Early Treatment of High Risk Chronic Lymphocytic Leukemia with Alemtuzumab, Rituximab, and PGG Beta Glucan: A Phase I Clinical Trial

The primary aim of this IRB approved study (NCT01269385) was to determine the maximum tolerated dose (MTD) of PGG beta glucan that could be safely combined with ALM and RTX. The MTD was defined as the PGG beta glucan dose level below that which induced dose limiting toxicity in at least one third of patients, or the highest dose level tested if all levels were tolerated. Eligibility for the trial required a diagnosis of CLL by standard (IWCLL-NCI 2008) criteria, no prior treatment for CLL, high risk CLL based on molecular markers, absence of standard indications for initiation of therapy for CLL, and adequate performance status and organ function. High risk CLL was defined as at least one of the following: 17p13-; 11q22-; either unmutated (<2%) IGHV or use of VH3–21 as well as CD38+ and/or ZAP70+. Patients received standard premedication for mAb, antimicrobial and allopurinol prophylaxis and weekly PCR testing for CMV reactivation with treatment of viremia. The duration of treatment was 33 days. PGG beta glucan was administered IV on days 1, 5, 10, 17, 24, and 31 and the first dose was premedicated with hydrocortisone 100mg IV, oral acetaminophen 1000 mg and diphenhydramine 50 mg. The starting dose level of PGG beta glucan was 1 mg/kg, 2^nd dose level was 2 mg/kg and the 3^rd dose level 4 mg/kg. Subcutaneous ALM therapy started on day 3 with daily dose escalation (3 – 10 – 30 mg) and then 30 mg Mon-Wed-Friday for 4 weeks. Weekly RTX started on day 10 at 375 mg/m² IV × 4 doses.

Thirteen patients were enrolled from February 2011 to April 2012. The 11 evaluable patients had a median age of 61 years (range 47 – 77), 73% were male, 3 had early stage disease (Rai 0) and 8 had intermediate stage disease (Rai I n = 7, Rai II n = 1). High-risk parameters were 17p- in 4 patients, 11q22- in 3 patients, and unmutated IGHV and expression of ZAP70 and/or CD38 in 4 patients. There were no dose limiting toxicities. One patient had grade 4 febrile neutropenia, with no grade 3–4 anemias or thrombocytopenias, and there were no grade 3–4 non-hematological toxicities. All patients responded to therapy with 7 CR, 1 CCR, 1 nPR, and 2 PR (IWCLL-NCI 2008 criteria). Median follow up was 6.9 months (2.3 – 13.2) and one patient progressed at 9.7 months. No patients have required treatment for progressive disease and there have been no patient deaths. Two patients were not evaluable: One developed neutropenia and therapy was not held per protocol, and the other developed a grade 2 skin reaction to ALM and treatment was stopped.

The combination of PGG beta glucan with ALM and RTX is well tolerated at a PGG beta glucan dose of 4 mg/kg. All patients responded to therapy with 64% achieving a CR. These data support continuation of this study in a phase II component.

This study was funded by the University of Iowa/Mayo Clinic Lymphoma SPORE (CA097274) and Biothera.

Zent:Biothera: Research Funding; Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding. Off Label Use: Phase I study using PGG beta glucan in CLL.