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Published in: Journal of Cancer Research and Clinical Oncology 6/2011

01-06-2011 | Original Paper

Low dose of homoharringtonine and cytarabine combined with granulocyte colony-stimulating factor priming on the outcome of relapsed or refractory acute myeloid leukemia

Authors: Liu-Fang Gu, Wang-Gang Zhang, Fang-Xia Wang, Xing-Mei Cao, Yin-Xia Chen, Ai-Li He, Jie Liu, Xiao-Rong Ma

Published in: Journal of Cancer Research and Clinical Oncology | Issue 6/2011

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Abstract

Background

To explore the effect of low dose of homoharringtonine (HHT) and cytarabine (Ara-c) combined with granulocyte colony-stimulating factor (G-CSF) priming (HAG regimen) on relapsed or refractory acute myeloid leukemia (AML).

Methods

Sixty-seven patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled. All the patients were treated with HAG regimen (HHT 1.5 mg/m2/day, 1–14d; Ara-C 7.5 mg/m2/12 h, 1–14d; G-CSF 150 μg/m2/day, according to the counting of the peripheral white blood cells). Blood cell counting, liver, kidney function, ECG and myocardial enzymes were monitored regularly.

Results

Thirty-five of 67 (52.2%) patients achieved complete remission (CR) and 8/67 (11.9%) partial remission (PR). The overall response rate was 64.1%. Myelosuppression was the most frequently observed adverse effect. Sixty of 67 (89.5%) patients suffered from grade 1–4 adverse effects of hematologic toxicity (according to World Health Organization criteria) and non-hematologic toxicity was mild.

Conclusion

In conclusion, HAG regimen was effective and tolerated well in refractory or relapsed AML. As a promising regimen for relapse or refractory AML, further observations should be made.
Literature
go back to reference Bai A et al (1999) Priming with G-CSF effectively enhances low-dose Ara-C-induced in vivo apoptosis in myeloid leukemia cells. Exp Hematol 27(2):259–265PubMedCrossRef Bai A et al (1999) Priming with G-CSF effectively enhances low-dose Ara-C-induced in vivo apoptosis in myeloid leukemia cells. Exp Hematol 27(2):259–265PubMedCrossRef
go back to reference Bennett JM et al (1985) Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 103(4):620–625PubMed Bennett JM et al (1985) Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 103(4):620–625PubMed
go back to reference Camera A, Rinaldi CR et al (2009) Sequential continuous infusion of fludarabine and cytarabine associated with liposomal daunorubicin (DaunoXome) (FLAD) in primary refractory or relapsed adult acute myeloid leukemia patients. Ann Hematol 88(2):151–158PubMedCrossRef Camera A, Rinaldi CR et al (2009) Sequential continuous infusion of fludarabine and cytarabine associated with liposomal daunorubicin (DaunoXome) (FLAD) in primary refractory or relapsed adult acute myeloid leukemia patients. Ann Hematol 88(2):151–158PubMedCrossRef
go back to reference Cephalotaxine Esters in the Treatment of Acute Leukemia (1976) A preliminary clinical assessment. Chin Med J (Engl). 2(4):263–72 Cephalotaxine Esters in the Treatment of Acute Leukemia (1976) A preliminary clinical assessment. Chin Med J (Engl). 2(4):263–72
go back to reference De La Luz Sierra M et al (2007) Transcription factor Gfi-1 induced by G-CSF is a negative regulator of CXCR4 in myeloid cells. Blood 110(7):2276–2285PubMedCrossRef De La Luz Sierra M et al (2007) Transcription factor Gfi-1 induced by G-CSF is a negative regulator of CXCR4 in myeloid cells. Blood 110(7):2276–2285PubMedCrossRef
go back to reference de la Rubia J, Regadera A, Martín G et al (2002) FLAG-IDA regimen (fludarabine, cytarabine, idarubicin and G-CSF) in the treatment of patients with high-risk myeloid malignancies. Leuk Res 26(8):725–730CrossRef de la Rubia J, Regadera A, Martín G et al (2002) FLAG-IDA regimen (fludarabine, cytarabine, idarubicin and G-CSF) in the treatment of patients with high-risk myeloid malignancies. Leuk Res 26(8):725–730CrossRef
go back to reference Erba HP, Kantarjian H, Claxton DF et al (2008) Phase II study of single agent clofarabine in previously untreated older adult patients with acute myelogenous leukemia (AML) unlikely to benefit from standard induction chemotherapy. Blood 112(209) (abstr 558) Erba HP, Kantarjian H, Claxton DF et al (2008) Phase II study of single agent clofarabine in previously untreated older adult patients with acute myelogenous leukemia (AML) unlikely to benefit from standard induction chemotherapy. Blood 112(209) (abstr 558)
go back to reference Faderl S et al (2005) Results of a phase 1–2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood 105(3):940–947PubMedCrossRef Faderl S et al (2005) Results of a phase 1–2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood 105(3):940–947PubMedCrossRef
go back to reference Fanucchi MP, KongXR, Chou TC (1986) Hexamethylene bisacetamide(HMBA) does not enhance the cytotoxic effects of adriamycin (ADR), 1,b-D-arabinofuranosylcytosine(Ara-C) and harringtonine (HT) in HL-60 cells. Proc Am Assoc Cancer Res 27:(376) (abstract 1492) Fanucchi MP, KongXR, Chou TC (1986) Hexamethylene bisacetamide(HMBA) does not enhance the cytotoxic effects of adriamycin (ADR), 1,b-D-arabinofuranosylcytosine(Ara-C) and harringtonine (HT) in HL-60 cells. Proc Am Assoc Cancer Res 27:(376) (abstract 1492)
go back to reference Feldman E et al (1992) Homoharringtonine in combination with cytarabine for patients with acute myelogenous leukemia. Leukemia 6(11):1189–1191PubMed Feldman E et al (1992) Homoharringtonine in combination with cytarabine for patients with acute myelogenous leukemia. Leukemia 6(11):1189–1191PubMed
go back to reference Fiedler W et al (2005) A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 105(3):986–993PubMedCrossRef Fiedler W et al (2005) A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 105(3):986–993PubMedCrossRef
go back to reference Fresno M, Jimenez A, Vazquez D (1977) Inhibition of translation in eukaryotic systems by harringtonine. Eur J Biochem 72(2):323–330PubMedCrossRef Fresno M, Jimenez A, Vazquez D (1977) Inhibition of translation in eukaryotic systems by harringtonine. Eur J Biochem 72(2):323–330PubMedCrossRef
go back to reference Hamblin TJ (1995) 1st International Conference on Reversal of Multidrug Resistance in Cancer. St. Gallen, Switzerland, 1–3 September 1994. Leuk Res 19(6):427–428PubMedCrossRef Hamblin TJ (1995) 1st International Conference on Reversal of Multidrug Resistance in Cancer. St. Gallen, Switzerland, 1–3 September 1994. Leuk Res 19(6):427–428PubMedCrossRef
go back to reference Hanel M, Friedrichsen K et al (2001) Mito-flag as salvage therapy for relapsed and refractory acute myeloid leukemia. Onkologie 24(4):356–360PubMedCrossRef Hanel M, Friedrichsen K et al (2001) Mito-flag as salvage therapy for relapsed and refractory acute myeloid leukemia. Onkologie 24(4):356–360PubMedCrossRef
go back to reference Hofmann WK et al (2004) Intensive chemotherapy with idarubicin, cytarabine, etoposide, and G-CSF priming in patients with advanced myelodysplastic syndrome and high-risk acute myeloid leukemia. Ann Hematol 83(8):498–503PubMedCrossRef Hofmann WK et al (2004) Intensive chemotherapy with idarubicin, cytarabine, etoposide, and G-CSF priming in patients with advanced myelodysplastic syndrome and high-risk acute myeloid leukemia. Ann Hematol 83(8):498–503PubMedCrossRef
go back to reference Huang MT (1975) Harringtonine, an inhibitor of initiation of protein biosynthesis. Mol Pharmacol 11(5):511–519PubMed Huang MT (1975) Harringtonine, an inhibitor of initiation of protein biosynthesis. Mol Pharmacol 11(5):511–519PubMed
go back to reference Jackson G, Taylor P et al (2001) A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation. Br J Haematol 112(1):127–137PubMedCrossRef Jackson G, Taylor P et al (2001) A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation. Br J Haematol 112(1):127–137PubMedCrossRef
go back to reference Kantarjian HM et al (1989) Phase II study of low-dose continuous infusion homoharringtonine in refractory acute myelogenous leukemia. Cancer 63(5):813–817PubMedCrossRef Kantarjian HM et al (1989) Phase II study of low-dose continuous infusion homoharringtonine in refractory acute myelogenous leukemia. Cancer 63(5):813–817PubMedCrossRef
go back to reference Kern W, Schoch C et al (2000) Multivariate analysis of prognostic factors in patients with refractory and relapsed acute myeloid leukemia undergoing sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) salvage therapy: relevance of cytogenetic abnormalities. Leukemia 14(2):226–231PubMedCrossRef Kern W, Schoch C et al (2000) Multivariate analysis of prognostic factors in patients with refractory and relapsed acute myeloid leukemia undergoing sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) salvage therapy: relevance of cytogenetic abnormalities. Leukemia 14(2):226–231PubMedCrossRef
go back to reference Legha SS et al (1984) Phase I clinical investigation of homoharringtonine. Cancer Treat Rep 68(9):1085–1091PubMed Legha SS et al (1984) Phase I clinical investigation of homoharringtonine. Cancer Treat Rep 68(9):1085–1091PubMed
go back to reference Levy V et al (2006) A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia. Br J Cancer 95(3):253–259PubMedCrossRef Levy V et al (2006) A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia. Br J Cancer 95(3):253–259PubMedCrossRef
go back to reference Li YH et al (1983) Combined harringtonine or homoharringtonine chemotherapy for acute nonlymphocytic leukemia in 25 children. Chin Med J (Engl) 96(4):303–305 Li YH et al (1983) Combined harringtonine or homoharringtonine chemotherapy for acute nonlymphocytic leukemia in 25 children. Chin Med J (Engl) 96(4):303–305
go back to reference Li JM, Shen Y et al (2005) Aclarubicin and low-dose Cytosine arabinoside in combination with granulocyte colony-stimulating factor in treating acute myeloid leukemia patients with relapsed or refractory disease and myelodysplastic syndrome: a multicenter study of 112 Chinese patients. Int J Hematol 82(1):48–54PubMedCrossRef Li JM, Shen Y et al (2005) Aclarubicin and low-dose Cytosine arabinoside in combination with granulocyte colony-stimulating factor in treating acute myeloid leukemia patients with relapsed or refractory disease and myelodysplastic syndrome: a multicenter study of 112 Chinese patients. Int J Hematol 82(1):48–54PubMedCrossRef
go back to reference Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP (1991) Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukaemia in childhood. N Engl J Med 324:808–815PubMedCrossRef Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP (1991) Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukaemia in childhood. N Engl J Med 324:808–815PubMedCrossRef
go back to reference List AF, Kopecky KJ et al (2001) Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest oncology group study. Blood 98(12):3212–3220PubMedCrossRef List AF, Kopecky KJ et al (2001) Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest oncology group study. Blood 98(12):3212–3220PubMedCrossRef
go back to reference Lowenberg B, Burnett AK (2005) Acute myeloid leukemia in adults. In: Degos L, Linch DC, Lowenberg B (eds) Textbook of malignant hematology. London: Taylor & Francis, p 645 Lowenberg B, Burnett AK (2005) Acute myeloid leukemia in adults. In: Degos L, Linch DC, Lowenberg B (eds) Textbook of malignant hematology. London: Taylor & Francis, p 645
go back to reference Mai WY, Lin MF (2005) Induction of apoptosis by homoharringtonine in G1 phase human chronic myeloid leukemic cells. Chin Med J (Engl) 118(6):487–492 Mai WY, Lin MF (2005) Induction of apoptosis by homoharringtonine in G1 phase human chronic myeloid leukemic cells. Chin Med J (Engl) 118(6):487–492
go back to reference Mao YQ, Li XR, Lei S (2006) Effect of several anti-tumor drugs on apoptosis induction in Jurkat cell line. Zhong guo Shi Yan Xue Ye Xue Za Zhi 14(4):681–685 Mao YQ, Li XR, Lei S (2006) Effect of several anti-tumor drugs on apoptosis induction in Jurkat cell line. Zhong guo Shi Yan Xue Ye Xue Za Zhi 14(4):681–685
go back to reference O’Brien S et al (1995) Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. Blood 86(9):3322–3326PubMed O’Brien S et al (1995) Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. Blood 86(9):3322–3326PubMed
go back to reference Ohno R, Naoe T et al (1994) A double-blind controlled study of granulocyte colony-stimulating factor started two days before induction chemotherapy in refractory acute myeloid leukemia. Kohseisho Leukemia Study Group. Blood 83(8):2086–2092 Ohno R, Naoe T et al (1994) A double-blind controlled study of granulocyte colony-stimulating factor started two days before induction chemotherapy in refractory acute myeloid leukemia. Kohseisho Leukemia Study Group. Blood 83(8):2086–2092
go back to reference Qian SX, Li JY, Tian T, Shen YF et al (2007) Effect of low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor priming (CAG regimen) on the outcome of elderly patients with acute myeloid leukemia. Leuk Res (10):1383–1388. Epub 2007 Apr 8 Qian SX, Li JY, Tian T, Shen YF et al (2007) Effect of low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor priming (CAG regimen) on the outcome of elderly patients with acute myeloid leukemia. Leuk Res (10):1383–1388. Epub 2007 Apr 8
go back to reference Rombouts EJ et al (2004) Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood 104(2):550–557PubMedCrossRef Rombouts EJ et al (2004) Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood 104(2):550–557PubMedCrossRef
go back to reference Saito K et al (2000) Low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (CAG regimen) for previously treated patients with relapsed or primary resistant acute myelogenous leukemia (AML) and previously untreated elderly patients with AML, secondary AML, and refractory anemia with excess blasts in transformation. Int J Hematol 71(3):238–244PubMed Saito K et al (2000) Low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (CAG regimen) for previously treated patients with relapsed or primary resistant acute myelogenous leukemia (AML) and previously untreated elderly patients with AML, secondary AML, and refractory anemia with excess blasts in transformation. Int J Hematol 71(3):238–244PubMed
go back to reference Semerad CL et al (2005) G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 106(9):3020–3027PubMedCrossRef Semerad CL et al (2005) G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 106(9):3020–3027PubMedCrossRef
go back to reference Smith CR Jr, Powell RG, Mikolajczak KL (1976) The genus Cephalotaxus: source of homoharringtonine and related anticancer alkaloids. Cancer Treat Rep 60(8):1157–1170PubMed Smith CR Jr, Powell RG, Mikolajczak KL (1976) The genus Cephalotaxus: source of homoharringtonine and related anticancer alkaloids. Cancer Treat Rep 60(8):1157–1170PubMed
go back to reference Spoo AC, Wierda WG, Burger JA (2004) The CXCR4 score: a new prognostic marker in acute myelogenous leukemia [abstract]. Blood 104:304a Spoo AC, Wierda WG, Burger JA (2004) The CXCR4 score: a new prognostic marker in acute myelogenous leukemia [abstract]. Blood 104:304a
go back to reference Sugiyama T et al (2006) Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25(6):977–988PubMedCrossRef Sugiyama T et al (2006) Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25(6):977–988PubMedCrossRef
go back to reference Takemura Y et al (1985) Biologic and pharmacologic effects of harringtonine on human leukemia-lymphoma cells. Cancer Chemother Pharmacol 14(3):206–210PubMedCrossRef Takemura Y et al (1985) Biologic and pharmacologic effects of harringtonine on human leukemia-lymphoma cells. Cancer Chemother Pharmacol 14(3):206–210PubMedCrossRef
go back to reference Warrell RP Jr, Coonley CJ, Gee TS (1985) Homoharringtonine: an effective new drug for remission induction in refractory nonlymphoblastic leukemia. J Clin Oncol 3(5):617–621PubMed Warrell RP Jr, Coonley CJ, Gee TS (1985) Homoharringtonine: an effective new drug for remission induction in refractory nonlymphoblastic leukemia. J Clin Oncol 3(5):617–621PubMed
go back to reference Yamada K et al (1995) Concurrent use of granulocyte colony-stimulating factor with low-dose cytosine arabinoside and aclarubicin for previously treated acute myelogenous leukemia: a pilot study. Leukemia 9(1):10–14PubMed Yamada K et al (1995) Concurrent use of granulocyte colony-stimulating factor with low-dose cytosine arabinoside and aclarubicin for previously treated acute myelogenous leukemia: a pilot study. Leukemia 9(1):10–14PubMed
go back to reference Ye XJ, Lin MF (2004) Homoharringtonine induces apoptosis of endothelium and down-regulates VEGF expression of K562 cells. J Zhejiang Univ Sci 5(2):230–234PubMedCrossRef Ye XJ, Lin MF (2004) Homoharringtonine induces apoptosis of endothelium and down-regulates VEGF expression of K562 cells. J Zhejiang Univ Sci 5(2):230–234PubMedCrossRef
go back to reference Zhang ZY et al (1987) Curative effect of harringtonine semisynthetic harringtonine and HOAP on nonlymphocytic leukemias. Analysis of 304 cases. Chin Med J (Engl) 100(7):565–568 Zhang ZY et al (1987) Curative effect of harringtonine semisynthetic harringtonine and HOAP on nonlymphocytic leukemias. Analysis of 304 cases. Chin Med J (Engl) 100(7):565–568
go back to reference Zhou JY et al (1990) Effect of homoharringtonine on proliferation and differentiation of human leukemic cells in vitro. Cancer Res 50(7):2031–2035PubMed Zhou JY et al (1990) Effect of homoharringtonine on proliferation and differentiation of human leukemic cells in vitro. Cancer Res 50(7):2031–2035PubMed
Metadata
Title
Low dose of homoharringtonine and cytarabine combined with granulocyte colony-stimulating factor priming on the outcome of relapsed or refractory acute myeloid leukemia
Authors
Liu-Fang Gu
Wang-Gang Zhang
Fang-Xia Wang
Xing-Mei Cao
Yin-Xia Chen
Ai-Li He
Jie Liu
Xiao-Rong Ma
Publication date
01-06-2011
Publisher
Springer-Verlag
Published in
Journal of Cancer Research and Clinical Oncology / Issue 6/2011
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-010-0947-z

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