The initial clinical trials of diphtheria-based fusion protein toxins were conducted using DAB486IL-2 and DAB389IL-2 to establish their relative safety, pharmacokinetics, and potential efficacy in the treatment of non-Hodgkin's lymphoma. Non-Hodgkin's lymphoma represents a group of common neoplasms of lymphocytic origin, and are clonal expansions of lymphocytic elements blocked at particular stages of B- and T-cell differentiation. The malignant lymphomas comprise approximately 10% of all malignant tumors in the United States. Alarmingly, these malignant diseases are also increasing in incidence. Although B cells represent 65% of all non-Hodgkin's lymphoma, approximately 30% of all non-Hodgkin's lymphoma are of the T-cell type. There are three T-cell variants of non-Hodgkin's lymphoma which are cutaneous T-cell lymphoma, node based T-cell lymphomas, and lymphoblastic lymphoma. Older patients predominately present with skin or node-based disease, whereas younger patients often present with lymphoblastic lymphoma.
The predominate T-cell variant of non-Hodgkin's lymphoma is CTCL, which is also known as mycosis fungoides. As described by Broder and Bunn (1980), CTCL is a low grade epidermotropic disease mediated by CD4+ T cells which invade the skin. Skin lesions associated with this disease usually progress through patch, plaque, and tumor phases. Patch lesions are flat, scaly, erythrematous macules which are often pruritic. Plaques are generally raised, red to purple in color, thick and scaly, and pruritic. Nodules, which predominate in the face and intertriginous areas of the body, are susceptible to ulceration. Once the disease progresses beyond 10% of the total body surface area, spontaneous remission rarely occurs and the disease is invariably fatal. Patients are compromised by both the breakdown of the normal skin barrier and a depression in cell-mediated immunity, predisposing them towards infection (Axelrod et al., 1992). In addition to epidermotropic spread, disease progression leads to lymph node, spleen, liver, and other organ involvement. In some cases an erythrodermic leukemic state, also known as Sezary syndrome, may develop. The lymphocyte infiltration of the bone marrow in these patients renders the marrow functionally aplastic, leading to death by infection or hemorrhage through the depletion of normally functioning white cells and platelets. Although the 8-10 year overall survival rate for these patients is similar to that for other non-Hodgkin's lymphomas, once the disease has progressed to lymph node or organ system involvement, the median survival is less than four years. Patients with advanced disease are often refractory to chemotherapeutic protocols.
DAB486IL-2 was used in the first series of clinical trials conducted to evaluate the efficacy of IL-2-receptor targeted cytotoxic therapy in lymphoma (LeMaistre et al., 1992; 1993; Schwartz et al., 1992; Hesketh et al., 1993; Foss et al., 1998). Patients enrolled in these studies presented with refractory disease and had failed at least two prior chemotherapy treatment regimens. Since fresh tissue samples were not available from all of the patients, tumor expression of the IL-2 receptor was not a prerequisite for study enrollment. However, detection of the IL-2 receptor can be performed by immunostaining with the anti-Tac (p55) antibody, which recognizes the a subunit (CD25) of the IL-2 receptor (Uchimaya et al., 1985). These initial trials were designed as a three patient cohort in which single and multiple doses of the fusion protein toxin were administered by intravenous injection as a bolus or as 90 min infusions. Dose escalation was performed starting at 700 ng/kg/day, and gradually increased to 400 ^g/kg/day.
As reported by LeMaistre et al. (1993), clinical responses occurred in 8% (4/51) of patients with low and intermediate grade non-Hodgkin's lymphoma, 7% (1/14) of patients with Hodgkin's disease, and 17% (6/36) patients with CTCL. One patient with tumor stage CTCL had a complete remission and has remained disease-free for over five years (Hesketh et al., 1993). All patients who responded to therapy with DAB486IL-2 had lymphomas expressing the IL-2 receptor. Within the dose range of 200-400 ^g/kg/day, the t1/2 for clearance of the fusion protein toxin from plasma was 11 min (LeMaistre et al., 1993). Renal insufficiency was observed at doses greater than 400 ^g/kg/day, defining the maximum tolerated dose. Adverse effects associated with intravenous administration of the fusion protein toxins were transient and included increased levels of hepatic transaminases, malaise, fever, hypersensitivity, and nausea/vomiting. Although the serum levels of soluble IL-2 receptor were increased, there was no apparent effect on either clearance rates or potential efficacy of DAB486IL-2. Half of the patients developed antibodies to IL-2, but there were no observable changes in treatment response. It remains to be determined whether or not the establishment of antibodies recognizing IL-2 results in decreased levels of IL-2, leading to post-therapy clinical manifestations of autoimmune deficiency. Prior childhood immunization against diphtheria also had no apparent effect upon fusion protein toxin clearance and treatment response.
As a result of greater biological activity and increased ease of purification, DAB389IL-2 was substituted for DAB486IL-2 in future clinical trials for IL-2 targeted cytotoxic therapy in the treatment of CTCL, non-Hodgkin's lymphoma, and Hodgkin's lymphoma. Furthermore, only patients who presented with tumors expressing the IL-2 receptor were enrolled. As reported by LeMaistre et al. (1998), the patient population had a mean of five previous therapies and included 25 patients who had received a bone marrow transplant. A cohort dose escalation was once again employed and patients received doses ranging from 3 to 31 ^g/kg/day for five days and treatment cycles were repeated every three weeks. A similar side effect profile was observed and included fever, malaise, nausea/vomiting, and reversible elevation of serum transaminases. Based upon malaise, the dose-limiting toxicity was 31 ^g/kg/day. Eight of the patients with CTCL experienced hypoalbuminemia, hypertension, and edema; these are all clinical manifestations of vascular leak syndrome. All observed toxicities were reversible and not cumulative.
Following the promising results from the open label phase II clinical trials with DAB389IL-2, a phase III clinical trial was designed to test rigorously the potential efficacy of treating CTCL patients with this fusion protein toxin. This trial included two randomized, double blinded studies in mutually exclusive patient populations. One group included patients with advanced refractory disease, who were treated intravenously over eight courses of therapy at doses of either 9 or 18 ^g/kg/day. The second group included patients with less advanced disease, who were also treated at doses of 9 or 18 ^g/kg/day. This second group also included a placebo, and patients whose disease progressed were unblinded. Those receiving placebo were allowed to enroll in an open-label study at a dose of 18 ^g/kg/day. The same adverse effects as seen in the previous clinical studies were observed in both patient groups.
The phase III clinical trial clearly demonstrated that therapy with DAB389IL-2 offers a substantial reduction in tumor burden and relief from constitutional symptoms in patients with refractory CTCL. Within the first patient group, 30% of the patients had a 50% or greater reduction in tumor burden for at least six weeks following treatment. Within the total patient population, 10% of patients that could be evaluated had a complete clinical response and were histologically free of disease. Patients receiving the higher dose of 18 ^g/kg/day exhibited a higher response rate (36%) compared to patients treated with the lower dose of 9 ^g/kg/day (23%). However, due to the limited sample size, these groups are statistically inseparable. Based upon success of DAB389IL-2 in these clinical trials, the fusion protein toxin received FDA approval as a therapeutic for refractory CTCL in patients whose neoplasms express the IL-2 receptor alpha subunit (CD25).
Several clinical studies have recently been conducted to assess combinatorial therapies using either steroids or cytokines to augment response rates to DAB389IL-2 in patients with refractory CTCL. The administration of DAB389IL-2 in combination with steroids doubled the response rate to 60% in patients with CTCL (Foss and Reich, unpublished). To assess the impact of steroids on tolerability and response in DAB389IL-2 treated patients, 20 patients with histologically confirmed CTCL were treated with either dexamethasone (8mg) or prednisone (20 mg) and Ontak (18 ^g/kg/day) for five consecutive days. While infusion related events were significantly decreased, delayed hypersensitivity was noted in three patients. The incidence of clinically apparent vascular leak syndrome (20%) was not statistically different with the addition of steroids, despite a significant decrease in the occurrence of edema. The response rate to DAB389IL-2 alone is only 30% in patients with CTCL. Other clinical trials have also suggested that combination therapy using cytokines to upregulate IL-2 receptor expression on neoplastic cells may have potential benefit in augmenting response to IL-2 receptor targeted therapies, including DAB389IL-2 (Foss and Reich, unpublished).
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