Skip to main content

Advertisement

Log in

Hairy Cell Leukemia—New Genes, New Targets

  • Lymphomas (C Dearden, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

Hairy cell leukemia (HCL), a B cell malignancy comprising 2 % of all leukemias, has become quite exciting recently with regard to the development of new targets for therapy. This review will focus on advancements made within the past 1–2 years in targeted therapy for this disease. These advances may be grouped into two very difference categories, namely targeting of CD22 with the recombinant immunotoxin moxetumomab pasudotox, and targeting of the mutated BRAF component of the MAP kinase pathway. Moxetumomab pasudotox in phase I testing was recently reported to be associated with an overall response rate of 86 % and a complete remission (CR) rate of 46 % in 28 patients with relapsed and refractory HCL. Many of the CRs are without minimal residual disease (MRD). Severe or dose limiting toxicity was not observed on this trial, but a completely reversible and largely asymptomatic form of grade 2 hemolytic uremic syndrome occurred in two patients during retreatment. This agent has commenced phase III multicenter testing to validate its phase I results. An extensive number of studies have documented the V600E mutation in nearly all HCL patients, but not in similar hematologic malignancies. The thymidine kinase inhibitor vemurafenib, which inhibits the V600E mutant of BRAF, was reported to induce a CR in multiply relapsed and refractory HCL, with nearly complete clearing of MRD. One additional partial and one additional complete remission were subsequently reported.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Bouroncle BA, Wiseman BK, Doan CA. Leukemic reticuloendotheliosis. Blood. 1958;13:609–30.

    PubMed  CAS  Google Scholar 

  2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.

    Article  PubMed  Google Scholar 

  3. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49:1374–403.

    Article  PubMed  CAS  Google Scholar 

  4. Frassoldati A, Lamparelli T, Federico M, Annino L, Capnist G, Pagnucco G, et al. Hairy cell leukemia: a clinical review based on 725 cases of the Italian Cooperative Group (ICGHCL). Italian Cooperative Group for Hairy Cell Leukemia. Leuk Lymphoma. 1994;13:307–16.

    Article  PubMed  CAS  Google Scholar 

  5. Bouroncle BA. Leukemic reticuloendotheliosis (hairy cell leukemia). Blood. 1979;53:412–36.

    PubMed  CAS  Google Scholar 

  6. Hoffman MA. Clinical presentations and complications of hairy cell leukemia. Hematol Oncol Clin North Am. 2006;20:1065–73.

    Article  PubMed  Google Scholar 

  7. Juliusson G, Vitols S, Liliemark J. Disease-related hypocholesterolemia in patients with hairy cell leukemia. Positive correlation with spleen size but not with tumor cell burden or low density lipoprotein receptor activity. Cancer. 1995;76:423–8.

    Article  PubMed  CAS  Google Scholar 

  8. Bouroncle BA. Thirty-five years in the progress of hairy cell leukemia. Leuk Lymphoma. 1994;14 Suppl 1:1–12.

    PubMed  Google Scholar 

  9. Matutes E, Wotherspoon A, Catovsky D. The variant form of hairy-cell leukaemia. Best Pract Res Clin Haematol. 2003;16:41–56.

    Article  PubMed  CAS  Google Scholar 

  10. Matutes E, Morilla R, Owusu-Ankomah K, Houliham A, Meeus P, Catovsky D. The immunophenotype of hairy cell leukemia (HCL). Proposal for a scoring system to distinguish HCL from B cell disorders with hairy or villous lymphocytes. Leuk Lymphoma. 1994;14(1):57–61.

    PubMed  Google Scholar 

  11. Robbins BA, Ellison DJ, Spinosa JC, Carey CA, Lukes RJ, Poppema S, et al. Diagnostic application of two-color flow cytometry in 161 cases of hairy cell leukemia. Blood. 1993;82:1277–87.

    PubMed  CAS  Google Scholar 

  12. Venkataraman G, Aguhar C, Kreitman RJ, Yuan CM, Stetler-Stevenson M. Characteristic CD103 and CD123 Expression Pattern Defines Hairy Cell Leukemia: Usefulness of CD123 and CD103 in the Diagnosis of Mature B cell Lymphoproliferative Disorders. Am J Clin Pathol. 2011;136:625–30.

    Article  PubMed  Google Scholar 

  13. DelGiudice I, Matutes E, Morilla R, Morilla A, OwusuAnkomah K, Rafiq F, et al. The diagnostic value of CD123 in B cell disorders with hairy or villous lymphocytes. Haematologica. 2004;89:303–8.

    Google Scholar 

  14. Shao H, Calvo KR, Grönborg M, Tembhare PR, Kreitman RJ, Stetler-Stevenson M, et al. Distinguishing Hairy Cell Leukemia Variant from Hairy Cell Leukemia: Development and Validation of Diagnostic Criteria. Leuk Res. 2012;37:401–9.

    Article  CAS  Google Scholar 

  15. Cawley JC. The pathophysiology of the hairy cell. Hematol Oncol Clin North Am. 2006;20:1011–21.

    Article  PubMed  CAS  Google Scholar 

  16. Dunphy CH. Reaction patterns of TRAP and DBA.44 in hairy cell leukemia, hairy cell variant, and nodal and extranodal marginal zone B cell lymphomas. Appl Immunohistochem Mol Morphol. 2008;16:135–9.

    Article  PubMed  Google Scholar 

  17. Falini B, Tiacci E, Liso A, Basso K, Sabattini E, Pacini R, et al. Simple diagnostic assay for hairy cell leukaemia by immunocytochemical detection of annexin A1 (ANXA1). Lancet. 2004;363:1869–70.

    Article  PubMed  CAS  Google Scholar 

  18. Cawley JC, Burns GF, Hayhoe FG. A chronic lymphoproliferative disorder with distinctive features: a distinct variant of hairy-cell leukaemia. Leuk Res. 1980;4:547–59.

    Article  PubMed  CAS  Google Scholar 

  19. Matutes E, Wotherspoon A, Brito-Babapulle V, Catovsky D. The natural history and clinico-pathological features of the variant form of hairy cell leukemia. Leukemia. 2001;15:184–6.

    Article  PubMed  CAS  Google Scholar 

  20. Polliack A. Hairy cell leukemia: Biology, clinical diagnosis, unusual manifestations and associated disorders. Rev Clin Exp Hematol. 2002;6:366–88. discussion 449–50.

    Article  PubMed  Google Scholar 

  21. Matutes E, Oscier D, Montalban C, Berger F, CalletBauchu E, Dogan A, et al. Splenic marginal zone lymphoma proposals for a revision of diagnostic, staging and therapeutic criteria. Leukemia. 2008;22:487–95.

    Article  PubMed  CAS  Google Scholar 

  22. Arons E, Suntum T, Stetler-Stevenson M, Kreitman RJ. VH4-34+ hairy cell leukemia, a new variant with poor prognosis despite standard therapy. Blood. 2009;114:4687–95.

    Article  PubMed  CAS  Google Scholar 

  23. 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;310:15–8.

    Article  PubMed  CAS  Google Scholar 

  24. Habermann TM. Splenectomy, interferon, and treatments of historical interest in hairy cell leukemia. Hematol Oncol Clin North Am. 2006;20:1075–86.

    Article  PubMed  Google Scholar 

  25. Grever M, Kopecky K, Foucar MK, Head D, Bennett JM, Hutchison RE, et al. Randomized comparison of pentostatin versus interferon alfa-2a in previously untreated patients with hairy cell leukemia: an intergroup study. J Clin Oncol. 1995;13:974–82.

    PubMed  CAS  Google Scholar 

  26. Flinn IW, Kopecky KJ, Foucar MK, Head D, Bennett JM, Huchison R, et al. Long-term follow-up of remission duration, mortality, and second malignancies in hairy cell leukemia patients treated with pentostatin. Blood. 2000;96:2981–6.

    PubMed  CAS  Google Scholar 

  27. Kraut EH, Bouroncle BA, Grever MR. Pentostatin in the treatment of advanced hairy cell leukemia. J Clin Oncol. 1989;7:168–72.

    PubMed  CAS  Google Scholar 

  28. Johnston JB, Eisenhauer E, Wainman N, Corbett WEN, Zaentz SD, Daeninck P. Long-term outcome following treatment of hairy cell leukemia with pentostatin (Nipent): A National Cancer Institute of Canada Study. Semin Oncol. 2000;27:32–6.

    PubMed  CAS  Google Scholar 

  29. Rafel M, Cervantes F, Beltran JM, Zuazu F, Hernandez Nieto L, Rayon C, et al. Deoxycoformycin in the treatment of patients with hairy cell leukemia: results of a Spanish collaborative study of 80 patients. Cancer. 2000;88:352–7.

    Article  PubMed  CAS  Google Scholar 

  30. Maloisel F, Benboubker L, Gardembas M, Coiffier B, Divine M, Sebban C, et al. Long-term outcome with pentostatin treatment in hairy cell leukemia patients. A French retrospective study of 238 patients. Leukemia. 2003;17:45–51.

    Article  PubMed  CAS  Google Scholar 

  31. Else M, Ruchlemer R, Osuji N, DelGiudice I, Matutes E, Woodman A, et al. Long remissions in hairy cell leukemia with purine analogs - A report of 219 patients with a median follow-up of 12.5 years. Cancer. 2005;104:2442–8.

    Article  PubMed  CAS  Google Scholar 

  32. 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;322:1117–21.

    Article  PubMed  CAS  Google Scholar 

  33. Saven A, Burian C, Koziol JA, Piro LD. Long-term follow-up of patients with hairy cell leukemia after cladribine treatment. Blood. 1998;92:1918–26.

    PubMed  CAS  Google Scholar 

  34. Goodman GR, Burian C, Koziol JA, Saven A. Extended follow-up of patients with hairy cell leukemia after treatment with cladribine. J Clin Oncol. 2003;21:891–6.

    Article  PubMed  Google Scholar 

  35. Cheson BD, Sorensen JM, Vena DA, Montello MJ, Barrett JA, Damasio E, 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. 1998;16:3007–15.

    PubMed  CAS  Google Scholar 

  36. Robak T, Blasinska-Morawiec M, Krykowski E, Hansz J, Komarnicki M, Kazimierczak M, 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. 1996;22:107–11.

    Article  PubMed  CAS  Google Scholar 

  37. von Rohr A, Schmitz SF, Tichelli A, Hess U, Piguet D, Wernli M, et al. Treatment of hairy cell leukemia with cladribine (2-chlorodeoxyadenosine) by subcutaneous bolus injection: a phase II study. Ann Oncol. 2002;13:1641–9.

    Article  Google Scholar 

  38. Juliusson G, Heldal D, Hippe E, Hedenus M, Malm C, Wallman K, et al. Subcutaneous injections of 2-chlorodeoxyadenosine for symptomatic hairy cell leukemia. J Clin Oncol. 1995;13:989–95.

    PubMed  CAS  Google Scholar 

  39. Sonderegger T, Betticher DC, Cerny T, Lauterburg BH. Pharmacokinetics of 2-chloro-2 '-deoxyadenosine administered subcutaneously or by continuous intravenous infusion. Cancer Chemother Pharmacol. 2000;46:40–2.

    Article  PubMed  CAS  Google Scholar 

  40. Damasio EE, Resegotti L, Masoudi B, Bruni R, Cerri R, Isaza A, et al. 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;89:68–73.

    PubMed  CAS  Google Scholar 

  41. Robak T, Blasinska-Morawiec M, Blonski J, Hellmann A, Halaburda K, Konopka L, et al. 2-chlorodeoxyadenosine (cladribine) in the treatment of hairy cell leukemia and hairy cell leukemia variant: 7-year experience in Poland. Eur J Haematol. 1999;62:49–56.

    Article  PubMed  CAS  Google Scholar 

  42. Tetreault SA, Robbins BA, Saven A. Treatment of hairy cell leukemia-variant with cladribine. Leuk Lymphoma. 1999;35:347–54.

    Article  PubMed  CAS  Google Scholar 

  43. Machii T, Chou T, Suzuki M, Ohe Y, Katagiri S, Kitano EK, et al. Phase II clinical study of cladribine in the treatment of hairy cell leukemia. Int J Hematol. 2005;82:230–5.

    Article  PubMed  CAS  Google Scholar 

  44. Palomera L, Domingo JM, Sola C, Azaceta G, Calvo MT, Gutierrez M. Cladribine (2-chlorodeoxyadenosine) therapy in hairy cell leukemia variant. A report of three cases. Haematologica. 2002;87:107–8.

    PubMed  Google Scholar 

  45. Ott G, Balague-Ponz O, de Leval L, de Jong D, Hasserjian RP, Elenitoba-Johnson KS. Commentary on the WHO classification of tumors of lymphoid tissues (2008): indolent B cell lymphomas. J Hematop. 2009;2:77–81.

    Article  PubMed  Google Scholar 

  46. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4 edition, Vol. 2. World Health Organization, 2008.

  47. Else M, Dearden CE, Matutes E, Garcia-Talavera J, Rohatiner AZ, Johnson SA, 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. 2009;145:733–40.

    Article  PubMed  CAS  Google Scholar 

  48. Sigal DS, Sharpe R, Burian C, Saven A. Very long-term eradication of minimal residual disease in patients with hairy cell leukemia after a single course of cladribine. Blood. 2010;115:1893–6.

    Article  PubMed  CAS  Google Scholar 

  49. Seymour JF, Kurzrock R, Freireich EJ, Estey EH. 2-chlorodeoxyadenosine induces durable remissions and prolonged suppression of CD4+ lymphocyte counts in patients with hairy cell leukemia. Blood. 1994;83:2906–11.

    PubMed  CAS  Google Scholar 

  50. Seymour JF, Talpaz M, Kurzrock R. Response duration and recovery of CD4+ lymphocytes following deoxycoformycin in interferon-alpha-resistant hairy cell leukemia: 7- year follow-up. Leukemia. 1997;11:42–7.

    Article  PubMed  CAS  Google Scholar 

  51. Cheson BD, Vena DA, Foss FM, Sorensen JM. Neurotoxicity of purine analogs: A review. J Clin Oncol. 1994;12:2216–28.

    PubMed  CAS  Google Scholar 

  52. Villamor N, Montserrat E, Colomer D. Mechanism of action and resistance to monoclonal antibody therapy. Semin Oncol. 2003;30:424–33.

    Article  PubMed  CAS  Google Scholar 

  53. Zinzani PL, Ascani S, Piccaluga PP, Bendandi M, Pileri S, Tura S. Efficacy of rituximab in hairy cell leukemia treatment. J Clin Oncol. 2000;18:3875–7.

    PubMed  CAS  Google Scholar 

  54. Hagberg H. Chimeric monoclonal anti-CD20 antibody (rituximab)–an effective treatment for a patient with relapsing hairy cell leukaemia. Med Oncol. 1999;16:221–2.

    Article  PubMed  CAS  Google Scholar 

  55. Hoffman M, Auerbach L. Bone marrow remission of hairy cell leukaemia induced by rituximab (anti-CD20 monoclonal antibody) in a patient refractory to cladribine. Br J Haematol. 2000;109:900–1.

    Article  PubMed  CAS  Google Scholar 

  56. Sokol L, Agosti SJ. Simultaneous manifestation of chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL). American Journal of Hematology. 2004;75:107–9.

    Article  PubMed  Google Scholar 

  57. Pollio F, Pocali B, Palmieri S, Morabito P, Scalia G, Del Vecchio L, et al. Rituximab: a useful drug for a repeatedly relapsed hairy cell leukemia patient. Ann Hematol. 2002;81:736–8.

    Article  PubMed  CAS  Google Scholar 

  58. Hagberg H, Lundholm L. Rituximab, a chimaeric anti-CD20 monoclonal antibody, in the treatment of hairy cell leukaemia. Br J Haematol. 2001;115:609–11.

    Article  PubMed  CAS  Google Scholar 

  59. Lauria F, Lenoci M, Annino L, Raspadori D, Marotta G, Bocchia M, et al. Efficacy of anti-CD20 monoclonal antibodies (Mabthera) in patients with progressed hairy cell leukemia. Haematologica. 2001;86:1046–50.

    PubMed  CAS  Google Scholar 

  60. Nieva J, Bethel K, Saven A. Phase 2 study of rituximab in the treatment of cladribine-failed patients with hairy cell leukemia. Blood. 2003;102:810–3.

    Article  PubMed  CAS  Google Scholar 

  61. Thomas DA, O'Brien S, Bueso-Ramos C, Faderl S, Keating MJ, Giles FJ, et al. Rituximab in relapsed or refractory hairy cell leukemia. Blood. 2003;102:3906–11.

    Article  PubMed  CAS  Google Scholar 

  62. Angelopoulou MK, Pangalis GA, Sachanas S, Kokoris SI, Anargyrou K, Galani Z, et al. Outcome and toxicity in relapsed hairy cell leukemia patients treated with rituximab. Leuk Lymphoma. 2008;49:1817–20.

    Article  PubMed  Google Scholar 

  63. Zenhausern R, Simcock M, Gratwohl A, Hess U, Bargetzi M, Tobler A. Rituximab in patients with hairy cell leukemia relapsing after treatment with 2-chlorodeoxyadenosine (SAKK 31/98). Haematol Hematol J. 2008;93:1426–8.

    Article  CAS  Google Scholar 

  64. Fietz T, Rieger K, Schmittel A, Thiel E, Knauf W. Alemtuzumab (Campath 1H) in hairy cell leukaemia relapsing after rituximab treatment. Hematol J. 2004;5:451–2.

    Article  PubMed  CAS  Google Scholar 

  65. Quigley MM, Bethel KJ, Sharpe RW, Saven A. CD52 expression in hairy cell leukemia. Am J Hematol. 2003;74:227–30.

    Article  PubMed  CAS  Google Scholar 

  66. Endo Y, Mitsui K, Motizuki M, Tsurugi K. The mechanism of action of ricin and related toxic lectins on eukaryotic ribosomes. J Biol Chem. 1987;262:5908–12.

    PubMed  CAS  Google Scholar 

  67. Eiklid K, Olsnes S, Pihl A. Entry of lethal doses of abrin, ricin and modeccin into the cytosol of HeLa cells. Exp Cell Res. 1980;126:321–6.

    Article  PubMed  CAS  Google Scholar 

  68. Yamaizumi M, Mekada E, Uchida T, Okada Y. One molecule of diphtheria toxin fragment A introduced into a cell can kill the cell. Cell. 1978;15:245–50.

    Article  PubMed  CAS  Google Scholar 

  69. Kreitman RJ. Getting plant toxins to fuse. Leukemia Res. 1997;21:997–9.

    Article  CAS  Google Scholar 

  70. Chaudhary VK, Queen C, Junghans RP, Waldmann TA, FitzGerald DJ, Pastan I. A recombinant immunotoxin consisting of two antibody variable domains fused to Pseudomonas exotoxin. Nature. 1989;339:394–7.

    Article  PubMed  CAS  Google Scholar 

  71. Reiter Y, Brinkmann U, Kreitman RJ, Jung S-H, Lee B, Pastan I. Stabilization of the Fv fragments in recombinant immunotoxins by disulfide bonds engineered into conserved framework regions. Biochemistry. 1994;33:5451–9.

    Article  PubMed  CAS  Google Scholar 

  72. Kreitman RJ, Pastan I. Targeting Pseudomonas exotoxin to hematologic malignancies. Semin Cancer Biol. 1995;6:297–306.

    Article  PubMed  CAS  Google Scholar 

  73. Kreitman RJ. Recombinant immunotoxins for the treatment of chemoresistant hematologic malignancies. Current Pharmaceutical Design. 2009;15:2652–64.

    Article  PubMed  CAS  Google Scholar 

  74. Kreitman RJ, Wilson WH, Robbins D, Margulies I, Stetler-Stevenson M, Waldmann TA, et al. Responses in refractory hairy cell leukemia to a recombinant immunotoxin. Blood. 1999;94:3340–8.

    PubMed  CAS  Google Scholar 

  75. Kreitman RJ, Wilson WH, White JD, Stetler-Stevenson M, Jaffe ES, Waldmann TA, et al. Phase I trial of recombinant immunotoxin Anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J Clin Oncol. 2000;18:1614–36.

    Google Scholar 

  76. Cordone I, Annino L, Masi S, Pescarmona E, Rahimi S, Ferrari A, et al. Diagnostic relevance of peripheral blood immunocytochemistry in hairy cell leukaemia. J Clin Pathol. 1995;48:955–60.

    Article  PubMed  CAS  Google Scholar 

  77. Poe JC, Tedder TF. CD22 and Siglec-G in B cell function and tolerance. Trends Immunol. 2012;33:413–20.

    Article  PubMed  CAS  Google Scholar 

  78. Sato S, Tuscano JM, Inaoki M, Tedder TF. CD22 negatively and positively regulates signal transduction through the B lymphocyte antigen receptor. Semin Immunol. 1998;10:287–97.

    Article  PubMed  CAS  Google Scholar 

  79. Babusikova O, Tomova A, Kusenda J, Gyarfas J. Flow cytometry of peripheral blood and bone marrow cells from patients with hairy cell leukemia: phenotype of hairy cells, lymphocyte subsets and detection of minimal residual disease after treatment. Neoplasma. 2001;48:350–7.

    PubMed  CAS  Google Scholar 

  80. Jasper GA, Arun I, Venzon D, Kreitman RJ, Wayne AS, Yuan CM, et al. Variables affecting the quantitation of CD22 in neoplastic B cells. Cytometry B Clin Cytom. 2011;80:83–90.

    PubMed  Google Scholar 

  81. Kreitman RJ, Wang QC, FitzGerald DJP, Pastan I. Complete regression of human B cell lymphoma xenografts in mice treated with recombinant anti-CD22 immunotoxin RFB4(dsFv)-PE38 at doses tolerated by Cynomolgus monkeys. Int J Cancer. 1999;81:148–55.

    Article  PubMed  CAS  Google Scholar 

  82. Kreitman RJ, Margulies I, Stetler-Stevenson M, Wang QC, FitzGerald DJP, Pastan I. Cytotoxic activity of disulfide-stabilized recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) towards fresh malignant cells from patients with B cell leukemias. Clin Cancer Res. 2000;6:1476–87.

    PubMed  CAS  Google Scholar 

  83. Kreitman RJ, Wilson WH, Bergeron K, Raggio M, Stetler-Stevenson M, FitzGerald DJ, et al. Efficacy of the Anti-CD22 Recombinant Immunotoxin BL22 in Chemotherapy-Resistant Hairy-Cell Leukemia. New Engl J Med. 2001;345:241–7.

    Article  PubMed  CAS  Google Scholar 

  84. Kreitman RJ, Squires DR, Stetler-Stevenson M, Noel P, Fitzgerald DJ, Wilson WH, et al. Phase I trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with B cell malignancies. J Clin Oncol. 2005;23:6719–29.

    Article  PubMed  CAS  Google Scholar 

  85. Kreitman RJ, Stetler-Stevenson M, Margulies I, Noel P, FitzGerald DJP, Wilson WH, et al. Phase II trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with hairy cell leukemia. J Clin Oncol. 2009;27:2983–90.

    Article  PubMed  CAS  Google Scholar 

  86. Salvatore G, Beers R, Margulies I, Kreitman RJ, Pastan I. Improved Cytotoxic activity towards cell lines and fresh leukemia cells of a mutant anti-CD22 immunotoxin obtained by antibody phage display. Clin Cancer Res. 2002;8:995–1002.

    PubMed  CAS  Google Scholar 

  87. Decker T, Oelsner M, Kreitman RJ, Salvatore G, Wang QC, Pastan I, et al. Induction of Caspase-Dependent Programmed Cell Death in B cell Chronic Lymphocytic Leukemia Cells by Anti-CD22 Immunotoxins. Blood. 2004;103:2718–26.

    Article  PubMed  CAS  Google Scholar 

  88. Ho M, Kreitman RJ, Onda M, Pastan I. In vitro antibody evolution targeting germline hot spots to increase activity of an anti-CD22 immunotoxin. J Biol Chem. 2005;280:607–17.

    Article  PubMed  CAS  Google Scholar 

  89. •• Kreitman RJ, Tallman MS, Robak T, Coutre S, Wilson WH, Stetler-Stevenson M, 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. 2012;30:1822–8. Phase I dose-escalation trial of moxetumomab pasudotox in patients with HCL. The agent is now undergoing multicenter pivotal phase III testing.

    Article  PubMed  CAS  Google Scholar 

  90. •• Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011;364:2305–15. First report showing that BRAF V600E is found in 100 % of HCL compared to 0 % of other hematologic malignancies. This driving mutation is considered to be of etiologic importance in addition to diagnostic utility, and is a target for V600E-directed agents.

    Article  PubMed  CAS  Google Scholar 

  91. Jang S, Atkins MB. Which drug, and when, for patients with BRAF-mutant melanoma? Lancet Oncol. 2013;14:e60–9.

    Article  PubMed  CAS  Google Scholar 

  92. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.

    Article  PubMed  CAS  Google Scholar 

  93. Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002;62:6997–7000.

    PubMed  CAS  Google Scholar 

  94. Kamiguti AS, Harris RJ, Slupsky JR, Baker PK, Cawley JC, Zuzel M, et al. Regulation of hairy-cell survival through constitutive activation of mitogen-activated protien kinase pathways. Oncogene. 2003;22:2272–84.

    Article  PubMed  CAS  Google Scholar 

  95. Boyd EM, Bench AJ, van Veer MB, Wright P, Bloxham DM, Follows GA, et al. High resolution melting analysis for detection of BRAF exon 15 mutations in hairy cell leukaemia and other lymphoid malignancies. Br J Haematol. 2011;155:609–12.

    Article  PubMed  CAS  Google Scholar 

  96. Blombery PA, Wong SQ, Hewitt CA, Dobrovic A, Maxwell EL, Juneja S, et al. Detection of BRAF mutations in patients with hairy cell leukemia and related lymphoproliferative disorders. Haematologica. 2012;97:780–3.

    Article  PubMed  CAS  Google Scholar 

  97. Packham D, Ward RL, Ap Lin V, Hawkins NJ, Hitchins MP. Implementation of novel pyrosequencing assays to screen for common mutations of BRAF and KRAS in a cohort of sporadic colorectal cancers. Diagn Mol Pathol. 2009;18:62–71.

    Article  PubMed  CAS  Google Scholar 

  98. Li J, Wang L, Mamon H, Kulke MH, Berbeco R, Makrigiorgos GM. Replacing PCR with COLD-PCR enriches variant DNA sequences and redefines the sensitivity of genetic testing. Nat Med. 2008;14:579–84.

    Article  PubMed  CAS  Google Scholar 

  99. • Xi L, Arons E, Navarro W, Calvo KR, Stetler-Stevenson M, Raffeld M, et al. Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation. Blood. 2012;119:3330–2. First demonstration that HCL cases immunophenotypically consistent with classic HCL, but expressing the IGHV4-34 immunoglobulin rearrangement, are wild-type for BRAF.

    Article  PubMed  CAS  Google Scholar 

  100. Verma S, Greaves WO, Ravandi F, Reddy N, Bueso-Ramos CE, O'Brien S, et al. Rapid detection and quantitation of BRAF mutations in hairy cell leukemia using a sensitive pyrosequencing assay. Am J Clin Pathol. 2012;138:153–6.

    Article  PubMed  CAS  Google Scholar 

  101. Laurini JA, Aoun P, Iqbal J, Chan W, Greiner TC. Investigation of the BRAF V600E mutation by pyrosequencing in lymphoproliferative disorders. Am J Clin Pathol. 2012;138:877–83.

    Article  PubMed  Google Scholar 

  102. Lennerz JK, Klaus BM, Marienfeld RB, Moller P. Pyrosequencing of BRAF V600E in routine samples of hairy cell leukaemia identifies CD5+ variant hairy cell leukaemia that lacks V600E. Br J Haematol. 2012;157:267–9.

    Article  PubMed  CAS  Google Scholar 

  103. Arcaini L, Zibellini S, Boveri E, Riboni R, Rattotti S, Varettoni M, et al. The BRAF V600E mutation in hairy cell leukemia and other mature B cell neoplasms. Blood. 2012;119:188–91.

    Article  PubMed  CAS  Google Scholar 

  104. Tiacci E, Schiavoni G, Forconi F, Santi A, Trentin L, Ambrosetti A, et al. Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. Blood. 2012;119:192–5.

    Article  PubMed  CAS  Google Scholar 

  105. Langabeer SE, O’Brien D, Liptrot S, Flynn CM, Hayden PJ, Conneally E, et al. Correlation of the BRAF V600E mutation in hairy cell leukaemia with morphology, cytochemistry and immunophenotype. International Journal of Laboratory Hematology. 2012;34:417–21.

    Article  PubMed  CAS  Google Scholar 

  106. Langabeer SE, O'Brien D, McElligott AM, Lavin M, Browne PV. BRAF V600E-negative hairy cell leukaemia. Case Reports in Hematology. 2013;2013:3.

    Article  Google Scholar 

  107. Ewalt M, Nandula S, Phillips A, Alobeid B, Murty VV, Mansukhani MM, et al. Real-time PCR-based analysis of BRAF V600E mutation in low and intermediate grade lymphomas confirms frequent occurrence in hairy cell leukaemia. Hematol Oncol. 2012;30:190–3.

    Article  PubMed  CAS  Google Scholar 

  108. Schnittger S, Bacher U, Haferlach T, Wendland N, Ulke M, Dicker F, et al. Development and validation of a real-time quantification assay to detect and monitor BRAFV600E mutations in hairy cell leukemia. Blood. 2012;119:3151–4.

    Article  PubMed  CAS  Google Scholar 

  109. Jebaraj BM, Kienle D, Buhler A, Winkler D, Dohner H, Stilgenbauer S, et al. BRAF mutations in chronic lymphocytic leukemia. Leuk Lymphoma 2012:in press.

  110. Ping N, Wang Q, Wang Q, Dong S, Wu L, Xue Y, et al. Absence of BRAF V600E mutation in hematologic malignancies excluding hairy-cell leukemia. Leuk Lymphoma. 2012;53:2498–9.

    Article  PubMed  CAS  Google Scholar 

  111. Andrulis M, Penzel R, Weichert W, von Deimling A, Capper D. Application of a BRAF V600E mutation-specific antibody for the diagnosis of hairy cell leukemia. Am J Surg Pathol. 2012;36:1796–800.

    Article  PubMed  Google Scholar 

  112. Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116:1919–23.

    Article  PubMed  CAS  Google Scholar 

  113. Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471:467–72.

    Article  PubMed  CAS  Google Scholar 

  114. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. 2003;63:1454–7.

    PubMed  CAS  Google Scholar 

  115. Caronia LM, Phay JE, Shah MH. Role of BRAF in thyroid oncogenesis. Clin Cancer Res. 2011;17:7511–7.

    Article  PubMed  CAS  Google Scholar 

  116. Hostein I, Faur N, Primois C, Boury F, Denard J, Emile JF, et al. BRAF mutation status in gastrointestinal stromal tumors. Am J Clin Pathol. 2010;133:141–8.

    Article  PubMed  CAS  Google Scholar 

  117. Mayer F, Wermann H, Albers P, Stoop H, Gillis AJ, Hartmann JT, et al. Histopathological and molecular features of late relapses in non-seminomas. BJU Int. 2011;107:936–43.

    Article  PubMed  Google Scholar 

  118. Honecker F, Wermann H, Mayer F, Gillis AJ, Stoop H, van Gurp RJ, et al. Microsatellite instability, mismatch repair deficiency, and BRAF mutation in treatment-resistant germ cell tumors. J Clin Oncol. 2009;27:2129–36.

    Article  PubMed  CAS  Google Scholar 

  119. Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, et al. Discovery and prioritization of somatic mutations in diffuse large B cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A. 2012;109:3879–84.

    Article  PubMed  CAS  Google Scholar 

  120. Schonleben F, Qiu W, Allendorf JD, Chabot JA, Remotti HE, Su GH. Molecular analysis of PIK3CA, BRAF, and RAS oncogenes in periampullary and ampullary adenomas and carcinomas. J Gastrointest Surg. 2009;13:1510–6.

    Article  PubMed  Google Scholar 

  121. Warth A, Kloor M, Schirmacher P, Blaker H. Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP. Mod Pathol. 2011;24:564–70.

    Article  PubMed  CAS  Google Scholar 

  122. Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 2011;121:397–405.

    Article  PubMed  CAS  Google Scholar 

  123. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.

    Article  PubMed  CAS  Google Scholar 

  124. Rochet NM, Kottschade LA, Markovic SN. Vemurafenib for melanoma metastases to the brain. N Engl J Med. 2011;365:2439–41.

    Article  PubMed  CAS  Google Scholar 

  125. Schafer N, Scheffler B, Stuplich M, Schaub C, Kebir S, Rehkamper C, et al. Vemurafenib for leptomeningeal melanomatosis. J Clin Oncol. 2013;31:e173–4.

    Article  PubMed  Google Scholar 

  126. •• Dietrich S, Glimm H, Andrulis M, von Kalle C, Ho AD, Zenz T. BRAF inhibition in refractory hairy-cell leukemia. N Engl J Med. 2012;366:2038–40. First report showing efficacy of Vemurafenib targeting V600E in HCL.

    Article  PubMed  Google Scholar 

  127. Dietrich S, Hullein J, Hundemer M, Lehners N, Jethwa A, Capper D, et al. Continued Response Off Treatment After BRAF Inhibition in Refractory Hairy Cell Leukemia. J Clin Oncol 2013.

  128. Follows GA, Sims H, Bloxham DM, Zenz T, Hopper MA, Liu H, et al. Rapid response of biallelic BRAF V600E mutated hairy cell leukaemia to low dose vemurafenib. Br J Haematol. 2013;161:150–3.

    Article  PubMed  CAS  Google Scholar 

  129. Peyrade F, Re D, Ginet C, Gastaud L, Allegra M, Ballotti R, et al. Low-dose vemurafenib induces complete remission in a case of hairy-cell leukemia with a V600E mutation. Haematologica. 2013;98:e20–2.

    Article  PubMed  Google Scholar 

  130. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–65.

    Article  PubMed  CAS  Google Scholar 

  131. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.

    Article  PubMed  CAS  Google Scholar 

  132. Catalanotti F, Solit DB, Pulitzer MP, Berger MF, Scott SN, Iyriboz T, et al. Phase II Trial of MEK Inhibitor Selumetinib (AZD6244, ARRY-142886) in Patients with BRAFV600E/K-Mutated Melanoma. Clin Cancer Res. 2013;19:2257–64.

    Article  PubMed  CAS  Google Scholar 

  133. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703.

    Article  PubMed  CAS  Google Scholar 

  134. Brown JR. Ibrutinib in CLL and B Cell Malignancies. Leuk Lymphoma 2013.

Download references

Compliance with Ethics Guidelines

Conflict of interest

R. Kreitman: employed by NIH, patents from NIH, royalties from NIH regarding moxetumomab pasudotox, has collaborated with Plexxikon, Roche and GSK regarding MAPK targeting.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert J. Kreitman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kreitman, R.J. Hairy Cell Leukemia—New Genes, New Targets. Curr Hematol Malig Rep 8, 184–195 (2013). https://doi.org/10.1007/s11899-013-0167-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-013-0167-0

Keywords

Navigation