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Originally published as JCO Early Release 10.1200/JCO.2007.11.4207 on August 20 2007 © 2007 American Society of Clinical Oncology. Phase II Trial of Proteasome Inhibitor Bortezomib in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma
From the Institute of Hematology and Medical Oncology "L. & A. Seràgnoli", University of Bologna, Bologna, Italy Address reprint requests to Pier Luigi Zinzani, MD, Institute of Hematology and Oncology "L. & A. Seràgnoli", Via Massarenti 9, 40138 Bologna, Italy; e-mail: plzinzo{at}med.unibo.it
Purpose To determine the antitumor activity of the proteasome inhibitor bortezomib in patients with cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma unspecified (PTCLU) with isolated skin involvement. Patients and Methods From May 2005 to June 2006 at our institute, we treated patients with previously pretreated CTCL or PTCLU using bortezomib as a single agent, at a dose of 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, every 21 days for a total of six cycles. Results Fifteen patients were registered, of whom 12 (10 CTCL, all mycosis fungoides, and two PTCLU with isolated skin involvement) were assessable. The overall response rate was 67%, with two (17%) complete remissions and six (50%) partial remissions. The remaining four patients had disease progression. Histologically, the responder patients were seven with CTCL and one with PTCLU with isolated skin involvement. All responses were durable, lasting from 7 to 14 or more months. Overall, the drug was well tolerated, with no grade 4 toxicity. The most common grade 3 toxicities were neutropenia (n = 2), thrombocytopenia (n = 2), and sensory neuropathy (n = 2). Conclusion This study suggests that bortezomib was well tolerated and has significant single-agent activity in patients with cutaneous T-cell lymphoma.
Cutaneous T-cell lymphoma (CTCL) is the most common type of primary cutaneous lymphoma, representing 65% of cases of skin lymphoma. Primary cutaneous lymphomas often have a different clinical behavior and prognosis from histologically similar systemic lymphomas involving the skin secondarily, and therefore require different types of therapies. For that reason, the new WHO–European Organisation for Research and Treatment of Cancer (EORTC) classification1 has been developed on the basis of the EORTC classification for cutaneous lymphomas2 and the WHO classification for nodal lymphomas.3 When approaching the topic of chemotherapy in different subtypes of CTCL,1 the first issue to be made clear is the target of this type of treatment. The use of systemic chemotherapy as a first-line treatment should be restricted, with few exceptions, to advanced or aggressive forms of CTCL. Of course, chemotherapy is one of the options in any refractory CTCL. The second issue concerns the selection of chemotherapy regimens. The choice of treatment is often determined by institutional experience, particularly as there is a paucity of data from phase III trials and a lack of consensus concerning treatment for the later stages of CTCL. A careful and balanced evaluation of specific diagnosis, tumor load, cutaneous lesion features, age, and performance status is obviously the standard to date. Monochemotherapy is one of the options indicated in CTCL refractory to or relapsing after first-line treatments. Gemcitabine4-6 and pegylated liposomal doxorubicin7,8 should be considered among the most suitable options to date, with overall response rates (ORRs) of 70% and 88%, respectively. Other regimens, like 2-chlorodeoxyadenosine9,10 and pentostatin11 have shown lower ORRs, albeit with the limitation of small patient series. Polychemotherapy regimens, whether VICOP-B (idarubicin, etoposide, cyclophosphamide, vincristine, prednisone, bleomycin)12 or EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, prednisone),13 have shown comparable results in terms of ORR, and obviously had a worse benefit/risk profile.
Inhibition of the proteasome via bortezomib has been associated with clinical effects in a variety of hematologic malignancies, including multiple myeloma and non-Hodgkin's lymphoma.14-17 Recently, some authors have reported that a key role may be played by NF- In view of these findings, we decided to investigate the efficacy and safety of bortezomib in a single-center, single-agent phase II trial for patients with relapsed/refractory cutaneous T-cell lymphomas, including advanced mycosis fungoides and peripheral T-cell lymphoma unspecified (PTCLU) with isolated skin involvement.
Patient Eligibility Patients older than 18 years with biopsy-proven, pretreated (second or more relapsed or refractory disease), bidimensionally measurable, any-stage CTCL/PTCLU (with only skin involvement) were eligible for this trial if they had a WHO performance status of 0 to 2. All patients were notified of the investigational nature of this study and signed a written informed consent approved in accordance with institutional guidelines, including the Declaration of Helsinki. The study was approved by the institutional review board. All diagnostic biopsies were reviewed by expert pathologists (S.P., E.S.) from our institute to confirm the diagnosis of CTCL/PTCLU (with only skin involvement) according to the WHO-EORTC classification.1
Baseline Studies
Treatment Plan Patients were treated at a dose of 1.3 mg/m2 twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 1-week rest period (one cycle); patients were treated for up to a total of six cycles unless removed from study for failure to respond or toxicity. All cycles were delivered on an outpatient basis. If there were fewer than 1,500/µL granulocytes or fewer than 100,000/µL platelets by the time the next cycle was due, treatment was delayed for 1 week, and counts were repeated. If after 2 weeks, counts had not recovered, the patient was treated at the 1 mg/m2 dose. Re-escalation was at the discretion of the treating physician. Growth-stimulating factors were not administered to prevent neutropenia, but patients who experienced grade 3 or 4 neutropenia or developed neutropenic fever between cycles might have received growth factors for subsequent cycles of therapy, at the discretion of the treating physician.
Restaging Safety and tolerability were assessed by monitoring the incidence, severity, and type of any adverse event. Adverse events were graded according to WHO criteria for toxicity.
Statistical Analysis
Patient Characteristics Fifteen consecutive patients were registered in this trial between May 2005 and June 2006 when the study reached completion and was closed. Only 12 patients were assessable because three patients completed only one cycle of therapy: two patients because of logistic and familiar problems; one patient was lost to follow-up. Patient characteristics are listed in Table 1. The median age of patients on the trial was 62 years (range, 48 to 80 years). Eleven (92%) were male and one (8%) was female. Ten patients had CTCL (all mycosis fungoides [MF]) and two had PTCLU with isolated skin involvement. Table 2 summarizes the previous treatments for each patient.
Clinical Response The median number of cycles was six. The doses received were more than 95% for all patients. Clinical results are summarized in Table 3. The ORR was 67%, including two complete remissions (CR; 17%) and six partial remissions (PR; 50%). According to the histologic subtypes, patients with MF had a CR rate of 10% (one of 10 patients) and a PR rate of 60% (six of 10 patients). Conversely, of the two PTCLUs there was one (50%) CR.
The likelihood of response was only marginally influenced by the number of prior regimens. Thus, of the five patients who had received only two previous regimens, the ORR was 80% (one CR and three PR)—a figure only slightly higher than the 57% ORR (one CR and three PR) recorded in the seven patients who had received three previous regimens. Both CRs were histologic when re-evaluated by local biopsy. Both of these histologic CRs (one MF and one PTCLU) were confirmed by immunohistochemistry. Of the two patients who obtained CR, one (MF patient) was still in remission after 12 months, whereas the other one relapsed 10 months after completion of treatment. Three of the six PRs remained in PR after 14, 8, and 7 months, respectively; the remaining PRs showed a disease progression within 7, 9, and 12 months, respectively. Figures 1 and 2 show the response in two patients.
Toxicity Bortezomib was generally well tolerated, and all responding patients completed the treatment (Table 4). Concerning the hematologic toxicity, no WHO grade 4 toxicity was observed; grade 3 neutropenia was recorded in two patients (17%), grade 3 thrombocytopenia was observed in two patients (17%), while no grade 3 anemia was recorded. With regard to nonhematologic toxicity, the most significant toxicity was sensory neuropathy: grade 1 to 3 was observed in 50% of patients, but only one patient reported grade 3 toxicity (he had a complete recovery within 6 weeks). None showed grade 4 sensory neuropathy.
There was no observation of rashes during therapy, and there was no GI toxicity, orthostatic hypotension, dehydration, or fatigue. Neither infections nor treatment-related deaths were recorded.
A small number of efficacious therapeutic approaches are available to the various stages of MF and PTCLU with isolated skin involvement. The lack of convincing survival benefit to patients in aggressive multimodality therapy trials as compared with palliative treatments, suggests that long disease-free remissions may be observed after therapy but reflect disease biology rather than inherent curative potential of the modality applied.27 Thus, it remains an important goal to develop new agents and approaches with single and specific action mechanisms. In this way, either better cosmetic and symptomatic palliation may be achieved for patients with this disease or, ultimately, curative treatments may be identified.
Among the newly-targeted therapies, bortezomib exerts an antitumor activity by mechanisms that may vary among tumor types, while the extent to which each affected pathway is critical to the inhibition of tumor growth also seems to differ. In particular, in CTCL cell lines, the significant decrease in nuclear NF- In the present study of a group of previously treated patients, we have shown that bortezomib indeed induces remission (67% ORR including the observation of CRs) in MF and PTCLU with isolated skin involvement. Bortezomib shows similar efficacy in both histologic subtypes, and also seems to be equally effective in pretreated and heavily pretreated patients. In addition, the whole therapy was performed in an outpatient setting, and related toxicity was modest. Standard antiemetics were not used, and no cumulative toxicity patterns were observed. This report represents the first evidence in the literature concerning the potential role of bortezomib in patients with MF and PTCLU. Bortezomib-treated patients had a higher or at least comparable overall response rate compared with literature data on such patients when treated with gemcitabine,4-6 pegylated liposomal doxorubicin,7,8 2-chlorodeoxyadenosine,9,10 or pentostatin.11 These findings lead us to conclude that bortezomib has a good activity and acceptable toxicity in previously treated MF and PTCLU patients with isolated skin involvement. Larger trials will be necessary to further explore the therapeutic potential of bortezomib in pretreated and untreated MF and PTCLU with isolated skin involvement.
The author(s) indicated no potential conflicts of interest.
Conception and design: Pier Luigi Zinzani Collection and assembly of data: Gerardo Musuraca, Monica Tani, Vittorio Stefoni, Enrica Marchi, Mariapaola Fina, Cinzia Pellegrini, Lapo Alinari, Enrico Derenzini, Elena Sabattini Data analysis and interpretation: Antonio de Vivo Manuscript writing: Pier Luigi Zinzani Final approval of manuscript: Stefano Pileri, Michele Baccarani
published online ahead of print at www.jco.org on August 20, 2007. Supported in part by Sezione di Bologna dell’Associazione Italiana contro le leucemie, linformi e mieloma (BolognAIL). Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification for cutaneous lymphomas. Blood 105:3768-3785, 2005 2. Willemze R, Kerl H, Sterry W, et al: EORTC classification for primary cutaneous lymphomas: A proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 90:354-365, 1997 3. Jaffe E, Nancy LH, Stein H, Vardiman JW (eds): Tumors of Hematopoietic and Lymphoid Tissues. Lyon, France, IARC, 2001 4. Zinzani PL, Magagnoli M, Bendandi M, et al: Therapy with gemcitabine in pretreated peripheral T-cell lymphoma patients. Ann Oncol 9:1351-1353, 1998 5. Zinzani PL, Baliva G, Magagnoli M, et al: Gemcitabine treatment in pretreated cutaneous T-cell lymphoma: Experience in 44 patients. J Clin Oncol 18:2603-2606, 2000 6. Marchi E, Alinari L, Tani M, et al: Gemcitabine as frontline treatment for cutaneous T-cell lymphoma: Phase II study of 32 patients. Cancer 104:2437-2441, 2005[CrossRef][Medline] 7. Wollina U, Graefe T, Karte K: Treatment of relapsing or recalcitrant cutaneous T-cell lymphoma with pegylated liposomal doxorubicin. J Am Acad Dermatol 42:40-46, 2000[CrossRef][Medline] 8. Wollina U, Dummer R, Brockmeyer NH, et al: Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma. Cancer 98:993-1001, 2003[CrossRef][Medline] 9. Kuzel TM, Hurria A, Samuelson E, et al: Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma. Blood 87:906-911, 1996 10. Trautinger F, Schwarzmeier J, Honigsmann H, et al: Low-dose 2-chlorodeoxyadenosine for the treatment of mycosis fungoides. Arch Dermatol 135:1279-1280, 1999 11. Kurzrock R, Pilat S, Duvic M: Pentostatin therapy of T-cell lymphomas with cutaneous manifestation. J Clin Oncol 17:3117-3121, 1999 12. Fierro MT, Doveil GC, Quaglino P, et al: Combination of etoposide, idarubicin, cyclophosphamide, vincristine, prednisone and bleomycin (VICOP-B) in the treatment of advanced cutaneous T-cell lymphoma. Dermatology 194:268-272, 1997[Medline] 13. Akpek G, Koh HK, Bogen S, et al: Chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophophamide, and oral prednisone in patients with refractory cutaneous T-cell lymphoma. Cancer 86:1368-1376, 1999[CrossRef][Medline] 14. Chauhan D, Hideshima T, Mitsiades C, et al: Proteasome inhibitor therapy in multiple myeloma. Mol Cancer Ther 4:686-692, 2005 15. Orlowski RZ, Stinchcombe TE, Mitchell BS, et al: Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 20:4420-4427, 2002 16. Goy A, Younes A, McLaughlin P, et al: Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol 23:667-675, 2005 17. O'Connor OA, Wright J, Moskowitz C, et al: Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol 23:676-684, 2005 18. Izban KF, Ergin M, Qin JZ, et al: Costitutive expression of NF-kappa B is a characteristic feature of mycosis fungoides: Implications for apoptosis resistance and pathogenesis. Hum Pathol 31:1482-1490, 2000[CrossRef][Medline] 19. Martinez-Delgado B, Melendez B, Cuadros M, et al: Expression profiling of T-cell lymphomas differentiates peripheral and lymphoblastic lymphomas and defines survival related genes. Clin Cancer Res 10:4971-4982, 2004 20. Nasr R, El-Sabban ME, Karam JA, et al: Efficacy and mechanism of action of the proteasome inhibitor PS-341 in T-cell lymphomas and HTLV-1 associated adult T-cell leukaemia/lymphoma. Oncogene 24:419-430, 2005[CrossRef][Medline] 21. Sors A, Jean-Louis F, Pellet C, et al: Down-regulation constitutive activation of the NF-kappaB canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apoptosis. Blood 107:2354-2363, 2006 22. Carbone PP, Kaplan HS, Musshoff K, et al: Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 31:1860-1861, 1971 23. Cheson BD, Horning SJ, Coiffer B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas: NCI-Sponsored International Working Group. J Clin Oncol 17:1244-1253, 1999 24. Fleming TR: One-sample multiple testing procedure for phase II clinical trials. Biometrics 38:143-151, 1982[CrossRef][Medline] 25. Machin D, Campbell MJ: Statistical tables for the design of clinical trials. Oxford, UK, Blackwell, 1987 26. A'Hern RP: Sample size tables for exact single-stage phase II designs. Stat Med 20:859-866, 2001[CrossRef][Medline] 27. Kaye FJ, Bunn PA Jr, Steinberg SM, et al: A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med 321:1784-1790, 1989[Abstract] Submitted February 23, 2007; accepted June 20, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
B in the CTCL resistance to apoptosis, which supports a potential therapeutic role for bortezomib in the treatment of patients with CTCL.
1.5 x 109/L), platelet count (
2.0 mg/dL], liver function tests [AST and ALT 
0 as the proportion of response below which treatment does not warrant further investigation and 
) at .05 (two-sided) and a power of 1 – β = 80%, is 12, and the number of successes (responses) is seven. If, by the end of the trial, at least seven responses (successes) are observed, the treatment will be accepted for a phase III trial.
