Highlights from: 38th Annual Meeting of the American Society of Clinical Oncology May 18–21, 2002; Orlando, Florida

Meeting Highlights From: 38th Annual Meeting of the American Society of Clinical Oncology May 18-21, 2002 Orlando, Florida Activity of Yttrium-90 Ibritumomab (Zevalin™) in Relapsed Aggressive B-Cell Non-Hodgkin’s Lymphoma Non-Hodgkin’s lymphoma (NHL) is a radiosensitive malignancy. High objective response rates (ORRs, > 50%) and complete remissions (CRs) have been reported using a variety of radiolabeled antibodies to treat this tumor type.1 Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin™) has recently been approved by the US Food and Drug Administration for use in patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL.2 From the 4 clinical trials that led to the approval of 90Y ibritumomab tiuxetan, 8 of 15 patients who had transformed NHL also responded to this treatment (13% CR, 40% partial response [PR]).3 Based on these patients’ response, Dr Gordon and colleagues undertook a phase I/II study of 90Y ibritumomab tiuxetan in aggressive B-cell NHL. The results were recently reported at the 38th annual meeting of the American Society of Clinical Oncology (ASCO) in Orlando, Florida.4 Patients with relapsed aggressive Bcell NHL were enrolled in this trial. Patients were required to have an absolute neutrophil count > 1500/μL, platelets > 100,000/μL, and < 25% of the bone marrow involved with lymphoma in order to be included in this trial. Treatment consisted of a preinfusion with rituximab 250 mg/m2 to clear peripheral B cells and to block nonspecific Medical Writers: Angelia Gibson, PhD, and Heather DeGrendele, PhD Reviewed by: Mark S. Kaminski, MD, and James W. Lynch, MD

12 • Clinical Lymphoma June 2002

Table 1

Response to 90Y Ibritumomab Tiuxetan in Aggressive B-Cell NHL Number of Patients (n = 12)

Overall Response

58%

Complete Response

33%

Partial Response

25%

Median Duration of Response, Months (Range)

> 35.5 (2.4-40+)

Abbreviations: 90Y = yttrium 90; NHL = nonHodgkin's lymphoma

binding sites, followed by a tracer dose (5 mCi) of indium In-111 ibritumomab tiuxetan on day 1 for imaging. Patients were then treated with a therapeutic dose (0.3-0.4 mCi/kg) of 90Y ibritumomab tiuxetan on day 8. Twelve patients with either diffuse mixed lymphoma (3 patients) or diffuse large-cell lymphoma (9 patients) were included in this trial. The patients had a median age of 58 years and had been treated with a median of 2 prior regimens (range, 1-4), including ESHAP (etoposide/methylprednisolone/cytarabine/platinum), DHAP (dexamethasone/cytosine/cytarabine/cisplatin), and ICE (ifosfamide/carboplatin/etoposide). All patients had received prior CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) or CHOPlike regimens. None had undergone stem cell transplantation. The ORR to 90Y ibritumomab tiuxetan was encouraging at 58% in these patients, with 33% achieving a CR (Table 1). The responses to 90Y ibritumomab tiuxetan were sustained and median duration of response had not yet been reached at 35.5 months (range, 2.4-40+ months).

Hematologic toxicities included grade 4 neutropenia in 17% of the patients and thrombocytopenia in 8%. Clinical Relevance: 90Y ibritumomab tiuxetan appears to be active in patients with multiple relapsed aggressive B-cell NHL, with an ORR of 58% and 33% of patients achieving a CR. Additional trials of 90Y ibritumomab tiuxetan in aggressive NHL are needed to confirm these preliminary findings. __________________________________________________

Combination of Rituximab and Epratuzumab Is Active and Well Tolerated in Relapsed B-Cell NHL Encouraging clinical results with rituximab in patients with NHL have prompted interest in combining the anti-CD20 antibody with other agents, with goals of improving rates and durations of response in indolent and aggressive NHLs. Epratuzumab is a humanized monoclonal antibody that binds to CD22, an antigen that is expressed on most neoplastic and normal B lymphocytes. Dr Leonard and colleagues recently reported the activity of epratuzumab in patients with relapsed Bcell NHL.5,6 Responses were seen both in patients with indolent and aggressive NHL when epratuzumab was administered in 4 weekly doses ≥ 240 mg/m2. Adverse events were mainly grade 1/2 infusion reactions. A phase II trial was conducted to evaluate the safety and activity of epratuzumab administered together with rituximab every week for 4 weeks in patients with relapsed B-cell NHL.7 Dr Leonard reported the results of this phase II trial at

Meeting Highlights tients with aggressive NHL were heavily pretreated with a Epratuzumab Combination Therapy median of 4 prior therapies Attributed to Attributed to (range, 1-6). Two of the 5 paEpratuzumab Rituximab tients had undergone previous high-dose chemotherapy with 48% 57% All Adverse Events* stem cell transplantation. The 10% 24% Fever patients with indolent NHL 14% 19% Rigors had received 1-3 prior therapies 14% 14% Fatigue (median, 1). Approximately half of the patients had elevated 14% 14% Nausea lactate dehydrogenase, and 10% 14% Flu-Like Symptoms about 60% of the patient popu10% 15% Flushing lation had lymph nodes ≥ 5 cm in diameter. *Adverse events occurring in ≥ 20% of patients. Grade was not indicated. The combination of epratuzumab and rituximab was well tolerated, with mostly the 2002 ASCO meeting. The first cograde 1/2 infusional adverse events hort of patients enrolled in the trial re(Table 2). The most frequent adverse ceived epratuzumab 360 mg/m2 intraevents were fever, rigors, fatigue, nauvenously over 1 hour on day 1 of the sea, flu-like symptoms, and flushing. first treatment week followed 2 days There were no significant declines in later by rituximab 375 mg/m2. During red blood cell, neutrophil, or platelet weeks 2-4, patients received epratuzumcounts during therapy. ab followed immediately by rituximab, The response rates are shown in Table both given on day 1. Since this regimen 3. In total, 13 of 20 evaluable patients rewas well tolerated without any severe adsponded to therapy, including 7 CRs, 4 verse events in the first group, the second unconfirmed CRs, and 2 PRs. Three of 4 cohort of patients received both evaluable patients with DLBCL reepratuzumab and rituximab on the same sponded to therapy, and 2 achieved a day weekly for all 4 weekly treatments. CR. This was encouraging, as these paThe trial enrolled 21 patients with tients had refractory DLBCL and had relapsed or refractory indolent or agfailed multiple previous chemotherapies. gressive B-cell NHL. The median age Ten of 16 evaluable patients with indowas 63 years (range, 26-86 years). Sixlent histologies responded. Three additeen patients had indolent lymphoma tional patients had stable disease. With (follicular small-cleaved, follicular mixed, more than 5 months of median followor marginal zone histology), and 5 paup (range, 1-16 months), none of the retients had aggressive NHL (diffuse large sponders had progressed. B-cell lymphoma [DLBCL]). The paClinical Relevance: This study shows that these 2 B-cell–specific antibodies Table 3 Response to Epratuzumab/Rituximab (epratuzumab and rituximab) in Relapsed B-Cell NHL can be combined in patients Indolent NHL Aggressive NHL with relapsed or refractory B(n = 16) (n = 4) cell NHL without a significant 63% 75% Objective Response increase in adverse events. The response rate, especially the CR 31% 50% Complete Response rate, in this highly pretreated Unconfirmed Complete 25% 0 patient population is encouragResponse ing. A multicenter phase II 6% 25% Partial Response trial is ongoing to confirm these findings. Abbreviation: NHL = non-Hodgkin’s lymphoma

Table 2 Toxicities with Rituximab/

__________________________________________________

Rituximab Has Activity in Lymphocyte-Predominant Hodgkin’s Disease Lymphocyte-predominant Hodgkin’s disease (LPHD) is an uncommon variant of Hodgkin’s disease (HD) that is characterized by presentation with limited disease bulk, slow progression, and late relapses.8-10 Patients generally have long survival times following local therapy (radiation therapy [RT]) or chemotherapy such as ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine). LPHD is distinguished immunologically from classical HD by expression of the B-cell marker, CD20. The malignant cells of LPHD typically have an immunophenotype of CD20+, CD45+, CD15-, CD30-, whereas the immunophenotype of malignant cells in classical HD is generally CD20-, CD45-, CD15+, and CD30+.10 Rehwald and colleagues reported a 100% response rate in 5 previously treated patients with LPHD who were treated with 4 weekly infusions of rituximab 375 mg/m2 as part of a phase II trial (Table 4).11 Anecdotal evidence has also suggested that rituximab has activity in chemotherapy-refractory LPHD.12-14 Investigators at Stanford and Washington universities have conducted a phase II trial to evaluate the efficacy of 4 weekly infusions of rituximab (375 mg/m2) in patients with CD20+ LPHD.15 Both previously untreated and relapsed patients were eligible for the trial if they had CD20+ lymphoma cells, measurable disease, and normal organ and bone marrow function. Patients who had received chemotherapy or RT within 4 weeks of trial entry were not eligible for enrollment. Among the 22 patients enrolled, 10 had received prior chemotherapy or radiation therapy. Patient characteristics are shown in Table 5. Patients were treated with rituximab 375 mg/m2 once weekly for 4 weeks. Therapy was well tolerated with no grade 3/4 adverse events. Rituximab was very active in

Clinical Lymphoma June 2002 • 13

Meeting Highlights

Table 4 Clinical Experience with Rituximab in Lymphocyte-Predominant Hodgkin’s Disease Reference

Patients

Rehwald et al11

5 previously treated

Response 4 CRs (80%)

Comments No grade 3/4 adverse events

1 PR (20%) Trials

8/19 CRs (42%) Ekstrand et al

15

12 previously untreated and 10 previously treated

2/19 CRus (11%)

Median freedom from progression 10 months

9/19 PRs (47%)

Case Reports

Lush et al12

1 previously treated

Clinical remission with persistent T-cell infiltration of the bone marrow

Keilholz et al13

1 previously treated

Regression of disease

Papadaki et al14

1 previously treated

CR

Remission ongoing 21 months ___ Disease progression at 4 months Persistent neutropenia without infectious complications

Abbreviation: CRu = unconfirmed complete response

LPHD, and 21 of 22 evaluable patients achieved a response. Forty-six percent and 50% of patients achieved a CR and PR, respectively. Despite the high response rate, the response duration was short and the remissions were not durable. The median freedom from progression interval was 10 months; 7 of the 9 patients who progressed had achieved only a PR. Three patients who relapsed with CD20+ LPHD were retreated with an additional 4 infusions of rituximab, which resulted in a CR in 1 patient and stable disease in the other 2 patients. Although the response duration of initial treatment was short, the

Table 5 Characteristics of Lymphocyte-Predominant Hodgkin’s Disease Patients Enrolled in a Phase II Rituximab Trial 22

Number Enrolled Median Age, Years (Range)

45 (18-61)

Prior Therapy

10

1st Relapse

6

2nd Relapse

3

4th Relapse

1

Disease Stage (Among Previously Untreated) I

2

II

4

III

6

14 • Clinical Lymphoma June 2002

investigators were encouraged by the prompt tumor reduction and the ability to achieve clinical benefit with rituximab retreatment. Clinical Relevance: The investigators acknowledged that the responses to rituximab were shortlived but were encouraged by the high response rate and the absence of severe adverse events. The data do suggest a potential role for rituximab in the management of LPHD. Future approaches may include combining rituximab plus chemotherapy in LPHD. __________________________________________________

No Benefit of Consolidation with High-Dose Chemotherapy and Transplant in First Remission in Advanced Hodgkin’s Disease Patients with HD who have bulky mediastinal disease (mediastinal mass ratio of ≥ 0.45), ≥ 5 involved nodal areas, or ≥ 2 noncontiguous visceral sites have a 10year freedom from progression and survival of about 50%-60% following treatment with the standard regimen of ABVD.16,17 Better treatment options are clearly needed in this patient population. A subset analysis of 51 patients enrolled in the HD01 trial suggested that highdose chemotherapy with autologous

stem cell transplantation (ASCT) might be superior to 8 cycles of ABVD in very high-risk patients with HD.18 The German Lymphoma Study Group has reported that the dose-intensified chemotherapy regimen BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone), designed to administer higher doses of chemotherapy over a shorter time period (21-day cycles instead of 28-day cycles), produced better failure-free and overall survival compared with standard ABVD-based chemotherapy in patients with highrisk HD. Although toxicity was higher with the dose-intensified regimen, the escalated dosing schedule was thought to be especially beneficial in patients with poor prognostic HD.18,19 At the 2002 ASCO meeting, the Groupe Ouest Est d’etude des Leucenies et Autres Maladies du Sang (GOELAMS) from France reported the 4-year follow-up results from a randomized trial (H-97) comparing high-dose chemotherapy followed by ASCT and RT with a regimen of initial intensive chemotherapy plus radiation (without ASCT) in patients with very high-risk HD. Patients on the high-dose chemotherapy arm received 4 cycles of ABVD plus methylprednisolone, and those who achieved a PR or CR went on to receive a myeloablative regimen

Meeting Highlights nodal areas involved with lymTable 6 Comparison of Results of ASCT Versus phoma, 49 had a mediastinal Intensive Chemotherapy for High-Risk mass ratio ≥ 0.45, and 24 had Hodgkin’s Disease ≥ 2 involved visceral sites. Initial Intensive Table 6 shows that high-dose ASCT Arm Chemotherapy Arm chemotherapy with ASCT 92% 89% Complete Response was no better than intensive chemotherapy in achieving 4-Year Freedom from 73% 87% Progression durable remissions. Approximately 90% of patients 83% 90% 4-Year Overall Survival achieved a CR in both treatment arms. Four-year freedom Abbreviation: ASCT = autologous stem cell transplantation from progression and overall tively) compared to patients in the survival rates were higher, though not high-dose chemotherapy/ASCT arm statistically significant, for patients who (73% and 83%, respectively). Febrile underwent intensive chemotherapy neutropenia was observed in 66% of the without ASCT (87% and 90%, respecchemotherapy cycles in the ASCT arm and in 61% of the cycles in the intenFigure 1 GOELAMS H-97 GM Trial: Treatment Schema sive chemotherapy (VABEM) arm. There were 2 toxic deaths during inVery High-Risk HD tensive initial chemotherapy with VABEM.

of BEAM (carmustine/etoposide/cytarabine/melphalan) followed by ASCT and RT. Patients randomized to intensive chemotherapy without ASCT received 3 cycles of VABEM (vindesine/ doxorubicin/carmustine/etoposide/met hylprednisolone) with granulocyte colony-stimulating factor. The cycles were repeated every 28 days, and responders were consolidated with RT. The treatment schema, including doses, is shown in Figure 1.20 The trial enrolled 152 eligible patients and, as of May 2002, 108 patients were evaluable for response and toxicity. Eighty-eight patients had nodular sclerosis histology, 59 had ≥ 5

RANDOMIZE

ABVD Doxorubicin 25 mg/m2, days 1 and 15 Bleomycin 10 mg/m2, days 1 and 15

Intensive Chemotherapy Vindesine 1 mg/m2, days 1-5 Doxorubicin 33 mg/m2, CI days 1-3

Vinblastine 6 mg/m2, days 1 and 15 Dacarbazine 375 mg/m2, days 1 and 15

Carmustine 140 mg/m2, day 3 Etoposide 300 mg/m2, days 3-5 Methylprednisolone 120 mg/m2, days 1-5 G-CSF Cycles repeat every 28 days x 3

Cycles repeat every 28 days x 4

Conditioning and Stem Cell Harvest Cyclophosphamide 4 g/m2, day 1

Clinical Relevance: These data indicate that consolidation with high-dose chemotherapy and ASCT after 4 cycles of ABVD is no better than up-front intensive chemotherapy in patients with high-risk HD. Whether either of these intensive treatments are superior to standard ABVD or other regimens will need to be addressed in future randomized studies. __________________________________________________

Depsipeptide, a Novel Histone Deacetylase Inhibitor, Produces Rapid and Durable Objective Responses in T-Cell Lymphoma

G-CSF 5 mg/kg G-CSF 5 mg/kg Followed by stem cell harvest

BEAM Carmustine 300 mg/m2, day 1 Etoposide 200 mg/m2, days 2-5 Cytarabine 400 mg/m2, days 2-5 Melphalan 140 mg/m2, day 6 I.V. Followed by stem cell reinfusion Radiation Therapy

Radiation Therapy 20 Gy to involved field

36 Gy on involved lymph nodal areas that measured ≥ 5 cm initially

16 Gy to involved lymph nodal areas measured ≥ 5 cm initially

Abbreviations: ABVD = doxorubicin/bleomycin/vinblastine/dacarbazine; BEAM = carmustine/ etoposide/cytarabine/melphalan; CI = continuous infusion; G-CSF = granulocyte colony-stimulating factor; GOELAMS = Groupe Ouest Est d’etude des Leucenies et Autres Maladies du Sang; HD = Hodgkin’s disease

Histone acetylation and deacetylation are key processes in the regulation of transcription in eukaryotic cells.21 Chromatin is a highly specialized structure that is usually tightly compacted around the nucleosomal core comprised of an octamer of histone proteins. The structural organization of chromatin, and accessibility to the transcriptional machinery of the cell, is regulated through the acetylation and deacetylation of the histone proteins,

Clinical Lymphoma June 2002 • 15

Meeting Highlights Table 7

Activity of Depsipeptide in T-Cell Lymphoma Number of Patients (%) (n = 13)

Median Treatment Duration (Weeks)

11 (85%)

17+

1 (8%)

110+

Partial Response

10 (77%)

16.5+

Disease Progression

2 (15%)

6.5

Lymphoma Type PTCL n = 2

Response Rate Complete Response

CTCL n = 9 PTCL n = 1 PTCL n = 1 CTCL n = 9 PTCL n = 2

Abbreviations: CTCL = cutaneous T-cell lymphoma; PTCL = peripheral T-cell lymphoma

mediated by acetylase and deacetylase enzymes. There is evidence to suggest that several neoplasms, including T-cell lymphomas, may have deregulation of histone acetylation and deacetylation, which may drive the neoplastic process.21 Depsipeptide (FR901228, NSC 630176) is a novel histone deacetylase inhibitor that has been shown in preclinical studies to alter the transcriptional profile of cancer cells through hyperacetylation, leading to terminal differentiation, the induction of cell cycle arrest and/or apoptosis, and, in some models, inhibition of angiogenesis.22-25 A phase I dose-finding and pharmacokinetic study of depsipeptide in patients with various neoplasms was recently reported.26 Eligible patients were refractory to available treatments,

were ≥ 18 years of age, and had an Eastern Cooperative Oncology Group performance status of 0-2. Patients received escalating doses of depsipeptide (1.0-24.9 mg/m2) given days 1 and 5 every 21 days. Dose-limiting toxicities were seen at the 24.9 mg/m2 dose level and included grade 3 fatigue, grade 3 nausea/vomiting, grade 3 neutropenia, grade 4 thrombocytopenia, and grade 4 cardiac arrhythmia (1 patient). The first patient enrolled at the maximum tolerated dose was a patient with peripheral T-cell lymphoma (PTCL) who rapidly achieved a complete disease remission, which was sustained for 18+ months.27 Additional T-cell lymphoma patients were therefore enrolled at this dose level, 7 with mycosis fungoides and 3 with Sézary syndrome. All 7 patients with mycosis fungoides

achieved an objective response. Based on these encouraging results, a phase II trial has been initiated with depsipeptide (14 mg/m2 given days 1, 8, and 15 every 28 days) in patients with PTCL and cutaneous T-cell lymphoma (CTCL). An assessment of 13 evaluable patients from both trials was presented by Dr Piekarz at the 2002 ASCO meeting.28 Seventeen patients with T-cell lymphoma have been treated in phase I/II studies, of whom 6 patients had PTCL and 11 had CTCL. Of 13 evaluable patients, there was 1 CR in a patient with PTCL and 10 PRs, for an ORR of 85% (Table 7). Two other patients with PTCL progressed. Of note, in 2 patients with Sézary syndrome, a marked decrease in circulating Sézary cells along with the induction of surface CD25 expression was observed. In all patients tested, increased histone acetylation was observed for ≥ 24 hours using immunoblot analysis. Clinical Relevance: The activity of the novel histone deacetylase inhibitor depsipeptide in 13 patients with T-cell lymphoma is encouraging. Objective responses have been seen in 85% of 13 patients. Further follow-up and additional trials will be required to more completely define the efficacy and safety of depsipeptidase in T-cell lymphoma.

References 01. Gordon LI, Witzig TE, Wiseman GA, et al. Yttrium 90 ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory low-grade non-Hodgkin's lymphoma. Semin Oncol 2002; 29:87-92. 02. Crawford LM, Jr. From the Food and Drug Administration. JAMA 2002; 287:1640. 03. Bartlett NL, Witzig TE, Gordon L, et al. Y 90-ibritumomab tiuxetan (Zevalin) radioimmunotherapy for transformed B-cell non-Hodgkin's lymphoma (NHL) patients. Proc Am Soc Clin Oncol 2002; 21:14a (Abstract #51). 04. Gordon LI, Witzig TE, Emmanouilides CE, et al. Y 90 ibritumomab (Zevalin) in aggressive non-Hodgkin's lymphoma: analysis of response and toxicity. Proc Am Soc Clin Oncol 2002; 21:266a (Abstract #1061). 05. Leonard JP, Coleman M, Schuster M. Immunotherapy of NHL with epratuzumab (anti-CD22 monoclonal antibody): excellent tolerability with objective responses. Proc Am Soc Clin Oncol 2000; 19:17a (Abstract #60). 06. Leonard J, Coleman M, Chadburn A, et al. Epratuzumab (HLL2, anti-CD22 humanized monoclonal anti-

16 • Clinical Lymphoma June 2002

body) is an active and well-tolerated therapy for refractory/relapsed diffuse large B-cell non-Hodgkin's lymphoma (NHL). Blood 2000; 96(suppl 1):578a (Abstract #2482). 07. Leonard J, Coleman M, Matthews J, et al. Epratuzumab (Anti-CD22) and rituximab (Anti-CD20) combination immunotherapy for non-Hodgkin's lymphoma: preliminary response data. Proc Am Soc Clin Oncol 2002; 21:266a (Abstract #1060). 08. Anagnostopoulos I, Hansmann ML, Franssila K, et al. European Task Force on Lymphoma project on lymphocyte predominance Hodgkin disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes. Blood 2000; 96:18891899. 09. Franklin J, Tesch H, Hansmann ML, et al. Lymphocyte predominant Hodgkin's disease: pathology and clinical implication. Ann Oncol 1998; 9(suppl 5):S39-S44. 10. von Wasielewski R, Werner M, Fischer R, et al. Lymphocyte-predominant Hodgkin's disease. An immunohistochemical analysis of 208 reviewed Hodgkin's dis-

ease cases from the German Hodgkin Study Group. Am J Pathol 1997; 150:793-803. 11. Rehwald U, Engert A, Diehl V. Monoclonal anti-CD20 antibody rituximab (Rituxan) for treatment of CD20positive Hodgkin's lymphoma: the German experience. Blood 2000; 96:729a (Abstract #3153). 12. Lush RJ, Jones SG, Haynes AP. Advanced-stage, chemorefractory lymphocyte-predominant Hodgkin's disease: long-term follow-up of allografting and monoclonal antibody therapy. Br J Haematol 2001; 114:734735. 13. Keilholz U, Szelenyi H, Siehl J, et al. Rapid regression of chemotherapy refractory lymphocyte predominant Hodgkin's disease after administration of rituximab (anti CD 20 monoclonal antibody) and interleukin-2. Leuk Lymphoma 1999; 35:641-642. 14. Papadaki T, Stamatopoulos K, Stavroyianni N, et al. Evidence for T-large granular lymphocyte-mediated neutropenia in Rituximab-treated lymphoma patients: report of two cases. Leuk Res 2002; 26:597-600. 15. Ekstrand B, Lucas J, Horwitz S, et al. Rituximab in lymphocyte predominant Hodgkin’s disease (LPHD):

Meeting Highlights results of a phase II trial. Proc Am Soc Clin Oncol 2002; 21:264a (Abstract #1052). 16. Andrieu JM, Jais JP, Colonna P, et al. Ten-year results of a strategy combining three cycles of ABVD and high-dose extended irradiation for treating Hodgkin's disease at advanced stages. Ann Oncol 1998; 9:195203. 17. Colonna P, Jais JP, Desablens B, et al. Mediastinal tumor size and response to chemotherapy are the only prognostic factors in supradiaphragmatic Hodgkin's disease treated by ABVD plus radiotherapy: ten-year results of the Paris-Ouest-France 81/12 trial, including 262 patients. J Clin Oncol 1996; 14:1928-1935. 18. Federico M, Clo V, Carella AM. High-dose therapy autologous stem cell transplantation vs conventional therapy for patients with advanced Hodgkin's disease responding to first-line therapy: analysis of clinical characteristics of 51 patients enrolled in the HD01 protocol. EBMT/ANZLG/Intergroup HD01 Trial. Leukemia 1996; 10(suppl 2):S69-S71. 19. Diehl V, Franklin J, Hasenclever D, et al. BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with ad-

vanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol 1998; 16:3810-3821. 20. Saghatchian M, Djeridane M, Escoffre BM, et al. Very high risk Hodgkin's disease (HD): ABVD (4 cycles) plus BEAM followed by autologous stem cell transplantation (ASCT) and radiotherapy (RT) versus intensive chemotherapy (3 cycles) (INT.CT) and RT. Four-year results of the GOELAMS H97-GM multicentric randomized trial. Proc Am Soc Clin Oncol 2002; 21:263a (Abstract #1051). 21. Marks P, Rifkind RA, Richon VM, et al. Histone deacetylases and cancer: causes and therapies. Nature Rev Cancer 2001; 1:194-202. 22. Kwon HJ, Kim MS, Kim MJ, et al. Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis. Int J Cancer 2002; 97:290-296. 23. 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. 24. Weiser TS, Guo ZS, Ohnmacht GA, et al. Sequential 5-Aza-2'-deoxycytidine-depsipeptide FR901228 treat-

ment 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. 25. Kosugi H, Ito M, Yamamoto Y, et al. In vivo effects of a histone deacetylase inhibitor, FK228, on human acute promyelocytic leukemia in NOD/Shi-scid/scid mice. Jpn J Cancer Res 2001; 92:529-536. 26. Sandor V, Bakke S, Robey RW, et al. Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin Cancer Res 2002; 8:718-728. 27. Piekarz RL, Robey RW, Sandor V, et al. Potential value of the histone deacetylase inhibitor depsipeptide (FR901228) in the treatment of peripheral and cutaneous T cell lymphoma. Proc AACR-NCI-EORTC Int Conf 2001:74 (Abstract #360). 28. Piekarz RL, Robey RW, Fojo T. 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; 21:232a (Abstract #88).

Clinical Lymphoma June 2002 • 17