Multicenter study of pegylated liposomal ... - Wiley Online Library

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Multicenter Study of Pegylated Liposomal Doxorubicin in Patients with Cutaneous T-Cell Lymphoma Uwe Wollina, M.D.1 Reinhard Dummer, M.D.2 Norbert H. Brockmeyer, M.D.3 Helga Konrad, M.D.1 J.-O. Busch, M.D.4 Martin Kaatz, M.D.5 Burkhard Knopf, M.D.6 Hans-Ju¨rgen Koch, M.D.7 Axel Hauschild, M.D.4 1

Department of Dermatology, Hospital DresdenFriedrichstadt, Dresden, Germany.

2

Department of Dermatology, University of Zu¨rich, Zu¨rich, Switzerland. 3

Department of Dermatology, Ruhr-University, Bochum, Germany.

4

Department of Dermatology, University of Schleswig-Holstein, Campus Kiel, Germany.

5

Department of Dermatology and Dermatological Allergology, University of Jena, Jena, Germany.

6

Department of Dermatology, Heinrich-BraunKlinikum, Zwickau, Germany.

7

Department of Dermatology, Deutsches Rotes Kreut (DRK)-Krankenhaus, Chemnitz, Germany.

Supported by an unrestricted grant from Essex Pharma, Munich, Germany. Address for reprints: Uwe Wollina, M.D., Department of Dermatology, Hospital Dresden-Friedrichstadt, Friedrichstrasse 41, 01067 Dresden, Germany; Fax: (011) 49 –3514801219; E-mail: [email protected] Received April 10, 2003; revision received May 21, 2002; accepted May 23, 2003. © 2003 American Cancer Society DOI 10.1002/cncr.11593

BACKGROUND. In single center studies and case reports, it was shown that pegylated liposomal doxorubicin (PEG-DOXO) was effective as second-line therapy for patients with cutaneous T-cell lymphoma (CTCL). The objective of this study was to evaluate the efficacy and toxicity of single-agent PEG-DOXO as second-line chemotherapy in patients with CTCL. METHODS. A retrospective, multicenter study was performed evaluating 34 patients (31 male patients and 3 female patients). Twenty-seven patients received PEGDOXO 20 mg/m2, 5 patients received PEG-DOXO 20 –30 mg/m2, and 2 patients received PEG-DOXO 40 mg/m2. PEG-DOXO was administered intravenously every 2 weeks in 6 patients, every 2–3 weeks in 4 patients, and every 4 weeks in 23 patients. One patient received only a single course of PEG-DOXO. Outcomes were evaluated, and adverse effects were recorded. RESULTS. Thirty-four patients received at least 1 cycle of PEG-DOXO. Disease was classified as mycosis fungoides in 28 patients, mycosis fungoides with follicular mucinosis in 2 patients, small or medium-sized pleomorphic CTCL in 2 patients, Se`zary syndrome in 1 patient, and CD30 positive CTCL in 1 patient. Fifteen patients achieved a complete response (CR), including patients who achieved a CR and patients who achieved a CR defined by clinical criteria only with no biopsy (CRu), and 15 patients achieved a partial response (PR), resulting in a response rate (CRs, CRus, and PRs) of 88.2%. Two patients dropped out: one patient after a single PEG-DOXO infusion because of Grade 3 capillary leakage syndrome and one patient after two cycles because of a suicide attempt that was not related to treatment or to CTCL. All other patients received at least four cycles of PEG-DOXO. Overall survival was 17.8 months ⫾ 10.5 months (n ⫽ 33 patients), event-free survival was 12.0 months ⫾ 9.5 months, and disease-free survival was 13.3 ⫾ 10.5 months (n ⫽ 16 patients). Adverse effects were seen in 14 of 34 patients (41.2%); they were temporary and generally mild. Only 6 patients had Grade 3 or 4 adverse effects. CONCLUSIONS. This multicenter study provided evidence of high efficacy of PEGDOXO monotherapy with a low rate of severe adverse effects compared with other chemotherapy protocols in patients with CTCL. Cancer 2003;98:993–1001. © 2003 American Cancer Society.

KEYWORDS: cutaneous T-cell lymphoma, doxorubicin, liposomal drug formulation, pegylation, multicenter study.

C

utaneous T-cell lymphomas (CTCL) are neoplasias of malignant T-lymphocytes that usually present a helper/inducer phenotype. Characteristically, CTCL shows a skin specific homing in which adhesion molecules, such as cutaneous lymphocyte antigen, chemokine/chemokine receptor, and lectin/lectin binding site interactions are involved.1–3 The most common CTCL is mycosis fungoides. The 5-year survival rate of patients with mycosis fungoides is approxi-

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CANCER September 1, 2003 / Volume 98 / Number 5

mately 87%.4 The prognosis for patients with advanced-stage disease is poor, with a median survival of approximately 40 months.5–7 Doxorubicin is an anthracycline with antineoplastic activity in patients with non-Hodgkin lymphoma as a part of the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen or its modifications.8 –10 Conversely, the therapeutic index of doxorubicin is low, and hematotoxicity is a common and dose dependent side effect. Severe neutropenia develops in nearly all patients who receive doxorubicin doses ⬎ 120 mg/m2. Gastrointestinal side effects, palmoplantar erythrodysesthesia (PPE), and reversible alopecia are common. Anthracycline-induced cardiomyopathy may lead to congestive heart failure. To prevent this irreversible side effect, the cumulative life-time dose of doxorubicin should not exceed 450 – 550 mg/m2.8 Liposomal-encapsulated cytotoxic drugs offer potential advantages over the corresponding unencapsulated agents. The liposome prolongs the half-life of the drug in the circulation and alters its biodistribution pattern such that drug deposition is increased in tumor tissue and decreased in dose-limiting normal tissues: Doxil/Caelyx威 is comprised of doxorubicin encapsulated in a small, unilamellar vesicle with a mean dimension 96 nanometers (nm). The liposome matrix is comprised of hydrogenated soybean phosphatidylcholine (56.2%), cholesterol (38.3%), and N-(carbamoyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phospho-ethanolamine sodium salt (5.3%). These liposomes are modified further by attachment to polyethylene glycol (pegylation). Pegylation improves pharmacokinetics and pharmacodynamics.11 Recently, the first data on the efficacy and safety of pegylated liposomal doxorubicin (PEG-DOXO) were published for patients with CTCL.12–14 The response rate in a group of 10 patients with CTCL was 80%.13 The current report provides what to our knowledge are the first multicenter data concerning the safety, efficacy, and disease-free survival of patients with recurrent or recalcitrant CTCL who were treated with PEG-DOXO.

clines, previous anthracycline doses ⬎ 200 mg/m2; or who had received radiotherapy or chemotherapy within 4 weeks before PEG-DOXO treatment were excluded. There was no additional selection of patients. Pretreatments included phototherapy (selective ultraviolet [UV] therapy [SUP], UVA-photochemotherapy with 8 methoxypsoralen [PUVA], or extracorporeal photochemotherapy [ECP]; n ⫽ 24 patients); immunotherapy with interferon ␣2a or ␣2b (n ⫽ 8 patients); radiotherapy (Grenz rays or electron beam; n ⫽ 7 patients); and chemotherapy regimens, including polychemotherapy (n ⫽ 8 patients). Patients had been informed in detail about the treatment, the study objectives and limitations, and side effects in accordance with the Declaration of Helsinki (June 1964) as amended by the 41st World Medical Assembly, Hong Kong (September 1989), and in compliance with the principals of good (clinical) research practice.15

Pretreatment Evaluation A complete medical history, including previous treatments for CTCL, was taken; and a physical examination, including performance status, concurrent nonmalignant disease, and staging of disease, was done for each patient. In patients with T3 tumors, a transformation was ruled out by biopsy. Four patients with Stage IIB or higher disease underwent bone marrow biopsies. Patients had chest X-rays and lymph node and abdominal sonographic images taken. Routine laboratory examinations were performed. Fluorescent-activated cell sorter analysis of peripheral blood and repeated differential blood counts were performed in 10 patients. Patients with one of the following parameters present at pretreatment evaluations were excluded: a leukocyte count ⬍ 2.0 ⫻ 109/L, granulocyte count ⬍ 1.0 ⫻ 109/L, hemoglobin ⬍ 10 g/dL, platelet count ⬍ 75.0 ⫻ 109/L, serum transaminase level ⬎ 2.5 times the upper limit of normal, and creatinine level ⬎ 2.0 mg/dL1. Histologic examination was performed on a biopsy of a typical CTCL lesion. Immunohistology was available in 25 patients. T-cell receptor polymerase chain reaction and Southern blot gene rearrangement validated clonality in nine of nine patients and in two of two patients, respectively.

MATERIALS AND METHODS Patient Eligibility Criteria

Treatment

Only patients with histologic proof of CTCL who had recurrent disease, were unresponsive to previous treatments, or had rapid disease progression after confirmation of diagnosis were eligible. Patients younger than 18 years; female patients who were pregnant or lactating; patients with severe or untreated heart disease, active infection, allergy to anthracy-

PEG-DOXO (Caelyx威; Essex Pharma GmbH, Munich, Germany) was administered intravenously during a 2-hour infusion at a dose of 20 mg (n ⫽ 28 patients), 20 –30 mg (n ⫽ 4 patients), or 40 mg/m2 (n ⫽ 2 patients). The frequency in the induction phase was once per month (n ⫽ 19 patients) or twice per month (n ⫽ 6 patients). Eight patients received the infusion

Doxorubicin in Cutaneous T-Cell Lymphoma/Wollina et al.

every 2–3 weeks. The objective was to induce a complete response (CR). Two patients who developed recurrent disease after the first course of 8 cycles were given a second course that was limited to 10 cycles. Most patients received 4 – 8 mg ondansetron (Zofran威; Glaxo Wellcome GmbH, Hamburg, Germany) orally or before the PEG-DOXO infusion as an antiemetic approach. No other chemotherapy or radiotherapy was given. Topical steroids were allowed. Adjuvant, systemic interferon ␣ treatment was given to two patients. All other patients received PEG-DOXO as a monotherapy.

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Determination of Endpoints The following major endpoints were determined: Overall survival and failure free survival were measured from the onset of treatment with PEG-DOXO until death from any cause or until death or progression of disease. Progression-free survival was measured from the time of entry into treatment with PEG-DOXO until disease progression or death from CTCL. Disease-free survival was measured for patients who achieved a CR from the first assessment that documented the response to the date of disease progression. Response duration was measured for all patients who achieved a CR or a PR from the first documentation of response to the time of disease recurrence or progression.18

Classification of Patients and Assessment of Response CTCL subtypes were classified according to the European Organization for Research and Treatment of Cancer (EORTC) criteria.4 Erythrodermic CTCL was classified into Se`zary syndrome, erythrodermic mycosis fungoides, and erythrodermic CTCL not otherwise defined.16 CTCL stages were defined according to the EORTC Cutaneous Lymphoma Project Group17 as follows: Stage IA (T1N0M0), Stage IB (T2N0M0), Stage IIA (T1–T2N1PB0M0), Stage IIB (T3N0M0), Stage III (T4N0 –N1M0), Stage IVA (T1–T4N2–N3M0), and Stage IVB (T1–T4N0 –N3M1). Response criteria18 were applied and controlled by clinical, radiologic, and skin pathology criteria within 4 weeks after PEG-DOXO therapy: A CR was defined as the absence of clinically detectable residual disease for at least 1 month. Postinflammatory hyperpigmentation was not classified as residual disease. A CR that was defined by clinical criteria only without a biopsy was called a CRu. A partial response (PR) was defined as a decrease ⬎ 50% in the size of preexisting lesions for at least 1 month. A classification of PR was also made if ⬎ 50% nodular or plaque-like lesions became macules without evidence of internal involvement. Stable disease (SD) was defined as any response that did not meet the criteria for a CR, PR, or disease progression. Progressive disease (PD) was defined as the appearance of new lesions, an increase ⬎ 25% in previously existing lesions, a change from macular to plaque-like or nodular in ⬎ 25% of previously existing lesions, or any evidence of developing internal manifestation. Monthly efficacy evaluations included evaluation of tumor response and assessment of quality of life according to Karnofsky performance status. Patients were withdrawn from the treatment due to profound and persistent neutropenia, anemia or thrombocytopenia, biochemical abnormalities (ⱖ Grade 3), intercurrent illness, pregnancy, patient request, capillary leak syndrome, or proven evidence of cardiotoxicity.

Adverse Effects Patients were evaluated at least twice per month for toxicity. Complete blood counts were performed 72 hours before and after dosing throughout the treatment. Side effects were classified according to the Common Toxicity Criteria.19 Skin toxicity was evaluated according to Lotem et al.20

RESULTS Efficacy Thirty-four patients with CTCL were treated. Their demographics are given in Table 1. The patient population included mycosis fungoides (n ⫽ 28 patients); mycosis fungoides with follicular mucinosis (n ⫽ 2 patients); pleomorphic small or medium-sized CTCL (n ⫽ 2 patients); Se`zary syndrome (n ⫽ 1 patient); and anaplastic, CD30 positive, large cell CTCL (n ⫽ 1 patient). The TNM status and tumor stage for all patients are shown in Table 1. Details on 10 patients were published previously in connection with a multicenter trial.13 Herein, their follow-up data have been enlarged as far as possible. A clinical response was seen during the first three infusions. Fourteen patients achieved a CR (with 1 additional patient who achieved a CRu in Stage IA), 15 patients achieved a PR, 2 patients had SD, and 2 patients had PD during the first course. No internal involvement developed during the treatment. Two patients with recurrent disease were referred for a second course of PEG-DOXO and had a PR as their best response. Their final outcome was a PR and SD, respectively (Table 2). Patients with Stage I–II CTCL had better survival, with 22.9 months ⫾ 12.4 months (mean ⫾ standard deviation) compared with patients who had Stage III–IV CTCL (14.6 months ⫾ 8.6 months; 31 patients received at least 4 cycles of PEG-DOXO; P ⬍ 0.001). However, comparing all patients who had Stage IA–IIA disease with

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TABLE 1 Demographic Data on Regarding Patients, Pretreatment(s), and Pegylated Liposomal Doxorubicin Therapy

Result

Caelyyx dosage (in mg/m2)

Interval (weeks)

ECP, IFN, radiation PUVA, ECP, radiation ECP, IFN, MTX ECP —

PR PD PD PD —

20 20 20 20 20

4 4 4 4 4

IIB IVA III

ECP, IFN, COP Cyclosporin A IFN

PD — PD

20 20 20

3 4 4

T4N1PB0M0

IVA

PD

20

4

7 1 4 84 36

T3N1PB0M0 T3N0PB0M0 T3N0PB0M0 T2N1PB0M0 T1N0PB0M0

IVA IIB IIB IIA IA

PUVA, corticosteroids, IFN, radiation — PUVA, IFN, radiation UV — Radiation

— PR PD — PD

20 40 40 20 20

4 4 4 2 2

18

T3N1PB0M0

IVA

PD

20

2

PD PD PD

20 20 20

2 2 2

PR PD PR PD PD PD PD PD PR — PD PR PD

20 20 20 20 20 20 20 20 20 30–20 20 30–20 30–20

4 4 4 4 — 4 4 4 3–2 3 3 3–2 3–2

PR PD PD

30–20 20 20

2–3 2–3 4

Patient

Gender

Age (yrs)

History (months)

TNPBMa

Stage

Pretreatment(s)

1 2 3 4 5

M F M M M

59 71 78 50 66

MF MF MF MF Large cell anaplastic CD30 ⫹ CTCL MF MF Small/medium-sized pleomorphic CTCL MF

24 160 96 15 7

T3N0PB0M0 T3N0PB0M0 T3N0PB0M0 T2N1PB0M0 T2N1PB0M0

IIB IIB IIB IIA IIA

6 7 8

M M M

71 65 71

50 3 12

T3N0PB0M0 T3N1PB0M0 T4N0PB0M0

9

M

62

42

10 11 12 13 14

M M F M M

73 66 40 80 56

15

M

62

MF MF MF MF Small/medium-sized pleomorphic CTCL MF

16 17 18

M M M

57 62 65

MF with mcinosis MF MF

12 180 156


IB IVA IB

19 20 21 22 23 24 25 26 27 28 29 30 31

M M M M M M M M M M F M M

52 71 68 76 70 70 78 64 65 69 85 71 53

MF MF with mucinosis MF MF MF MF MF MF MF MF MF MF MF

36 86 38 38 50 27 36 30 20 21 16 14 49

T2N0PB0M0 T3N0PB0M0 T1N0PB0M0 T2N0PB0M0 T2N1PB0M0 T2N1PB0M0 T1N0PB0M0 T3N1PB0M0 T2N0PB0M0 T3N1PB0M0 T2N1PB0M0 T3N1PB0M0 T3N1PB0M0

IB IIB IA IB IIA IIA IB IVA IIA IVA IVA IVA IVA

32 33 34

M M M

73 59 45

Se`zary syndrome MF MF

14 21 15


IVA IVA IIB

Diagnosis

PUVA; leukeran, corticosteroids Radiation PUVA Leukeran, corticosteroids, IFN, radiation, mitoxantron, clorambucil ECP, IFN ECP, IFN PUVA, acitretin, ECP UV, PUVA PUVA ECP, IFN UV UV, PUVA ECP, IFN, fludarabin — PUVA, IFN, MTX PUVA, IFN IFN, acitretin, ECP, fludarabin PUVA, IFN, fludarabin PUVA, ECP PUVA, IFN, radiation

M: male; F: female; MF: mycosis fungoides; CTCL: cutaneous T-cell lymphoma; TNPBM: ECP: extracorporeal photochemotherapy; IFN: interferon; PR: partial response; PUVA: ultraviolet A-photochemotherapy with 8-methoxypsoralen; PD: progressive disease; MTX: methotrexate; COP: cyclophosphamide, vincristine, and prednisone; PUVA: ultraviolet A-photochemotherapy with 8-methoxypsoralen; UV; ultraviolet therapy. a TNPBM: staging criteria, including tumor status (T), lymph node status (N), peripheral blood involvement (PB), and metastatic status (M).

patients who had Stage IIB–IVB disease, the difference in overall survival was not significant (17.0 months ⫾ 12.2 months vs. 17.9 months ⫾ 10.4 months). The follow-up after the first course was 2– 44 months (17.8 months ⫾ 10.5 months). During this time, three patients died. One patient had a CR after

PEG-DOXO and died because of a lung embolism unrelated to CTCL or treatment 12 months later without evidence of CTCL recurrence. The second patient died 19 months after the first course of PEG-DOXO with advanced tumor stage. The third patient died after 4 months due to disease progression (see Table 2).


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TABLE 2 Outcome Measures and Next Treatment Overall Event-free Disease-free Response Time to survival survival Progression-free Recurrence-free survival duration next Rx Cause-specific Patient Response KPS (mos) (mos) survival (mos) survival (mos) (mos) (mos) (mos) death (mos) Next Rx

Drop out

1

PR

70

24

8

8

0

—

8

5

24

—

2 3

CR PR

80 90

14⫹ 33⫹

4⫹ 24⫹

12⫹ 24⫹

4⫹ 0

4⫹ —

9⫹ 24⫹

— —

— —

4 5 6 7

PR CR CR PR

80 80 90 90

35⫹ 44⫹ 3⫹ 36⫹

5⫹ 42⫹ 1⫹ 34⫹

5⫹ 42⫹ 1⫹ 34⫹

0 42⫹ 1⫹ 34⫹

— 42⫹ 1⫹ —

5⫹ 42⫹ 1⫹ 34⫹

1 — — 1

— — — —

8

PR

70

21⫹

4⫹

4⫹

4⫹

—

4⫹

1

—

9 10 11 12 13 14 15 16 17 18

PR PD PR PR PD Cru PR CR CR CR

50 90 80 40a 50 90 80 100 100 80

19⫹ 6⫹ 8 25⫹ 4 12⫹ 12⫹ 12⫹ 12⫹ 1⫹

5⫹ 2 6 14 0 12 12 12 12 1⫹

5⫹ 2 6 14 0 5 12 12 12 1⫹

5⫹ 2 6 14 0 5 12 12 12 1⫹

— — — — — 5 — 12 12 1⫹

5⫹ 2 6 23 — 5 12 12 12 1⫹

6 1 — 1 — 1 — 15 1 —

— — 8b — 4b — — — — —

19 20

CR CR

90 90

13⫹ 28⫹

11⫹ 23

11⫹ 23

11⫹ 23

11⫹ 23

11⫹ 28⫹

— 3

— —

21 22 23

CR CR SD

100 18⫹ 100 25⫹ 30 6⫹

15⫹ 25⫹ —

15⫹ 25⫹ —

15⫹ 18⫹ —

15⫹ 25⫹ —

18⫹ 18⫹ —

1 1 1

— — —

24 25 26

PR CR PR

100 21⫹ 100 18 100 10⫹

18⫹ 18 10⫹

15⫹ 18 10⫹

15⫹ 18 10⫹

— 12 —

15⫹ 18 10⫹

— — 1

— 18c —

27 28 29 30 31 32 33 34

CR PR SD PR PR CR CR PR

80 90 60 80 70 100 80 80

12⫹ 20⫹ 3⫹ 11⫹ 14⫹ 18⫹ 12⫹ 11⫹

12⫹ 20⫹ 3⫹ 7⫹ 14⫹ 18⫹ 12⫹ 11⫹

12⫹ 20⫹ — 7⫹ 14⫹ 18⫹ 12⫹ 11⫹

3⫹ 17⫹ — — — 18⫹ 12⫹ —

12⫹ 20⫹ — 3⫹ 14⫹ 18⫹ 12⫹ 9⫹

— — — 1 1 — — —

— — — — — — — —

12⫹ 20⫹ 21⫹ 11⫹ 14⫹ 18⫹ 12⫹ 38⫹

Second Caelyx course — IFN 2 ⫻ 5 mioU/ week ECP — — IFN 3 ⫻ 3 mioU/ week Pegylated IFN 50 ␮g/week — — — MTX — CHOP — Caelyx every 6 weeks Caelyx every 6 weeks — — Second Caeylx course PUVA PUVA Bleomycin, vincristine, prednisolone — — IFN 3 ⫻ 9 mioU/ week — — PUVA PUVA PUVA — — PUVA

— — — — — After 7 cycles — — — — — — — — — Suicide attempt — — — — Capillary leak syndrome — — — — — — — — — — —

KPS: Karnofsky performance status; Rx: treatment; PR: partial response; CR: complete response; PD: progressive disease; CRu: a CR defined by clinical criteria only without a biopsy; SD: stable disease; IFN: interferon; mioU: million units; ECP: extracorporeal photochemotherapy; MTX: methotrexate; CHOP: cyclophosphamide, doxorubicin, vincristin, and prednisone; PUVA: ultraviolet A-photochemotherapy with 8-methoxypsoralen. a Preexisting. b Cutaneous T-cell lymphoma. c Lung embolism.

Adverse Effects Clinical and laboratory data were available for all patients. In general, the treatment was tolerated well (Table 3). Adverse effects ⱖ Grade 1 were noted in 41.2% of all patients. We did not observe any nausea,

emesis, stomatitis, constipation, diarrhea, or alopecia. One patient had Grade 4 anemia during the second course, leading to a blood transfusion. One patient developed a Grade 3 capillary leak syndrome of with a 4-week delay after 1 infusion (drop-out) with weight

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TABLE 3 Adverse Effects (Grade > 1) and Supportive Therapy Patient

Adverse effects

Supportive therapy

1 2 3 4 5

— — — — Lymphopenia Grade 3, anemia Grade 3, leukopenia Grade 3, prolongation of partial thromboplastin time Grade 1 Leukopenia Grade 1, thrombopenia Grade 1 Lymphopenia Grade 3, increase of serum transaminases Grade 1 — Lymphopenia Grade 1 — Stenocardia Grade 1 — PPE Grade 3 PPE Grade 2 — — — — — Weight loss Grade 1 — Stenocardia Grade 1 — Capillary leak syndrome Grade 3 Anemia Grade 3, lymphopenia Grade 3, increase of serum transaminases Grade 1 Anemia Grade 4 Stomatitis Grade 2 — Nausea Grade 2 — Pancytopenia Grade 2, creatinin increase Grade 2 Leukopenia Grade 2 — PPE Grade 2

— — — — —

6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

— — — — — Metoclopramide — Pyridoxin Pyridoxin — — — — — — — — — Diuretics, intensive care unit — Blood transfusion — — Ondansetron — G-CSF G-CSF — —

PPE: palmoplantar erythrodysesthesia; G-CSF: granulocyte-colony stimulating factor.

gain, generalized edema, and central nervous involvement. Grade 3 hematologic side effects were present in 3 patients (3 episodes of lymphopenia, 2 episodes of anemia, and 1 episode of leucopenia) only once during treatment. PPE was observed in 2 patients (Grade 2 and 3) who were on a 2-week schedule for PEG-DOXO. One of the patients with longer treatment intervals (3– 4 weeks) developed Grade 2 PPE. Other symptoms of skin toxicity, such as diffuse follicular rash, intertrigolike eruption, or new formation of melanocytic macules, were not recorded. Grade 1 side effects included stenocardia in two patients; increased transaminases in two patients; and prolonged partial thromboplastine time, loss of weight, leukopenia, lymphopenia, and thrombopenia in one patient each.

Supportive Therapy Supportive therapy for drug-induced adverse effects was necessary in five patients (Table 3). One patient received blood transfusions because of Grade 4 anemia, and 1 patient needed hospitalization and intensive care treatment because of capillary leak syndrome. Two patients received pyridoxine 300 mg per day because of PPE. Another patient who complained of stenocardia received metoclopramide because he had evidence of gastric reflux: His complaints resolved.

Drop-Out There were two drop-outs after one or after two PEGDOXO infusions. One male patient developed a capillary leak syndrome after the first infusion. Another


male patient made a suicide attempt that was not considered treatment-related by the physician. He responded with a CR after only two cycles of PEG-DOXO but was hospitalized in a psychiatric clinic and was lost to follow-up.

DISCUSSION The current study provides the first multicenter data on PEG-DOXO in the treatment of patients with CTCL. The study covered 34 patients with recurrent or recalcitrant CTCL (Stage I–IV) who received PEG-DOXO as monochemotherapy, including data on 10 patients that were published in a previous report.13 Two patients received adjuvant, low-dose interferon ␣ (3 ⫻ 3 million units per week subcutaneously). Responders usually showed a clinical improvement during the first 3 months of treatment with PEG-DOXO. The best response was seen between one infusion and eight infusions. The outcome after 1 course of treatment was CR or CRu in 15 patients (2 patients with Stage IA disease, 5 patients with Stage IB disease, 2 patients with Stage IIA disease, 3 patients with Stage IIV disease, and 3 patients with Stage IVA disease), PR in 11 patients (2 patients with Stage IIA disease, 5 patients with Stage IIB disease, 1 patient with Stage III disease, and 7 patients with Stage IVA disease), SD in 2 patients (1 patient with Stage IIA disease and 1 patient with Stage IVA disease), and PD in 2 patients (1 patient with Stage IIA disease and 1 patient with Stage IVA disease). In the two patients who received a second course of PEG-DOXO, a PR was noted as the best response: Their final outcomes were a PR and SD, respectively. The distribution of CRs among patients who had tumors classified from Stage IA to Stage IVA provided no evidence of a stage-related response pattern. Patients who achieved a CR during the first course of treatment had a disease-free interval of ⱖ 1– 44 months (mean ⫾ standard deviation: 13.3 months ⫾ 10.5 months). Ten patients had a disease-free interval ⱖ 12 months.14 Prolonged treatment with PEGDOXO some patients received or the introduction of patients to a second course of PEG-DOXO did not result in increased rates of unwanted side effects; in particular, there were no cardiac adverse reactions, supporting earlier data on patients with cumulative doses of PEG-DOXO ⬎ 400 mg.21,22 PEG-DOXO therapy resulted in a response rate of 88.2% and seemed to be more effective compared with ECP (50% response) compared with and antitumor treatment with methotrexate, cyclophosphamide, and cisplatin (60 –70% response rate).23–25 We observed an event-free survival of 12.0 months ⫾ 9.5 months and an overall survival of 17.8 months ⫾ 10.5 months with

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a maximum survival of ⬎ 44 months. CHOP chemotherapy has been defined as a standard treatment for patients with advanced-stage, intermediate-grade, or high-grade non-Hodgkin lymphoma.7 Patients with advanced CTCL who were treated with the CHOP regimen or with cyclophosphamide, vincristine, and prednisone achieved an objective response rate of 40% and a disease-free interval of 5.7 months.24 In a Phase II study with the EPOCH regimen (etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisolone) in 15 patients with refractory CTCL (including patients with Se`zary syndrome and anaplastic, CD30 positive, large-cell CTCL), 27% of patients achieved a CR, and 53% of patients achieved a PR, resulting in a total response rate of 80%. The median progression-free interval was 8 months, and the median overall survival was 13.5 months. Grade 3 or 4 hematotoxicity occurred in 61% of patients.26 Pentostatin, a purine analogue, also has been evaluated in patients with cutaneous CTCL. Of 22 patients with mycosis fungoides and 21 patients with Se`zary syndrome who were treated on a Phase II trial with pentostatin 4 mg/m2, the response rates were 22.7% and 33.4%, respectively, with mild-to-moderate toxicity.27 Findings from two single-center studies supported these results.28,29 Gemcitabine, a novel pyrimidine antimetabolite, was investigated at 2 centers in a Phase II trial at a dosage of 1.2 g/m2 in 44 patients with Stage IIB–IV CTCL. The outcome was CR in 11.5% of patients and PR in 26% of patients, with a median duration of 15 months and 10 months, respectively.30 Oral bexarotene, a retinoid that has been approved for patients with all stages of refractory CTCL, has achieved an overall response rate of approximately 50% at a dosage ⱖ 300 mg/m2.31 In a multicenter trial in 94 patients with Stage IIB–IVG CTCL, the overall response rate was 45% for patients who received the 300 mg/m2 bexarotene dose and 55% for patients who received a bexarotene dose ⬎ 300 mg/m2.32 However, patients require monitoring for hypertriglyceridemia and hyperthyroidism, which are reversible and manageable with concomitant medication. Liposomal pegylated formulations of antitumor drugs are capable of improving safety and efficacy compared with conventional chemotherapy. In particular, PEG-DOXO is less cardiotoxic and nephrotoxic compared with doxorubicin HCl.33,34 The ability of PEG-DOXO to ameliorate the familiar side effects of unencapsulated doxorubicin also has been reported widely. Nausea and emesis,35,36 alopecia,35,36 local tissue vesicant activity,37 and doxorubicin-induced cardiomyopathy22 all are reduced significantly by encapsulation of the drug in pegylated liposomes. However,

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the administration of repeated doses of PEG-DOXO can be associated with PPE or hand-foot syndrome, which manifests as painful swelling and inflammation of the hands and feet, intertriginous areas, and sites of trauma.20,38 A similar mucosal toxicity associated with superficial mouth ulcers also occurs. These mucocutaneous adverse effects, as discussed above, are dose dependent, and it has been shown that they are doselimiting. A number of attempts have been made to define therapies to limit this toxicity, including the use of pyridoxine39 and topical dimethyl sulfoxide.40 Such interventions may offer the prospect of safely administering larger doses of PEG-DOXO, although, to date, no interventions have demonstrated effectiveness in a randomized study. The tolerability of PEG-DOXO was very good. Only two drop-outs were noted, one because of a capillary leakage syndrome that developed with a 4-week delay after the first infusion and another because of a suicide attempt that was not related to treatment. Toxicity was low to moderate. Adverse effects were reported in 41.2% of patients and was mostly Grade ⱕ 2. Monitoring of toxicity revealed temporary Grade 4 events (anemia in 1 patient) and Grade 3 events (anemia and lymphopenia in 4 patients, PPE in 1 patient) but no neutropenia. PPE occurred in only two patients who received PEG-DOXO twice per months and in only one patient who received PEGDOXO at longer intervals (i.e., 3– 4 weeks). This may argue for the initial suggestion of once-monthly treatment (cf. Gordon et al.38). The current study did not provide evidence for improved efficacy with dose increases (20 mg/m2 vs. 40 mg/m2) or increases in the frequency of application (once per month vs. twice per month). There is a lack of data regarding adjuvant treatment and the best (if any) treatment after patients achieve a CR. Current data support the use of PEG-DOXO as a monochemotherapy given once per month at a dose of 20 mg/m2. Because no curative treatment has been established and because the more aggressive treatments, although they have a better initial response rate, do not improve the prognosis of patients with CTCL,5,7 limiting toxicity is a rational approach for the development of effective new treatments. The treatment schedule in the current study with PEG-DOXO was less toxic than most of the established chemotherapy regimens but was effective, suggesting this treatment as a promising second-line alternative. Randomized, prospective, multicenter studies are needed to confirm our observations.

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