib
● Anti-CD22 CAR T-cell therapy
These treatments have shown encouraging early results, particularly in heavily pretreated patients, although they remain investigational.
The importance of clinical trials cannot be overstated. We strongly encourage patients to consider participating in clinical trials because this is how promising new therapies ultimately become available to everyone.
Understanding Hairy Cell Leukemia Variant (HCLv)
Dr. Clive Zent
Mike said some very kind things about me, but I want to remind everyone that Mike was the person who helped bring purine analog therapy into Hairy Cell Leukemia treatment many years ago.
Hairy Cell Leukemia Variant is a distinct disease. It was not initially recognized as being different from classic Hairy Cell Leukemia when the disease was first described in the late 1950s.
It began to be recognized as a separate entity around 1980 and has since been established as a distinct disease.
It is one of the splenic lymphomas, along with Hairy Cell Leukemia, but it differs in several important ways.
It does not carry the BRAF V600E mutation and generally does not respond well to chemotherapy alone.
Treatment Advances in Hairy Cell Leukemia Variant
Dr. Clive Zent
Cladribine or other purine analogs used as single agents are not very effective.
We now know that Hairy Cell Leukemia Variant responds much better to the combination of cladribine and rituximab.
This approach has improved response rates dramatically, with approximately 95% of patients responding.
Five-year progression-free survival is approximately 63%.
While this is not as favorable as classic Hairy Cell Leukemia, it is substantially better than what we achieved previously with cladribine alone.
The Importance of Genetic Testing in HCLv
Dr. Clive Zent
Anyone diagnosed with Hairy Cell Leukemia Variant should undergo additional genetic testing at diagnosis.
We recommend testing for:
● TP53 mutations
● MAP2K1 mutations
● IGHV mutation status
These markers provide important prognostic information and may help guide treatment decisions.
Infection Prevention and Supportive Care
Dr. Clive Zent
These low-grade B-cell lymphomas can cause significant immune suppression, even before treatment begins.
Patients should understand their infection risks, how to reduce those risks, and how to recognize infections early.
We recommend that patients receiving purine analog therapy receive antimicrobial prophylaxis to prevent:
● Herpes simplex virus
● Varicella-zoster virus (shingles)
● Pneumocystis jirovecii pneumonia (PJP)
I would also emphasize what Dr. Grever mentioned earlier: cladribine should be used very cautiously in patients with active, uncontrolled infections.
Vaccination Recommendations
Dr. Clive Zent
We recommend vaccinations for all patients with these diseases.
Live vaccines should generally be avoided. Examples include:
● Yellow fever vaccine
● Measles-containing vaccines
We do recommend seasonal influenza vaccines and COVID-19 vaccines.
Patients receiving vemurafenib can respond appropriately to vaccines.
Patients actively receiving cladribine, pentostatin, or other purine analogs should generally wait until immune recovery before receiving vaccinations.
Why Irradiated Blood Transfusions Are Recommended
Dr. Clive Zent
Blood transfusions can contain donor lymphocytes that may cause a serious immune reaction known as graft-versus-host disease.
Therefore, if a patient requires a blood or platelet transfusion, we strongly recommend using irradiated blood products.
Irradiation prevents donor lymphocytes from dividing and causing this rare but serious complication.
Avoiding Unnecessary Use of Allopurinol
Dr. Clive Zent
Another supportive-care recommendation concerns allopurinol. Allopurinol is commonly used with many chemotherapy regimens to prevent complications associated with rapid tumor cell breakdown.
However, in Hairy Cell Leukemia, allopurinol is generally unnecessary and can increase the risk of drug-related reactions that may interfere with treatment.
Dr. Clive Zent
These are the references for the 2017 and 2026 International Consensus Guidelines for the Diagnosis and Management of Hairy Cell Leukemia and Hairy Cell Leukemia Variant.
Q&A Session
Immune Suppression and Recovery After Cladribine: Does cladribine permanently impair white blood cells and the immune system?
Dr. Clive Zent
"It's very important to understand that lymphoid malignancies, and that's what both of these diseases are, cause early onset and profound immune suppression. We have a partial understanding of why that happens, but there is no therapy that we have to date that can reverse that completely.
If a patient then gets a purine analog drug, that suppression is increased considerably, especially within the first six weeks after treatment is completed. The residual problems can be important for six months to a year, and actually it can take two to three years before your immune system gets back to what it was like before you got cladribine.
But it never gets back to normal because the effects of the lymphoma on the immune system are not repairable in adults. So it's not necessarily only the purine analogs; the disease itself is immunosuppressive.
That's why it's important to remain vigilant about infections, second cancers, and possibly autoimmune complications indefinitely."
Dr. Michael Grever
We follow certain T-cell numbers, and whenever they are down, they're almost always down for a number of months, sometimes out to a year or longer after you use the purine analogs.
I keep my patients on prophylactic therapies until those T-cells show some recovery. The disease itself suppresses the immune system, but there is a definite impact on the immune system from these drugs.
Until the immune system has had adequate time to partially recover, I keep my patients on prophylactic medicines to try and prevent infections such as herpes zoster, or shingles, which can be fatal in immunosuppressed patients."
Vaccines and Anti-CD20 Therapy: Does vemurafenib plus obinutuzumab affect a patient's ability to receive vaccines?
Dr. Michael Grever
"The use of an anti-CD20 monoclonal antibody, either rituximab or obinutuzumab, is immunosuppressive.
These drugs markedly improve the duration of response. While vemurafenib may not impair the immune system significantly, the addition of a monoclonal antibody does entail some immunosuppression.
These anti-CD20 monoclonal antibodies are very important for improving the response and the duration, but they do contribute to suppression of the immune system."
Dr. Clive Zent
"Both rituximab and obinutuzumab suppress the ability to react by making antibodies to infections and vaccines while you're getting the drug, and for at least six months to a year afterwards, and even longer.
Using these drugs does come at a cost, and one component of that cost is worsening immune function during and after therapy."
Concurrent vs Delayed Rituximab: Should rituximab be given concurrently with cladribine or later? What are the advantages and disadvantages?
Dr. Michael Grever
"The rationale for giving them together was put forth by Dr. Kreitman and his colleagues at the National Cancer Institute.
Their reasoning was that if you give rituximab simultaneously with cladribine, you increase the sensitivity of the leukemia cells to chemotherapy. You kill more leukemia cells and get rid of more disease acutely.
However, you probably also have more immunosuppression.
One of the side effects is that rituximab given simultaneously can lower the platelet count dramatically. Somewhere around a third of the patients treated at the National Cancer Institute required platelet transfusions because platelets could fall significantly.
Dr. Ravandi and other colleagues have shown that the benefit can be delayed. If you give them in sequence, leukemia cells continue decreasing in number.
Many physicians use delayed administration because you still get very good results while potentially avoiding some of the side effects."
Dr. Clive Zent
"The studies have shown that progression-free survival is better, but there's no randomized controlled trial comparing cladribine with or without rituximab.
One option is to give everybody cladribine upfront and then treat the people who relapse with cladribine and rituximab, because many patients will go more than ten years before needing additional therapy.
Adding rituximab definitely increases the risks of therapy. In anybody who doesn't need that additional risk, that's a risk you may not want to take."
Rituximab vs Obinutuzumab: If someone has a severe reaction to rituximab, could obinutuzumab be used instead?
Dr. Clive Zent
"This is a very difficult question, and there's no easy answer.
These drugs switch on your own immune system to kill cells. When patients have a large reaction, it's often because the immune system has been activated.
If you get rituximab or obinutuzumab and have a very big reaction, it's usually a first-dose reaction. If you receive the same drug again a week or two later, the risk is much lower.
True allergic reactions to rituximab are very rare, less than one in two thousand patients.
Rituximab contains a mouse antibody component. If someone has a true allergic reaction, they should never receive rituximab again. Obinutuzumab does not contain a mouse component and could potentially be tolerated.
However, obinutuzumab is actually more likely to cause infusion reactions and is routinely given with corticosteroids to reduce those reactions."
Dr. Michael Grever
“It's important to review how the drug was administered because the rate of administration can contribute to the severity of an infusion reaction.
Most patients experience less toxicity with subsequent infusions."
Defining Remission: How do you determine if a patient is in remission?
Dr. Michael Grever
"Our definition of a complete remission was normalization of the blood counts, or near normalization of the blood counts, and no hairy cells identifiable in the bone marrow biopsy by morphology.
Today we also look for measurable residual disease.
We can use flow cytometry, immunohistochemical stains, or molecular studies that look for the BRAF mutation.
A patient may meet the criteria for a complete remission and still have measurable residual disease."
When Should Remission Be Assessed? How long after treatment do you determine whether a patient is in remission?
Dr. Michael Grever
"With cladribine, many physicians recommend waiting three to four months before doing a bone marrow biopsy because improvement can continue over time.
With pentostatin, treatment extends over a longer period and evaluation is generally performed around six months."
Dr. Clive Zent
"This disease is caused by failure of programmed cell death. These cells accumulate over very long periods of time.
When you treat them, they may take a long time before they die. This is not like treating an aggressive fast-growing tumor.
Three months is the minimum time to assess response, and I generally wait six months.
Many times we have seen patients evaluated one month after treatment who still have disease, and then at six months everything is gone.
You really need to give these drugs a chance to work."
Follow-Up After Remission: How often should patients have blood counts checked after remission?
Dr. Michael Grever
"I usually follow patients every three months for the first two years.
They may not be relapsing, but they can still have problems related to immune suppression.
I want to make sure they are taking their prophylactic medicines and that their counts are stabilizing."
Dr. Clive Zent
"After two years, I usually see patients every six months for another two years, and then annually.
More than half of patients will relapse at some point.
It's important not just to check labs. You need to see the patient, make sure the spleen is not enlarged, and assess for other problems."
Antiviral and Pneumocystis Prophylaxis: How long should prophylaxis continue after cladribine and rituximab? What if a patient develops a rash from Bactrim?
Dr. Clive Zent
"There's no definitive data. I think a minimum of six months, and I usually don't go more than a year, although some patients remain on prophylaxis for a year.
The important recommendation in the new guidelines is that antiviral and anti-Pneumocystis therapy should not be given at the same time as cladribine.
We recommend starting prophylaxis after cladribine is finished because cladribine, allopurinol, and Bactrim together cause a large number of rashes.
For patients who cannot tolerate Bactrim, alternatives include atovaquone or inhaled pentamidine."
Irradiated Blood Products: Should irradiated blood products be used only during treatment or also after treatment?
Dr. Clive Zent
"Irradiated blood for many cancer centers is recommended for everybody.
The immunosuppression caused by low-grade lymphoma may be sufficient to allow donor lymphocytes to survive and cause graft-versus-host disease.
If irradiated blood is available, it should be used for all blood products given to anybody who has cancer or is immunocompromised."
Treatment of Older Patients: Are there special treatment recommendations for patients over age 75 or 80?
Dr. Michael Grever
"Tamara Tadmor wrote a paper on how to approach patients over age 75.
Most experts recommended cladribine, provided that kidney function is adequate, there is no active infection, and the patient has a reasonable performance status.
For patients who are frail, we sometimes modify the dose of pentostatin or extend the interval between treatments.
If patients are older, you still want to give them the most effective therapy, but you must factor in kidney function and performance status."
Dr. Clive Zent
"Cladribine and pentostatin are probably equally effective. Pentostatin gives you more flexibility because you can modify the dose and duration. Bone marrow reserve decreases with age, and that must be considered. For some older, frail patients with BRAF V600E-positive disease, vemurafenib plus rituximab is also a reasonable option."
Rituximab in Very Elderly Patients: Is there an age limit for rituximab?
Dr. Clive Zent
"Age is just one factor. Biological fitness is probably more important. You have to individualize treatment for each patient. You need to balance risks and benefits carefully."
Accessing the Guidelines: How can patients make sure their hematologists have access to the 2026 guidelines?
Anna Lambertson
"The guidelines were published in Blood, which is an internationally recognized journal. They are also available through the Hairy Cell Leukemia Foundation website under Patient Support and Research. If patients or physicians cannot find them, they can contact the Foundation and we will provide a link. Physicians are also welcome to contact the guideline authors directly with questions about how the guidelines apply to individual patients."
This transcript was edited for clarity.