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Pentostatin Therapy of T-Cell Lymphomas With Cutaneous Manifestations

From the Departments of Bioimmunotherapy and Medical Specialties, University of Texas, M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Razelle Kurzrock, MD, 1515 Holcombe Blvd, Box 302, Houston, Texas 77030.

	ABSTRACT

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PURPOSE: To determine the side effects of and response to pentostatin in patients with T-cell lymphomas with cutaneous manifestations.

PATIENTS AND METHODS: Pentostatin was administered to 28 patients who had relapsed cutaneous T-cell lymphoma or peripheral T-cell lymphoma with prominent cutaneous disease. The starting dose was between 3.75 to 5.0 mg/m²/d intravenous for 3 days every 3 weeks.

RESULTS: Of the 24 patients assessable for response, 17 (71%) achieved a partial remission (46%) or complete remission (25%). The patients had a median number of three (range, one to 12) prior therapies. Of the 86 courses of pentostatin given, 39 were administered at doses of 5.0 mg/m²/d and 30 at doses of 3.75 mg/m²/d. Dose escalation to 6.25 mg/m²/d was possible in only five courses, and toxicity necessitated dose reduction to 2.8 mg/m²/d in 12 courses. The most common side effects were granulocytopenia, nausea, and nonneutropenic fever. Most patients developed significant lowering of CD4 counts. Herpes zoster was seen within 1 year after pentostatin in five patients (19%).

CONCLUSION: Pentostatin is an active agent in heavily pretreated T-cell lymphomas with cutaneous manifestations.

	INTRODUCTION

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CUTANEOUS LYMPHOMAS represent a heterogeneous group of T- and B-cell lymphomas.¹ Infiltration of the skin by lymphoma may reflect the presence of a primary cutaneous lymphoma. Alternatively, skin disease in lymphoma may be secondary to involvement of the nodal system. The most common primary cutaneous lymphomas are mycosis fungoides (MF) and Sézary syndrome (SS).

In the early stages, MF primarily involves the skin, with patches/plaques being the typical feature. After a variable period of time, the disease progresses with the development of cutaneous tumors and, in some patients, lymph node and/or visceral involvement.^2,3 SS is an erythrodermic stage of advanced MF associated with the presence of circulating tumor cells in the blood. Patients with early MF generally have a long survival. The outlook is, however, considerably worse for patients with advanced disease. Indeed, patients with erythroderma, tumors, nodal, or visceral involvement generally live between 1 to 3 years.³

Peripheral T-cell lymphomas (PTCLs) may also present in the skin. These lymphomas have been more difficult to clearly classify.² PTCLs include adult T-cell leukemia/lymphoma (associated with human T-cell leukemia-1 retroviral infection), as well as other subtypes. Although the outcome of different subtypes is variable, many have a poor prognosis.²

Pentostatin (2'-deoxycoformycin) is a purine analog that is a potent inhibitor of adenosine deaminase. Adenosine deaminase levels are higher in normal circulating T cells than in B cells.⁴ Inhibition of adenosine deaminase is associated with selective lymphotoxicity, which seems to correlate with accumulation of deoxyadenosine triphosphate (dATP).^5,6 Several reports have suggested activity for pentostatin in cutaneous T-cell lymphomas (CTCLs).^7-10 However, most of these studies have included small numbers of patients, and the dose regimen used has varied widely between studies.

The objective of the current study was to expand the experience with pentostatin administered at maximum tolerated doses to patients with T-cell lymphoma with skin manifestations.

	PATIENTS AND METHODS

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Eligibility Criteria
Patients were eligible for study if they had histologic proof of CTCLs or PTCLs. All relevant pathology slides were reviewed at M.D. Anderson Cancer Center. Patients with PTCL or stage IIb to IV MF/SS must have failed at least one prior therapy, and patients with stage I to IIa MF, two prior therapies.¹¹ Patients must not have been treated within 3 weeks before study entry. All patients were expected to have adequate hepatic function (bilirubin 1.5 mg/dL), adequate renal function (serum creatinine 1.5 mg/dL), and adequate bone marrow function (platelet counts 100,000/µL and neutrophils 1,500/µL). Patients with serious intercurrent illness, significant cardiac disease (New York Heart Association Class 3 or 4), and those with active infection were not eligible for study. All patients signed informed consent in accordance with institutional procedures.

Patient Evaluations
All patients had a baseline history and physical examination as well as complete blood counts with differential, chemistries for renal and hepatic function, chest roentgenogram, bone marrow aspirate and biopsy, skin score assessment, computed tomography scan of the abdomen and pelvis, enumeration of peripheral-blood CD4 counts, and skin biopsy. Lymph node fine-needle aspirate or biopsy was performed if lymphadenopathy (lymph nodes 1 cm) was found. While on study, a complete blood count with differential, and chemistries for hepatic and renal function tests were performed at least one to two times a week. Patients were seen in clinic and a physical examination was performed at least every 3 weeks. Repeat skin scores, tumor measurements, bone marrow aspirate and biopsy, and computed tomography scan or assessment of other tumor markers, as appropriate, were performed after the second course of treatment and then approximately every 1 to 3 months, thereafter. Fasting amylase and lipase measurements were obtained on patients at baseline and approximately every 3 weeks, thereafter. Peripheral-blood CD4 counts were enumerated every 1 to 2 months.

Treatment
Patients received pentostatin administered by intravenous bolus daily over a consecutive 3-day period. This course was repeated at 3-week intervals. Hydration with 500 to 1,000 cc of normal saline was given daily, both before and after pentostatin administration. Dose levels were as follows: (i) dose level 0 was 5.0 mg/m²/d for 3 days; (ii) dose level -1 was 3.75 mg/m²/d for 3 days; (iii) dose level -2 was 2.8 mg/m²/d for 3 days; and (iv) dose level +1 was 6.25 mg/m²/d for 3 days. Patients without toxicity could receive dose level +1 on subsequent courses. Patients with grade 1 toxicity stayed at the same dose level or could be escalated to level +1. Patients with grade 2 toxicity received the same dose level. Patients with grade 3 toxicity received the next lower dose level or had the drug discontinued. All patients were given allopurinol 300 mg by mouth daily. Because keratitis is occasionally seen after pentostatin administration, all patients were given prophylactic PredForte eye drops (two drops in each eye every 4 hours while awake) for the first 7 days of each course. Therapy with pentostatin was continued for at least two courses unless there was rapidly progressive disease or grade 3 to 4 toxicity. In addition, it was planned to continue responders on pentostatin for as long as they responded (one to two courses past complete response/remission [CR]) unless serious toxicity supervened.

Response Definitions
The following response definitions were used. CR indicated disappearance of all evidence of disease for at least 4 weeks. Partial response/remission (PR) indicated a 50% or greater decrease in the sum of the products of the diameter of all lesions for at least 4 weeks. For patients with SS, there was also a 50% improvement in skin scores¹² and in Sézary cell counts. Progressive disease denoted any increase of 25% in the sum of the products of any measurable lesions or an increase of 25% in skin score. Appearance of new lesions or growth in any lesion also indicated progressive disease. Response durations were measured from the time of response until there was evidence of progressive disease.

	RESULTS

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Patient Characteristics
Twenty-eight patients were registered onto the study, 13 men and 15 women. Of these patients, 27 were considered assessable for toxicity. One patient was not assessable for toxicity because of erroneous registration onto the protocol. Twenty-four patients were assessable for response. Four patients were not assessable for response because they were erroneously registered (one patient), ineligible for study at baseline because of serious intercurrent disease (two patients), and lost to follow-up (one patient).

The median age of the participants was 63 years (range, 39 to 78 years). Diagnosis of the individuals eligible for response evaluation included SS (14 patients), tumor stage of MF (six patients), immunoblastic transformation of MF (one patient), and PTCL (three patients). All of the PTCL patients had prominent cutaneous manifestations. Two of the patients had cutaneous and/or subcutaneous tumors; one patient had HTLV-1–associated adult T-cell leukemia/lymphoma with skin lesions, hypercalcemia, and significantly elevated WBC count despite multiagent chemotherapy (WBC count = 50 x 10⁹/L with 64% lymphoma cells). Patients had failed a median of three prior therapies (range, one to 12) (Table 1).

Side Effects
In the 27 patients assessable for toxicity, the most common side effects were granulocytopenia, nausea, and nonneutropenic fever. In most patients, side effects were assessed as grade 1 or 2 severity (National Cancer Institute Criteria) (Table 2). However, severe granulocytopenia and thrombocytopenia were seen in 11% and 4% of patients, respectively. One patient developed irreversible renal failure. In addition, one patient developed pancreatitis, which resolved. Sustained elevations of amylase or lipase were not seen in any other patient on study. One patient with a history of asthma had exacerbation of bronchospasm requiring hospitalization (Table 2). Two patients died soon after starting pentostatin (on days 7 and 18). Both of these patients had serious intercurrent infections and/or cytopenias before starting pentostatin. The intercurrent problems were felt to be the cause of death, together with the advanced state of their disease. Several patients with erythrodermic SS developed a "flare" of their skin disease within 1 week after treatment. This resolved soon after and was in most cases seen in responders. In addition, one patient with PTCL developed what seemed to be "cellulitis" at the site of her tumor after each of the first three courses of pentostatin. This resolved within a few days, and she attained a durable CR. CD4 counts were lowered in the vast majority of patients (Fig 1). Five patients (19%) developed herpes zoster within 1 year after pentostatin treatment. One patient developed Guillain Barre Syndrome several months after pentostatin. (Most of these patients were also exposed to other treatment modalities after pentostatin.) No other opportunistic infections were seen in this cohort of patients. To date, second malignancies have not developed.

View larger version (25K): [in this window] [in a new window]   Fig 1. Peripheral-blood CD4 counts before and after pentostatin therapy.

Most courses of pentostatin were administered at dose levels 0 or -1 (5.0 or 3.75 mg/m²/d) (Table 3). A small number of patients were able to tolerate dose escalation to 6.25 mg/m²/d.

Responses
Response data are listed in Table 4. Seventeen (71%) of 24 assessable patients responded to pentostatin therapy. Six patients (25%) had CR, and 11 patients (46%) had PR. Of the 14 patients with SS, 10 (71%) achieved a response. Four (66%) of six patients with tumor stage MF achieved a response. All three patients with PTCL responded. Median response duration of patients with tumor stage MF was short (2 months; range, 1 to 2 months). Of those with SS, however, two patients had prolonged responses lasting longer than 1 year (19 months and ongoing response at 17 months). Median response duration for patients with SS was 3.5 months. All three patients with PTCL responded (Table 4). One patient has CR ongoing at 20 months. Response in the patient with adult T-cell leukemia/lymphoma lasted 7 months, at which time CNS relapse occurred. Most responders had failed several prior therapies (median number of prior therapies in responders, three; range, one to 12). The median number of courses that patients who achieved CR received was six (range, three to nine). The median number of courses that patients who achieved PR received was four (range, one to seven). Patients who achieved PR were generally taken off the study because of toxicity, a plateau in response, or renewed disease progression.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Pentostatin is a potent inhibitor of adenosine deaminase, the purine salvage enzyme involved in the irreversible deamination of adenosine and deoxyadenosine. Adenosine deaminase is detected in virtually all mammalian tissues, but the greatest activity is in the lymphoid system. Cellular deoxyadenosine triphosphate (dATP) levels increase concomitantly with inhibition of ADA after pentostatin administration, and there is a strong correlation between dATP accumulation and lymphoblast lysis.¹³

Pentostatin is an extremely effective agent in hairy cell leukemia, with the vast majority of patients responding to this compound.^14-16 Pentostatin has also been used as a treatment for CTCLs, with response rates ranging from 26% to 54%.^7-10 Generally, small numbers of patients have been treated on these studies, and the dosing regimen has varied from study to study. The doses used have ranged from 4 mg/m² every 1 to 4 weeks to 5 mg/m² on each of 3 to 5 consecutive days at monthly intervals. The doses administered most frequently in this study were 5 mg/m² (45% of courses) or 3.75 mg/m² (35% of courses) given on three consecutive days every 3 weeks (Table 3).

In the current study, the patients were, in general, heavily pretreated and had advanced MF/SS or PTCL (Tables 1 and 4). Responses (CR or PR) were seen in 17 (71%) of 24 assessable patients. Six patients (25%) achieved CR. The 17 responders had failed a median of three prior therapies and nine of them had failed one or more regimens of multiagent chemotherapy. Responses were seen in 71% of the SS patients, 66% of the tumor stage MF patients, and in all of the PTCL patients. Although many of the responses were short-lived, two patients with SS had more durable responses (CR durations = 19 months and ongoing at 17 months), and one patient with PTCL remains in CR at 20 months.

The most common side effect observed was a significant lowering of CD4 counts (Fig 1). Subsequently, several patients developed herpes zoster infection (within 1 year after pentostatin) (Table 2). Although these patients were treated with other modalities in the intervening period, we cannot rule out the possibility that this infection arose as a clinical sequela of the lowered CD4 counts. Therefore, we have initiated a regimen of prophylactic oral antiviral therapy in pentostatin-treated patients. To date, we have not seen second malignancies in these patients. Our experience with pentostatin-treated hairy cell leukemia patients suggests that CD4 counts recover, albeit slowly; median time to attainment of CD4 counts within the normal range was 54 months.¹⁶ Clinical manifestations of immunodeficiency were not observed in our hairy cell leukemia patients,¹⁶ but the dose of pentostatin was lower than that administered in the current study. Other frequent side effects at the dose levels used herein were lowering of blood counts, nausea, and renal insufficiency, which was reversible except in one case (Table 2).

Interestingly, several of the SS responders developed an initial "flare" of their disease within 1 week after pentostatin. The increased redness generally resolved within several days. One patient with PTCL developed significant erythema, warmth, and edema at her tumor site soon after pentostatin. This "reaction" had the appearance of a cellulitis, and she was treated with antibiotics. However, the phenomenon recurred with the second and third course of treatment. This patient attained a durable CR. The reason for these transient flares could conceivably be because of immune cell recruitment or cytokine release.

To summarize, pentostatin administered intravenously at doses of 3.75 to 5.0 mg/m²/d for 3 days every 3 weeks is an active agent in heavily pretreated patients with advanced T-cell lymphomas with skin manifestations. These doses were tolerable in the vast majority of patients treated. However, blood counts and renal function tests need to be monitored. Ongoing follow-up of CD4 counts should reveal if recovery eventually occurs, as has been previously reported in hairy cell leukemia.¹⁶ Future studies should address the activity of pentostatin in less-heavily pretreated patients with advanced CTCLs, especially those with SS, and in an expanded cohort of patients with PTCLs.

	ACKNOWLEDGMENTS

 
Supported by a grant from Supergen Inc.

	REFERENCES

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5. De Korte D, Haverkort WA, Van Leeuwen EF, et al: Biochemical consequences of 2'-deoxycoformycin treatment in a patient with T-cell lymphoma. Cancer60:750-755, 1987[Medline]

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Submitted March 31, 1999; accepted June 9, 1999.

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