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© 2002 American Society for Clinical Oncology Trimetrexate in Relapsed T-Cell Lymphoma With Skin InvolvementByFrom the Departments of Lymphoma and Myeloma, Dermatology, and Hematopathology and Divisions of Pharmacy and Radiology, University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Andreas H. Sarris, MD, PhD, Hygeia Hospital, Evythrou Stavrou 4, 15123 Marousi, Greece; email: a.sarris{at}hygeia.gr
PURPOSE: Methotrexate (MTX) is active against lymphomas, but transport or polyglutamylation mutations confer MTX resistance. Because trimetrexate (TMTX) enters cells by passive diffusion and is not polyglutamylated, its activity in relapsed T-cell lymphoma was investigated. PATIENTS AND METHODS: Eligible patients had histologically confirmed relapsed T-cell lymphoma involving the skin, had received more than one previous regimen, were older than 16 years, had normal organ function, and had no CNS disease or serious infections, including human immunodeficiency virus. TMTX (200 mg/m2) was given intravenously every 14 days without topical or systemic corticosteroids. Patients who responded received up to 12 doses. RESULTS: Twenty patients were assessable for response. Median age was 59 years (range, 45 to 87 years); 13 patients were men. Three patients had anaplastic large-cell lymphoma, 15 had mycosis fungoides or Sézary syndrome (14 with large-cell transformation), and two had peripheral T-cell lymphoma. Serum lactate dehydrogenase was high in 35%, and beta-2 microglobulin was more than 3.0 mg/L in 35% of patients. The median number of previous regimens was three (range, two to 15) and included MTX in five patients. Disease was refractory to the regimen immediately preceding TMTX in 85% of patients. Responses were complete in one and partial in eight patients (overall response rate, 45%). Two of five patients previously treated with MTX responded. Grade 3 or 4 mucositis was observed after 4%, infection after 3%, neutropenic fever after 6%, neutrophils less than 100/µL after 4%, and platelets less than 10,000/µL after 3% of TMTX doses. CONCLUSION: TMTX is active with acceptable toxicity in this population and merits further investigation.
MYCOSIS FUNGOIDES (MF) and Sézary syndrome (SS) are indolent cutaneous T-cell lymphomas (CTCL) that often require little or no initial therapy. However, treatment is eventually needed for most patients. Responses are common,1 but patients often receive salvage treatment and may survive with lymphoma for decades.2 Many eventually suffer tumor transformation to large-cell lymphoma, and most of those presenting with advanced disease die either as a result of infections associated with skin breakdown or as a result of organ failure caused by visceral lymphomatous infiltration. Therefore, there is a need for new agents to be incorporated into salvage therapy and up-front regimens for these patients. Methotrexate (MTX) is an antifolate active against CTCL with an objective responses 63% in a small series involving 11 patients.3 MTX is a competitive inhibitor of dihydrofolate reductase, the enzyme responsible for maintenance of intracellular reduced folate pools. Mechanisms of MTX resistance include impaired facilitated transport, alterations in the affinity of dihydrofolate reductase for MTX, and overproduction of normal dihydrofolate reductase.4,5 Trimetrexate (TMTX) is a lipophilic antifolate that enters cells by passive diffusion, bypassing possible MTX resistance mechanisms.6 TMTX achieves intracellular concentrations 10 to 100 times greater than those of achieved by MTX.7 In addition, TMTX is not polyglutamated and is not retained in cells for prolonged periods. This probably accounts for its relatively low hepatotoxicity.8 Phase II studies of TMTX administered at 200 mg/m2 intravenously every 14 days in non–small-cell lung carcinoma demonstrated modest clinical activity. On the basis of the clinical activity of MTX in CTCL and the potential for TMTX to bypass facilitated transport and polyglutamylation defects often associated with MTX resistance, we conducted a phase II study of TMTX in previously treated patients with T-cell lymphoma involving the skin.
Eligibility Criteria Patients were eligible if they met the following criteria: had relapsed or refractory MF/SS, cutaneous involvement by anaplastic large-cell lymphoma (ALCL), or peripheral T-cell lymphoma (PTCL) defined according to the Revised European-American Lymphoma classification9; had received at least one previous combination regimen; were older than 16 years; had measurable or assessable disease; had Zubrod performance status  3; had no CNS involvement; serum creatinine less than 1.5 mg/dL, serum bilirubin less than 1.5 mg/dL, serum transaminases less than two times the upper limit of normal; had neutrophil counts of more than 1,000/µL and a platelet count of more than 100,000/µL (unless due to lymphoma infiltration of bone marrow or to hypersplenism); had a predicted life expectancy more than 6 weeks; were not pregnant; were not infected by human immunodeficiency virus or other serious pathogens; had received no chemotherapy within 3 weeks; and had no previous autologous transplantation of stem cells or bone marrow. The study was approved by the investigational review board at the M.D. Anderson Cancer Center.
Study Staging
Treatment Plan
Response Determination Patients who achieved a complete or partial response after four injections received a maximum of 12 injections of TMTX, with complete restaging after eight and 12 injections. Patients who were eligible for stem-cell or bone marrow transplantation were restaged after receiving a minimum of four TMTX doses. For the purposes of this study, these patients were censored at the time the high-dose therapy was started. Progression-free survival was measured from the time treatment was started to the time of the last follow-up, treatment failure, or disease progression, and was estimated according to the method of Kaplan and Meier.11
Patient Population Twenty-two patients with relapsed or refractory lymphoma were entered onto the study. Two of them were considered unassessable because they refused any further therapy 7 and 8 days after the first TMTX dose, electing instead to receive just palliative therapy. Thus, their response to TMTX could not be determined, and so they were not assessable for response. However, they were assessable for toxicity. The presenting clinical and laboratory features of the remaining 20 patients assessable for response are listed in Table 1. Fifteen patients had MF/SS, and the majority of them (14 of 15) had large-cell transformation, despite the relatively short interval from diagnosis to TMTX treatment (median, 24 months; range, 1 to 217 months). ALCL was observed in three and PTCL in two patients. Therefore, this was a heavily pretreated patient population, with 55% of the patients being refractory to their initial regimen and 85% being refractory to the last regimen administered before TMTX. Elevations of serum LDH and ß2-microglobulin levels were also frequent, reflecting the adverse clinical features of this cohort of patients (Table 1).
Response The overall response rate for all 20 assessable patients was 45% (Table 2). For patients with MF/SS, the response rate was 0% for those patients with histologically indolent disease, and 50% for those with evidence of large-cell transformation. Responses were also observed in one (33%) of three ALCL, and one (50%) of two patients with PTCL (Table 2). Five of the 20 patients assessable for response had received previous MTX therapy, and two of them achieved a partial response, for an overall response rate of 40%. These two TMTX responses were observed among the three patients who had responded previously to MTX. By contrast, the two patients who had previously not responded to MTX did not respond to TMTX. As a measure of response duration, we used progression-free survival, the median duration of which was 3 months for responding patients (Fig 1). There was concordant response in both skin lesions and nodal or visceral disease. Since most patients with MF had already suffered transformation to large-cell lymphoma, progression after TMTX was not associated with a change in histology.
Toxicity Overall, 74 doses of TMTX were administered to the patients eligible for toxicity, and 84% were at the 200-mg/m2 dose level. The median total dose of TMTX was 380 mg and ranged from 275 to 480 mg. Serious toxicity was uncommon. Mild anorexia was found in only one patient. Grade 3 or 4 toxicity included nausea after 6%, mucositis after 4%, and vomiting after 3% of TMTX doses. Hematologic toxicity was frequent, but severe suppression of counts was uncommon, and there was usually complete hematologic recovery by day 14. This allowed the administration of full doses of TMTX (200 mg/m2) in 83% of cycles. Neutropenic fevers were observed after 6% of TMTX doses, and were culture-negative, without any associated deaths. Nonneutropenic fever was observed after 4% of TMTX doses. Multiple organisms were often isolated from patients during episodes of nonneutropenic fevers. Those included organisms usually found colonizing the skin of patients with cutaneous T-cell lymphoma (Table 3).
Two patients died during or after TMTX therapy. The first patient had PTCL and had experienced a significant partial response after three TMTX doses and was admitted after the third TMTX dose for nonneutropenic fever. Peripheral blood counts for this patient were normal, but cultures demonstrated bacteremia with Staphylococcus epidermidis and bronchitis with Xanthomonas maltophilia. He initially responded to broad-spectrum antibiotics, but he remained febrile. Subsequently, antibiotics were stopped; the patient became septic and decided to abandon therapy, pursuing only palliative therapy. After death, autopsy revealed residual CD30-positive large-cell lymphoma but no source of infection. This patient was assessable for both response and toxicity. One additional patient had SS and responded to the first TMTX treatment, as demonstrated by a drop of the Sézary cell count and improvement of the erythroderma. However, the sixth day after TMTX, he abandoned therapy and was transferred to a hospice, where he died on day 12. This patient was assessable for toxicity but not response.
We report the activity of single-agent TMTX in relapsed or refractory T-cell lymphoma involving the skin. The response rate was 47% for all patients with MF/SS, 93% of whom had histologic evidence of large-cell transformation. The one patient with indolent MF/SS did not respond to TMTX. One of three patients with ALCL and one of two patients with PTCL responded. TMTX was also active in those patients who had previously received MTX. The TMTX response rate is encouraging, especially because this was a heavily pretreated population with many adverse clinical and laboratory features. These include large-cell transformation of MF/SS, which has been associated with short survival.12,13 These patients had also not responded to many previously administered systemic agents (median, six agents; range, one to 14 agents), reflecting the intensity and the complexity of previous salvage therapy. In addition, 55% of the patients had primary refractory disease, and 85% were refractory to the last regimen administered before TMTX was started. This is reflected by the detection of elevated serum levels ß2-microglobulin in 35% and of LDH in 35% of the patients. These elevations have been associated with inferior response rates in patients with relapsed lymphoma treated either with single agents or with various combination regimens.14 The frequent presence of these adverse clinical and laboratory features may account for the short response duration observed during this study, which nevertheless is within the range observed for salvage regimens used in MF/SS.15 It is difficult to directly compare these results to the previously reported activity of MTX in relapsed MF/SS because the patient populations are different between these two studies. None of the patients treated with MTX and reported 23 years ago had histologic evidence of transformation to large-cell lymphoma. In addition, the median number of previous regimens administered to these patients was two (range, one to five regimens), and the median number of all previous agents, excluding radiation, was one (range, one to four agents). The median number of previously administered systemic (oral or intravenous) agents was zero (range, zero to three agents), with most of these patients not responding to topical agents. In contrast, in the current study, 93% of patients with MF/SS had transformation to large-cell lymphoma, the median number of previous regimens was three (range, two to 15 regimens), but the median number of previous systemic agents was six (range, one to 14 agents). This reflects the intensity and complexity of previous salvage regimens for the patients enrolled onto the current TMTX study. The toxicity of TMTX was acceptable. Neutropenia, thrombocytopenia, and mucositis were frequent but short-lived. The single toxic death observed in this study was not associated with neutropenia; most likely, it reflects sequelae of skin infections, which are a common cause of death for patients with MF/SS. The second death was observed in a patient who abandoned therapy and antibiotics and chose only comfort hospice care. The combination of significant activity with tolerable toxicity might be due to achievement of high intracellular TMTX levels without needing facilitated transport, a known mechanism of MTX resistance. These levels, which have been reported to be as much as 100-fold higher than MTX,7 might explain the two responses observed among the five patients who had been previously treated with MTX. Because TMTX responses were limited to patients with previous MTX response, it seems that facilitated transport defects are an uncommon cause of MTX resistance. The tolerable toxicity, including lack of renal toxicity, might be due to the rapid exit of TMTX from cells by its lack of polyglutamylation. We conclude that TMTX seems to be a promising agent in patients with MF/SS and ALCL involving skin, and that its activity in combination regimens merits further investigation in both relapsed and previously untreated patients.
Supported in part by National Institutes of Health Cancer Center Support grant no. CA-16672 to the University of Texas M.D. Anderson Cancer Center. We thank the physicians, fellows, pharmacists, and social workers of the Department of Lymphoma, University of Texas M.D. Anderson Cancer Center, who participated in the care of these patients. We also thank Joyce Palmer for her assistance with the manuscript.
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Gorlick R, Goker E, Trippett T, et al: Defective transport is a common mechanism of acquired methotrexate resistance in acute lymphocytic leukemia and is associated with decreased reduced folate carrier expression. Blood 89: 1013-1018, 1997 6. Sigel CW, Macklin AW, Woolley JL Jr, et al: Preclinical biochemical pharmacology and toxicology of piritrexim, a lipophilic inhibitor of dihydrofolate reductase. NCI Monogr 5: 111-120, 1987 7. Fleming GF, Schilsky RL: Antifolates: The next generation. Semin Oncol 19: 707-719, 1992[Medline] 8. Rodriguez G, Brown TD, Balis FM, et al: A phase I trial of trimetrexate (NSC352122) on a daily x5 schedule in patients with refractory adult leukemia. Anticancer Drugs 4: 163-166, 1993[Medline]
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Diamandidou E, Colome-Grimmer M, Fayad L, et al: Transformation of mycosis fungoides/Sézary syndrome: Clinical characteristics and prognosis. Blood 92: 1150-1159, 1998 13. Diamandidou E, Colome M, Fayad L, et al: Prognostic factor analysis in mycosis fungoides/Sézary syndrome. J Am Acad Dermatol 40: 914-924, 1999[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50% reduction of bidimensional tumor area or skin score. Progressive disease was 
