Phase I trial of 7-hydroxystaurosporine and fludararbine phosphate: in vivo evidence of 7-hydroxystaurosporine induced apoptosis in chronic lymphocytic leukemia

Abstract

This is a phase I study of 7-hydroxystaurosporine (UCN-01) and fludararbine monophosphate (FAMP) in relapsed lymphoma. UCN-01 alone was administered in cycle 1 and with FAMP in cycles 2-6. FAMP was escalated in cohorts from 1 to 5 days. UCN-01 and FAMP pharmacokinetics and apoptosis of malignant lymphocytes was evaluated. Eighteen patients were enrolled. Standard FAMP with UCN-01 was tolerated without dose-limiting toxicity (DLT) and those seen were common to either agent alone. One patient died due to Stevens-Johnson syndrome. Seven of 18 patients responded. No pharmacological effect of UCN-01 by FAMP was noted. Lymphocytosis occurred in 15 of 18 patients following UCN-01 to paradoxically increase circulating tumor cells. UCN-01 induced apoptosis in six of eight patients with chronic lymphocytic leukemia (CLL). UCN-01 does not increase FAMP toxicity. Transient lymphocytosis followed by apoptosis occurs with UCN-01. Mobilization from tissue reservoirs may play a role in the induction of cell death in malignant lymphocytes.

Conflict of interest statement

Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

Figures

Figure 1.

Absolute lymphocyte count [(WBC × % lymphocyte differential) ALC] in patients with definite lymphocytosis after receiving UCN-01.

Figure 2.

Detection of apoptosis by annexin V staining in B cells. (A) Annexin V staining (y-axis) in positive control. (B) Low level (2.6%) apoptotic B cells (in box) staining positive for CD19 (x-axis) and annexin V (y-axis). (C) Low level (3.8%) apoptotic B cells (in box) staining positive for CD19 (x-axis) and annexin V (y-axis). (D) Moderate level (5.9%) apoptotic B cells (in box) staining positive for CD19 (I-axis) and annexin V (y-axis). (E) High level (38.9%) apoptotic B cells (in box) staining positive for CD19 (x-axis) and annexin V (y-axis). Patient 10 is shown in (B) and (D) while patient 17 is shown in (C) and (E).