Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy

Alfonso Quintás-Cardama, Hagop Kantarjian, Guillermo Garcia-Manero, Susan O'Brien, Stefan Faderl, Zeev Estrov, Francis Giles, Anthony Murgo, Nakia Ladie, Srdan Verstovsek, Jorge Cortes

Research output: Contribution to journalArticle

Abstract

BACKGROUND. Homoharringtonine (HHT) is a cephalotaxus alkaloid that inhibits the synthesis of proteins leading to apoptosis. Intravenous HHT has demonstrated activity in patients with chronic myeloid leukemia (CML) after failure with interferon. METHODS. A Phase I study was completed of subcutaneous (s.c.) HHT in patients with CML in accelerated or blast phases and demonstrated efficacy and good tolerance at the same doses used by intravenous (i.v.) administration. The maximal tolerated dose (MTD) was 1.25 mg/m2 s.c. twice daily. The cohort was then expanded to treated at the MTD to include patients in late chronic phase CML after imatinib failure. Therapy consisted of an i.v. loading dose of HHT 2.5 mg/m2 over 24 hours, followed by 1.25 mg/m2 s.c. twice daily for 14 days every 28 days until remission, then for 7 days every 28 days. Six patients (median age, 53 years) who had failed imatinib were treated and 5 were evaluable. Patients received a median of 4.5 courses of s.c. HHT. RESULTS. Complete hematologic remission was obtained in all 5 evaluable patients and 3 had cytogenetic (CG) responses: 1 complete and 2 minor. The 2 patients with BCR-ABL kinase domain mutations at the start of therapy with HHT had a CG response and in both instances the mutations became undetectable. All patients developed myelosuppression and 3 had their HHT dose reduced due to prolonged neutropenia. Nonhematologic toxicity was mild and manageable. CONCLUSIONS. Subcutaneous HHT is well tolerated and may have clinical activity in patients with CML after imatinib failure.

Original languageEnglish (US)
Pages (from-to)248-255
Number of pages8
JournalCancer
Volume109
Issue number2
DOIs
StatePublished - Jan 15 2007
Externally publishedYes

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Therapeutics
Maximum Tolerated Dose
Cytogenetics
Harringtonines
Leukemia, Myeloid, Chronic Phase
Blast Crisis
homoharringtonine
Mutation
Neutropenia
Intravenous Administration
Interferons
Phosphotransferases
Apoptosis

Keywords

  • ABL mutations
  • Chronic myelogenous leukemia
  • Homoharringtonine
  • Imatinib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Quintás-Cardama, A., Kantarjian, H., Garcia-Manero, G., O'Brien, S., Faderl, S., Estrov, Z., ... Cortes, J. (2007). Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy. Cancer, 109(2), 248-255. https://doi.org/10.1002/cncr.22398

Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy. / Quintás-Cardama, Alfonso; Kantarjian, Hagop; Garcia-Manero, Guillermo; O'Brien, Susan; Faderl, Stefan; Estrov, Zeev; Giles, Francis; Murgo, Anthony; Ladie, Nakia; Verstovsek, Srdan; Cortes, Jorge.

In: Cancer, Vol. 109, No. 2, 15.01.2007, p. 248-255.

Research output: Contribution to journalArticle

Quintás-Cardama, A, Kantarjian, H, Garcia-Manero, G, O'Brien, S, Faderl, S, Estrov, Z, Giles, F, Murgo, A, Ladie, N, Verstovsek, S & Cortes, J 2007, 'Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy', Cancer, vol. 109, no. 2, pp. 248-255. https://doi.org/10.1002/cncr.22398
Quintás-Cardama A, Kantarjian H, Garcia-Manero G, O'Brien S, Faderl S, Estrov Z et al. Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy. Cancer. 2007 Jan 15;109(2):248-255. https://doi.org/10.1002/cncr.22398
Quintás-Cardama, Alfonso ; Kantarjian, Hagop ; Garcia-Manero, Guillermo ; O'Brien, Susan ; Faderl, Stefan ; Estrov, Zeev ; Giles, Francis ; Murgo, Anthony ; Ladie, Nakia ; Verstovsek, Srdan ; Cortes, Jorge. / Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy. In: Cancer. 2007 ; Vol. 109, No. 2. pp. 248-255.
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abstract = "BACKGROUND. Homoharringtonine (HHT) is a cephalotaxus alkaloid that inhibits the synthesis of proteins leading to apoptosis. Intravenous HHT has demonstrated activity in patients with chronic myeloid leukemia (CML) after failure with interferon. METHODS. A Phase I study was completed of subcutaneous (s.c.) HHT in patients with CML in accelerated or blast phases and demonstrated efficacy and good tolerance at the same doses used by intravenous (i.v.) administration. The maximal tolerated dose (MTD) was 1.25 mg/m2 s.c. twice daily. The cohort was then expanded to treated at the MTD to include patients in late chronic phase CML after imatinib failure. Therapy consisted of an i.v. loading dose of HHT 2.5 mg/m2 over 24 hours, followed by 1.25 mg/m2 s.c. twice daily for 14 days every 28 days until remission, then for 7 days every 28 days. Six patients (median age, 53 years) who had failed imatinib were treated and 5 were evaluable. Patients received a median of 4.5 courses of s.c. HHT. RESULTS. Complete hematologic remission was obtained in all 5 evaluable patients and 3 had cytogenetic (CG) responses: 1 complete and 2 minor. The 2 patients with BCR-ABL kinase domain mutations at the start of therapy with HHT had a CG response and in both instances the mutations became undetectable. All patients developed myelosuppression and 3 had their HHT dose reduced due to prolonged neutropenia. Nonhematologic toxicity was mild and manageable. CONCLUSIONS. Subcutaneous HHT is well tolerated and may have clinical activity in patients with CML after imatinib failure.",
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AU - Quintás-Cardama, Alfonso

AU - Kantarjian, Hagop

AU - Garcia-Manero, Guillermo

AU - O'Brien, Susan

AU - Faderl, Stefan

AU - Estrov, Zeev

AU - Giles, Francis

AU - Murgo, Anthony

AU - Ladie, Nakia

AU - Verstovsek, Srdan

AU - Cortes, Jorge

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Y1 - 2007/1/15

N2 - BACKGROUND. Homoharringtonine (HHT) is a cephalotaxus alkaloid that inhibits the synthesis of proteins leading to apoptosis. Intravenous HHT has demonstrated activity in patients with chronic myeloid leukemia (CML) after failure with interferon. METHODS. A Phase I study was completed of subcutaneous (s.c.) HHT in patients with CML in accelerated or blast phases and demonstrated efficacy and good tolerance at the same doses used by intravenous (i.v.) administration. The maximal tolerated dose (MTD) was 1.25 mg/m2 s.c. twice daily. The cohort was then expanded to treated at the MTD to include patients in late chronic phase CML after imatinib failure. Therapy consisted of an i.v. loading dose of HHT 2.5 mg/m2 over 24 hours, followed by 1.25 mg/m2 s.c. twice daily for 14 days every 28 days until remission, then for 7 days every 28 days. Six patients (median age, 53 years) who had failed imatinib were treated and 5 were evaluable. Patients received a median of 4.5 courses of s.c. HHT. RESULTS. Complete hematologic remission was obtained in all 5 evaluable patients and 3 had cytogenetic (CG) responses: 1 complete and 2 minor. The 2 patients with BCR-ABL kinase domain mutations at the start of therapy with HHT had a CG response and in both instances the mutations became undetectable. All patients developed myelosuppression and 3 had their HHT dose reduced due to prolonged neutropenia. Nonhematologic toxicity was mild and manageable. CONCLUSIONS. Subcutaneous HHT is well tolerated and may have clinical activity in patients with CML after imatinib failure.

AB - BACKGROUND. Homoharringtonine (HHT) is a cephalotaxus alkaloid that inhibits the synthesis of proteins leading to apoptosis. Intravenous HHT has demonstrated activity in patients with chronic myeloid leukemia (CML) after failure with interferon. METHODS. A Phase I study was completed of subcutaneous (s.c.) HHT in patients with CML in accelerated or blast phases and demonstrated efficacy and good tolerance at the same doses used by intravenous (i.v.) administration. The maximal tolerated dose (MTD) was 1.25 mg/m2 s.c. twice daily. The cohort was then expanded to treated at the MTD to include patients in late chronic phase CML after imatinib failure. Therapy consisted of an i.v. loading dose of HHT 2.5 mg/m2 over 24 hours, followed by 1.25 mg/m2 s.c. twice daily for 14 days every 28 days until remission, then for 7 days every 28 days. Six patients (median age, 53 years) who had failed imatinib were treated and 5 were evaluable. Patients received a median of 4.5 courses of s.c. HHT. RESULTS. Complete hematologic remission was obtained in all 5 evaluable patients and 3 had cytogenetic (CG) responses: 1 complete and 2 minor. The 2 patients with BCR-ABL kinase domain mutations at the start of therapy with HHT had a CG response and in both instances the mutations became undetectable. All patients developed myelosuppression and 3 had their HHT dose reduced due to prolonged neutropenia. Nonhematologic toxicity was mild and manageable. CONCLUSIONS. Subcutaneous HHT is well tolerated and may have clinical activity in patients with CML after imatinib failure.

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KW - Homoharringtonine

KW - Imatinib

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