Predictors of complete responses with denileukin diftitox in cutaneous T‐cell lymphoma
Authors: Francine Foss, Madeleine Duvic, Elise A. Olsen
Journal: American Journal of Hematology (2011)

The clinical course of cutaneous T-cell lymphoma (CTCL) is typically chronic, often progressive, and variably response to existing therapeutic interventions. To date, few controlled clinical trials demonstrate durable complete responses (CR) in advanced-stage patients. Denileukin diftitox (DD) is a recombinant fusion protein targeting the interleukin-2 receptor of malignant cells. Of 263 relapsed and refractory CTCL patients treated with denileukin diftitox in three prospective, randomized Phase II and III clinical trials, 24 (9.1%) patients attained a durable complete response lasting beyond 3.6 years. This study evaluated the characteristics of the complete responders in these trials. CR patients had received a mean of 3.6 prior therapies. There was no difference in the frequency of CR based on stage of disease, dose of DD (9 vs. 18 μg/kg/day) (P = 0.646) or between CD25-positive and CD25-negative patients (P = 1.00). Response durations were 57–1,325+ days in the CD25-positive group and 190–400+ days in the CD25-negative group. These studies demonstrate that DD therapy resulted in durable complete responses in a subset of patients with early and advanced CTCL and CD25-positive and CD25-negative disease. CTCL are defined by the presence of skin lesions that are infiltrated with malignant T-lymphocytes [1, 2]. Therapeutic algorithms for CTCL, such as those recommended in the clinical practice guidelines of the National Comprehensive Cancer Network [3], typically use both topical skin-directed therapies and systemic therapies, and treatment is largely dictated by clinical stage and disease manifestations. Patients with stage I CTCL (patch/plaque disease with no extracutaneous involvement) generally receive only skin-directed therapy as primary treatment. Systemic therapies are typically reserved for patients with advanced disease (Stage IIB-IVB) or for patients with early stage disease (Stage IA-IIA) that is refractory to several lines of skin-directed therapy [3]. Although initial response rates to first-line therapies may be high, virtually all patients with stage IB or greater MF/SS ultimately relapse, and a cure is rare in all patients with MF/SS [4-12]. Denileukin diftitox (DD; ONTAK) is a genetically engineered fusion protein designed to target malignant T cells based on their expression of the interleukin-2 (IL-2) receptor. It is composed of the enzymatically active domain of the diphtheria toxin (fragment A and a portion of fragment B) followed by the full-length sequence of human IL-2 [13-17]. DD received accelerated US Food and Drug Administration approval for the treatment of patients with persistent or recurrent CTCL whose malignant cells express the CD25 component of the IL-2 receptor based in part on the results of a phase III trial (Study 93-04-10) conducted in heavily pretreated patients with advanced-stage MF/SS [18]. Two additional phase III studies-Study 93-04-11 [19] and Study 93-04-14-have since demonstrated that DD is effective in both early- and advanced-stage MF/SS that has progressed or is refractory to several prior treatments. In Study 93-04-11, the overall response rate was 44%, and in Study 93-04-14, overall response rates were 59.3% in patients from the placebo group of Study 93-04-11 who had progressive or stable disease, 40% in patients from three other trials including Study 93-04-11 who had relapsed after an initial response to DD, 0% in patients from Study 93-04-11 who had stable disease through eight courses of DD treatment, and 30.6% in patients excluded from Study 93-04-11 because their CD25 status was negative. To better understand the efficacy of DD across the spectrum of MF/SS, we analyzed the data for all patients who achieved a complete response (CR) in the three phase III studies of DD that have been undertaken to date: 93-04-10, 93-04-11, and 93-04-14. Table I summarizes patient demographics for all individuals enrolled in Studies 93-04-10, 93-04-11, and 93-04-14. Across the three studies, 263 patients received treatment with DD. Of these individuals, 227 had ≥20% CD25-positive skin infiltrates by immunohistochemistry according to the predetermined definition as confirmed by the reference pathologist; 36 patients had CD25-negative disease. For Study 93-04-10 [18], 58% of all skin samples from screened patients contained ≥20% of cells that expressed CD25, and the overall response rate was 30%, with a 10% CR/CCR rate and a median response duration of 4 months from the time of onset of first response for all responders. Overall response rates according to treatment regimen were 23% (8/35) for patients treated with DD 9 μg/kg/day with one patient achieving a CR and two achieving a CCR, and 36% (13/36) for patients treated with DD 18 μg/kg/day with two patients each achieving a CR and a CCR. The difference in response rates was not statistically significant between the two arms, although the number of patients in each arm was small (9 μg/kg/day: n = 35; 18 μg/kg/day: n = 36). For Study 93-04-11, [19] the overall response rate for both DD arms was 44% (44/100)-38% (17/45) for DD 9 μg/kg/day and 49% (27/55) for DD 18 μg/kg/day compared with a rate of 16% (7/44) for the placebo arm. Ten patients (10%) among the DD-treated population achieved a CR/CCR, reflecting CR/CCR rates of 11% (5/45) for the 9 μg/kg/day group and 9% (5/55) for the 18 μg/kg/day group. One patient (2.3%) in the placebo arm achieved a CCR. The placebo patient and three each of those in the 9 μg/kg/day and 18 μg/kg/day groups who had CR/CCR were early stage (≤IIA) at study entry, and two each in the 9 μg/kg/day and 18 μg/kg/day groups who experienced CR/CCR had stage ≥IIB disease. The median duration of response of 236 days for both DD groups, measured from the time of onset of first response for all responders, was significantly longer than the 81-day median response duration observed in the placebo group (P = 0.0016). The overall response rates for the various groups of patients included in Study 93-04-14 were 59% for the 27 patients who crossed over from the placebo arm, 40% for the 20 relapsed/retreated patients, and 31% for the 36 patients with CD25-negative MF/SS. Median PFS was 870 days for placebo-crossover patients, >487 days (last data point; median not reached) for patients with CD25-negative disease, 205 days for patients with disease relapse who were retreated with DD, and 183 days for patients who had stable disease after eight cycles of DD and who received additional DD therapy. None of the pair-wise comparisons were found to have statistically significant differences. Of the 263 patients in Studies 93-04-10, 93-04-11, and 93-04-14, 24 (9.1%) achieved a CR/CCR. The baseline characteristics of patients who achieved a CR/CCR are shown in Table II. These 24 individuals included 6 DD-naïve patients with CD25-positive disease who received DD 9 μg/kg/day (8% of the 80 patients who received this dose), 13 DD-naïve patients with CD25-positive disease who received DD 18 μg/kg/day (11% of the 118 patients who received this dose), 2 patients with CD25-positive disease who were retreated with DD 18 μg/kg/day (7% of the 29 patients who were retreated at this dose), and 3 DD-naïve patients with CD25-negative disease who received DD 18 μg/kg/day (8% of the 36 patients who received this dose) (Table II). Overall, the difference in CR/CCR rates between the 9 μg/kg/day group (n = 80) and 18 μg/kg/day group (n = 183) was not significant (P = 0.646). The difference in CR/CCR rates between patients with CD25-positive disease (n = 118) and CD25-negative disease (n = 36) who received de novo DD 18 μg/kg/day was also not significant, although the numbers of patients are too small for definitive conclusions to be made (P = 1.00). The time to CR/CCR was generally slightly longer in the DD 9 μg/kg/day arm (53.5 days) compared to the 18 μg/kg/day arm (41.5 days). The median time to response for the 3 CD25-negative patients treated with DD 18 μg/kg/day was 43 days (range: 22–57 days). The median duration of response (DOR) in the CR/CCR patients had not yet been attained in all arms at the time of analysis (Table II ). Among CD25-positive patients, the DOR ranged from 57 days to >1,325 days; in CD25-negative patients, DOR ranged from 190 to >400 days. Of the 24 patients who achieved a CR/CCR, 7 had experienced disease progression at the time of the analysis, whereas 17 had retained a CR/CCR. All patients with a CR/CCR experienced at least one adverse event (AE) and at least one DD-related adverse event. No patients received steroid premedication in these trials. Twenty (83%) experienced a moderately severe or severe AE, of which 18 (75%) were considered to be related to DD. Thirteen of 24 (54%) experienced a serious AE, of which 12 (50%) were considered to be related to DD. Most serious AEs occurred during the first DD course, and then dramatically decreased thereafter. Four patients (17%) experienced an adverse event that was reported as the primary reason for termination of treatment in these subjects. Of the 24 individuals with a CR/CCR, three patients had hypersensitivity reactions and three patients had capillary leak syndrome associated with DD treatment. In summary, this post-hoc analysis of three phase III clinical trials of DD identified a CR/CCR rate of 9.1%, with similar rates of CR/CCR in early-stage disease (≤IIA) (9.7%; 15/154) and late-stage disease (≥IIB) at baseline (8.3%; 9/109). Notably, 38% of CR/CCR were patients who had received at least three prior therapies for the treatment of CTCL, but there was no correlation between prior anticancer therapies and CR. No statistically significant difference was observed in the frequency of CR/CCR between patients who received DD 9 μg/kg/day versus those who received 18 μg/kg/day (7.5% vs. 9.8%); however, DD-naive patients who received the higher DD dose tended to have a faster time to CR/CCR compared with DD-naïve patients who received the lower dose. Interestingly, no statistically significant difference in CR/CCR was observed between patients with CD25-positive disease versus CD25-negative disease who received DD 18 μg/kg/day de novo. These analyses indicate that there is no way, prior to treatment, for a clinician to identify which patients will achieve a CR with DD. The occurrence and duration of CR/CCR in patients with CD25-negative disease is encouraging. Determination of the IL-2 receptor isoform is limited by the sensitivity of immunohistochemistry to accurately detect expression of the low levels of receptor and CD25 negative cells which express the intermediate and low affinity IL2R.The clinical trials analyzed herein established an arbitrary cut-off of CD25 positivity on ≥20% of T cells in biopsied skin lesions; therefore, it is likely that patients who were determined to be CD25 negative according to this cut-off may have had lower levels of CD25 expression and, alternatively, expression of the intermediate-affinity IL-2 receptor. In those patients who achieved a CR/CCR across the three phase III trials, the response has been durable. At the time of analysis, the median duration of response had not been attained but exceeded 1,325 days (3.6 years) for all complete responders treated with DD. This duration of response compares favorably with the length of response seen with bexarotene and vorinostat, two other novel systemic therapies approved for use in CTCL [20-22]. In conclusion, pooled analysis of the three phase III clinical trials demonstrates that a small proportion of patients with both early and advanced CTCL achieve a durable CR/CCR with DD therapy, at both the 9 and 18 μg/kg/day doses. Response rates in patients with CD25-negative disease suggest that the conventional immunohistochemical assay for CD25 expression is neither sensitive nor specific enough to predict which CTCL patients will respond to this therapy. Eligible patients for Studies 93-04-10, 93-04-11, and 93-04-14 had to have a histologically confirmed diagnosis of MF or SS. A skin biopsy from a representative skin lesion was obtained at baseline to determine the proportion of CD25 expression among infiltrating lymphocytes, and a blood sample was analyzed for the proportion of CD4+CD3+CD7- neoplastic lymphocytes. In all studies, for disease to be considered CD25 positive, lesional skin biopsies had to demonstrate CD25 expression on ≥20% of lymphocytes. CD25 expression was determined using immunohistochemical analysis of frozen lesional specimens by a central laboratory (Pathology Laboratory, University of Texas Health Science Center, San Antonio, TX, for Study 93-04-10; Quest Diagnostics, Inc., San Juan Capistrano, CA, for Studies 93-04-11 and 93-04-14). Study 93-04-10 was a multicenter, randomized, blinded, parallel-group, phase III trial of DD conducted in extensively pretreated patients with CD25-positive MF/SS. Eligible patients with stage IB-III MF/SS had recurrent or persistent disease following at least four prior therapies, whereas eligible patients with stage IVA MF/SS (nodal lymphoma) had recurrent or persistent disease following at least one prior therapy. Patients who had received more than two combination chemotherapy regimens were excluded, as were those who had previously received treatment with DD. A total of 71 patients were stratified by disease stage (≤IIA or ≥IIB) and randomly assigned to receive DD 9 μg/kg/day or 18 μg/kg/day given for 5 consecutive days every 3 weeks for up to 8 cycles. Study 93-04-11 was a multicenter, randomized, double-blind, placebo-controlled phase III trial of DD that was conducted to confirm the results of Study 93-04-10 in a less heavily pretreated population of patients with CD25-positive MF/SS. Eligible patients had recurrent or persistent stage IA-III disease following no more than three prior lines of therapy and no more than one prior combination chemotherapy regimen. Patients were excluded from the trial if they had previously received treatment with DD. A total of 144 patients were stratified by disease stage (i.e., ≤IIA or ≥IIB) and randomly assigned to receive DD 9 μg/kg/day, DD 18 μg/kg/day, or placebo given for 5 consecutive days every 3 weeks for up to 8 cycles. Of these patients, 100 received treatment with DD; 44 patients received placebo. Study 93-04-14 was a multicenter, open-label study that was conducted to evaluate the safety and efficacy of DD in patients with MF/SS. Eligible patients for this study fell into 1 of 4 subgroups: (1) nine patients in Study 93-04-11 who were randomized to a DD arm and who experienced stable disease through eight treatment courses, (2) 27 patients in Study 93-04-11 who were randomized to the placebo arm and who experienced progressive disease or stable disease through eight treatment courses, (3) 20 patients in Studies 93-04-10 and 93-04-11 who were randomized to a DD arm and who relapsed during follow-up after an initial response to DD, and (4) 36 patients who were excluded from Study 93-04-11 because they were CD25 assay negative (see Fig. 1). All patients received treatment with DD 18 μg/kg/day given for 5 consecutive days every 3 weeks for up to 8 cycles. Treatment arms included in study 93-04-14. Response assessment was based on the average percentage change in tumor burden at each study visit relative to baseline based on a global score of skin (SWAT), lymph node, and blood involvement. In all three studies, response had to be confirmed in three consecutive courses over 6 weeks and was adjudicated by an independent review committee. CCR was defined as no clinical evidence of disease based on tumor burden assessments and documentation by photography after a course of treatment, with either no confirmatory skin biopsy attained or a biopsy showing the presence of atypical lymphocytes. CR was defined as no clinical evidence of disease based on tumor burden assessments and documentation by photography after a course of treatment, along with the absence of atypical cells in a skin biopsy. PFS was defined as the time from Day 1 of Course 1 to the first observation of disease progression or death. Duration of response was measured from the date that a documented response was first observed until the date of relapse, the initiation of new anticancer treatment, or the last observation in the study. Time to treatment failure was measured from the date of initial treatment with DD to the date of relapse, the initiation of new anticancer treatment, progressive disease, or toxicities that resulted in discontinuation. Statistical analyses involved calculating Kaplan-Meier product limit estimates and 95% confidence intervals (CIs) for days to initial response. Dr. Foss generated the hypothesis and conducted the study. Dr. Foss generated the final draft of the manuscript. Drs. Olsen and Duvic participated in data collection and reviewed the manuscript. Drs. Foss, Duvic, and Olsen all enrolled patients and contributed to the design of the three clinical trials reviewed in this analysis. The authors thank Kara Nyberg, PhD, from Sui Generis Health, for providing editorial assistance to the authors during the preparation of this manuscript. There was no payment or support to the authors of the study. Francine Foss*, Madeleine Duvic , Elise A. Olsen , * Department of Medical Oncology and Bone Marrow Transplantation, Yale Cancer Center, New Haven, Connecticut, Department of Dermatology and Medicine, MD Anderson Cancer Center, Houston, Texas, Department of Dermatology, Duke University, Durham, North Carolina.