In a phase I trial for patients with relapsed CLL, lumiliximab demonstrated decrease in lymphocyte counts in 91 of patients and reduction in lymphadenopathy in 59 of patients.66 This was followed by a phase I II trial in which lumiliximab was given in combination with the FCR regimen to patients with relapsed CLL.67 This study enrolled 31 patients and lumiliximab was administered at 375 mg m2 or 500 mg m2 in combination with FCR for six cycles. ORR was 71 , 48 of patients showing CR and 10 achieving PR.67 69 The most common 3-Methyladenine PI3K Inhibitors side effects were nausea and pyrexia. Although the initial results were promising, subsequent studies did not validate the findings and an ongoing international multicenter phase III trial was halted due to the lack of efficacy of lumiliximab. Targeting CD25 The immunotoxin denileukin diftitox is a recombinant protein attached to the diphtheria toxin along with IL 2 targeting mAb. The antitumor activity is mainly mediated by binding to IL 2 receptors and releasing the diphtheria toxin. Denileukin diftitox has shown clinical eff icacy in hematological malignancies and has been approved for the treatment of T cell lymphomas.70 Frankel et al reported the activity of denileukin diftitox in relapsed CLL patients with CD25 expression of.20 .
71 Patients were treated with daily infusion of denileukin diftitox at 18 ?g kg day for 5 days every 21 days for eight cycles. Of a total of 30 treated patients, 22 exhibited 73 CD25 expression on at least 20 of circulating cells. Patients had received a median of four prior Polo-like kinase treatments.
The treatment was well tolerated with important toxicities reported as asymptomatic elevation of transaminases, fever, fatigue, hypoalbuminemia, nausea and vomiting, myalgias, rash, anorexia, vascular leak syndrome, elevated creatinine, and anaphylactic reaction. Patients on denileukin diftitox demonstrated PR of 8 , 50 showing minimal response.71 Morgan et al reported activity of denileukin diftitox in relapsed CLL patients irrespective of CD25 status. Seven patients with refractory CLL and CD25 negative status were treated with Ontak on the standard regimen of 18 ?g kg intravenously for 5 days repeated every 3 weeks or every 21 days. All patients experienced some toxicities such as serositis, hypoalbuminemia and asthenia. This study showed activity in heavily pretreated CLL patients with two objective PR and two minimal responses.72 Targeting the death receptor TRAIL Death receptors have also been targeted to induce apoptosis in hematological malignancies. Apoptosis 2 TNF related apoptosis inducing ligand is a protein ligand in the TNF family which binds to the death receptors TRAIL R1 and TRAIL R2. Along with Fas, TNF ??is the key component of extrinsic apoptotic cell death pathways.