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Review

Emerging alternatives to tyrosine kinase inhibitors for treating chronic myeloid leukemia

, &
Pages 51-62 | Received 13 Nov 2017, Accepted 22 Feb 2018, Published online: 03 Mar 2018

References

  • National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts - Chronic Myeloid Leukemia. 2017, Sept 14. Available from: https://seer.cancer.gov/statfacts/html/cmyl.html (Accessed December 18, 2017)
  • Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–2405.
  • Cilloni D, Saglio G. Molecular pathways: BCR-ABL. Clin Cancer Res. 2012;18(4):930–937.
  • Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov. 2014;13(2):140–156.
  • Giles FJ, Cortes JE, Kantarjian HM, et al. Accelerated and blastic phases of chronic myelogenous leukemia. Hematol Oncol Clin North Am. 2004;18(3):753–774.
  • Fabarius A, Leitner A, Hochhaus A, et al. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood. 2011;118(26):6760–6768.
  • Kantarjian HM, Smith TL, McCredie KB, et al. Chronic myelogenous leukemia: a multivariate analysis of the associations of patient characteristics and therapy with survival. Blood. 1985;66(6):1326–1335.
  • Sokal JE, Gomez GA, Baccarani M, et al. Prognostic significance of additional cytogenetic abnormalities at diagnosis of Philadelphia chromosome-positive chronic granulocytic leukemia. Blood. 1988;72(1):294–298.
  • Luatti S, Castagnetti F, Marzocchi G, et al. Additional chromosomal abnormalities in Philadelphia-positive clone: adverse prognostic influence on frontline imatinib therapy: a GIMEMA Working Party on CML analysis. Blood. 2012;120(4):761–767.
  • Chen Z, Cortes JE, Jorgensen JL, et al. Differential impact of additional chromosomal abnormalities in myeloid vs lymphoid blast phase of chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Leukemia. 2016;30(7):1606–1609.
  • Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–884.
  • Arun AK, Senthamizhselvi A, Mani S, et al. Frequency of rare BCR-ABL1 fusion transcripts in chronic myeloid leukemia patients. Int J Lab Hematol. 2017;39(3):235–242.
  • Verma D, Kantarjian HM, Jones D, et al. Chronic myeloid leukemia (CML) with P190BCR-ABL: analysis of characteristics, outcomes, and prognostic significance. Blood. 2009;114(11):2232–2235.
  • Castagnetti F, Gugliotta G, Breccia M, et al. The BCR-ABL1 transcript type influences response and outcome in Philadelphia chromosome-positive chronic myeloid leukemia patients treated frontline with imatinib. Am J Hematol. 2017;92(8):797–805.
  • National Comprehensive Cancer Network. National Comprehensive Cancer Network. 2017, Nov 2. Available from https://www.nccn.org/ (Accessed December 18, 2017).
  • O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994–1004.
  • Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119(5):1123–1129.
  • Milojkovic D, Apperley J. Mechanisms of resistance to imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia. Clin Cancer Res. 2009;15(24):7519–7527.
  • Verma D, Kantarjian H, Shan J, et al. Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy. Cancer. 2010;116(11):2673-2681.
  • Chen Z, Shao C, Wang W, et al. Cytogenetic landscape and impact in blast phase of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Leukemia. 2017;31(3):585–592.
  • Marcé S, Zamora L, Cabezón M, et al. Frequency of ABL gene mutations in chronic myeloid leukemia patients resistant to imatinib and results of treatment switch to second-generation tyrosine kinase inhibitors. Med Clínica. 2013;141(3):95–99.
  • Soverini S, Colarossi S, Gnani A, et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res. 2006;12(24):7374–7379.
  • O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16(5):401–412.
  • Marcucci G, Perrotti D, Caligiuri MA. Understanding the molecular basis of imatinib mesylate therapy in chronic myelogenous leukemia and the related mechanisms of resistance: commentary re: A. N. Mohamed et al., the effect of imatinib mesylate on patients with Philadelphia chromosome-positive chronic myeloid leukemia with secondary chromosomal aberrations. Clin. Cancer Res., 9: 1333–1337, 2003. Clin Cancer Res. 2003;9(4):1248–1252.
  • Hochhaus A. Educational session: managing chronic myeloid leukemia as a chronic disease. ASH Educ Program Book. 2011;2011(1):128–135.
  • Hughes T, White D. Which TKI? An embarrassment of riches for chronic myeloid leukemia patients. ASH Educ Program Book. 2013;2013(1):168–175.
  • Larson RA. Is there a best TKI for chronic phase CML? Blood. 2015;126(21):2370–2375.
  • Pasic I, Lipton JH. Current approach to the treatment of chronic myeloid leukaemia. Leuk Res. 2017;55:65–78.
  • Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031–1037.
  • Innes AJ, Milojkovic D, Apperley JF. Allogeneic transplantation for CML in the TKI era: striking the right balance. Nat Rev Clin Oncol. 2016;13(2):79–91.
  • Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome–positive leukemias. N Engl J Med. 2006;354(24):2531–2541.
  • Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260–2270.
  • Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34(20):2333–2340.
  • Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110(10):3540–3546.
  • Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251–2259.
  • Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044–1054.
  • Larson RA, Kim D-W, Issaragrilsil S, et al. Efficacy and safety of nilotinib (NIL) vs imatinib (IM) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): long-term follow-up (f/u) of ENESTnd. Blood. 2014;124(21):4541.
  • Cortes JE, Kim D-W, Kantarjian HM, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012;30(28):3486–3492.
  • Cortes JE, Gambacorti-Passerini C, Deininger MWN, et al. Bosutinib (BOS) versus imatinib (IM) for newly diagnosed chronic myeloid leukemia (CML): initial results from the BFORE trial. J Clin Oncol. 2017;35(15_suppl):7002.
  • Brümmendorf TH, Cortes JE, De Souza CA, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol. 2015;168(1):69–81.
  • Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome–positive leukemias. N Engl J Med. 2012;367(22):2075–2088.
  • Lipton JH, Chuah C, Guerci-Bresler A, et al. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(5):612–621.
  • Dorer DJ, Knickerbocker RK, Baccarani M, et al. Impact of dose intensity of ponatinib on selected adverse events: multivariate analyses from a pooled population of clinical trial patients. Leuk Res. 2016;48:84–91.
  • Biron CA. Interferons α and β as immune regulators – a new look. Immunity. 2001;14(6):661–664.
  • Platanias LC. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol. 2005;5(5):375–386.
  • Bonifazi F. Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood. 2001;98(10):3074–3081.
  • Kantarjian HM, O’Brien S, Cortes JE, et al. Complete cytogenetic and molecular responses to interferon-α-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer. 2003;97(4):1033–1041.
  • Sleijfer S, Bannink M, Gool AR, et al. Side effects of interferon-α therapy. Pharm World Sci. 2005;27(6):423–431.
  • Lipton JH, Khoroshko N, Golenkov A, et al. Phase II, randomized, multicenter, comparative study of peginterferon–α–2a (40 kD) (Pegasys®) versus interferon α-2a (Roferon®-A) in patients with treatment-naïve, chronic-phase chronic myelogenous leukemia. Leuk Lymphoma. 2007;48(3):497–505.
  • Pye SM, Cortes J, Ault P, et al. The effects of imatinib on pregnancy outcome. Blood. 2008;111(12):5505–5508.
  • Cortes JE, Abruzzese E, Chelysheva E, et al. The impact of dasatinib on pregnancy outcomes. Am J Hematol. 2015;90(12):1111–1115.
  • Cortes JE, Nicolini FE, Wetzler M, et al. Subcutaneous omacetaxine mepesuccinate in patients with chronic-phase chronic myeloid leukemia previously treated with 2 or more tyrosine kinase inhibitors including imatinib. Clin Lymphoma Myeloma Leuk. 2013;13(5):584–591.
  • Kantarjian HM, O’Brien S, Cortes J, et al. Results of decitabine (5-aza-2′deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer. 2003;98(3):522–528.
  • Issa J-PJ, Gharibyan V, Cortes J, et al. Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol. 2005;23(17):3948–3956.
  • Oki Y, Kantarjian HM, Gharibyan V, et al. Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia. Cancer. 2007;109(5):899–906.
  • Gorkin L, Kantarjian H. Targeted therapy: generic imatinib – impact on frontline and salvage therapy for CML. Nat Rev Clin Oncol. 2016;13(5):270–272.
  • Chen CT, Kesselheim AS. Journey of generic imatinib: a case study in oncology drug pricing. J Oncol Pract. 2017;13(6):352–355.
  • Padula WV, Larson RA, Dusetzina SB, et al. Cost-effectiveness of tyrosine kinase inhibitor treatment strategies for chronic myeloid leukemia in chronic phase after generic entry of imatinib in the United States. J Natl Cancer Inst. 2016;108(7):djw003.
  • Conti RM, Padula WV, Larson RA. Changing the cost of care for chronic myeloid leukemia: the availability of generic imatinib in the USA and the EU. Ann Hematol. 2015;94(0 2):S249–S257.
  • Ren R. Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005;5(3):172–183.
  • Corbin AS, Agarwal A, Loriaux M, et al. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest. 2011;121(1):396–409.
  • Mahon F-X, Réa D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11(11):1029–1035.
  • Ross DM, Branford S, Seymour JF, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013;122(4):515–522.
  • Etienne G, Guilhot J, Rea D, et al. Long-term follow-up of the French Stop Imatinib (STIM1) study in patients with chronic myeloid leukemia. J Clin Oncol. 2016;35(3):298–305.
  • Gale RP. Identical-twin bone marrow transplants for leukemia. Ann Int Med. 1994;120(8):646.
  • Wylie AA, Schoepfer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1. Nature. 2017;543(7647):733–737.
  • Qiang W, Antelope O, Zabriskie MS, et al. Mechanisms of resistance to the BCR-ABL1 allosteric inhibitor asciminib. Leukemia. 2017 Dec;31(12):2844-2847.
  • Lipton JH, Bryden P, Sidhu MK, et al. Comparative efficacy of tyrosine kinase inhibitor treatments in the third-line setting, for chronic-phase chronic myelogenous leukemia after failure of second-generation tyrosine kinase inhibitors. Leuk Res. 2015;39(1):58–64.
  • Preudhomme C, Guilhot J, Nicolini FE, et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010;363(26):2511–2521.
  • Simonsson B, Gedde-Dahl T, Markevarn B, et al. Combination of pegylated IFN- 2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia. Blood. 2011;118(12):3228–3235.
  • Hehlmann R, Lauseker M, Jung-Munkwitz S, et al. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia. j clin oncol. 2011;29(12):1634–1642.
  • Hehlmann R, Müller MC, Lauseker M, et al. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J Clin Oncol. 2014;32(5):415–423.
  • Cortes J, Quintás-Cardama A, Jones D, et al. Immune modulation of minimal residual disease in early chronic phase chronic myelogenous leukemia: a randomized trial of frontline high-dose imatinib mesylate with or without pegylated interferon alpha-2b and granulocyte-macrophage colony-stimulatin. Cancer. 2011;117(3):572–580.
  • Nicolini FE, Etienne G, Dubruille V, et al. Nilotinib and peginterferon alfa-2a for newly diagnosed chronic-phase chronic myeloid leukaemia (NiloPeg): a multicentre, non-randomised, open-label phase 2 study. Lancet Haematol. 2015;2(1):e37–e46.
  • Bailey CP, Budak-Alpdogan T, Sauter CT, et al. New interleukin-15 superagonist (IL-15SA) significantly enhances graft-versus-tumor activity. Oncotarget. 2017;8(27):44366–44378.
  • Miller JS, Cooley S, Holtan S, et al. “First-in-human” phase I dose escalation trial of IL-15N72D/IL-15Rα-Fc superagonist complex (ALT-803) demonstrates immune activation with anti-tumor activity in patients with relapsed hematological malignancy. Blood. 2015;126(23):1957.
  • Sakamoto C, Kohara H, Inoue H, et al. Therapeutic vaccination based on side population cells transduced by the granulocyte–macrophage colony-stimulating factor gene elicits potent antitumor immunity. Cancer Gene Ther. 2017;24(4):165–174.
  • Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A. 1993;90(8):3539–3543.
  • Dunussi-Joannopoulos K, Dranoff G, Weinstein HJ, et al. Gene immunotherapy in murine acute myeloid leukemia: granulocyte-macrophage colony-stimulating factor tumor cell vaccines elicit more potent antitumor immunity compared with B7 family and other cytokine vaccines. Blood. 1998;91(1):222–230.
  • Smith BD, Kasamon YL, Kowalski J, et al. K562/GM-CSF immunotherapy reduces tumor burden in chronic myeloid leukemia patients with residual disease on imatinib mesylate. Clin Cancer Res Off J Am Assoc Cancer Res. 2010;16(1):338–347.
  • Qin L, Smith BD, Tsai H-L, et al. Induction of high-titer IgG antibodies against multiple leukemia-associated antigens in CML patients with clinical responses to K562/GVAX immunotherapy. Blood Cancer J. 2013;3(9):e145.
  • Wang Y, Trepel JB, Neckers LM, et al. STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer. Curr Opin Invest Drugs Lond Engl 2000. 2010;11(12):1466–1476.
  • Ying W, Du Z, Sun L, et al. Ganetespib, a unique triazolone-containing hsp90 inhibitor, exhibits potent antitumor activity and a superior safety profile for cancer therapy. Mol Cancer Ther. 2012;11(2):475.
  • Bali P, Pranpat M, Bradner J, et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem. 2005;280(29):26729–26734.
  • Matsuda Y, Yamauchi T, Hosono N, et al. Combination of panobinostat with ponatinib synergistically overcomes imatinib-resistant CML cells. Cancer Sci. 2016;107(7):1029–1038.
  • Baines AT, Xu D, Der CJ. Inhibition of Ras for cancer treatment: the search continues. Future Med Chem. 2011;3(14):1787–1808.
  • Athuluri-Divakar SK, Carpio RV-D, Dutta K, et al. A small molecule RAS-mimetic disrupts RAS association with effector proteins to block signaling. Cell. 2016;165(3):643–655.
  • Liu X. Targeting polo-like kinases: a promising therapeutic approach for cancer treatment. Transl Oncol. 2015;8(3):185–195.
  • Okabe S, Tauchi T, Tanaka Y, et al. Efficacy of the polo-like kinase inhibitor rigosertib, alone or in combination with Abelson tyrosine kinase inhibitors, against break point cluster region-c-Abelson-positive leukemia cells. Oncotarget. 2015;6(24):20231–20240.
  • Garcia-Manero G, Fenaux P, Al-Kali A, et al. Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial. Lancet Oncol. 2016;17(4):496–508.
  • Wang Y, Krivtsov AV, Sinha AU, et al. The Wnt/β-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010;327(5973):1650–1653.
  • Zhao C, Blum J, Chen A, et al. Loss of β-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007;12(6):528–541.
  • Heidel FH, Bullinger L, Feng Z, et al. Genetic and pharmacologic inhibition of β-catenin targets imatinib resistant leukemia stem cells in CML. Cell Stem Cell. 2012;10(4):412–424.
  • Zhang B, Li M, McDonald T, et al. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt–β-catenin signaling. Blood. 2013;121(10):1824–1838.
  • El-Khoueiry AB, Ning Y, Yang D, et al. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors. J Clin Oncol. 2013;31(15_suppl):2501–2501.
  • Zhou H, Mak PY, Mu H, et al. Combined inhibition of β-catenin and Bcr–abl synergistically targets tyrosine kinase inhibitor-resistant blast crisis chronic myeloid leukemia blasts and progenitors in vitro and in vivo. Leukemia. 2017 Oct;31(10):2065-2074.
  • Lin M-L, Park J-H, Nishidate T, et al. Involvement of maternal embryonic leucine zipper kinase (MELK) in mammary carcinogenesis through interaction with Bcl-G, a pro-apoptotic member of the Bcl-2 family. Breast Cancer Res BCR. 2007;9(1):R17.
  • Nakano I, Masterman-Smith M, Saigusa K, et al. Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells. J Neurosci Res. 2008;86(1):48–60.
  • Gray D, Jubb AM, Hogue D, et al. Maternal embryonic leucine zipper kinase/murine protein serine-threonine kinase 38 is a promising therapeutic target for multiple cancers. Cancer Res. 2005;65(21):9751–9761.
  • Alachkar H, Mutonga MBG, Metzeler KH, et al. Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia. Oncotarget. 2014;5(23):12371–12382.
  • Rajan AM, Kumar S. New investigational drugs with single-agent activity in multiple myeloma. Blood Cancer J. 2016;6(7):e451.
  • Tunquist BJ, Woessner RD, Walker DH. Mcl-1 stability determines mitotic cell fate of human multiple myeloma tumor cells treated with the kinesin spindle protein inhibitor ARRY-520. Mol Cancer Ther. 2010;9(7):2046–2056.
  • Aichberger KJ, Mayerhofer M, Krauth M-T, et al. Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides. Blood. 2005;105(8):3303–3311.
  • Yin Y, Sun H, Xu J, et al. Kinesin spindle protein inhibitor SB743921 induces mitotic arrest and apoptosis and overcomes imatinib resistance of chronic myeloid leukemia cells. Leuk Lymphoma. 2015;56(6):1813–1820.
  • Saußele S, Richter J, Hochhaus A, et al. The concept of treatment-free remission in chronic myeloid leukemia. Leukemia. 2016;30(8):1638–1647.
  • Ji Y, Wang S-J. Modified toxicity probability interval design: a safer and more reliable method than the 3 + 3 design for practical phase I trials. J Clin Oncol. 2013;31(14):1785–1791.
  • Rousselot P, Prost S, Guilhot J, et al. Pioglitazone together with imatinib in chronic myeloid leukemia: a proof of concept study. Cancer. 2017;123(10):1791–1799.
  • Wang Z, Liu Z, Wu X, et al. ATRA-induced cellular differentiation and CD38 expression inhibits acquisition of BCR-ABL mutations for CML acquired resistance. PLoS Genet. 2014;10(6):e1004414.
  • Quintarelli C, De Angelis B, Errichiello S, et al. Selective strong synergism of Ruxolitinib and second generation tyrosine kinase inhibitors to overcome bone marrow stroma related drug resistance in chronic myelogenous leukemia. Leuk Res. 2014;38(2):236–242.

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