- Email: [email protected]
Depsipeptide, a Histone Deacetylase Inhibitor, Shows Promising Clinical Activity in T-Cell Lymphomas
Research in Brief Depsipeptide, a Histone Deacetylase Inhibitor, Shows Promising Clinical Activity in T-Cell Lymphomas Rationale • Depsipeptide (FR901228 or FK228) is a bicyclic novel histone deacetylase inhibitor (Figure 1) currently under evaluation in relapsed lymphoma. Histone acetylation and deacetylation are key steps involved in the regulation of transcription in eukaryotic cells.1 Chromatin is a highly specialized structure that is usually tightly compacted around the nucleosomal core consisting of an octamer of histone proteins. The structural organization of chromatin and accessibility to the transcriptional machinery of the cell are regulated through the acetylation and deacetylation of the histone proteins, mediated by acetylase and deacetylase enzymes, respectively. Specifically, histone acetylation has long been associated with transcriptional activation; whereas conversely, deacetylation of histones is associated with gene silencing and transcriptional repression. • Histone deacetylase inhibitors are a novel class of chemotherapeutic drugs initially identified by their ability to reverse the malignant phenotype of transformed cells.1-3 Histone deacetylase inhibitors have been shown to activate differentiation programs, inhibit the cell cycle, and induce apoptosis in a wide range of tumor-derived cell lines and to block angiogenesis and stimulate the immune system.1,4 • Preclinical studies have demonstrated that depsipeptide alters the transcriptional profile of cancer cells through hyperacetylation, leading to terminal Prepared by: G. Kesava Reddy, PhD Reviewed by: Susan Bates, MD, Vinay K. Jain, MD
differentiation, the induction of cell arrest, and eventually cell death (Figure 2).5-7 In addition, depsipeptide may target c-myc– and Bcl2-dependent apoptosis and, in some models, inhibition of angiogenesis contributing to antitumor efficacy.8,9 Other investigations of the effect of depsipeptide on G1 to S transition of the cell cycle showed that depsipeptide inhibits signal transduction through mitogen-activated protein kinase and causes p53-independent G1 arrest.10 • Depsipeptide, either alone or in combination with other hypomethylating agents, has been shown to induce a number of cellular proteins that may have direct effects on cell proliferation, susceptibility to immunologic manipulation, and apoptosis. In vivo studies demonstrated that higher doses of depsipeptide could be given and greater antitumor efficacy achieved when an intermittent administration schedule was used. The greater tumor activity observed with an intermittent schedule may be attributable to the higher individual doses that were administered because of the greater tolerance to depsipeptide.
Figure 1: Molecular Structure of Depsipeptide N
O O
O N
S
N O O
S O
OO N
Figure 2: Role of Depsipeptide in Acetylation of Histones and Subsequent Inhibition/ Apoptosis of Tumor Cells Histone Deacetylase Presence of Depsipeptide
Absence of Depsipeptide DNA
AC AC
AC
Histones
• This article provides an update on the clinical efficacy and safety of depsipeptide in clinical lymphoma.
Phase I/II Clinical Experience with Depsipeptide Piekarz et al from the National Cancer Institute conducted a phase I trial of depsipeptide.11 Patients received depsipeptide by a 4-hour intravenous (I.V.) infusion on days 1 and 5 every 21 days. The starting dose was 1.0 mg/m2 and dose escalation proceeded through
AC
Deacetylated Histones
Hyperacetylated Histones
Transcriptional Repression Pre-Programmed Set of Genes
Transcriptional Activation of Pre-Programmed Set of Genes
Cell Growth
Cell-Growth Arrest, Differentiation, and/or Apoptosis
Tumor Growth
Inhibition of Tumor Growth
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1526-9655, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Lymphoma June 2004 • 15
Table 1: Clinical Activity of Depsipeptide in T-Cell Lymphoma
Response
Number of Patients (CTCL, n = 21) (PTCL, n = 17)
Median Treatment Duration
Disease Type
Complete Response
3 (14%) 0
> 5 Weeks None
CTCL PTCL
Partial Response
5 (24%) 4 (24%)
> 6 Weeks > 2 Weeks
CTCL PTCL
Stable Disease
3 (14%) 0
> 4 Weeks None
CTCL PTCL
Disease Progression
8 (38%) 12 (71%)
NR NR
CTCL PTCL
Not Evaluable
1 (5%) 1 (6%)
–
CTCL PTCL
Response Rate
8 (38%) 4 (24%)
> 5 Weeks > 2 Weeks
CTCL PTCL
Abbreviations: CTCL= cutaneous T-cell lymphoma; NR = not reported; PTCL = peripheral T-cell lymphoma
a total of 8 dose levels to a maximum of 24.9 mg/m2. A total of 37 patients received 88 cycles of depsipeptide at 8 different dose levels. The maximum tolerated dose was found to be 17.8 mg/m2 given on days 1 and 5 every 21 days. However, dose-limiting toxicities were observed when patients were treated at 24.9 mg/m2. The dose-limiting toxicity included grade 3 fatigue (3 patients), grade 3 nausea and vomiting (1 patient), grade 4 thrombocytopenia (2 patients), and grade 4 cardiac arrhythmia (1 patient). Cardiac abnormalities such as asymptomatic, transient electrocardiogram changes, including ST-T wave flattening and inverted T waves, were observed with depsipeptide therapy. These changes are mostly evident by 24 hours after completion of drug infusion and typically resolve before day 5 of drug administration. No significant decline in cardiac ejection fraction was observed on multigated radionucleotide angiography scans. Preliminary results of this phase I trial at the National Cancer Institute suggested that depsipeptide has clinical activity in patients with cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). Following the definition of the maximum tolerated dose, a patient with PTCL was enrolled and achieved a com-
16 • Clinical Lymphoma June 2004
plete remission, which has been sustained for > 36 months. Additional patients with T-cell lymphoma, 7 with mycosis fungoides, and 3 with Sezary syndrome, were then enrolled at this dose level. All patients with mycosis fungoides achieved an objective response.
Ongoing Trials Based on these encouraging results, a multicenter phase II trial of depsipeptide administered by I.V. infusion at a dose of 14 mg/m2 on days 1, 8, and 15 of a 28-day cycle was initiated in patients with relapsed PTCL or CTCL.12 Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. A total of 38 patients with PTCL (n = 17) or CTCL (n = 21) have been enrolled in the study. Objective responses were reported in 8 of 21 evaluable patients with CTCL (38%) and in 4 of 17 patients with PTCL (24%; Table 1). Among 15 evaluable patients with CTCL who have received ≤ 2 systemic chemotherapy regimens, 8 responses (38%) have been observed: 3 patients with complete response with durations of 5, 21, and 26 months, respectively; and 5 patients with partial response. A multicenter phase II trial has recently been initiated combining depsipeptide with rituximab and fludarabine in
patients with relapsed or refractory lowgrade B-cell non-Hodgkin’s lymphoma. Clinical trials in solid tumors are open or under review in multiple centers.
Clinical Relevance Depsipeptide, a novel histone deacetylase inhibitor, has promising activity in Tcell lymphoma. Unusual toxicities attributed to depsipeptide included asymptomatic electrocardiogram changes and supraventricular arrhythmias, and these are being evaluated in ongoing trials. Several phase I/II clinical trials are currently evaluating the activity and safety of depsipeptide either as a single agent or in combination with other chemotherapy agents in patients with T-cell lymphomas.
References 1. Marks P, Rifkind RA, Richon VM, et al. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 2001; 1:194-202. 2. Peart MJ, Tainton KM, Ruefli AA, et al. Novel mechanisms of apoptosis induced by histone deacetylase inhibitors. Cancer Res 2003; 63:4460-4471. 3. Byrd JC, Shinn C, Ravi R, et al. Depsipeptide (FR901228): a novel therapeutic agent with selective, in vitro activity against human B-cell chronic lymphocytic leukemia cells. Blood 1999; 94:1401-1408. 4. Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 2002; 1:287-299. 5. Owa T, Yoshino H, Yoshimatsu K, et al. Cell cycle regulation in the G1 phase: a promising target for the development of new chemotherapeutic anticancer agents. Curr Med Chem 2001; 8:1487-1503. 6. Kwon HJ, Kim MS, Kim MJ, et al. Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis. Int J Cancer 2002; 97:290-296. 7. Weiser TS, Guo ZS, Ohnmacht GA, et al. Sequential 5Aza-2 deoxycytidine-depsipeptide FR901228 treatment induces apoptosis preferentially in cancer cells and facilitates their recognition by cytolytic T lymphocytes specific for NY-ESO-1. J Immunother 2001; 24:151-161. 8. Wang R, Brunner T, Zhang L, et al. Fungal metabolite FR901228 inhibits c-Myc and Fas ligand expression. Oncogene 1998; 17:1503-1508. 9. Ueda H, Nakajima H, Hori Y, et al. Action of FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum no. 968, on Haras transformed NIH3T3 cells. Biosci Biotechnol Biochem 1994; 58:1579-1583. 10. Sandor V, Robbins AR, Robey R, et al. FR901228 causes mitotic arrest but does not alter microtubule polymerization. Anticancer Drugs 2000; 11:445-454. 11. Piekarz RL, Wilson W, Bates SE. FK228, depsipeptide: current clinical data at the NIC. Presented at the International Congress on Hematological Malignancies: Focus on Leukemias, Lymphomas, and Myelomas, March 10-14, 2004, Whistler, British Columbia, Canada. 12. Piekarz RL, Robey R, Fojo AT, et al. Analysis of molecular markers and targets in trials of depsipeptide (FR901228), a histone deacetylase inhibitor with clinical activity in T-cell lymphoma. Proc Am Soc Clin Oncol 2002; 21:23a (Abstract #88).
differentiation, the induction of cell arrest, and eventually cell death (Figure 2).5-7 In addition, depsipeptide may target c-myc– and Bcl2-dependent apoptosis and, in some models, inhibition of angiogenesis contributing to antitumor efficacy.8,9 Other investigations of the effect of depsipeptide on G1 to S transition of the cell cycle showed that depsipeptide inhibits signal transduction through mitogen-activated protein kinase and causes p53-independent G1 arrest.10 • Depsipeptide, either alone or in combination with other hypomethylating agents, has been shown to induce a number of cellular proteins that may have direct effects on cell proliferation, susceptibility to immunologic manipulation, and apoptosis. In vivo studies demonstrated that higher doses of depsipeptide could be given and greater antitumor efficacy achieved when an intermittent administration schedule was used. The greater tumor activity observed with an intermittent schedule may be attributable to the higher individual doses that were administered because of the greater tolerance to depsipeptide.
Figure 1: Molecular Structure of Depsipeptide N
O O
O N
S
N O O
S O
OO N
Figure 2: Role of Depsipeptide in Acetylation of Histones and Subsequent Inhibition/ Apoptosis of Tumor Cells Histone Deacetylase Presence of Depsipeptide
Absence of Depsipeptide DNA
AC AC
AC
Histones
• This article provides an update on the clinical efficacy and safety of depsipeptide in clinical lymphoma.
Phase I/II Clinical Experience with Depsipeptide Piekarz et al from the National Cancer Institute conducted a phase I trial of depsipeptide.11 Patients received depsipeptide by a 4-hour intravenous (I.V.) infusion on days 1 and 5 every 21 days. The starting dose was 1.0 mg/m2 and dose escalation proceeded through
AC
Deacetylated Histones
Hyperacetylated Histones
Transcriptional Repression Pre-Programmed Set of Genes
Transcriptional Activation of Pre-Programmed Set of Genes
Cell Growth
Cell-Growth Arrest, Differentiation, and/or Apoptosis
Tumor Growth
Inhibition of Tumor Growth
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1526-9655, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Lymphoma June 2004 • 15
Table 1: Clinical Activity of Depsipeptide in T-Cell Lymphoma
Response
Number of Patients (CTCL, n = 21) (PTCL, n = 17)
Median Treatment Duration
Disease Type
Complete Response
3 (14%) 0
> 5 Weeks None
CTCL PTCL
Partial Response
5 (24%) 4 (24%)
> 6 Weeks > 2 Weeks
CTCL PTCL
Stable Disease
3 (14%) 0
> 4 Weeks None
CTCL PTCL
Disease Progression
8 (38%) 12 (71%)
NR NR
CTCL PTCL
Not Evaluable
1 (5%) 1 (6%)
–
CTCL PTCL
Response Rate
8 (38%) 4 (24%)
> 5 Weeks > 2 Weeks
CTCL PTCL
Abbreviations: CTCL= cutaneous T-cell lymphoma; NR = not reported; PTCL = peripheral T-cell lymphoma
a total of 8 dose levels to a maximum of 24.9 mg/m2. A total of 37 patients received 88 cycles of depsipeptide at 8 different dose levels. The maximum tolerated dose was found to be 17.8 mg/m2 given on days 1 and 5 every 21 days. However, dose-limiting toxicities were observed when patients were treated at 24.9 mg/m2. The dose-limiting toxicity included grade 3 fatigue (3 patients), grade 3 nausea and vomiting (1 patient), grade 4 thrombocytopenia (2 patients), and grade 4 cardiac arrhythmia (1 patient). Cardiac abnormalities such as asymptomatic, transient electrocardiogram changes, including ST-T wave flattening and inverted T waves, were observed with depsipeptide therapy. These changes are mostly evident by 24 hours after completion of drug infusion and typically resolve before day 5 of drug administration. No significant decline in cardiac ejection fraction was observed on multigated radionucleotide angiography scans. Preliminary results of this phase I trial at the National Cancer Institute suggested that depsipeptide has clinical activity in patients with cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). Following the definition of the maximum tolerated dose, a patient with PTCL was enrolled and achieved a com-
16 • Clinical Lymphoma June 2004
plete remission, which has been sustained for > 36 months. Additional patients with T-cell lymphoma, 7 with mycosis fungoides, and 3 with Sezary syndrome, were then enrolled at this dose level. All patients with mycosis fungoides achieved an objective response.
Ongoing Trials Based on these encouraging results, a multicenter phase II trial of depsipeptide administered by I.V. infusion at a dose of 14 mg/m2 on days 1, 8, and 15 of a 28-day cycle was initiated in patients with relapsed PTCL or CTCL.12 Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. A total of 38 patients with PTCL (n = 17) or CTCL (n = 21) have been enrolled in the study. Objective responses were reported in 8 of 21 evaluable patients with CTCL (38%) and in 4 of 17 patients with PTCL (24%; Table 1). Among 15 evaluable patients with CTCL who have received ≤ 2 systemic chemotherapy regimens, 8 responses (38%) have been observed: 3 patients with complete response with durations of 5, 21, and 26 months, respectively; and 5 patients with partial response. A multicenter phase II trial has recently been initiated combining depsipeptide with rituximab and fludarabine in
patients with relapsed or refractory lowgrade B-cell non-Hodgkin’s lymphoma. Clinical trials in solid tumors are open or under review in multiple centers.
Clinical Relevance Depsipeptide, a novel histone deacetylase inhibitor, has promising activity in Tcell lymphoma. Unusual toxicities attributed to depsipeptide included asymptomatic electrocardiogram changes and supraventricular arrhythmias, and these are being evaluated in ongoing trials. Several phase I/II clinical trials are currently evaluating the activity and safety of depsipeptide either as a single agent or in combination with other chemotherapy agents in patients with T-cell lymphomas.
References 1. Marks P, Rifkind RA, Richon VM, et al. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 2001; 1:194-202. 2. Peart MJ, Tainton KM, Ruefli AA, et al. Novel mechanisms of apoptosis induced by histone deacetylase inhibitors. Cancer Res 2003; 63:4460-4471. 3. Byrd JC, Shinn C, Ravi R, et al. Depsipeptide (FR901228): a novel therapeutic agent with selective, in vitro activity against human B-cell chronic lymphocytic leukemia cells. Blood 1999; 94:1401-1408. 4. Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 2002; 1:287-299. 5. Owa T, Yoshino H, Yoshimatsu K, et al. Cell cycle regulation in the G1 phase: a promising target for the development of new chemotherapeutic anticancer agents. Curr Med Chem 2001; 8:1487-1503. 6. Kwon HJ, Kim MS, Kim MJ, et al. Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis. Int J Cancer 2002; 97:290-296. 7. Weiser TS, Guo ZS, Ohnmacht GA, et al. Sequential 5Aza-2 deoxycytidine-depsipeptide FR901228 treatment induces apoptosis preferentially in cancer cells and facilitates their recognition by cytolytic T lymphocytes specific for NY-ESO-1. J Immunother 2001; 24:151-161. 8. Wang R, Brunner T, Zhang L, et al. Fungal metabolite FR901228 inhibits c-Myc and Fas ligand expression. Oncogene 1998; 17:1503-1508. 9. Ueda H, Nakajima H, Hori Y, et al. Action of FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum no. 968, on Haras transformed NIH3T3 cells. Biosci Biotechnol Biochem 1994; 58:1579-1583. 10. Sandor V, Robbins AR, Robey R, et al. FR901228 causes mitotic arrest but does not alter microtubule polymerization. Anticancer Drugs 2000; 11:445-454. 11. Piekarz RL, Wilson W, Bates SE. FK228, depsipeptide: current clinical data at the NIC. Presented at the International Congress on Hematological Malignancies: Focus on Leukemias, Lymphomas, and Myelomas, March 10-14, 2004, Whistler, British Columbia, Canada. 12. Piekarz RL, Robey R, Fojo AT, et al. Analysis of molecular markers and targets in trials of depsipeptide (FR901228), a histone deacetylase inhibitor with clinical activity in T-cell lymphoma. Proc Am Soc Clin Oncol 2002; 21:23a (Abstract #88).