Hairy Cell Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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.[1,2]

Clinical Presentation

Hairy cell leukemia usually presents with the following:

• 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.[3,4]

References:

1. Siegel RL, Miller KD, Jemal A: Cancer statistics, 2020. CA Cancer J Clin 70 (1): 7-30, 2020.
2. Kreitman RJ: Hairy cell leukemia: present and future directions. Leuk Lymphoma 60 (12): 2869-2879, 2019.
3. 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.
4. Naik RR, Saven A: My treatment approach to hairy cell leukemia. Mayo Clin Proc 87 (1): 67-76, 2012.

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. A low percentage of patients will never require therapy.

Treatment Options for Hairy Cell Leukemia

Treatment options for hairy cell leukemia include the following:

1. Watchful waiting, if feasible.
2. Rituximab.
3. Vemurafenib (or other BRAF inhibitors) with or without rituximab.
4. Recombinant interferon alfa.
5. Ibrutinib.
6. Moxetumomab pasudotox-tdfk.
7. Cladribine with or without rituximab.
8. Pentostatin.
9. Re-treatment with cladribine or pentostatin.
10. 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.[1,2,3] However, treatment with a purine analogue–based regimen leads to significant and prolonged neutropenia and impairment of T-cell function, both problematic during the pandemic in terms of fighting viral infection and establishing vaccination-induced immunity.

During the COVID-19 pandemic, some options for initial standard therapy, including cladribine or pentostatin, have been replaced in favor of other options with less toxicity, but these options also elicit 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.[4] 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.[5][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,[3] and pentostatin because of the risk of serious and prolonged immunosuppression.
3. Consider using BRAF inhibitors such as vemurafenib, dabrafenib, or encorafenib.[6,7,8,9] Most patients with hairy cell leukemia are BRAF mutation–positive, but this should be verified by flow cytometry. Despite extensive experience with vemurafenib in the relapsed setting, the U.S. Food and Drug Administration (FDA) has not approved oral vemurafenib in patients with hairy cell leukemia.
4. Consider using rituximab alone intravenously for 4 to 8 weeks or in combination with a BRAF inhibitor.[10] Anti-CD20 monoclonal antibodies can impair future vaccine response, but they do not affect immunity from prior vaccination.
5. Interferon use is well established and can avoid serious neutropenia or vaccine unresponsiveness.[11,12] 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 BTK inhibitor) and moxetumomab pasudotox-tdfk (the anti-CD22 recombinant immunotoxin).[13,14]

Rituximab

Rituximab can induce durable complete remissions (with minimal toxic effects) in patients with multiple relapses or refractory disease after treatment with a purine analogue or interferon.[10,15,16,17,18][Level of evidence C3]

Vemurafenib (or other BRAF inhibitors) with or without rituximab

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.[19][Level of evidence C3] Vemurafenib, or other BRAF inhibitors such as dabrafenib, can be given with rituximab.

Evidence (vemurafenib with or without rituximab):

1. Three phase II multicenter studies in the United States and Italy 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.[6,7,9][Level of evidence C3]
   1. After a median follow-up of 23 months, for the 50 patients treated with vemurafenib alone, the following was reported in two studies:[6,7][Level of evidence C3]
      • The overall response rate was 98%.
      • The complete response rate was 38%.
      • The median treatment-free survivals were 25 months and 18 months, respectively.
   2. After a median follow-up of 37 months, for the 30 patients treated with vemurafenib plus rituximab, the following was reported:[9][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 minimal residual disease (MRD).

Recombinant interferon alfa

Recombinant interferon alfa given subcutaneously (three times per week) for 1 year yields a 10% complete response rate and an 80% overall response rate.[11] The drug frequently produces an influenza-like syndrome early in the course of treatment. Late effects include depression and lethargy. Responding patients who relapse usually react positively to re-treatment with recombinant interferon alfa.[11] Remission can be prolonged with a low-dose maintenance regimen.[12]

Ibrutinib

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

Evidence (ibrutinib):

1. In a phase II study, with a median follow-up of 42 months, 37 patients with refractory hairy cell leukemia were treated with ibrutinib.[20][Level of evidence C3]
   • The response rate was 54%.
   • The estimated 36-month PFS rate was 73%.
   • The overall survival (OS) rate was 85%.

Moxetumomab pasudotox-tdfk

Moxetumomab pasudotox-tdfk is an anti-CD22 recombinant immunotoxin. It is approved by the FDA to treat patients with relapsed or refractory hairy cell leukemia.[21,22,23,24]

Evidence (moxetumomab pasudotox-tdfk):

1. In a phase II trial, moxetumomab pasudotox-tdfk was given to 80 patients with hairy cell leukemia who were previously treated with at least two regimens.[14][Level of evidence C3]
   • Seventy-five percent of patients responded to treatment and 30% had a durable complete response.

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. Cladribine was given by daily subcutaneous injections, or by daily 2-hour intravenous infusions for 5 to 7 days.[25,26,27][Level of evidence C3]
   • The complete response rate was 50% to 80%.
   • The overall response rate was 85% to 95%.
2. 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.[28] Responses were durable in patients treated with a short course of cladribine, and patients who relapse often respond to re-treatment with cladribine.[29,30,31]
3. A retrospective review included 83 patients, aged 40 years and younger.[1]
   • 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.
4. 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.[3][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.

   MRD testing in this setting has never been validated as a clinically significant end point, and this concept requires further study.

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.[2]

Pentostatin

Pentostatin given intravenously every other week for 3 to 6 months produced a 50% to 76% complete response rate and an 80% to 87% overall response rate.[32,33] Complete remissions were of substantial duration.

Evidence (pentostatin):

1. Two trials reported results on the 9-year median follow-up of patients treated with pentostatin.[34,35]
   • 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.[32]
   • Pentostatin demonstrated higher response rates and more durable responses.

Re-treatment with cladribine or pentostatin

Patients with hairy cell leukemia who 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 2 years.[31,33,36,37,38,39][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.[40] After a splenectomy, there is usually little or no change in the bone marrow, and virtually all patients will 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. 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.
2. 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.
3. 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.
4. 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.
5. Grever M, Andritsos L, Banerji V, et al.: Hairy cell leukemia and COVID-19 adaptation of treatment guidelines. Leukemia 35 (7): 1864-1872, 2021.
6. 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.
7. Dietrich S, Pircher A, Endris V, et al.: BRAF inhibition in hairy cell leukemia with low-dose vemurafenib. Blood 127 (23): 2847-55, 2016.
8. Falini B, Tiacci E: New treatment options in hairy cell leukemia with focus on BRAF inhibitors. Hematol Oncol 37 (Suppl 1): 30-37, 2019.
9. 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.
10. 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.
11. Golomb HM, Ratain MJ, Fefer A, et al.: Randomized study of the duration of treatment with interferon alfa-2B in patients with hairy cell leukemia. J Natl Cancer Inst 80 (5): 369-73, 1988.
12. Capnist G, Federico M, Chisesi T, et al.: Long term results of interferon treatment in hairy cell leukemia. Italian Cooperative Group of Hairy Cell Leukemia (ICGHCL). Leuk Lymphoma 14 (5-6): 457-64, 1994.
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. Kreitman RJ, Dearden C, Zinzani PL, et al.: Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia. Leukemia 32 (8): 1768-1777, 2018.
15. Gerrie AS, Zypchen LN, Connors JM: Fludarabine and rituximab for relapsed or refractory hairy cell leukemia. Blood 119 (9): 1988-91, 2012.
16. Hagberg H, Lundholm L: Rituximab, a chimaeric anti-CD20 monoclonal antibody, in the treatment of hairy cell leukaemia. Br J Haematol 115 (3): 609-11, 2001.
17. Lauria F, Lenoci M, Annino L, et al.: Efficacy of anti-CD20 monoclonal antibodies (Mabthera) in patients with progressed hairy cell leukemia. Haematologica 86 (10): 1046-50, 2001.
18. Thomas DA, O'Brien S, Bueso-Ramos C, et al.: Rituximab in relapsed or refractory hairy cell leukemia. Blood 102 (12): 3906-11, 2003.
19. 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.
20. 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.
21. Kreitman RJ, Tallman MS, Robak T, et al.: Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase 1 results and long-term follow-up. Blood 131 (21): 2331-2334, 2018.
22. Kreitman RJ, Wilson WH, White JD, et al.: Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J Clin Oncol 18 (8): 1622-36, 2000.
23. Kreitman RJ, Stetler-Stevenson M, Margulies I, et al.: Phase II trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with hairy cell leukemia. J Clin Oncol 27 (18): 2983-90, 2009.
24. Kreitman RJ, Tallman MS, Robak T, et al.: Phase I trial of anti-CD22 recombinant immunotoxin moxetumomab pasudotox (CAT-8015 or HA22) in patients with hairy cell leukemia. J Clin Oncol 30 (15): 1822-8, 2012.
25. Robak T, Błasińska-Morawiec M, Krykowski E, et al.: 2-chlorodeoxyadenosine (2-CdA) in 2-hour versus 24-hour intravenous infusion in the treatment of patients with hairy cell leukemia. Leuk Lymphoma 22 (1-2): 107-11, 1996.
26. Robak T, Jamroziak K, Gora-Tybor J, et al.: Cladribine in a weekly versus daily schedule for untreated active hairy cell leukemia: final report from the Polish Adult Leukemia Group (PALG) of a prospective, randomized, multicenter trial. Blood 109 (9): 3672-5, 2007.
27. 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.
28. 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.
29. Jehn U, Bartl R, Dietzfelbinger H, et al.: An update: 12-year follow-up of patients with hairy cell leukemia following treatment with 2-chlorodeoxyadenosine. Leukemia 18 (9): 1476-81, 2004.
30. Chadha P, Rademaker AW, Mendiratta P, et al.: Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA): long-term follow-up of the Northwestern University experience. Blood 106 (1): 241-6, 2005.
31. Else M, Dearden CE, Matutes E, et al.: Long-term follow-up of 233 patients with hairy cell leukaemia, treated initially with pentostatin or cladribine, at a median of 16 years from diagnosis. Br J Haematol 145 (6): 733-40, 2009.
32. 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.
33. Ribeiro P, Bouaffia F, Peaud PY, et al.: Long term outcome of patients with hairy cell leukemia treated with pentostatin. Cancer 85 (1): 65-71, 1999.
34. 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.
35. 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.
36. Hoffman MA, Janson D, Rose E, et al.: Treatment of hairy-cell leukemia with cladribine: response, toxicity, and long-term follow-up. J Clin Oncol 15 (3): 1138-42, 1997.
37. Goodman GR, Burian C, Koziol JA, et al.: Extended follow-up of patients with hairy cell leukemia after treatment with cladribine. J Clin Oncol 21 (5): 891-6, 2003.
38. Zinzani PL, Magagnoli M, Bendandi M, et al.: Long-term follow-up of hairy cell leukemia patients treated with 2-chlorodeoxyadenosine. Haematologica 85 (9): 922-5, 2000.
39. Gidron A, Tallman MS: 2-CdA in the treatment of hairy cell leukemia: a review of long-term follow-up. Leuk Lymphoma 47 (11): 2301-7, 2006.
40. 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.

Changes to This Summary (12 / 21 / 2022)

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.

Reviewers and Updates

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: 2022-12-21