Phase I/II trial of adding semisynthetic homoharringtonine in chronic myeloid leukemia patients who have achieved partial or complete cytogenetic response on imatinib

Abstract

BACKGROUNDA Phase I/II study was designed to show whether the addition of semisynthetic homoharringtonine (sHHT) would reduce the level of residual disease in patients with Ph‐positive chronic myeloid leukemia who appeared to have achieved a suboptimal response to imatinib alone.METHODSPatients with CML who had achieved ≥ 35% Ph‐negativity on imatinib were included. All patients had been treated with imatinib at ≥ 400 mg/day for at least 2 years and had achieved a plateau in BCR‐ABL transcripts defined by measuring BCR‐ABL transcripts on at least 4 occasions over a minimum period of 1 year with the latest value not lower than the previous minimum value. Initially sHHT was given subcutaneously at a dose of 1.25 mg/m2 twice daily for 1 day. Courses were repeated every 28 days. The dosage of sHHT was escalated by adding one day of treatment every two days. Efficacy was assessed by serial monitoring of blood levels of BCR‐ABL transcripts.RESULTSOf 10 evaluable patients, 7 had an appreciable decline in BCR‐ABL transcript levels; in 5 cases the reduction was greater than 1 log. Asthenia (n = 10) and cytopenias (n = 3) were prominent side‐effects, but the drug was generally well tolerated. Mutations in the P‐loop of the BCR‐ABL kinase domain were found in 2 of the patients who responded to the addition of sHHT.CONCLUSIONSThe addition of sHHT should be considered for patients on imatinib who fail to obtain low levels of minimal residual disease. Cancer 2005. © 2005 American Cancer Society.

Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009

“…Patients were continued on the same dose of imatinib in addition to starting omacetaxine at 1.25 mg/m 2 SC twice daily for 2 to 6 consecutive doses every 28 days. 62 The dose of omacetaxine was increased every 2 courses by 1 dosage level in the absence of cytopenias. The addition of omacetaxine resulted in a decline of BCR-ABL1 transcripts by >0.5 log in 7 patients and by >1 log in 5 patients.…”

“…Moreover, 2 patients had a complete molecular response, and 2 other patients who had BCR-ABL1 kinase mutations before omacetaxine therapy (both with the exchange of methionine and valine at position 224 [M244V] P-loop mutation), had a >1-log reduction in BCR-ABL1 transcripts. 62 Preliminary results from a phase 2 trial that was designed to study the concept of ''sequential blockade,'' in which omacetaxine inhibits BCR-ABL1 protein synthesis, whereas imatinib inhibits the kinase activity of the enzyme, were reported in 2006. 63 Therapy consisted of omacetaxine 2.5 mg/m 2 daily as a continuous intravenous infusion on Days 1 through 5 every 4 weeks along with imatinib 400 mg daily for patients in CP or 600 mg daily for those in AP or BP.…”

A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia

“…Moreover, consideration should be given to re-exploring the potential value of ssHHT in other haematological malignancies such as CML (O'Brien et al, 2003;Marin et al, 2005), specially in cases of bcr-abl mutation T315I, refractory to several tyrosine kinase inhibitors. Furthermore, manipulation in the side chain of ssHHT may provide second-generation analogues that may have a broader or different spectrum of activity.…”

Interferon-α or homoharringtonine as salvage treatment for chronic myeloid leukemia patients who acquire the T315I BCR-ABL mutation

“…6 Because the mechanisms of action of rIFN and HHT differ from that of tyrosine kinase inhibitors (TKIs), we evaluated their effect in these 2 patients with a predominant T315I clone. 2,7,8 Although longer follow-up is needed, both patients BLOOD…”