Confirmation of the Activity of the Interleukin-2 Fusion Toxin Denileukin Diftitox against Chemorefractory Chronic Lymphocytic Leukemia, including Cases with Chromosome 17p Deletions and without Detectable CD25 Expression

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Abstract
The study by Frankel et al. (1) is the first published report of a novel treatment for fludarabine-refractory CD25-positive chronic lymphocytic leukemia (CLL), using the immunotoxin denileukin diftitox (Ontak). This fusion protein is proposed to kill cells expressing the interleukin 2 (IL-2) receptor via internalization of diphtheria toxin bound to IL-2 (2). The IL-2 receptor is a trimeric complex composed of CD25 (α subunit), CD122 (β subunit), and CD132 (γ subunit). Although denileukin diftitox is registered in the United States only for the treatment of cutaneous T-cell lymphoma, its evaluation in CLL is logical, because approximately one-half of CLL patients have tumor cells that express CD25 (3). In addition, previous trials of the parent compound, DAB486IL-2, demonstrated an objective response in 2 of 13 patients with CLL (4, 5, 6, 7).We wish to report an additional seven CLL patients treated with denileukin diftitox and to highlight its efficacy in instances of CD25-negative and highly chemorefractory disease with a chromosome 17p abnormality. Two patients were treated as part of a clinical trial using denileukin diftitox in B-cell lymphoproliferative disorders; the remaining five were not eligible for the trial and were treated on a compassionate use basis after obtaining informed consent with national regulatory and institutional ethics approval. Patient characteristics are presented in Table 1. Six patients were initially given a standard regimen of daily 18 μg/kg i.v. doses for 5 days, repeated at three-weekly intervals. Because of advanced age and poor performance status, patient 5 initially received 9 μg/kg/day for two courses, with a subsequent increase to 13.5 μg/kg/day for the remainder of the treatment.In all cases, denileukin diftitox was chosen to treat profoundly chemoresistant disease. All of the patients had been extensively pretreated, all having received fludarabine as well as alkylating agents. Patients 1 and 7 had profound cytopenias precluding the use of further conventional chemotherapy. Four additional patients had only a minor response to their most recent fludarabine-containing regimen, with rapid relapse (patients 3–5) or progression (patient 6) while on therapy. Patient 2 had progressed only 14 days after receiving ifosphamide, carboplatin, etoposide, and rituximab.All of the patients suffered some adverse effects, of various severity (Table 2). Patient 1 required treatment cessation after developing severe vascular leak syndrome, manifested as symptomatic ascites, bilateral pleural effusions, and a hemorrhagic pericardial effusion with tamponade requiring pericardiocentesis. Pretreatment hypoalbuminemia in this patient is likely to have predisposed her to this complication. Patient 4 tolerated only one cycle of therapy, subsequently requiring prolonged hospital admission for grade III fatigue; grade IV anorexia requiring enteral feeding; clinical hepatitis with abdominal pain, nausea, and diarrhea, followed by disseminated Herpes simplex infection. The patient died of pneumonia 3 months after this course of denileukin diftitox.Five of the six patients who received the drug at a dose of 18 μg/kg/day for 5 days developed abnormal liver function tests, with asymptomatic increases between 1.5 and 10 times baseline levels. Only patient 4 had symptomatic hepatitis. Hypoalbuminemia and a rise in serum lactate dehydrogenase levels were seen in all six patients treated at this dose. All biochemical abnormalities resolved spontaneously and completely, but in one case, the abnormalities resulted in treatment delays and a reduction in the total dose given in additional cycles. Dose reduction in the patient (patient 5) avoided any biochemical abnormalities; however, the lympholytic effect appears to have been much slower in consequence.Of the seven patients treated, two had an objective partial response, and there were two minor responses (Table 2). Patient 1 (with the poor prognosis 17p deletion) had a clinically significant hematological response, becoming platelet independent after previously requiring weekly platelet transfusions. Patient 2 has had an excellent response overall, with normalization of peripheral lymphocyte count, >90% reduction in nodal size, and conversion from a diffuse bone marrow infiltrate to scattered lymphoid nodules with intervening normal hemopoiesis (Figs. 1 and 2). Six of the seven patients had a significant and rapid reduction in peripheral blood lymphocytosis (Fig. 3), indicating drug activity even in two patients who otherwise had no significant response. The observed responses have been relatively durable. One partial response lasted 16 months, and the other is ongoing at 15+ months. One minor response patient died of infectious complications in ongoing response at 3 months, and the other developed progressive disease at 10 months.These results confirm the efficacy of denileukin diftitox in chemotherapy-refractory CLL. A rapid reduction in circulating clonal lymphocytes is characteristic of treatment with this agent. Slower nodal response may be related to poor drug access into large nodal masses due to the large molecular weight of the molecule (Mr > 50,000). This problem seems to have been overcome in patient 2, in whom a progressive reduction in nodal size was noted after multiple cycles of treatment given for a shorter duration (3 or 4 days).In contrast to the series by Frankel et al. (1), we have demonstrated that denileukin diftitox has activity in cases without detectable CD25 expression (one partial response, one minor response, two no response). There are a number of potential reasons for this. Re et al. (8) have demonstrated that the β subunit of the IL-2 receptor (and not CD25 positivity) is critical for denileukin diftitox-mediated cytotoxicity in vitro. The β- and γ-chains dimerize to form intermediate-affinity receptors that are capable of signal...