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

A 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. Patients 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/m(2) 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. Of 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. The addition of sHHT should be considered for patients on imatinib who fail to obtain low levels of minimal residual disease.

Marin D ，Kaeda JS ，Andreasson C ，Saunders SM ，Bua M ，Olavarria E ，Goldman JM ，Apperley JF ... -  《CANCER》

Phase IV study evaluating efficacy of escalated dose of imatinib in chronic myeloid leukemia patients showing suboptimal response to standard dose imatinib.

Koh Y ，Kim I ，Yoon SS ，Kim BK ，Kim DY ，Lee JH ，Lee KH ，Park E ，Kim HJ ，Sohn SK ，Joo YD ，Kim SJ ，Chung J ，Shin HJ ，Kim SH ，Kim CS ，Song HS ，Kim MK ，Hyun MS ，Ahn JS ，Jung CW ，Park S ，Korean Society of Hematology CML working party ... -  《-》

Not all imatinib resistance in CML are BCR-ABL kinase domain mutations.

Wei Y ，Hardling M ，Olsson B ，Hezaveh R ，Ricksten A ，Stockelberg D ，Wadenvik H ... -  《ANNALS OF HEMATOLOGY》

Results of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase.

Before the discovery of imatinib mesylate, a Bcr-Abl selective tyrosine kinase inhibitor, three agents, interferon-alpha (IFN-alpha), cytarabine (ara-C), and homoharringtonine (HHT), had demonstrated activity against Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) as single agents and in couplet combinations. The goals of the current study were to evaluate the efficacy of the triple combination regimen with IFN-alpha, ara-C, and HHT in newly diagnosed Ph-positive CML and to assess the impact of the added sequential therapy with imatinib on overall prognosis. Ninety patients with Ph-positive CML in early chronic phase received the triple regimen. Therapy consisted of 5 million units (MU)/m(2) IFN-alpha subcutaneously (s.c. daily, ara-C 10 mg s.c. daily, and HHT 2.5 mg/m(2) by continuous infusion over 24 hours daily x 5 every month. After a median duration of 16.5 months of therapy, 78 patients had their therapy changed to 400 mg orally administered imatinib daily. With the triple regimen, 85 patients (94%) achieved complete hematologic response and 67 patients (74%) had a cytogenetic response (Ph suppression to < or = 90%) which was complete (Ph 0%) in 20 patients (22%) and major in 42 patients (46%). Myelosuppression was significant, resulting in considerable reductions in the dose schedules. After 12 months of therapy, the median IFN-alpha dose was 1.6 MU/m(2) daily, the median ara-C dose was 1.85 mg daily, and the median number of HHT days was 2 every month. Only three patients developed blastic phase while receiving the triple regimen. With the change to imatinib therapy, currently 57 patients (63%) are in complete cytogenetic response and 69 patients (76%) in major cytogenetic response. With a median follow-up time of 46 months for the total study group, the estimated 5-year survival rate was 88%, and only 8 patients (9%) to date have developed blastic phase. The sequence of IFN-alpha, ara-C, and HHT followed by imatinib (imposed by the discovery of the latter drug) resulted in an estimated 5-year survival rate of 88%. This finding suggests that imatinib combination regimens may improve the prognosis in CML.

O'Brien S ，Giles F ，Talpaz M ，Cortes J ，Rios MB ，Shan J ，Thomas D ，Andreeff M ，Kornblau S ，Faderl S ，Garcia-Manero G ，White K ，Mallard S ，Freireich E ，Kantarjian HM ... -  《CANCER》

[The monitoring of residual disease for chronic myelogenous leukemia patients treated with imatinib mesylate: detection of T315I mutation in ATP binding site of BCR/ABL gene].

Miyanishi S ，Umeki K ，Hayashi T ，Fukutsuka K ，Okumura A ，Kishimori C ... -  《-》