Cladribine in the remission induction of adult acute myeloid leukemia: where do we stand?

  • Ayman QasrawiEmail author
  • Waled Bahaj
  • Lien Qasrawi
  • Omar Abughanimeh
  • John Foxworth
  • Rakesh Gaur
Review Article


The combination of cytarabine and an anthracycline has been the standard of care for the induction of remission in acute myeloid leukemia (AML). The response to treatment and survival of adult patients with AML are still variable and depend on multiple factors. Therefore, there have been many efforts to improve the response to treatment and survival rates by either increasing the cytarabine dose or adding a third agent to the standard induction chemotherapy regimen. Unfortunately, attempts to improve response and survival have been mostly unsuccessful. Recent clinical trials and retrospective studies explored the addition of cladribine to standard induction chemotherapy for AML. Some of these studies showed higher rates of complete remission, and one showed improved survival. In this review, we will discuss the antileukemic properties of cladribine and summarize the recent clinical data regarding its incorporation into the induction therapy for adult AML.


Cladribine Acute myeloid leukemia Remission Induction Chemotherapy 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

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


  1. 1.
    Döhner H, Weisdorf DJ, Bloomfield CD (2015) Acute myeloid leukemia. N Engl J Med 373(12):1136–1152. CrossRefPubMedGoogle Scholar
  2. 2.
    American Cancer Society (2017) Cancer facts & figures 2017. American Cancer Society, AtlantaGoogle Scholar
  3. 3.
    Visser O, Trama A, Maynadié M, Stiller C, Marcos-Gragera R, De Angelis R, Mallone S, Tereanu C, Allemani C, Ricardi U, Schouten HC, Group RW (2012) Incidence, survival and prevalence of myeloid malignancies in Europe. Eur J Cancer 48(17):3257–3266. CrossRefPubMedGoogle Scholar
  4. 4.
    Percival ME, Tao L, Medeiros BC, Clarke CA (2015) Improvements in the early death rate among 9380 patients with acute myeloid leukemia after initial therapy: a SEER database analysis. Cancer 121(12):2004–2012. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Löwenberg B, Bloomfield CD (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129(4):424–447. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Creutzig U, Kaspers GJ (2004) Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 22(16):3432–3433. CrossRefPubMedGoogle Scholar
  7. 7.
    Ferrara F, Palmieri S, Leoni F (2008) Clinically useful prognostic factors in acute myeloid leukemia. Crit Rev Oncol Hematol 66(3):181–193. CrossRefPubMedGoogle Scholar
  8. 8.
    Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald GW, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Tallman MS (2009) Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 361(13):1249–1259. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Gong Q, Zhou L, Xu S, Li X, Zou Y, Chen J (2015) High doses of daunorubicin during induction therapy of newly diagnosed acute myeloid leukemia: a systematic review and meta-analysis of prospective clinical trials. PLoS One 10(5):e0125612. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Trifilio S, Zhou Z, Mehta J, Czerniak C, Pi J, Greenberg D, Koslosky M, Pantiru M, Altman J (2013) Idarubicin appears equivalent to dose-intense daunorubicin for remission induction in patients with acute myeloid leukemia. Leuk Res 37(8):868–871. CrossRefPubMedGoogle Scholar
  11. 11.
    Dombret H, Gardin C (2016) An update of current treatments for adult acute myeloid leukemia. Blood 127(1):53–61. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Li X, Xu S, Tan Y, Chen J (2015) The effects of idarubicin versus other anthracyclines for induction therapy of patients with newly diagnosed leukaemia. Cochrane Database Syst Rev 6:CD010432. CrossRefGoogle Scholar
  13. 13.
    Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L, McMullin MF, Cahalin P, Dennis M, Friis L, Thomas IF, Milligan D, Clark RE, Group UNAS (2015) A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood 125(25):3878–3885. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Burnett AK, Russell NH, Hills RK, Group UKNCRIAMLS (2016) Higher daunorubicin exposure benefits FLT3 mutated acute myeloid leukemia. Blood 128(3):449–452. CrossRefPubMedGoogle Scholar
  15. 15.
    Schlenk RF, Benner A, Hartmann F, del Valle F, Weber C, Pralle H, Fischer JT, Gunzer U, Pezzutto A, Weber W, Grimminger W, Preiss J, Hensel M, Fröhling S, Döhner K, Haas R, Döhner H, AML Study Group Ulm (AMLSG ULM) (2003) Risk-adapted postremission therapy in acute myeloid leukemia: results of the German multicenter AML HD93 treatment trial. Leukemia 17(8):1521–1528. CrossRefPubMedGoogle Scholar
  16. 16.
    Li W, Gong X, Sun M, Zhao X, Gong B, Wei H, Mi Y, Wang J (2014) High-dose cytarabine in acute myeloid leukemia treatment: a systematic review and meta-analysis. PLoS One 9(10):e110153. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Willemze R, Suciu S, Meloni G, Labar B, Marie JP, Halkes CJ, Muus P, Mistrik M, Amadori S, Specchia G, Fabbiano F, Nobile F, Sborgia M, Camera A, Selleslag DL, Lefrère F, Magro D, Sica S, Cantore N, Beksac M, Berneman Z, Thomas X, Melillo L, Guimaraes JE, Leoni P, Luppi M, Mitra ME, Bron D, Fillet G, Marijt EW, Venditti A, Hagemeijer A, Mancini M, Jansen J, Cilloni D, Meert L, Fazi P, Vignetti M, Trisolini SM, Mandelli F, de Witte T (2014) High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMA AML-12 trial. J Clin Oncol 32(3):219–228. CrossRefPubMedGoogle Scholar
  18. 18.
    Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC (2018) CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol:JCO2017776112. CrossRefGoogle Scholar
  19. 19.
    Miyawaki S, Tanimoto M, Kobayashi T, Minami S, Tamura J, Omoto E, Kuriyama K, Hatake K, Saito K, Kanamaru A, Oh H, Ohtake S, Asou N, Sakamaki H, Yamada O, Jinnai I, Tsubaki K, Takeyama K, Hiraoka A, Matsuda S, Takahashi M, Shimazaki C, Adachi K, Kageyama S, Ohno R (1999) No beneficial effect from addition of etoposide to daunorubicin, cytarabine, and 6-mercaptopurine in individualized induction therapy of adult acute myeloid leukemia: the JALSG-AML92 study. Japan Adult Leukemia Study Group Int J Hematol 70(2):97–104Google Scholar
  20. 20.
    Estey EH, Thall PF, Cortes JE, Giles FJ, O’Brien S, Pierce SA, Wang X, Kantarjian HM, Beran M (2001) Comparison of idarubicin + ara-C-, fludarabine + ara-C-, and topotecan + ara-C-based regimens in treatment of newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts in transformation, or refractory anemia with excess blasts. Blood 98(13):3575–3583CrossRefGoogle Scholar
  21. 21.
    Hann IM, Stevens RF, Goldstone AH, Rees JK, Wheatley K, Gray RG, Burnett AK (1997) Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council’s 10th AML trial (MRC AML10). Adult and childhood leukaemia working parties of the Medical Research Council. Blood 89(7):2311–2318PubMedGoogle Scholar
  22. 22.
    Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H (2017) Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 377(5):454–464. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Leick MB, Levis MJ (2017) The future of targeting FLT3 activation in AML. Curr Hematol Malig Rep 12:153–167. CrossRefPubMedGoogle Scholar
  24. 24.
    Appelbaum FR, Bernstein ID (2017) Gemtuzumab ozogamicin for acute myeloid leukemia. Blood 130(22):2373–2376. CrossRefPubMedGoogle Scholar
  25. 25.
    Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, de Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H, Association ALF (2012) Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 379(9825):1508–1516. CrossRefPubMedGoogle Scholar
  26. 26.
    Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S (2018) Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase 3 ALFA-0701 trial. Haematologica, haematol.2018.188888
  27. 27.
    Queiroz KC, Ruela-de-Sousa RR, Fuhler GM, Aberson HL, Ferreira CV, Peppelenbosch MP, Spek CA (2010) Hedgehog signaling maintains chemoresistance in myeloid leukemic cells. Oncogene 29(48):6314–6322. CrossRefPubMedGoogle Scholar
  28. 28.
    Munchhof MJ, Li Q, Shavnya A, Borzillo GV, Boyden TL, Jones CS, LaGreca SD, Martinez-Alsina L, Patel N, Pelletier K, Reiter LA, Robbins MD, Tkalcevic GT (2012) Discovery of PF-04449913, a potent and orally bioavailable inhibitor of smoothened. ACS Med Chem Lett 3(2):106–111. CrossRefPubMedGoogle Scholar
  29. 29.
    Martinelli G, Oehler VG, Papayannidis C, Courtney R, Shaik MN, Zhang X, O’Connell A, McLachlan KR, Zheng X, Radich J, Baccarani M, Kantarjian HM, Levin WJ, Cortes JE, Jamieson C (2015) Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: a phase 1 safety and pharmacokinetics study. Lancet Haematol 2(8):e339–e346. CrossRefPubMedGoogle Scholar
  30. 30.
    Savona MR, Pollyea DA, Stock W, Oehler VG, Schroeder MA, Lancet J, McCloskey J, Kantarjian HM, Ma WW, Shaik MN, Laird AD, Zeremski M, O’Connell A, Chan G, Cortes JE (2018) Phase Ib study of glasdegib, a hedgehog pathway inhibitor, in combination with standard chemotherapy in patients with AML or high-risk MDS. Clin Cancer Res 24(10):2294–2303. CrossRefPubMedGoogle Scholar
  31. 31.
    Cortes JE, Heidel FH, Heuser M, Fiedler W, Smith BD, Robak T, Fernandez PM, Ma WW, Shaik MN, Zeremski M, O’Connell A, Chan G (2016) A phase 2 randomized study of low dose Ara-C with or without glasdegib (PF-04449913) in untreated patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood 128:99Google Scholar
  32. 32.
    Cortes JE, Douglas Smith B, Wang ES, Merchant A, Oehler VG, Arellano M, DeAngelo DJ, Pollyea DA, Sekeres MA, Robak T, Ma WW, Zeremski M, Naveed Shaik M, Douglas Laird A, O’Connell A, Chan G, Schroeder MA (2018) Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: phase 2 study results. Am J Hematol 93(11):1301–1310. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Harvey RA, Ferrier DR (2011) Biochemistry, 5th edn. Wolters Kluwer Health/Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  34. 34.
    Meisenberg G, Simmons WH (2012) Principles of medical biochemistry, 3rd edn. Elsevier/ Saunders, PhiladelphiaGoogle Scholar
  35. 35.
    Galmarini CM, Jordheim L, Dumontet C (2003) Role of IMP-selective 5′-nucleotidase (cN-II) in hematological malignancies. Leuk Lymphoma 44(7):1105–1111. CrossRefPubMedGoogle Scholar
  36. 36.
    Fasullo M, Endres L (2015) Nucleotide salvage deficiencies, DNA damage and neurodegeneration. Int J Mol Sci 16(5):9431–9449. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Sabini E, Ort S, Monnerjahn C, Konrad M, Lavie A (2003) Structure of human dCK suggests strategies to improve anticancer and antiviral therapy. Nat Struct Biol 10(7):513–519. CrossRefPubMedGoogle Scholar
  38. 38.
    Sabini E, Hazra S, Ort S, Konrad M, Lavie A (2008) Structural basis for substrate promiscuity of dCK. J Mol Biol 378(3):607–621. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Galmarini CM, Thomas X, Calvo F, Rousselot P, El Jafaari A, Cros E, Dumontet C (2002) Potential mechanisms of resistance to cytarabine in AML patients. Leuk Res 26(7):621–629CrossRefGoogle Scholar
  40. 40.
    Van Rompay AR, Johansson M, Karlsson A (2003) Substrate specificity and phosphorylation of antiviral and anticancer nucleoside analogues by human deoxyribonucleoside kinases and ribonucleoside kinases. Pharmacol Ther 100(2):119–139CrossRefGoogle Scholar
  41. 41.
    Bianchi V, Spychala J (2003) Mammalian 5′-nucleotidases. J Biol Chem 278(47):46195–46198. CrossRefGoogle Scholar
  42. 42.
    Vannoni D, Bernini A, Carlucci F, Civitelli S, Di Pietro MC, Leoncini R, Rosi F, Tabucchi A, Tanzini G, Marinello E (2004) Enzyme activities controlling adenosine levels in normal and neoplastic tissues. Med Oncol 21(2):187–195. CrossRefPubMedGoogle Scholar
  43. 43.
    Buckley RH, Schiff RI, Schiff SE, Markert ML, Williams LW, Harville TO, Roberts JL, Puck JM (1997) Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatr 130(3):378–387CrossRefGoogle Scholar
  44. 44.
    Sauer AV, Brigida I, Carriglio N, Aiuti A (2012) Autoimmune dysregulation and purine metabolism in adenosine deaminase deficiency. Front Immunol 3:265. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Carson DA, Wasson DB, Kaye J, Ullman B, Martin DW, Robins RK, Montgomery JA (1980) Deoxycytidine kinase-mediated toxicity of deoxyadenosine analogs toward malignant human lymphoblasts in vitro and toward murine L1210 leukemia in vivo. Proc Natl Acad Sci U S A 77(11):6865–6869CrossRefGoogle Scholar
  46. 46.
    Piro LD, Carrera CJ, Carson DA, Beutler E (1990) Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl J Med 322(16):1117–1121. CrossRefPubMedGoogle Scholar
  47. 47.
    Piro LD, Carrera CJ, Beutler E, Carson DA (1988) 2-Chlorodeoxyadenosine: an effective new agent for the treatment of chronic lymphocytic leukemia. Blood 72(3):1069–1073PubMedGoogle Scholar
  48. 48.
    Carson DA, Wasson DB, Beutler E (1984) Antileukemic and immunosuppressive activity of 2-chloro-2′-deoxyadenosine. Proc Natl Acad Sci U S A 81(7):2232–2236CrossRefGoogle Scholar
  49. 49.
    Santana VM, Mirro J, Harwood FC, Cherrie J, Schell M, Kalwinsky D, Blakley RL (1991) A phase I clinical trial of 2-chlorodeoxyadenosine in pediatric patients with acute leukemia. J Clin Oncol 9(3):416–422. CrossRefPubMedGoogle Scholar
  50. 50.
    Owen RP, Badagnani I, Giacomini KM (2006) Molecular determinants of specificity for synthetic nucleoside analogs in the concentrative nucleoside transporter, CNT2. J Biol Chem 281(36):26675–26682. CrossRefGoogle Scholar
  51. 51.
    Pastor-Anglada M, Molina-Arcas M, Casado FJ, Bellosillo B, Colomer D, Gil J (2004) Nucleoside transporters in chronic lymphocytic leukaemia. Leukemia 18(3):385–393. CrossRefPubMedGoogle Scholar
  52. 52.
    Lotfi K, Juliusson G, Albertioni F (2003) Pharmacological basis for cladribine resistance. Leuk Lymphoma 44(10):1705–1712. CrossRefPubMedGoogle Scholar
  53. 53.
    Johnston JB (2011) Mechanism of action of pentostatin and cladribine in hairy cell leukemia. Leuk Lymphoma 52(Suppl 2):43–45. CrossRefPubMedGoogle Scholar
  54. 54.
    Carson DA, Wasson DB, Taetle R, Yu A (1983) Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes. Blood 62(4):737–743PubMedGoogle Scholar
  55. 55.
    Griffig J, Koob R, Blakley RL (1989) Mechanisms of inhibition of DNA synthesis by 2-chlorodeoxyadenosine in human lymphoblastic cells. Cancer Res 49(24 Pt 1):6923–6928PubMedGoogle Scholar
  56. 56.
    Freyer CW, Gupta N, Wetzler M, Wang ES (2015) Revisiting the role of cladribine in acute myeloid leukemia: an improvement on past accomplishments or more old news? Am J Hematol 90(1):62–72. CrossRefPubMedGoogle Scholar
  57. 57.
    Schellens J, McLeod H, Newell D (2005) Cancer clinical pharmacology. 1st edn. Oxford University Press,Google Scholar
  58. 58.
    Hentosh P, Grippo P (1994) Template 2-chloro-2′-deoxyadenosine monophosphate inhibits in vitro DNA synthesis. Mol Pharmacol 45(5):955–961PubMedGoogle Scholar
  59. 59.
    Chunduru SK, Appleman JR, Blakley RL (1993) Activity of human DNA polymerases alpha and beta with 2-chloro-2′-deoxyadenosine 5′-triphosphate as a substrate and quantitative effects of incorporation on chain extension. Arch Biochem Biophys 302(1):19–30. CrossRefPubMedGoogle Scholar
  60. 60.
    Galmarini CM, Mackey JR, Dumontet C (2001) Nucleoside analogues: mechanisms of drug resistance and reversal strategies. Leukemia 15(6):875–890CrossRefGoogle Scholar
  61. 61.
    Valdez BC, Li Y, Murray D, Ji J, Liu Y, Popat U, Champlin RE, Andersson BS (2015) Comparison of the cytotoxicity of cladribine and clofarabine when combined with fludarabine and busulfan in AML cells: enhancement of cytotoxicity with epigenetic modulators. Exp Hematol 43(6):448–461.e442. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Warzocha K, Fabianowska-Majewska K, Bloński J, Krykowski E, Robak T (1997) 2-Chlorodeoxyadenosine inhibits activity of adenosine deaminase and S-adenosylhomocysteine hydrolase in patients with chronic lymphocytic leukaemia. Eur J Cancer 33(1):170–173CrossRefGoogle Scholar
  63. 63.
    Wyczechowska D, Fabianowska-Majewska K (2003) The effects of cladribine and fludarabine on DNA methylation in K562 cells. Biochem Pharmacol 65(2):219–225CrossRefGoogle Scholar
  64. 64.
    Genini D, Adachi S, Chao Q, Rose DW, Carrera CJ, Cottam HB, Carson DA, Leoni LM (2000) Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. Blood 96(10):3537–3543PubMedGoogle Scholar
  65. 65.
    Pettitt AR, Sherrington PD, Cawley JC (2000) Role of poly (ADP-ribosyl)ation in the killing of chronic lymphocytic leukemia cells by purine analogues. Cancer Res 60(15):4187–4193PubMedGoogle Scholar
  66. 66.
    Sigal DS, Miller HJ, Schram ED, Saven A (2010) Beyond hairy cell: the activity of cladribine in other hematologic malignancies. Blood 116(16):2884–2896. CrossRefPubMedGoogle Scholar
  67. 67.
    Petzer AL, Bilgeri R, Zilian U, Haun M, Geisen FH, Pragnell I, Braunsteiner H, Konwalinka G (1991) Inhibitory effect of 2-chlorodeoxyadenosine on granulocytic, erythroid, and T-lymphocytic colony growth. Blood 78(10):2583–2587PubMedGoogle Scholar
  68. 68.
    Plunkett W, Gandhi V, Kantarjian H, Keating M (1992) Pharmacologically guided leukemia therapy. In: Hiddemann W, Büchner T, Wörmann B et al (eds) Acute leukemias: pharmacokinetics and management of relapsed and refractory disease. Springer, BerlinGoogle Scholar
  69. 69.
    Kim MY, Ives DH (1989) Human deoxycytidine kinase: kinetic mechanism and end product regulation. Biochemistry 28(23):9043–9047CrossRefGoogle Scholar
  70. 70.
    Gandhi V, Estey E, Keating MJ, Plunkett W (1993) Biochemical modulation of arabinosylcytosine for therapy of leukemias. Leuk Lymphoma 10(Suppl):109–114. CrossRefPubMedGoogle Scholar
  71. 71.
    Gandhi V, Estey E, Keating MJ, Chucrallah A, Plunkett W (1996) Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogenous leukemia: pharmacokinetic, pharmacodynamic, and molecular interactions. Blood 87(1):256–264PubMedGoogle Scholar
  72. 72.
    Kornblau SM, Gandhi V, Andreeff HM, Beran M, Kantarjian HM, Koller CA, O’Brien S, Plunkett W, Estey E (1996) Clinical and laboratory studies of 2-chlorodeoxyadenosine +/- cytosine arabinoside for relapsed or refractory acute myelogenous leukemia in adults. Leukemia 10(10):1563–1569PubMedGoogle Scholar
  73. 73.
    Liliemark J (1997) The clinical pharmacokinetics of cladribine. Clin Pharmacokinet 32(2):120–131. CrossRefPubMedGoogle Scholar
  74. 74.
    Saven A, Cheung WK, Smith I, Moyer M, Johannsen T, Rose E, Gollard R, Kosty M, Miller WE, Piro LD (1996) Pharmacokinetic study of oral and bolus intravenous 2-chlorodeoxyadenosine in patients with malignancy. J Clin Oncol 14(3):978–983. CrossRefPubMedGoogle Scholar
  75. 75.
    Liliemark J, Albertioni F, Hassan M, Juliusson G (1992) On the bioavailability of oral and subcutaneous 2-chloro-2′-deoxyadenosine in humans: alternative routes of administration. J Clin Oncol 10(10):1514–1518. CrossRefPubMedGoogle Scholar
  76. 76.
    Albertioni F, Juliusson G, Liliemark J (1993) On the bioavailability of 2-chloro-2′-deoxyadenosine (CdA). The influence of food and omeprazole. Eur J Clin Pharmacol 44(6):579–582CrossRefGoogle Scholar
  77. 77.
    Lindemalm S, Liliemark J, Juliusson G, Larsson R, Albertioni F (2004) Cytotoxicity and pharmacokinetics of cladribine metabolite, 2-chloroadenine in patients with leukemia. Cancer Lett 210(2):171–177. CrossRefPubMedGoogle Scholar
  78. 78.
    Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P, Vermersch P, Chang P, Hamlett A, Musch B, Greenberg SJ, Group CS (2010) A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 362(5):416–426. CrossRefPubMedGoogle Scholar
  79. 79.
    Beutler E, Piro LD, Saven A, Kay AC, McMillan R, Longmire R, Carrera CJ, Morin P, Carson DA (1991) 2-Chlorodeoxyadenosine (2-CdA): a potent chemotherapeutic and immunosuppressive nucleoside. Leuk Lymphoma 5(1):1–8. CrossRefPubMedGoogle Scholar
  80. 80.
    Beutler E (1992) Cladribine (2-chlorodeoxyadenosine). Lancet 340(8825):952–956CrossRefGoogle Scholar
  81. 81.
    Liliemark J, Juliusson G (1991) On the pharmacokinetics of 2-chloro-2′-deoxyadenosine in humans. Cancer Res 51(20):5570–5572PubMedGoogle Scholar
  82. 82.
    Liliemark J, Juliusson G (1995) Cellular pharmacokinetics of 2-chloro-2′-deoxyadenosine nucleotides: comparison of intermittent and continuous intravenous infusion and subcutaneous and oral administration in leukemia patients. Clin Cancer Res 1(4):385–390PubMedGoogle Scholar
  83. 83.
    Chabner B, Longo D (2011) Cancer chemotherapy and biotherapy: principles and practice, 5th Edition edn. Wolters Kluwer/Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  84. 84.
    Juliusson G, Höglund M, Karlsson K, Löfgren C, Möllgård L, Paul C, Tidefelt U, Björkholm M, Sweden LGM (2003) Increased remissions from one course for intermediate-dose cytosine arabinoside and idarubicin in elderly acute myeloid leukaemia when combined with cladribine. A randomized population-based phase II study. Br J Haematol 123(5):810–818CrossRefGoogle Scholar
  85. 85.
    Saven A, Kawasaki H, Carrera CJ, Waltz T, Copeland B, Zyroff J, Kosty M, Carson DA, Beutler E, Piro LD (1993) 2-Chlorodeoxyadenosine dose escalation in nonhematologic malignancies. J Clin Oncol 11(4):671–678. CrossRefPubMedGoogle Scholar
  86. 86.
    Saven A, Piro LD (1993) Complete remissions in hairy cell leukemia with 2-chlorodeoxyadenosine after failure with 2′-deoxycoformycin. Ann Intern Med 119(4):278–283CrossRefGoogle Scholar
  87. 87.
    Santana VM, Mirro J, Kearns C, Schell MJ, Crom W, Blakley RL (1992) 2-Chlorodeoxyadenosine produces a high rate of complete hematologic remission in relapsed acute myeloid leukemia. J Clin Oncol 10(3):364–370. CrossRefPubMedGoogle Scholar
  88. 88.
    Vahdat L, Wong ET, Wile MJ, Rosenblum M, Foley KM, Warrell RP (1994) Therapeutic and neurotoxic effects of 2-chlorodeoxyadenosine in adults with acute myeloid leukemia. Blood 84(10):3429–3434PubMedGoogle Scholar
  89. 89.
    Holowiecki J, Robak T, Kyrcz-Krzemień S, Grosicki S, Wrzesień-Kus A, Hellmann A, Skotnicki A, Jędrzejczak W, Konopka L, Zdziarska B (2002) Daunorubicin, cytarabine and 2-CdA (DAC-7) for remission induction in “de novo” adult acute myeloid leukaemia patients. Evaluation of safety, tolerance and antileukemic activity. Acta Haematol Pol 33(2):239–247Google Scholar
  90. 90.
    Holowiecki J, Grosicki S, Robak T, Kyrcz-Krzemien S, Giebel S, Hellmann A, Skotnicki A, Jedrzejczak WW, Konopka L, Kuliczkowski K, Zdziarska B, Dmoszynska A, Marianska B, Pluta A, Zawilska K, Komarnicki M, Kloczko J, Sulek K, Haus O, Stella-Holowiecka B, Baran W, Jakubas B, Paluszewska M, Wierzbowska A, Kielbinski M, Jagoda K, (PALG) PALG (2004) Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study. Leukemia 18(5):989–997. CrossRefPubMedGoogle Scholar
  91. 91.
    Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszynska A, Kloczko J, Jedrzejczak WW, Zdziarska B, Warzocha K, Zawilska K, Komarnicki M, Kielbinski M, Piatkowska-Jakubas B, Wierzbowska A, Wach M, Haus O (2012) Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol 30(20):2441–2448. CrossRefPubMedGoogle Scholar
  92. 92.
    Appelbaum FR (2012) Haematological cancer: the rule of three in AML induction—is cladribine the answer? Nat Rev Clin Oncol 9(7):376–377. CrossRefPubMedGoogle Scholar
  93. 93.
    Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N, Okumura H, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R (2011) Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood 117(8):2358–2365. CrossRefPubMedGoogle Scholar
  94. 94.
    Libura M, Giebel S, Piatkowska-Jakubas B, Pawelczyk M, Florek I, Matiakowska K, Jazwiec B, Borg K, Solarska I, Zawada M, Czekalska S, Libura J, Jakobczyk M, Karabin K, Paluszewska M, Calbecka M, Gajkowska-Kulik J, Gadomska G, Kielbinski M, Ejduk A, Kata D, Grosicki S, Wierzbowska A, Kyrcz-Krzemien S, Warzocha K, Kuliczkowski K, Skotnicki A, Holowiecki J, Jedrzejczak WW, Haus O (2016) Cladribine added to daunorubicin-cytarabine induction prolongs survival of FLT3-ITD+ normal karyotype AML patients. Blood 127(3):360–362. CrossRefPubMedGoogle Scholar
  95. 95.
    Boddu P, Kantarjian HM, Ravandi F, Jabbour EJ, Daver N, Pemmaraju N, DiNardo CD, Verstovsek S, Alvarado Y, Borthakur G, Jain N, Konopleva M, Benton CB, Slack R, Patel KP, Garcia-Manero G, Cortes JE, Kadia T (2017) Outcomes by treatment setting and genomic profile in patients with AML on cladribine, idarubicin, and cytarabine. Blood 130:3898Google Scholar
  96. 96.
    Grosicki S, Kriegler M, Bodzenta E, Twardosz M, Szypula I, Fejklowicz M, Haus O, Kurzawa T, Barchnicka A (2012) Comparable toxicity and outcome of acute myeloid leukemia (AML) fit patients therapy independently if daunorubicin or idarubicin were added to cytarabine/cladribine induction regimens—the single centre study. Blood 120:4337Google Scholar
  97. 97.
    Schoen MW, Woelich SK, Braun JT, Fesler MJ, Petruska PJ, Freter CE, Lionberger JM (2016) Acute myeloid leukemia induction with cladribine: effects of age and leukemia risk. Blood 128:3988Google Scholar
  98. 98.
    Wiedower E, Jamy O, Martin MG (2015) Induction of acute myeloid leukemia with idarubicin, cytarabine and cladribine. Anticancer Res 35(11):6287–6290PubMedGoogle Scholar
  99. 99.
    Shen Y, Chen J, Liu Y, Wu D (2014) Addition of cladribine to idarubicin and cytarabine during induction increases the overall efficacy rate in adult patients with acute myeloid leukemia: a matched-pair retrospective comparison. Chemotherapy 60(5–6):368–374. CrossRefPubMedGoogle Scholar
  100. 100.
    Seligson ND, Hobbs ALV, Leonard JM, Mills EL, Evans AG, Goorha S (2018) Evaluating the impact of the addition of cladribine to standard acute myeloid leukemia induction therapy. Ann Pharmacother 52(5):439–445. CrossRefPubMedGoogle Scholar
  101. 101.
    Robak T, Wrzesień-Kuś A, Lech-Marańda E, Kowal M, Dmoszyńska A (2000) Combination regimen of cladribine (2-chlorodeoxyadenosine), cytarabine and G-CSF (CLAG) as induction therapy for patients with relapsed or refractory acute myeloid leukemia. Leuk Lymphoma 39(1–2):121–129. CrossRefPubMedGoogle Scholar
  102. 102.
    Wierzbowska A, Robak T, Pluta A, Wawrzyniak E, Cebula B, Hołowiecki J, Kyrcz-Krzemień S, Grosicki S, Giebel S, Skotnicki AB, Piatkowska-Jakubas B, Kuliczkowski K, Kiełbiński M, Zawilska K, Kłoczko J, Wrzesień-Kuś A, Group PAL (2008) Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol 80(2):115–126. CrossRefPubMedGoogle Scholar
  103. 103.
    Martin MG, Welch JS, Augustin K, Hladnik L, DiPersio JF, Abboud CN (2009) Cladribine in the treatment of acute myeloid leukemia: a single-institution experience. Clin Lymphoma Myeloma 9(4):298–301. CrossRefPubMedGoogle Scholar
  104. 104.
    Jaglal MV, Duong VH, Bello CM, Al Ali NH, Padron E, Fernandez HF, List AF, Lancet JE, Komrokji RS (2014) Cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) compared to standard induction in acute myeloid leukemia from myelodysplastic syndrome after azanucleoside failure. Leuk Res 38(4):443–446. CrossRefPubMedGoogle Scholar
  105. 105.
    Halpern AB, Othus M, Huebner EM, Scott BL, Becker PS, Percival MM, Hendrie PC, Gardner KM, Chen TL, Buckley SA, Orlowski KF, Anwar A, Appelbaum FR, Erba HP, Estey EH, Walter RB (2018) Phase 1/2 trial of GCLAM with dose-escalated mitoxantrone for newly diagnosed AML or other high-grade myeloid neoplasms. Leukemia 32:2352–2362. CrossRefGoogle Scholar
  106. 106.
    Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR (2013) A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood 121(24):4854–4860. CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Pluta A, Robak T, Wrzesien-Kus A, Katarzyna Budziszewska B, Sulek K, Wawrzyniak E, Czemerska M, Zwolinska M, Golos A, Holowiecka-Goral A, Kyrcz-Krzemien S, Piszcz J, Kloczko J, Mordak-Domagala M, Lange A, Razny M, Madry K, Wiktor-Jedrzejczak W, Grosicki S, Butrym A, Kuliczkowski K, Warzocha K, Holowiecki J, Giebel S, Szydlo R, Wierzbowska A (2017) Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly acute myeloid leukemia patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial. Am J Hematol 92(4):359–366. CrossRefPubMedGoogle Scholar
  108. 108.
    Kadia TM, Cortes J, Ravandi F, Jabbour E, Konopleva M, Benton CB, Burger J, Sasaki K, Borthakur G, DiNardo CD, Pemmaraju N, Daver N, Ferrajoli A, Wang X, Patel K, Jorgensen JL, Wang S, O’Brien S, Pierce S, Tuttle C, Estrov Z, Verstovsek S, Garcia-Manero G, Kantarjian H (2018) Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial. Lancet Haematol 5(9):e411–e421. CrossRefPubMedGoogle Scholar
  109. 109.
    Kadia T, Cortes J, Borthakur G, Jabbour E, Daver N, Pemmaraju N, Verstovsek S, Burger J, Ferrajoli A, Wierda W, Konopleva M, DiNardo C, Jain N, Brandt M, Tuttle C, Wang X, Ravandi F, Garcia-Manero G, Kantarjian H (2016) Phase II study of cladribine and low-dose araC alternating with decitabine in older patients with AML. EHA Learning Center:133175Google Scholar
  110. 110.
    Cladribine plus low dose cytarabine (LDAC) alternating with decitabine in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Identifier: NCT01515527 National Library of Medicine, USA.
  111. 111.
    Saven A, Burian C, Koziol JA, Piro LD (1998) Long-term follow-up of patients with hairy cell leukemia after cladribine treatment. Blood 92(6):1918–1926PubMedGoogle Scholar
  112. 112.
    Tadmor T (2011) Purine analog toxicity in patients with hairy cell leukemia. Leuk Lymphoma 52(Suppl 2):38–42. CrossRefPubMedGoogle Scholar
  113. 113.
    Giovannoni G, Soelberg Sorensen P, Cook S, Rammohan K, Rieckmann P, Comi G, Dangond F, Adeniji AK, Vermersch P (2018) Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: results from the randomized extension trial of the CLARITY study. Mult Scler 24(12):1594–1604. CrossRefPubMedGoogle Scholar
  114. 114.
    Lech-Maranda E, Seweryn M, Giebel S, Holowiecki J, Piatkowska-Jakubas B, Wegrzyn J, Skotnicki A, Kielbinski M, Kuliczkowski K, Paluszewska M, Jedrzejczak WW, Dutka M, Hellmann A, Flont M, Zdziarska B, Palynyczko G, Konopka L, Szpila T, Gawronski K, Sulek K, Sokolowski J, Kloczko J, Warzocha K, Robak T (2010) Infectious complications in patients with acute myeloid leukemia treated according to the protocol with daunorubicin and cytarabine with or without addition of cladribine. A multicenter study by the Polish Adult Leukemia Group (PALG). Int J Infect Dis 14(2):e132–e140. CrossRefPubMedGoogle Scholar
  115. 115.
    Jones G, Parry-Jones N, Wilkins B, Else M, Catovsky D, British Committee for Standards in Haematology (2012) Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant*. Br J Haematol 156(2):186–195. CrossRefPubMedGoogle Scholar
  116. 116.
    Maertens J, Cesaro S, Maschmeyer G, Einsele H, Donnelly JP, Alanio A, Hauser PM, Lagrou K, Melchers WJ, Helweg-Larsen J, Matos O, Bretagne S, Cordonnier C, 5th European Conference on Infections in Leukaemia (ECIL-5) ajvotEGfBaMTE, the European Organisation for Research and Treatment of Cancer (EORTC), the Immunocompromised Host Society (ICHS) and the European LeukemiaNet (ELN) (2016) ECIL guidelines for preventing pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients. J Antimicrob Chemother 71(9):2397–2404. CrossRefPubMedGoogle Scholar
  117. 117.
    Treleaven J, Gennery A, Marsh J, Norfolk D, Page L, Parker A, Saran F, Thurston J, Webb D (2011) Guidelines on the use of irradiated blood components prepared by the British Committee for Standards in Haematology Blood Transfusion Task Force. Br J Haematol 152(1):35–51. CrossRefPubMedGoogle Scholar
  118. 118.
    Ganzel C, Gatt ME, Maly A, Ben-Yehuda D, Goldschmidt N (2012) High incidence of skin rash in patients with hairy cell leukemia treated with cladribine. Leuk Lymphoma 53(6):1169–1173. CrossRefPubMedGoogle Scholar
  119. 119.
    Cheson BD, Vena DA, Foss FM, Sorensen JM (1994) Neurotoxicity of purine analogs: a review. J Clin Oncol 12(10):2216–2228. CrossRefPubMedGoogle Scholar
  120. 120.
    Pakpoor J, Disanto G, Altmann DR, Pavitt S, Turner BP, Marta M, Juliusson G, Baker D, Chataway J, Schmierer K (2015) No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol Neuroimmunol Neuroinflamm 2(6):e158. CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Decitabine, filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride in treating patients with newly diagnosed, relapsed, or refractory acute myeloid leukemia or high-risk myelodysplastic syndrome. Identifier: NCT02921061.
  122. 122.
    Filgrastim, cladribine, cytarabine, and mitoxantrone with sorafenib tosylate in treating patients with newly-diagnosed, acute myeloid leukemia or high-risk myelodysplastic syndrome. Identifier: NCT02728050.
  123. 123.
    Cladribine plus idarubicin plus cytarabine (ARAC) in patients with acute myeloid leukemia (AML), high risk myelodysplastic syndrome (HR MDS) or myeloid blast phase of chronic myeloid leukemia (CML). Identifier: NCT02115295.
  124. 124.
    4-Arm phase II study of SGI-110 in elderly acute myeloid leukemia (AML). Identifier: NCT02096055
  125. 125.
    Higher or lower dose cladribine, cytarabine, and mitoxantrone in treating medically less fit patients with newly diagnosed acute myeloid leukemia or myeloid neoplasm. Identifier: NCT03012672
  126. 126.
    Idarubicin plus cytarabine (IA) vs IA plus cladribine (IAC) as induction regimen to treat initially diagnosed acute myeloid leukemia (AML). Identifier: NCT02323022
  127. 127.
    A PALG prospective multicenter clinical trial to compare the efficacy of two standard induction therapies (DA-90 vs DAC) and two standard salvage regimens (FLAG-IDA vs CLAG-M) in AML patients ≤ 60 years old (PALG-AML1/2016)

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Hematology and Blood & Marrow Transplant, Markey Cancer Center, College of MedicineUniversity of KentuckyLexingtonUSA
  2. 2.Department of Internal Medicine, School of MedicineUniversity of Missouri-Kansas CityKansas CityUSA
  3. 3.Walmart PharmacyRoeland ParkUSA
  4. 4.NCI Community Oncology Research Program - Kansas City (NCORP-KC)Prairie VillageUSA
  5. 5.KIM Cancer and Blood CenterLenexaUSA

Personalised recommendations