Hairy cell leukemia

Section editor
	Sanjai Sharma, MD Sequoia Regional Cancer Center Visalia, CA

12 regimens on this page 17 variants on this page

Guidelines

ESMO

• 2015: Robak et al. Hairy cell leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Hairy Cell Leukemia Foundation

• 2017: Grever et al. Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia

NCCN

• NCCN Guidelines - Hairy Cell Leukemia

Untreated

Cladribine monotherapy

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Regimen variant #1, 0.09 mg/kg/day x 7 days

Study	Years of enrollment	Evidence
Saven et al. 1998	1986-1993	Non-randomized (RT)

Chemotherapy

• Cladribine (Leustatin) 0.09 mg/kg/day IV continuous infusion over 7 days, started on day 1 (total dose: 0.63 mg/kg)

7-day course

Regimen variant #2, 0.1 mg/kg/day x 7 days

Study	Evidence
Piro et al. 1990	Pilot, <20 pts
Tallman et al. 1996	Phase II

Chemotherapy

• Cladribine (Leustatin) 0.1 mg/kg/day IV continuous infusion over 7 days, started on day 1 (total dose: 0.7 mg/kg)

7-day course

Regimen variant #3, 0.12 mg/kg/day x 5 days

Study	Evidence	Comparator	Comparative Efficacy
Robak et al. 1999	Phase II
Robak et al. 2007	Phase III (C)	Cladribine; weekly	Did not meet primary endpoint of CR rate

Chemotherapy

Cladribine (Leustatin) 0.12 mg/kg IV over 2 hours once per day on days 1 to 5

5-day course

Regimen variant #4, 0.14 mg/kg/day x 5 days

Study	Evidence	Comparator	Comparative Efficacy
Zenhäusern et al. 2009 (SAKK 32/98)	Phase III (C)	Cladribine; weekly	Did not meet primary endpoint of average leukocyte count within 6 weeks from randomization

Chemotherapy

• Cladribine (Leustatin) 0.14 mg/kg SC once per day on days 1 to 5

5-day course

Regimen variant #5, 0.15 mg/kg/day x 5 days

Study	Evidence
Damasio et al. 1998	Phase II

Chemotherapy

Cladribine (Leustatin) 0.15 mg/kg IV over 2 hours once per day on days 1 to 5

5-day course

References

1. Piro LD, Carrera CJ, Carson DA, Beutler E. Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl J Med. 1990 Apr 19;322(16):1117-21. link to original article contains protocol PubMed
2. Tallman MS, Hakimian D, Rademaker AW, Zanzig C, Wollins E, Rose E, Peterson LC. Relapse of hairy cell leukemia after 2-chlorodeoxyadenosine: long-term follow-up of the Northwestern University experience. Blood. 1996 Sep 15;88(6):1954-9. link to original article contains verified protocol PubMed
   1. Update: Chadha P, Rademaker AW, Mendiratta P, Kim B, Evanchuk DM, Hakimian D, Peterson LC, Tallman MS. Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA): long-term follow-up of the Northwestern University experience. Blood. 2005 Jul 1;106(1):241-6. Epub 2005 Mar 10. link to original article contains protocol PubMed content property of HemOnc.org
3. Damasio EE, Resegotti L, Masoudi B, Bruni R, Cerri R, Isaza A, Clavio M, Risso M, Rossi E, Spriano M, Truini M. Five day intermittent vs seven day continuous 2-chlorodeoxyadenosine infusion for the treatment of hairy cell leukemia: a study by Italian Group for the Hairy Cell Leukemia. Recenti Prog Med. 1998 Feb;89(2):68-73. PubMed
4. Saven A, Burian C, Koziol JA, Piro LD. Long-term follow-up of patients with hairy cell leukemia after cladribine treatment. Blood. 1998 Sep 15;92(6):1918-26. link to original article PubMed
5. Robak T, Błasińska-Morawiec M, Błoński J, Hellmann A, Hałaburda K, Konopka L, Kotlarek-Haus S, Potoczek S, Hansz J, Dmoszyńska A, Urasiński I, Zdziarska B, Dwilewicz-Trojaczek J, Hołowiecki J, Skotnicki AB. 2-chlorodeoxyadenosine (cladribine) in the treatment of hairy cell leukemia and hairy cell leukemia variant: 7-year experience in Poland. Eur J Haematol. 1999 Jan;62(1):49-56. PubMed
6. Robak T, Jamroziak K, Gora-Tybor J, Blonski JZ, Kasznicki M, Dwilewicz-Trojaczek J, Wiater E, Zdunczyk A, Dybowicz J, Dmoszynska A, Wojtaszko M, Zdziarska B, Calbecka M, Kostyra A, Hellmann A, Lewandowski K, Stella-Holowiecka B, Sulek K, Gawronski K, Skotnicki AB, Nowak W, Zawilska K, Molendowicz-Portala L, Kloczko J, Sokolowski J, Warzocha K, Seferynska I, Ceglarek B, Konopka L. 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. 2007 May 1;109(9):3672-5. Epub 2007 Jan 5. link to original article contains verified protocol PubMed
7. SAKK 32/98: Zenhäusern R, Schmitz SF, Solenthaler M, Heim D, Meyer-Monard S, Hess U, Leoncini L, Bargetzi M, Rufener B, Tobler A. 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. 2009 Sep;50(9):1501-11. link to original article contains verified protocol PubMed

Cladribine & Rituximab

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Protocol

Study	Evidence
Ravandi et al. 2011	Phase II

Chemotherapy, part 1

• Cladribine (Leustatin) 5.6 mg/m² IV over 2 hours once per day on days 1 to 5

Supportive medications

All were administered at the discretion of the treating physician.

• Levofloxacin (Levaquin)
• Valacyclovir (Valtrex)
• Fluconazole (Diflucan)
• Filgrastim (Neupogen)

5-day course

28 days after administration of cladribine, bone marrow examination was repeated, and then rituximab was started:

Chemotherapy, part 2

• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36, 43, 50

8-week course

References

1. Ravandi F, O'Brien S, Jorgensen J, Pierce S, Faderl S, Ferrajoli A, Koller C, Challagundla P, York S, Brandt M, Luthra R, Burger J, Thomas D, Keating M, Kantarjian H. Phase 2 study of cladribine followed by rituximab in patients with hairy cell leukemia. Blood. 2011 Oct 6;118(14):3818-23. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Chihara D, Kantarjian H, O'Brien S, Jorgensen J, Pierce S, Faderl S, Ferrajoli A, Poku R, Jain P, Thompson P, Brandt M, Luthra R, Burger J, Keating M, Ravandi F. Long-term durable remission by cladribine followed by rituximab in patients with hairy cell leukaemia: update of a phase II trial. Br J Haematol. 2016 Sep;174(5):760-6. Epub 2016 Jun 15. link to original article link to PMC article PubMed

Pentostatin monotherapy

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Regimen variant #1

Study	Evidence
Spiers et al. 1987	Non-randomized

Chemotherapy

• Pentostatin (Nipent) 5 mg/m² IV over 2 minutes once per day on days 1 & 2

14-day cycles, continued to the point of maximal response or treatment failure

Regimen variant #2

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Grever et al. 1995 (SWOG 8691)	1986-1989	Phase III (E-RT-switch-ooc)	Interferon alfa-2a	Superior RFS

Note: patients who had complete response before 6 months were given 2 additional cycles of pentostatin, and then treatment was stopped. Patients with objective partial response after 6 months of treatment received an additional 6 months of additional therapy, until they had a complete response or progression of disease.

Chemotherapy

• Pentostatin (Nipent) 4 mg/m² IV rapid injection once on day 1
  • Patients with performance status of 3 received an initial dose of 2 mg/m² IV rapid injection once on day 1, which would be increased in later cycles to 4 mg/m² IV rapid injection once on day 1 if patients had no adverse reactions.
  • Doses of pentostatin were held for patients who had an increase in the serum creatinine concentration greater than 20% above their baseline. Pentostatin was not given until renal function returned to baseline or if 24-hour creatinine clearance was greater than 50 mL/min/1.73m².

Supportive medications

• 1.5 liters of IV fluid hydration with every dose

14 day cycles (see note)

References

1. Spiers AS, Moore D, Cassileth PA, Harrington DP, Cummings FJ, Neiman RS, Bennett JM, O'Connell MJ. Remissions in hairy-cell leukemia with pentostatin (2'-deoxycoformycin). N Engl J Med. 1987 Apr 2;316(14):825-30. link to original article contains verified protocol PubMed
   1. Update: Cassileth PA, Cheuvart B, Spiers AS, Harrington DP, Cummings FJ, Neiman RS, Bennett JM, O'Connell MJ. Pentostatin induces durable remissions in hairy cell leukemia. J Clin Oncol. 1991 Feb;9(2):243-6. link to original article contains protocol PubMed
2. SWOG 8691: Grever M, Kopecky K, Foucar MK, Head D, Bennett JM, Hutchison RE, Corbett WE, Cassileth PA, Habermann T, Golomb H, Rai K, Eisenhauer E, Appelbaum F, Cheson BD. Randomized comparison of pentostatin versus interferon alfa-2a in previously untreated patients with hairy cell leukemia: an intergroup study. J Clin Oncol. 1995 Apr;13(4):974-82. link to original article contains verified protocol PubMed
   1. Update: Flinn IW, Kopecky KJ, Foucar MK, Head D, Bennett JM, Hutchison R, Corbett W, Cassileth P, Habermann T, Golomb H, Rai K, Eisenhauer E, Appelbaum F, Cheson B, Grever MR. Long-term follow-up of remission duration, mortality, and second malignancies in hairy cell leukemia patients treated with pentostatin. Blood. 2000 Nov 1;96(9):2981-6. link to original article contains verified protocol PubMed

Relapsed or refractory

BR

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BR: Bendamustine, Rituximab

Regimen

Study	Evidence
Burotto et al. 2013	Pilot, <20 patients

Note: this was a dose-escalation study and the bendamustine dose was selected for further study based on absence of DLT.

Chemotherapy

• Bendamustine 90 mg/m² IV once per day on days 1 & 2
• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1 & 15

28-day cycle for 6 cycles

References

1. Burotto M, Stetler-Stevenson M, Arons E, Zhou H, Wilson W, Kreitman RJ. Bendamustine and rituximab in relapsed and refractory hairy cell leukemia. Clin Cancer Res. 2013 Nov 15;19(22):6313-21. Epub 2013 Oct 28. link to original article link to PMC article PubMed

Cladribine & Rituximab

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Protocol

Study	Evidence
Ravandi et al. 2011	Phase II, <20 pts in this cohort

Chemotherapy, part 1

• Cladribine (Leustatin) 5.6 mg/m² IV over 2 hours once per day on days 1 to 5

Supportive medications

All were administered at the discretion of the treating physician.

• Levofloxacin (Levaquin)
• Valacyclovir (Valtrex)
• Fluconazole (Diflucan)
• Filgrastim (Neupogen)

5-day course

28 days after administration of cladribine, bone marrow examination was repeated, and then rituximab was started:

Chemotherapy, part 2

• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36, 43, 50

8-week course

References

1. Ravandi F, O'Brien S, Jorgensen J, Pierce S, Faderl S, Ferrajoli A, Koller C, Challagundla P, York S, Brandt M, Luthra R, Burger J, Thomas D, Keating M, Kantarjian H. Phase 2 study of cladribine followed by rituximab in patients with hairy cell leukemia. Blood. 2011 Oct 6;118(14):3818-23. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Chihara D, Kantarjian H, O'Brien S, Jorgensen J, Pierce S, Faderl S, Ferrajoli A, Poku R, Jain P, Thompson P, Brandt M, Luthra R, Burger J, Keating M, Ravandi F. Long-term durable remission by cladribine followed by rituximab in patients with hairy cell leukaemia: update of a phase II trial. Br J Haematol. 2016 Sep;174(5):760-6. Epub 2016 Jun 15. link to original article link to PMC article PubMed

Interferon alfa-2b monotherapy

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Regimen

Study	Years of enrollment	Evidence
Quesada et al. 1984		Pilot, <20 pts
Golomb et al. 1986		Non-randomized
Golomb et al. 1988	1985-1987	Non-randomized portion of RCT (RT)

Of historic interest. Most patients had previously undergone splenectomy.

Immunotherapy

• Interferon alfa-2b (Intron-A)

References

1. Quesada JR, Reuben J, Manning JT, Hersh EM, Gutterman JU. Alpha interferon for induction of remission in hairy-cell leukemia. N Engl J Med. 1984 Jan 5;310(1):15-8. link to original article PubMed
2. Golomb HM, Jacobs A, Fefer A, Ozer H, Thompson J, Portlock C, Ratain M, Golde D, Vardiman J, Burke JS, Brady J, Bonnem E, Spiegel R. Alpha-2 interferon therapy of hairy-cell leukemia: a multicenter study of 64 patients. J Clin Oncol. 1986 Jun;4(6):900-5. link to original article PubMed
3. Golomb HM, Ratain MJ, Fefer A, Thompson J, Golde DW, Ozer H, Portlock C, Silber R, Rappeport J, Bonnem E, Spiegel R, Tensen L, Burke JS, Vardiman JW. Randomized study of the duration of treatment with interferon alfa-2B in patients with hairy cell leukemia. J Natl Cancer Inst. 1988 May 4;80(5):369-73. link to original article PubMed

Moxetumomab pasudotox monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence
Kreitman et al. 2012 (Study 1053)	2007-2009	Phase I (RT)

Chemotherapy

• Moxetumomab pasudotox (Lumoxiti) 0.04 mg/kg IV over 30 minutes once per day on days 1, 3, 5

28-day cycle for up to 6 cycles

References

1. Phase 1: Kreitman RJ, Tallman MS, Robak T, Coutre S, Wilson WH, Stetler-Stevenson M, Fitzgerald DJ, Lechleider R, Pastan I. Phase I trial of anti-CD22 recombinant immunotoxin moxetumomab pasudotox (CAT-8015 or HA22) in patients with hairy cell leukemia. J Clin Oncol. 2012 May 20;30(15):1822-8. Epub 2012 Feb 21. link to original article link to PMC article PubMed
   1. Update: Kreitman RJ, Tallman MS, Robak T, Coutre S, Wilson WH, Stetler-Stevenson M, FitzGerald DJ, Santiago L, Gao G, Lanasa MC, Pastan I. Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase 1 results and long-term follow-up. Blood. 2018 May 24;131(21):2331-2334. Epub 2018 Feb 27. link to original article PubMed

Rituximab monotherapy

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Regimen

Study	Evidence
Nieva et al. 2003	Phase II

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22

Supportive medications

• Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 7

4-week course

References

1. Nieva J, Bethel K, Saven A. Phase 2 study of rituximab in the treatment of cladribine-failed patients with hairy cell leukemia. Blood. 2003 Aug 1;102(3):810-3. link to original article contains verified protocol PubMed

Vemurafenib monotherapy

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Regimen

Study	Evidence	Efficacy
Tiacci et al. 2015 (MSKCC 12-200)	Phase II	ORR: 96-100%

Note that a pooled analysis of two phase II trials is reported; they have slightly different durations - please see original text for details.

Chemotherapy

• Vemurafenib (Zelboraf) 960 mg PO twice per day

28-day cycle for up to 4 cycles (Italian trial) or 6 cycles (MSKCC 12-200)

References

1. MSKCC 12-200: Tiacci E, Park JH, De Carolis L, Chung SS, Broccoli A, Scott S, Zaja F, Devlin S, Pulsoni A, Chung YR, Cimminiello M, Kim E, Rossi D, Stone RM, Motta G, Saven A, Varettoni M, Altman JK, Anastasia A, Grever MR, Ambrosetti A, Rai KR, Fraticelli V, Lacouture ME, Carella AM, Levine RL, Leoni P, Rambaldi A, Falzetti F, Ascani S, Capponi M, Martelli MP, Park CY, Pileri SA, Rosen N, Foà R, Berger MF, Zinzani PL, Abdel-Wahab O, Falini B, Tallman MS. Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med. 2015 Oct 29;373(18):1733-47. Epub 2015 Sep 9. link to original article contains verified protocol link to PMC article PubMed

Hairy cell leukemia variant (HCLv), all lines of therapy

Note: this is a distinct disease process from hairy cell leukemia, but will be included on this page for now given the similarities. We may create a dedicated page in the future.

Cladribine & Rituximab

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Protocol

Study	Evidence
Ravandi et al. 2011	Phase II, <20 pts in this cohort

Chemotherapy, part 1

• Cladribine (Leustatin) 5.6 mg/m² IV over 2 hours once per day on days 1 to 5

Supportive medications

All were administered at the discretion of the treating physician.

• Levofloxacin (Levaquin)
• Valacyclovir (Valtrex)
• Fluconazole (Diflucan)
• Filgrastim (Neupogen)

5-day course

28 days after administration of cladribine, bone marrow examination was repeated, and then rituximab was started:

Chemotherapy, part 2

• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36, 43, 50

8-week course

References

1. Ravandi F, O'Brien S, Jorgensen J, Pierce S, Faderl S, Ferrajoli A, Koller C, Challagundla P, York S, Brandt M, Luthra R, Burger J, Thomas D, Keating M, Kantarjian H. Phase 2 study of cladribine followed by rituximab in patients with hairy cell leukemia. Blood. 2011 Oct 6;118(14):3818-23. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Chihara D, Kantarjian H, O'Brien S, Jorgensen J, Pierce S, Faderl S, Ferrajoli A, Poku R, Jain P, Thompson P, Brandt M, Luthra R, Burger J, Keating M, Ravandi F. Long-term durable remission by cladribine followed by rituximab in patients with hairy cell leukaemia: update of a phase II trial. Br J Haematol. 2016 Sep;174(5):760-6. Epub 2016 Jun 15. link to original article link to PMC article PubMed