International Journal of Hematology

, Volume 99, Issue 3, pp 272–278 | Cite as

Phase I study of cladribine, cytarabine, granulocyte colony stimulating factor (CLAG regimen) and midostaurin and all-trans retinoic acid in relapsed/refractory AML

  • Giridharan Ramsingh
  • Peter Westervelt
  • Ali McBride
  • Keith Stockerl-Goldstein
  • Ravi Vij
  • Mark Fiala
  • Geoffrey Uy
  • Amanda Cashen
  • John F. DiPersio
  • Camille N. Abboud
Original Article


We conducted a phase I study using midostaurin (25 or 50 mg orally twice daily), all-trans retinoic acid (ATRA) and CLAG chemotherapy to target multiple pathways in relapsed/refractory AML. 10 patients received the combination and no dose-limiting toxicities were observed. Two patients (22 %) achieved complete remission and 1 patient (11 %) achieved complete remission with incomplete count recovery. Pharmacokinetic data showed that the 25 mg dosing of midostaurin achieved therapeutic levels with no significant interaction between midostaurin and ATRA. With evidence of activity of ATRA in NPM1-mutated AML and midostaurin in FLT3-ITD AML, this combination warrants further investigation.


AML Midostaurin ATRA Phase I Targeted therapy CLAG 



Acute myelogenous leukemia


Cladribine 5 mg/m2 given intravenously on days 2–6, Ara-C 2 g/m2 given intravenously on days 2–6, G-CSF 300 μg given subcutaneously on days 1–6


All-trans retinoic acid


Institute for Clinical and Translational Science




Granulocyte colony stimulating factor


Myelodysplastic syndrome


Complete remission


Partial remission


Complete remission with incomplete count recovery


Maximum tolerated dose


Dose-limiting toxicity


Conflict of interest

C.N.A. obtained research support for this study from Novartis and serves in the advisory board for Novartis.


  1. 1.
    Kornblau SM, Womble M, Qiu YH, Jackson CE, Chen W, Konopleva M, et al. Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia. Blood. 2006;108(7):2358–65.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Price SL, Lancet JE, George TJ, Wetzstein GA, List AF, Ho VQ, et al. Salvage chemotherapy regimens for acute myeloid leukemia: is one better? Efficacy comparison between CLAG and MEC regimens. Leuk Res. 2011;35(3):301–4.PubMedCrossRefGoogle Scholar
  3. 3.
    Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, et al. 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. 2012;30(20):2441–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Walker AR, Komrokji RS, Ifthikharuddin J, Messina P, Mulford D, Becker M, et al. Phase I study of cladribine, cytarabine (Ara-C), granulocyte colony stimulating factor (G-CSF) (CLAG Regimen) and simultaneous escalating doses of imatinibmesylate (Gleevec) in relapsed/refractory AML. Leuk Res. 2008;32(12):1830–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Santos FP, Jones D, Qiao W, Cortes JE, Ravandi F, Estey EE, et al. Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia. Cancer. 2011;117(10):2145–55.PubMedCrossRefGoogle Scholar
  6. 6.
    Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood. 2010;116(24):5089–102.PubMedCrossRefGoogle Scholar
  7. 7.
    Fabbro D, Ruetz S, Bodis S, Pruschy M, Csermak K, Man A, et al. PKC412—a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des. 2000;15(1):17–28.PubMedGoogle Scholar
  8. 8.
    Millward MJ, House C, Bowtell D, Webster L, Olver IN, Gore M, et al. The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. Br J Cancer. 2006;95(7):829–34.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, et al. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(28):4339–45.CrossRefGoogle Scholar
  10. 10.
    Stone RM, Fischer T, Paquette R, Schiller G, Schiffer CA, Ehninger G, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia Off J Leuk Soc Am Leuk Res Fund UK. 2012;26(9):2061–8.CrossRefGoogle Scholar
  11. 11.
    Manfredini R, Trevisan F, Grande A, Tagliafico E, Montanari M, Lemoli R, et al. Induction of a functional vitamin D receptor in all-trans-retinoic acid-induced monocytic differentiation of M2-type leukemic blast cells. Cancer Res. 1999;59(15):3803–11.PubMedGoogle Scholar
  12. 12.
    Delia D, Aiello A, Soligo D, Fontanella E, Melani C, Pezzella F, et al. bcl-2 proto-oncogene expression in normal and neoplastic human myeloid cells. Blood. 1992;79(5):1291–8.PubMedGoogle Scholar
  13. 13.
    Freund A, Rossig C, Lanvers C, Gescher A, Hohenlochter B, Jurgens H, et al. All-trans-retinoic acid increases cytosine arabinoside cytotoxicity in HL-60 human leukemia cells in spite of decreased cellular ara-CTP accumulation. Ann Oncol Off J Eur Soc Med Oncol ESMO. 1999;10(3):335–8.CrossRefGoogle Scholar
  14. 14.
    Scholl S, Muller R, Clement JH, Loncarevic IF, Bohmer FD, Hoffken K. ATRA can enhance apoptosis that is induced by Flt3 tyrosine kinase inhibition in Flt3-ITD positive cells. Leuk Res. 2006;30(5):633–42.PubMedCrossRefGoogle Scholar
  15. 15.
    Di Noto R, Schiavone EM, Lo Pardo C, Ferrara F, Manzo C, Vacca C, et al. Differential regulation of GPI-linked molecules on leukaemic promyelocytes treated in vitro with all-trans retinoic acid. Br J Haematol. 1996;93(2):392–3.PubMedCrossRefGoogle Scholar
  16. 16.
    Nwajei F, Konopleva M. The bone marrow microenvironment as niche retreats for hematopoietic and leukemic stem cells. Adv Hematol. 2013;2013:953–82.CrossRefGoogle Scholar
  17. 17.
    Schlenk RF, Frohling S, Hartmann F, Fischer JT, Glasmacher A, del Valle F, et al. Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia Off J Leuk Soc Am Leuk Res Fund UK. 2004;18(11):1798–803.CrossRefGoogle Scholar
  18. 18.
    Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. 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. 2003;21(24):4642–9.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2014

Authors and Affiliations

  • Giridharan Ramsingh
    • 1
  • Peter Westervelt
    • 2
  • Ali McBride
    • 3
    • 4
  • Keith Stockerl-Goldstein
    • 2
  • Ravi Vij
    • 2
  • Mark Fiala
    • 2
  • Geoffrey Uy
    • 2
  • Amanda Cashen
    • 2
  • John F. DiPersio
    • 2
  • Camille N. Abboud
    • 2
  1. 1.Jane Anne Nohl Division of Hematology, Department of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.Section BMT and Leukemia, Division of OncologyWashington University School of MedicineSt LouisUSA
  3. 3.Department of PharmacyThe University of Arizona Cancer CenterTucsonUSA
  4. 4.The University of Arizona College of PharmacyTucsonUSA

Personalised recommendations