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© 2000 American Society for Clinical Oncology Gemcitabine Treatment in Pretreated Cutaneous T-Cell Lymphoma: Experience in 44 PatientsFrom the Institute of Hematology and Medical Oncology "Seràgnoli," University of Bologna, and Institute of Dermatology "Immacolata," Rome, Italy. Address reprint requests to Pier Luigi Zinzani, MD, Istituto di Ematologia ed Oncologia Medica "L. e A. Seràgnoli," Policlinico S. Orsola, Via Massarenti 9, 40138 Bologna, Italy; email plzinzo{at}med.unibo.it
PURPOSE: To evaluate the efficacy and toxicity of gemcitabine, a novel pyrimidine antimetabolite with a low-toxicity profile and activity in several solid tumors, in patients with relapsed or refractory cutaneous T-cell lymphomas. PATIENTS AND METHODS: Between May 1997 and February 1999, 44 previously treated patients with mycosis fungoides (MF; n = 30) and peripheral T-cell lymphoma unspecified (PTCLU) with exclusive skin involvement (n = 14) were enrolled onto a two-institution, phase II trial and treated with gemcitabine. This drug was given on days 1, 8, and 15 of a 28-day schedule at a dose of 1,200 mg/m2 intravenously over 30 minutes for a total of three courses. RESULTS: Of the 44 patients, five (11.5%) achieved complete responses (CRs), 26 (59%) partial responses (PRs), and the remaining 13 showed no benefit from the treatment. Two of the CRs were histologically confirmed. The CR and PR rates were the same for patients with MF and those with PTCLU, respectively. No difference in terms of overall response rate was observed between relapsed and refractory patients. The median durations of CR and PR were 15 months (range, 6 to 22 months) and 10 months (range, 2 to 15 months), respectively. Treatment was well tolerated; hematologic toxicity was mild, and no nausea/vomiting or organ toxicity was recorded. CONCLUSION: The results of the present phase II study show activity of gemcitabine as a single agent in patients with pretreated cutaneous T-cell lymphoma. Further studies that use gemcitabine alone or in combination with other drugs in earlier stages of the disease are needed.
A NUMBER OF NEW approaches to the treatment of lymphoma have emerged in recent years, including high-dose sequential courses of chemotherapy,1,2 anti-CD20 monoclonal antibody alone or combined with either conventional chemotherapy or high-dose therapy,3,4 and radioimmunotherapy.5,6 Despite the apparent success of these treatments, a number of histologic subtypes of lymphoma remain difficult to treat, including mantle-cell lymphoma and peripheral T-cell neoplasms.7 In particular, for advanced-stage mycosis fungoides (MF) and peripheral T-cell lymphoma unspecified (PTCLU) with exclusive skin involvement, there is a pressing need to evaluate new agents, because conventional forms of treatment, including chemotherapy, radiotherapy, combined-modality approaches, and the DAB-IL-2 immunotoxin conjugate treatment, do not produce long-term disease-free survival.8-11 However, encouraging data have been published recently on the possible role of pentostatin in the treatment of such lymphoma types.12 Gemcitabine (2',2'-difluorodeoxycytidine) is a novel pyrimidine antimetabolite13 with a low-toxicity profile and activity in several solid tumors, such as lung, pancreas, breast, ovary, and bladder cancer.14,15 In this study, we report the clinical findings and response to gemcitabine in 44 consecutive, previously treated patients with MF and PTCLU with exclusive skin involvement enrolled onto two institutions in a prospective phase II trial.
Between May 1997 and February 1999, 44 consecutive patients with previously treated MF and PTCLU completed treatment with gemcitabine either at the Institute of Hematology and Medical Oncology "L. e A. Seragnoli" in Bologna or the Institute of Dermatology "Immacolata" in Rome. Inclusion criteria of the study included the following: histologic (with immunohistochemistry) diagnosis of MF or PTCLU according to the Revised European-American Lymphoma classification7; relapsed or refractory disease after at least two conventional therapeutic approaches (chemotherapy and/or radiotherapy); isolated cutaneous involvement and lesions limited to a single (bulky) cutaneous region or disseminated, involving at least two nonadjacent regions; World Health Organization (WHO) performance status  2; time lapse of 8 weeks since prior chemotherapy or radiation; age greater than 18 years; and normal renal, hepatic, and cardiac function. Informed consent was obtained from all patients in accordance with the ethics policy of the participating institutes; the study was performed in accordance with the Helsinki declaration. The extent of disease was determined at diagnosis and at the end of the treatment, as well as during the follow-up, by complete skin examination, computed tomography scanning of the chest, abdomen, and pelvis, and bone marrow biopsy (at diagnosis only). All patients presented disease only in the skin. At the time of study entry, patients were completely evaluated for the extension of their skin lesions, but no skin scoring system was used to assess erythema.
Patients’ Characteristics
Treatment Protocol Gemcitabine hydrochloride (Gemzar, Eli Lilly, Indianapolis, IN) was supplied as a lyophilized powder. The drug was diluted in normal saline and administered intravenously over 30 minutes. Gemcitabine was given to all patients on days 1, 8, and 15 of a 28-day schedule at a dose of 1,200 mg/m2 for a total of three cycles. All cycles were delivered on an outpatient basis.
Evaluation of Response Patients were evaluated by weekly history and physical examinations, complete blood counts, and chemistry profiles. All signs, symptoms, or laboratory abnormalities were assessed using WHO criteria for toxicities.
Response and Survival Clinical results are summarized in Table 2. The overall response rate (CR + PR) was 70.5% (31 of 44 patients); the CR and PR rates as defined above were 11.5% (five of 44 patients) and 59% (26 of 44 patients), respectively. According to the histologic subtypes, patients with MF had a CR rate of 10% (three of 30 patients) compared with 14.5% (two of 14 patients) among the patients with PTCLU. Patients with MF had a PR rate of 60% (18 of 30 patients) compared with 57% (eight of 14 patients) among the patients with PTCLU.
Concerning the disease status (Table 3), the CR and PR rates were 11.5% (four of 34 patients) and 59% (20 of 34 patients), respectively, for relapsed patients and 10% (one of 10 patients) and 60% (six of 10 patients) for refractory patients. The likelihood of response was only marginally influenced by the number of prior regimens (Table 3). In fact, among the 19 patients who had received only two previous regimens, the overall response rate was 79% (three CRs [16%] and 12 PRs [63%]), a figure only slightly higher than the 73% overall response rate (two CRs [13%] and nine PRs [60%]) recorded in the 15 patients who had received three previous regimens. On the other hand, among the 10 patients who had received four or more previous regimens, there were no CRs and a somewhat lower number of PRs (50%), although the difference is not statistically significant. Among the five CRs, two were histologic when re-evaluated with a local biopsy. Both of these histologic CRs (one MF and one PTCLU) were confirmed by immunohistochemistry.
Of the five patients who obtained CRs, four (including both histologic CRs) were still in remission after 6 to 22 months, whereas the remaining one relapsed 10 months after treatment completion; the median follow-up of CR was 15 months. Twelve of the 26 partial responders remained in PR for a median duration of 10 months (range, 2 to 15 months); five of 26 died, all because of disease progression. The remaining partial responders showed a disease progression within a median time of 6 months (range, 2 to 9 months); all of them were still alive and four had started over treatment with gemcitabine at the time of this writing.
Toxicity Three patients had transient elevated liver enzymes. No nausea/vomiting was recorded. Hair loss was mild to moderate, and no patient experienced complete alopecia.
The prognosis of peripheral T-cell lymphomas, including advanced-stage MF and PTCLU with exclusive skin involvement, is generally considered poor.8-11 Regarding PTCLU, extranodal presentations are frequent, with diagnostic material coming from tonsils, soft tissues, and especially skin, in which the histologic picture mimics the tumor phase of MF. In advanced-stage MF, treatment with chemotherapy is generally recommended, but few patients obtain a long-lasting remission. In particular, many chemotherapeutic strategies (eg, nitrogen mustard, methotrexate as a single agent, fludarabine, and even multidrug regimens followed or not by autologous bone marrow transplantation), as well as alternative therapies (ie, psoralen and ultraviolet A light, photopheresis, retinoids, interferon, DAB-IL-2, and so on), have proven of little efficacy, with the notable exception of pentostatin.12 Gemcitabine is a novel cytidine analog with a broad spectrum of antitumor activity in a variety of epithelial tumors. In the hematologic field, gemcitabine has been shown to be active in heavily pretreated Hodgkin’s disease patients18 and nodal-aggressive non-Hodgkin’s lymphomas.19 In the present study of a mixed group of previously treated patients, we have shown that gemcitabine effectively induces remission (70.5% of overall response rate) in previously treated patients with peripheral T-cell lymphoma. Gemcitabine has demonstrated similar efficacy in terms of CR and PR rates for both patients with MF and those with PTCLU. Furthermore, it also seems to be similarly effective in both relapsed and refractory patients. In addition, the whole therapy was given in an outpatient setting, and related toxicity was modest. This has to be regarded as an important feature as we analyze the possibly similar efficacy of gemcitabine and pentostatin. As a matter of fact, at the high dose of pentostatin used in patients with the same cutaneous lymphomas, general toxicity was somehow significant and associated with conspicuous lowering of the CD4 counts.12 In our study, neither organ toxicity nor opportunistic infections were reported, to such an extent that we never felt compelled to monitor the CD4 count in the patients. Standard antiemetics were not used, and no cumulative toxicity patterns were observed. All in all, these data allow us to consider treating the next responding patients with up to six cycles of this regimen; we refrained from doing so earlier because of the lack of toxicity data on the extensive use of this drug in heavily pretreated lymphoma patients. This report confirms our preliminary data on 13 patients,20 who are also included here with a longer follow-up, and it represents the first evidence in literature concerning the pivotal role of gemcitabine in a conspicuous number of patients with MF and PTCLU and with a follow-up that permits a reasonable estimate of the response and its duration. In this study, gemcitabine-treated patients had a higher or at least comparable overall response rate compared with literature data on patients with MF treated with other nucleoside analogs, such as fludarabine21 and pentostatin.12,22 Its modest toxicity profile and the easy schedule of administration make gemcitabine an ideal agent for consideration in the development of chemotherapy regimens. In particular, it would be interesting to evaluate the use of two different nucleoside analogs (fludarabine or pentostatin plus gemcitabine) in modulating the entry route into DNA23,24 and their action in terms of direct cytoxicity and apoptosis, respectively. Earlier investigations demonstrated the possibility of potentiating fludarabine with low doses of gemcitabine.25 These findings lead us to conclude that gemcitabine has substantial activity and acceptable toxicity in previously treated patients with MF and PTCLU. This study also suggests that gemcitabine has activity in relapsed or refractory disease and also in those heavily pretreated; histologic CRs were observed in these groups. Larger trials will be necessary to further explore the therapeutic potential of gemcitabine as front-line treatment for patients with peripheral T-cell lymphomas with isolated skin involvement.
1. Corradini P, Astolfi M, Cherasco C, et al: Molecular monitoring of minimal residual disease in follicular and mantle cell non-Hodgkin’s lymphomas treated with high-dose chemotherapy and peripheral blood progenitor cell autografting. Blood 89:724-731, 1997
2.
Gianni AM, Bregni M, Siena S, et al: High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 336:1290-1297, 1997 3. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998[Abstract]
4.
Coiffier B, Haioun C, Ketterer N, et al: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood 92:1927-1932, 1998 5. Press O, Eary J, Appelbaum F, et al: Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas. Lancet 346:336-340, 1995[Medline]
6.
Kaminski M, Zasadny K, Francis IR, et al: Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma. J Clin Oncol 14:1974-1981, 1996
7.
Harris N, Jaffe E, Stein H, et al: A revised European-American Classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361-1392, 1994
8.
Winkler CF, Sausville EA, Ihde DC, et al: Combined modality treatment of cutaneous T cell lymphoma: Results of a 6-year follow-up. J Clin Oncol 4:1094-1100, 1986
9.
Ascani S, Zinzani PL, Gherlinzoni F, et al: Peripheral T-cell lymphomas: Clinico-pathologic study of 168 cases diagnosed according to the R.E.A.L. classification. Ann Oncol 8:583-592, 1997
10.
Ansell SM, Habermann TM, Kurtin PJ, et al: Predictive capacity of the International Prognostic Factor Index in patients with peripheral T-cell lymphoma. J Clin Oncol 15:2296-2301, 1997 11. Saleh MN, LeMaistre CF, Kuzel TM, et al: Antitumor activity of DAB389IL-2 fusion toxin in mycosis fungoides. J Am Acad Dermatol 39:63-73, 1998[Medline]
12.
Kurzrock R, Pilat S, Duvic M: Pentostatin therapy of T-cell lymphomas with cutaneous manifestations. J Clin Oncol 17:3117-3121, 1999 13. Polplin EAD, Corbett T, Flaherty L, et al: Difluorodeoxycytidine (dFdC, gemcitabine): A phase I study. Invest New Drugs 10:165-170, 1992[Medline] 14. Abbruzzese JL, Grunewald R, Weeks EA, et al: A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491-498, 1991[Abstract] 15. Storniolo AM, Allerheiligen SRB, Pearce HL: Preclinical, pharmacologic, and phase I studies of gemcitabine. Semin Oncol 24:S7-2–S7-7, 1997 (suppl 7) 16. International Union Against Cancer (UICC):TNM classification of malignant tumours. New York, NY,Springer-Verlag, 1987 17. Carbone PP, Kaplan HS, Musshoff K: Report of committee on Hodgkin’s disease staging classification. Cancer 31:1860-1861, 1971 18. Tesch H, Santoro A, Fiedler F, et al: Phase II study with gemcitabine in patients with Hodgkin’s disease: Results of a multicenter study. Blood 90:1514-1518, 1997 19. Fossa A, Santoro A, Hiddemann W, et al: Gemcitabine as single agent in the treatment of relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). Proc Am Soc Clin Oncol 18:27a, 1999 (abstr 98)
20.
Zinzani PL, Magagnoli M, Bendandi M, et al: Therapy with gemcitabine in pretreated peripheral T-cell lymphoma patients. Ann Oncol 9:1351-1353, 1998
21.
Von Hoff DD, Dahlberg S, Hartstock RJ, et al: Activity of fludarabine monophosphate in patients with advanced mycosis fungoides: A Southwest Oncology Group Study. J Natl Cancer Inst 82:1353-1355, 1990 22. Greiner D, Olsen EA, Petroni G: Pentostatin (2'-deoxycoformycin) in the treatment of cutaneous T-cell lymphoma. J Am Acad Dermatol 36:950-955, 1997[Medline] 23. Huang P, Plunkett W: Fludarabine- and gemcitabine-induced apoptosis: Incorporation of analogs into DNA is a critical event. Cancer Chemother Pharmacol 36:181-188, 1995[Medline]
24.
Iwasaki H, Huang P, Keating MJ, et al: Differential incorporation of ara-c, gemcitabine, and fludarabine into replicating and repairing DNA in proliferating human leukemia cells. Blood 90:270-278, 1997
25.
Tosi P, Pellacani S, Zinzani PL, et al: In vitro study of the combination gemcitabine + fludarabine on freshly isolated chronic lymphocytic leukemia cells. Haematologica 84:794-798, 1999 Submitted September 22, 1999; accepted March 6, 2000. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
