Vorinostat Combined With Gemtuzumab Ozogamicin, Idarubicin and Cytarabine in Acute Myeloid Leukemia

Summary

The prognosis of elderly patients with relapsed or refractory acute myeloid leukemia (AML) is grave. Because of their chronological age and/or the presence of multiple co-morbidities, treatment-related mortality in elderly patients with AML is quite high although higher intensive treatment is mandatory to overcome chemoresistant characteristic of their disease. Several regimens have been evaluated as salvage chemotherapy for relapsed or refractory AML such as Mitoxantrone/High dose Cytarabine or Amsacrine/High dose Cytarabine. These regimens could achieve complete remission (CR) in a part of patients, but resulted in higher treatment related mortality (TRM). Accordingly, less intensive salvage regimen is needed for elderly patients with relapsed or refractory AML. The activity of histone deacetylase (HDAC) inhibitor, Vorinostat or Suberoylanilide hydroxamic acid (SAHA), against AML has been suggested in cell line models and in animal model as well as in a phase 1 trial. The phase 1 study determined the MTD of oral Vorinostat as 200mg twice daily or 250mg thrice daily. In addition, the phase 1 trial showed the antitumor activity of Vorinostat with 17% of response rate in patients with advanced leukemia or myelodysplastic syndrome (MDS). Accordingly, further study is recommended to demonstrate the clinical activity of Vorinostat in AML. In terms of the combining drug with Vorinostat, anthracycline is one of the best candidate. A in vitro study demonstrated that the combination of anthracycline (esp. idarubicin) with HDAC inhibitor have significant clinical activity against leukemia. Another candidate is Gemtuzumab ozogamicin, which is a calicheamicin-conjugated antibody directed against CD33 antigen on AML blasts. The U.S. FDA also approved the use of GO in relapsed AML as a monotherapy. A study also showed that the combinational therapy of GO with attenuated doses of standard induction chemotherapy could successfully induce CR without increasing treatment-related mortality in AML patients aged 55 or older. A in vitro study reported that HDAC inhibitor valproic acid augmented the clinical activity of GO toward CD33+ AML cells. The study demonstrated that the strategy using HDAC inhibitor together with GO could potentially induce synergistic proapoptotic activity against AML blasts without increasing toxicity. In our center, so far we treated relapsed or refractory AML patients using the salvage regimen including GO (3mg/m2/dayx1day) plus attenuated Idarubicin/Cytarabine (Idarubicin 12mg/m2/day for 2 days and intermediate dose Cytarabine). So far, the CR rate from the regimen is around 50% without increasing TRM. Accordingly, we will determine the efficacy and toxicity of Vorinostat-incorporating salvage regimen based on the GO+IA chemotherapy in patients 50 years old or older with relapsed or refractory AML.

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Publications

• Background Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG, Faderl S, Koller C, Morris G, Rosner G, Loboda A, Fantin VR, Randolph SS, Hardwick JS, Reilly JF, Chen C, Ricker JL, Secrist JP, Richon VM, Frankel SR, Kantarjian HM. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 2008 Feb 1;111(3):1060-6. doi: 10.1182/blood-2007-06-098061. Epub 2007 Oct 25.
• Background Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, Roy S, Sridhara R, Rahman A, Williams G, Pazdur R. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001 Jun;7(6):1490-6.
• Background Eom KS, Kim HJ, Min WS, Lee S, Min CK, Cho BS, Kim SY, Kim YJ, Lee DG, Choi SM, Cho SG, Kim DW, Lee JW, Shin WS, Kim CC. Gemtuzumab ozogamicin in combination with attenuated doses of standard induction chemotherapy can successfully induce complete remission without increasing toxicity in patients with acute myeloid leukemia aged 55 or older. Eur J Haematol. 2007 Nov;79(5):398-404. doi: 10.1111/j.1600-0609.2007.00946.x. Epub 2007 Oct 4.
• Background Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov. 2002 Apr;1(4):287-99. doi: 10.1038/nrd772.
• Background Nimmanapalli R, Fuino L, Stobaugh C, Richon V, Bhalla K. Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood. 2003 Apr 15;101(8):3236-9. doi: 10.1182/blood-2002-08-2675. Epub 2002 Nov 21.
• Background Sanchez-Gonzalez B, Yang H, Bueso-Ramos C, Hoshino K, Quintas-Cardama A, Richon VM, Garcia-Manero G. Antileukemia activity of the combination of an anthracycline with a histone deacetylase inhibitor. Blood. 2006 Aug 15;108(4):1174-82. doi: 10.1182/blood-2005-09-008086. Epub 2006 May 4.
• Background ten Cate B, Samplonius DF, Bijma T, de Leij LF, Helfrich W, Bremer E. The histone deacetylase inhibitor valproic acid potently augments gemtuzumab ozogamicin-induced apoptosis in acute myeloid leukemic cells. Leukemia. 2007 Feb;21(2):248-52. doi: 10.1038/sj.leu.2404477. Epub 2006 Nov 23.

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