A Phase Ib/II Study of Combined Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) As Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)

High-dose methylprednisolone (HDMP) and rituximab (R) is an effective non-myelosuppressive treatment regimen for patients (pts) with chronic lymphocytic leukemia (CLL). Also, this combination has shown activity even in pts who have adverse leukemia-cytogenetics, such as del17p. Phase III studies have demonstrated that CLL pts treated with chlorambucil and obinutuzumab-Gazyva (G), another anti-CD20 mAb, had a superior outcome than comparable pts treated with R-chlorambucil. We hypothesized that G-HDMP is well-tolerated and effective in the treatment of pts with CLL. Accordingly, we initiated an open-label phase Ib/II clinical study.

A total of 40 pts were enrolled in two cohorts of 20 pts each (previously untreated (PU) and relapsed/refractory (RR) CLL) and treated with HDMP 1 g/m²on Day 1-3 of cycles 1-4 (28 days/cycle) and G administered based on FDA dosing recommendations for 6 cycles.

The pts had a median age of 67 years + 9.1 in the RR cohort and 63 years + 8.3 in the PU cohort. The median baseline absolute lymphocyte count was 30.7 + 7.3 x1,000/mm³ for pts in the RR cohort and 47.6 + 19.7 x1,000/mm³for pts in the PU cohort. Pts showed the following cytogenetic abnormalities: del(17p) in 30% RR vs. 0% PU, del(13q) in 60% RR vs. 70% PU, del(11q) in 20% RR vs. 35% PU, and trisomy 12 in 15% RR vs. 20% PU. Most AEs were grade 1-2 (RR=87%; PU=93%) without development of dose-limiting toxicities. Only two pts needed therapy discontinuation. One pt due to pulmonary embolism and the second pt due to asymptomatic gastrointestinal bleeding that required blood transfusion and resolved spontaneously. Grade 1-2 G-infusion-related reactions (IRR) were observed in 40% and 80% of pts in the RR and PU cohorts, respectively. Grade 3-4 IRR were observed in 10% of pts in the PU cohort only.

We observed cytopenias (neutropenia grade 3-4: RR=55%, PU=40%; thrombocytopenia grade 3-4: RR=35%, PU=20%; and anemia grade 3-4: RR=0%, PU=0%). There were no cases of febrile neutropenia. Two pts (10%) in the RR cohort and one pt (5%) in the PU cohort developed infection grade 1-2 that was treated with oral antibiotics but did not require study treatment discontinuation. The most frequent non-hematological adverse events (AEs) were transaminitis, hyperglycemia, and electrolyte alterations (grade 1-2). There were no treatment related deaths in either cohort.

The response assessment was performed in all 40 pts by iwCLL criteria. The ORR was 100% in the PU cohort and 95% in the RR cohort. 70% of the pts in the PU cohort and 85% of the pts in the RR cohort achieved a PR. CR was observed in 30% and 10% of the pts in the PU and RR cohorts, respectively. One pt (5%) in the RR cohort and four pts (20%) in the PU cohort achieved MRD^neg status (<0.01% CLL in the bone marrow by multiparameter flow cytometry). Only one pt in the RR cohort achieved SD.

At a median follow-up of 12.2 months, the RR cohort had a median Progression Free Survival (PFS) of 13.6 months and median Treatment Free Survival (TFS) of 14.7 months; the median Overall Survival (OS) has not been reached. In the PU cohort, the median PFS, TFS and OS have not been reached. One pt from the RR cohort and one pt from the PU cohort died during the follow-up period due to disease progression.

G-HDMP was well tolerated and all 40 pts showed hematological and clinical responses during the study treatment without development of unexpected AEs. In both cohorts, most of IRR were grade 1-2 and severe IRR (grade 3-4) were much less compared with previously published data (G-chlorambucil / CLL-11 study). Compared to pts in the CLL-11 study, cytopenias appeared to be more frequent, however, the rate of infection and need for IV antibiotics or hospitalizations was lower. Of note, the eligibility criteria allowed pts with severe cytopenias and transfusion requirement to participate in our study. Response in PU pts were higher in terms of ORR, CR and CR-MRD^negativecompared with the data from the CLL-11 study and suggests a possible synergistic activity between G and HDMP.

Overall, G-HDMP was well tolerated in the PU and RR CLL pts with a lower rate of IRR making this regimen more manageable in the outpatient setting. Responses were higher than previously reported in PU pts. Responses in RR pts appear to be comparable to our previous studies using R-HDMP. Our data supports G-HDMP as an alternative combination regimen for the treatment of CLL pts.