General Information About Hairy Cell Leukemia

Incidence and Mortality

Hairy cell leukemia is an indolent, low-grade, B-cell lymphoid malignancy. It is rare, with only 1,200 to 1,300 new cases annually in the United States.[1]

Clinical Presentation

Hairy cell leukemia usually presents with:

• Splenomegaly.
• Varying degrees of leukopenia (occasionally leukocytosis).
• Pancytopenia.
• Monocytopenia.
• Bone marrow infiltration by atypical cells with prominent cytoplasmic projections (i.e., hairy cells).

Lymphadenopathy is absent, except with multiply recurrent progressive disease.

Diagnostic Evaluation

The following tests and procedures may be used to diagnose hairy cell leukemia:

• Flow cytometry.
• Bone marrow aspiration and biopsy.
• Immunophenotyping.
• Cytogenetic analysis.
• BRAF gene testing.
• Computed tomography scan.

The bone marrow is usually fibrotic and is not easily aspirated. It has circulating B cells with cytoplasmic projections (hairy appearance). Although a bone marrow biopsy may be required to enroll in a clinical trial, the hairy cell leukemia diagnosis can usually be made by flow cytometry.

In addition to the B-cell antigens CD19, CD20 (very high levels), and CD22, the cells coexpress CD11c, CD25, and CD103. The BRAF V600E mutation is a hairy cell leukemia–defining genetic feature that can be used diagnostically.[2,3] A hairy cell leukemia variant (which accounts for 10% of hairy cell leukemia patients) is distinguished clinically by an elevated white blood cell count (15–50 × 10⁹ /L) and aberrant markers, including variable (instead of bright) CD103 and the absence of CD23, CD25, CD12, and CD43.[4,5] Hairy cell leukemia variant cells also lack BRAF mutations. Patients with this variant have a more aggressive clinical course, reduced disease response to purine nucleoside analogue-based therapy, and shorter durations of response.[5]

The depth of a complete remission can be evaluated with measurable residual disease (MRD) by using the mutant BRAF gene or immunoglobulin heavy chain gene rearrangement. However, the usefulness of MRD to alter therapeutic choices remains unclear and requires further evaluation.[6]

References:

1. Troussard X, Maître E, Cornet E: Hairy cell leukemia 2022: Update on diagnosis, risk-stratification, and treatment. Am J Hematol 97 (2): 226-236, 2022.
2. Tiacci E, Schiavoni G, Forconi F, et al.: Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. Blood 119 (1): 192-5, 2012.
3. Naik RR, Saven A: My treatment approach to hairy cell leukemia. Mayo Clin Proc 87 (1): 67-76, 2012.
4. Jones G, Parry-Jones N, Wilkins B, et al.: Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant*. Br J Haematol 156 (2): 186-95, 2012.
5. Troussard X, Grever MR: The revised guidelines for the diagnosis and management of hairy cell leukaemia and the hairy cell leukaemia variant. Br J Haematol 193 (1): 11-14, 2021.
6. Ravandi F, Kreitman RJ, Tiacci E, et al.: Consensus opinion from an international group of experts on measurable residual disease in hairy cell leukemia. Blood Cancer J 12 (12): 165, 2022.

Stage Information for Hairy Cell Leukemia

There is no generally accepted staging system used in the prognosis and treatment of hairy cell leukemia.

Treatment of Hairy Cell Leukemia

Hairy cell leukemia is highly treatable but rarely cured. Because it is easily controlled, many patients have prolonged survival with the use of sequential therapies. The decision to treat is based on signs of disease progression, including any of the following factors:

• Cytopenias (especially if symptomatic).
• Increasing splenomegaly.
• The presence of other, usually infectious, complications.

If the patient is asymptomatic and if blood counts are maintained in an acceptable range, therapy may not be needed.[1]

Treatment Options for Hairy Cell Leukemia

Treatment options for hairy cell leukemia include:

1. Watchful waiting, if feasible.
2. Rituximab.
3. BRAF inhibitors (vemurafenib or dabrafenib) with or without rituximab or trametinib.
4. Cladribine with or without rituximab.
5. Pentostatin.
6. Ibrutinib.
7. Re-treatment with cladribine or pentostatin.
8. Bendamustine with rituximab.
9. Splenectomy.

Impact of COVID-19 on treatment of hairy cell leukemia

Prior to the COVID-19 (SARS-CoV-2) pandemic, the standard initial therapy for patients with hairy cell leukemia was infusion of cladribine daily for 5 days, given with or without eight weekly doses of rituximab.[2,3,4] However, treatment with a purine analogue–based regimen led to significant and prolonged neutropenia and impairment of T-cell function, which were both problematic during the pandemic in fighting viral infection and establishing vaccination-induced immunity.

During the COVID-19 pandemic, some options for initial standard therapy, including cladribine or pentostatin, were replaced with other options with less toxicity; however, these options elicited less-durable responses.

The Hairy Cell Leukemia Foundation convened a virtual meeting of 39 experts from around the world to amend the 2017 consensus recommendations.[5] The adapted treatment guidelines, published in 2021, are based primarily on anecdotal experience and expert opinion, as controlled trials for this indolent leukemia cannot be completed expeditiously given the low incidence of this disease.[6][Level of evidence C3] The adapted treatment guidelines are summarized below.

1. Consider watchful waiting when feasible; asymptomatic patients with noncritical levels of pancytopenia can be monitored closely.
2. Avoid using cladribine, with or without rituximab,[4] and pentostatin because of the risk of serious and prolonged immunosuppression.
3. Consider using BRAF inhibitors such as vemurafenib, dabrafenib, or encorafenib.[7,8,9,10] Most patients with hairy cell leukemia are BRAF mutation–positive, but this status should be verified by flow cytometry. Despite extensive experience with vemurafenib for patients with relapsed disease, the U.S. Food and Drug Administration (FDA) has not approved oral vemurafenib for patients with hairy cell leukemia.
4. Consider using rituximab alone intravenously (IV) for 4 to 8 weeks or in combination with a BRAF inhibitor.[11] Anti-CD20 monoclonal antibodies can impair future vaccine response, but they do not affect immunity from prior vaccination.
5. Interferon alfa is no longer available because production has been halted.[12] According to the Hairy Cell Leukemia Foundation, ropeginterferon alfa-2b-njft is the best available preparation, but is not FDA approved for hairy cell leukemia.
6. In patients with relapsed disease, the previously mentioned options are available, along with ibrutinib (the Bruton tyrosine kinase inhibitor).[13]

Rituximab

Rituximab can induce durable remissions (with minimal toxic effects), but rarely complete remissions, in patients with multiple relapses or refractory disease after treatment with a purine analogue or interferon.[11,14,15][Level of evidence C3]

BRAF inhibitors (vemurafenib or dabrafenib) with or without rituximab or trametinib

The BRAF V600E mutation occurs in almost 100% of patients with classic-form hairy cell leukemia and almost never in patients with other B-cell lymphomas and leukemias, including hairy cell leukemia variants.[16][Level of evidence C3] Vemurafenib or other BRAF inhibitors such as dabrafenib can be given with rituximab.[10] The FDA has not approved BRAF inhibitors for hairy cell leukemia, but they can be used off-label in clinical practice.[15]

Evidence (vemurafenib with or without rituximab):

1. Several multicenter studies evaluated vemurafenib, given orally alone for 4 months or orally for 2 months with rituximab infused in eight doses over 18 weeks, in patients with relapsed or refractory hairy cell leukemia.[7,8,10,17][Level of evidence C3]
   1. After a median follow-up of 23 to 40 months, for the 86 patients treated with vemurafenib alone, the following was reported in two studies:[7,8,17][Level of evidence C3]
      • The overall response rate was 86% to 98%.
      • The complete response rate was 33% to 38%.
      • The median treatment-free survival was 18 to 25 months.
      • Re-treatment at relapse resulted in an 86% response rate, and the median relapse-free survival was 12.7 months in one of the trials with a 40-month median follow-up.[17][Level of evidence C2]
   2. After a median follow-up of 37 months, for the 30 patients treated with vemurafenib plus rituximab, the following was reported:[10][Level of evidence C3]
      • The complete response rate was 87%.
      • The progression-free survival (PFS) rate was 78% at 37 months.
      • In patients who had a complete response, 65% had no measurable residual disease (MRD).

Evidence (dabrafenib plus trametinib):

1. In a phase II trial of patients with relapsed or refractory disease, 55 patients received dabrafenib and trametinib orally until disease progression, unacceptable toxicity, or death.[18]
   • With a median follow-up of 43.2 months, the overall response rate was 89.0% (95% confidence interval [CI], 77.8%–95.9%), the complete response rate was 65.5%, the 2-year PFS rate was 94.5%, and the 2-year overall survival (OS) rate was 95.5%.[18][Level of evidence C1]

Cladribine with or without rituximab

Cladribine may be given with or without rituximab to treat hairy cell leukemia.

Evidence (cladribine with or without rituximab):

1. In a phase II study, 68 patients with previously untreated hairy cell leukemia were randomly assigned to receive cladribine (0.15 mg/kg IV) on days 1 to 5, with eight weekly doses of rituximab either concurrently (starting on day 1) or delayed (starting after 6 months of cladribine treatment) if still positive with MRD testing.[4][Level of evidence C3]
   • With a median follow-up of 96 months, 94% of patients who received concurrent therapy were MRD-free, compared with 12% of patients who received delayed therapy.
   • Although patients who underwent concurrent therapy had more need for platelet transfusions, they demonstrated higher neutrophil and platelet counts after 1 month.
   • A retrospective case series reported a median PFS of 67 months in patients with relapsed disease who received a purine nucleoside analogue (usually cladribine) plus rituximab.[19][Level of evidence C2]
   • A retrospective case series of nine patients with a hairy cell leukemia variant histology reported an 88% complete response rate and 3-year PFS rate of 42% (95% CI, 1%–84%) after treatment with a purine nucleoside analogue (usually cladribine) plus rituximab.[20][Level of evidence C2]
2. Cladribine was given by daily subcutaneous injections or by daily 2-hour IV infusions for 5 to 7 days.[5,21,22,23][Level of evidence C3] Purine analogues should be avoided in cases of active infection or moderate to severe hepatic or renal impairment.
   • The complete response rate was 50% to 80%.
   • The overall response rate was 85% to 95%.
3. A National Cancer Institute group C protocol of 979 patients treated with cladribine reported lower response rates (i.e., 50% complete remission rate, 37% partial remission rate) compared with other studies.[24] Responses were durable in patients treated with a short course of cladribine, and patients who had a relapse often responded to re-treatment with cladribine.[2,19,25]
4. A retrospective review included 83 patients, aged 40 years and younger.[2]
   • The median time to first relapse was 54 months for all responders, and the median OS was 21 years from diagnosis.
   • Cladribine may cause fever and immunosuppression; documented infection was found in 33% of treated patients.

In a retrospective study of patients with cladribine-associated neutropenic fever, filgrastim (G-CSF) did not reduce the percentage of febrile patients, number of febrile days, or frequency of hospital admissions to receive antibiotics.[3]

Pentostatin

Pentostatin given IV every other week for 3 to 6 months produced a 50% to 76% complete response rate and an 80% to 87% overall response rate.[26] Complete remissions were of substantial duration. Purine analogues should be avoided in cases of active infection or moderate to severe hepatic or renal impairment.

Evidence (pentostatin):

1. Two trials reported results on the 9-year median follow-up of patients treated with pentostatin.[27,28]
   • The relapse-free survival rates ranged from 56% to 67%.
   • Side effects included fever, immunosuppression, cytopenias, and renal dysfunction.
2. A randomized trial compared pentostatin to recombinant interferon alfa-2a.[26]
   • Pentostatin demonstrated higher response rates and more durable responses.

Ibrutinib

Ibrutinib, a tyrosine kinase inhibitor, has been studied in the treatment of hairy cell leukemia.

Evidence (ibrutinib):

1. In a phase II study, 37 patients with refractory hairy cell leukemia were treated with ibrutinib. The median follow-up was 42 months.[29][Level of evidence C3]
   • The response rate was 54%.
   • The estimated 36-month PFS rate was 73%.
   • The OS rate was 85%.

Re-treatment with cladribine or pentostatin

Patients with hairy cell leukemia who have a relapse after the first course of cladribine or pentostatin often respond well to re-treatment with the same or another purine analogue, especially if relapse occurs after several years.[19][Level of evidence C3]

Bendamustine with rituximab

Evidence (bendamustine with rituximab):

1. A phase II study evaluated 12 patients with relapsed or refractory disease, three of whom were negative for a BRAF mutation. Patients received the combination of bendamustine and rituximab.[30]
   • The overall response rate was 100%, and the complete remission rate was 50%.[30][Level of evidence C3]

Splenectomy

Splenectomy plays a decreasing role in treating hairy cell leukemia because effective alternatives are available. Splenectomy will partially or completely normalize the peripheral blood in most patients with hairy cell leukemia.[31] After a splenectomy, there is usually little or no change in the bone marrow, and virtually all patients have progressive disease within 12 to 18 months.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Troussard X, Maître E, Cornet E: Hairy cell leukemia 2022: Update on diagnosis, risk-stratification, and treatment. Am J Hematol 97 (2): 226-236, 2022.
2. Rosenberg JD, Burian C, Waalen J, et al.: Clinical characteristics and long-term outcome of young hairy cell leukemia patients treated with cladribine: a single-institution series. Blood 123 (2): 177-83, 2014.
3. Saven A, Burian C, Adusumalli J, et al.: Filgrastim for cladribine-induced neutropenic fever in patients with hairy cell leukemia. Blood 93 (8): 2471-7, 1999.
4. Chihara D, Arons E, Stetler-Stevenson M, et al.: Randomized Phase II Study of First-Line Cladribine With Concurrent or Delayed Rituximab in Patients With Hairy Cell Leukemia. J Clin Oncol 38 (14): 1527-1538, 2020.
5. Grever MR, Abdel-Wahab O, Andritsos LA, et al.: Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia. Blood 129 (5): 553-560, 2017.
6. Grever M, Andritsos L, Banerji V, et al.: Hairy cell leukemia and COVID-19 adaptation of treatment guidelines. Leukemia 35 (7): 1864-1872, 2021.
7. Tiacci E, Park JH, De Carolis L, et al.: Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia. N Engl J Med 373 (18): 1733-47, 2015.
8. Dietrich S, Pircher A, Endris V, et al.: BRAF inhibition in hairy cell leukemia with low-dose vemurafenib. Blood 127 (23): 2847-55, 2016.
9. Falini B, Tiacci E: New treatment options in hairy cell leukemia with focus on BRAF inhibitors. Hematol Oncol 37 (Suppl 1): 30-37, 2019.
10. Tiacci E, De Carolis L, Simonetti E, et al.: Vemurafenib plus Rituximab in Refractory or Relapsed Hairy-Cell Leukemia. N Engl J Med 384 (19): 1810-1823, 2021.
11. Angelopoulou MK, Pangalis GA, Sachanas S, et al.: Outcome and toxicity in relapsed hairy cell leukemia patients treated with rituximab. Leuk Lymphoma 49 (9): 1817-20, 2008.
12. Assanto GM, Riemma C, Malaspina F, et al.: The current role of interferon in hairy cell leukaemia: clinical and molecular aspects. Br J Haematol 194 (1): 78-82, 2021.
13. Jones J, Andritsos L, Kreitman RJ: Efficacy and safety of the Bruton tyrosine kinase inhibitor ibrutinib in patients with hairy cell leukemia: stage 1 results of a phase 2 study. [Abstract] Blood 128 (22): A-1215, 2016.
14. Thomas DA, O'Brien S, Bueso-Ramos C, et al.: Rituximab in relapsed or refractory hairy cell leukemia. Blood 102 (12): 3906-11, 2003.
15. Falini B, De Carolis L, Tiacci E: How I treat refractory/relapsed hairy cell leukemia with BRAF inhibitors. Blood 139 (15): 2294-2305, 2022.
16. Pettirossi V, Santi A, Imperi E, et al.: BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity. Blood 125 (8): 1207-16, 2015.
17. Handa S, Lee JO, Derkach A, et al.: Long-term outcomes in patients with relapsed or refractory hairy cell leukemia treated with vemurafenib monotherapy. Blood 140 (25): 2663-2671, 2022.
18. Kreitman RJ, Moreau P, Ravandi F, et al.: Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia. Blood 141 (9): 996-1006, 2023.
19. Hu R, Wei W, Mian A, et al.: Treatment outcomes with purine nucleoside analog alone or with rituximab for hairy cell leukemia at first relapse. Eur J Haematol 108 (5): 379-382, 2022.
20. Wang Y, Wang T, Yu Y, et al.: Purine nucleoside analogs plus rituximab are an effective treatment choice for hairy cell leukemia-variant. Ann Hematol 101 (6): 1201-1210, 2022.
21. Pagano L, Criscuolo M, Broccoli A, et al.: Long-term follow-up of cladribine treatment in hairy cell leukemia: 30-year experience in a multicentric Italian study. Blood Cancer J 12 (7): 109, 2022.
22. Zenhäusern R, Schmitz SF, Solenthaler M, et al.: Randomized trial of daily versus weekly administration of 2-chlorodeoxyadenosine in patients with hairy cell leukemia: a multicenter phase III trial (SAKK 32/98). Leuk Lymphoma 50 (9): 1501-11, 2009.
23. Hermel DJ, Cheng B, Bhangoo MS, et al.: Long-term outcomes of elderly hairy cell leukemia patients treated with cladribine. Ann Hematol 101 (5): 1089-1096, 2022.
24. Cheson BD, Sorensen JM, Vena DA, et al.: Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine via the Group C protocol mechanism of the National Cancer Institute: a report of 979 patients. J Clin Oncol 16 (9): 3007-15, 1998.
25. Else M, Dearden CE, Catovsky D: Long-term follow-up after purine analogue therapy in hairy cell leukaemia. Best Pract Res Clin Haematol 28 (4): 217-29, 2015.
26. Grever M, Kopecky K, Foucar MK, et al.: Randomized comparison of pentostatin versus interferon alfa-2a in previously untreated patients with hairy cell leukemia: an intergroup study. J Clin Oncol 13 (4): 974-82, 1995.
27. Johnston JB, Eisenhauer E, Wainman N, et al.: Long-term outcome following treatment of hairy cell leukemia with pentostatin (Nipent): a National Cancer Institute of Canada study. Semin Oncol 27 (2 Suppl 5): 32-6, 2000.
28. Flinn IW, Kopecky KJ, Foucar MK, et al.: Long-term follow-up of remission duration, mortality, and second malignancies in hairy cell leukemia patients treated with pentostatin. Blood 96 (9): 2981-6, 2000.
29. Rogers KA, Andritsos LA, Wei L, et al.: Phase 2 study of ibrutinib in classic and variant hairy cell leukemia. Blood 137 (25): 3473-3483, 2021.
30. Burotto M, Stetler-Stevenson M, Arons E, et al.: Bendamustine and rituximab in relapsed and refractory hairy cell leukemia. Clin Cancer Res 19 (22): 6313-21, 2013.
31. Golomb HM, Vardiman JW: Response to splenectomy in 65 patients with hairy cell leukemia: an evaluation of spleen weight and bone marrow involvement. Blood 61 (2): 349-52, 1983.

Latest Updates to This Summary (09 / 20 / 2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of hairy cell leukemia. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Hairy Cell Leukemia Treatment is:

• Eric J. Seifter, MD (Johns Hopkins University)

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PDQ® Adult Treatment Editorial Board. PDQ Hairy Cell Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/hairy-cell-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389184]

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Last Revised: 2024-09-20