Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) Combination for Patients with Chronic Lymphocytic Leukemia (CLL) - a Phase Ib/II Study

High-dose methylprednisolone (HDMP) and the anti-CD20 mAb 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 cytogenetics, such as del17p. Obinutuzumab (G) is a glycoengineered type 2 humanized anti-CD20 mAb with activity superior to that of R when administered with the same chemotherapy. We hypothesized that HDMP+G would be a highly effective treatment for pts with CLL. To examine the safety and activity of this regimen, we initiated an open-label phase Ib/II study involving 41 pts enrolled in either of two cohorts: 21 who had not received prior therapy (1L) and 20 who had relapsed/refractory (R/R) CLL. Of note, the eligibility criteria allowed pts with severe cytopenias and transfusion requirement to participate in our study. All pts received HDMP at 1 g/m² on day 1-3 of cycles 1-4 and G for 6 cycles (28 days/cycle). The first infusion of G was administered over a period of 2 days (100 mg on day 1 and 900 mg on day 2) and the subsequent infusions were given at 1 g on days 8 and 15 of cycle 1, and on day 1 of cycles 2-6.

The pts had a median age of 67 years (± 9.1) in the R/R cohort and 64 years (± 8.4) in the 1L cohort. The median baseline absolute lymphocyte count was 30.7 ± 7.3 x1,000/µL for pts in the R/R cohort and 49.3 ± 18.9 x 1,000/µL for pts in the 1L cohort. Pts had the following cytogenetic abnormalities: del(17p) in 30% R/R vs. 0% 1L, del(13q) in 60% R/R vs. 71.4% 1L, del(11q) in 20% R/R vs. 33.3% 1L, and trisomy 12 in 15% R/R vs. 19% 1L. Grade 1-2 AEs were observed in R/R=87%; 1L=92.3% without dose-limiting toxicity. Only two pts discontinued therapy; one due to grade 2 gastrointestinal bleeding and the other due to grade 3 pulmonary embolism (1L cohort). Grade 1-2 infusion-related reactions (IRR) with G were observed in 40% and 81% of pts in the R/R and 1L cohorts respectively. Grade 3-4 IRR were observed only in 1L cohort pts (9.5%).

We observed neutropenia grade 3-4: R/R= 11/20 (55%), 1L= 8/21 (38.1%); thrombocytopenia grade 3-4: R/R= 7/20 (35%), 1L= 6/21 (28.5%); and no grade 3-4 anemia in any of the cohorts. There were no cases of febrile neutropenia. Two pts in the R/R cohort (10%) and three pts in the 1L cohort (14.3%) developed grade 2 infections that were treated with oral antibiotics, but did not require study treatment discontinuation. The most frequent non-hematological AEs were transaminitis, hyperglycemia, and electrolyte alterations (grade 1-2). There were no treatment related deaths in either cohort.

We assessed the response using iwCLL criteria in all pts in an intention to treat analysis, involving CT scans. The ORR was 100% in the 1L cohort and 95% in the R/R cohort. Sixteen pts (76.2%) in 1L cohort and eighteen pts (90%) in the R/R cohort achieved a PR. CR was observed in five (23.8%) and one (5%) pts in the 1L and R/R cohorts respectively. Four pts in the 1L cohort and one pt in the R/R cohort achieved MRD^neg status (<0.01% CLL in the bone marrow by multiparameter flow cytometry). One pt (5%) in the R/R cohort had SD.

At a median follow-up of 22.7 months (mo), the R/R cohort had a median Progression Free Survival (PFS) of 15.3 mo and a median Treatment Free Survival (TFS) of 19.3 mo; the median Overall Survival (OS) has not been reached. For pts in the 1L cohort, the median PFS was 24.3 mo, TFS was 28.2 mo, and OS has not been reached. During the long-term follow-up period, two pts from the R/R cohort and one pt from the 1L cohort had disease progression and died after receiving multiple additional treatments for CLL. None of these deaths were related to G+HDMP treatment.

Overall, G-HDMP was well tolerated and all 41 pts showed hematological and clinical responses during the study treatment. In both cohorts, 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.

Responses in 1L pts were higher in terms of ORR and CR compared with the data from the CLL-11 study and suggests a possible synergistic activity between G and HDMP. Additionally, responses in R/R pts appear to be comparable to that of R-HDMP. Our data supports G-HDMP as an alternative combination regimen for the treatment of CLL pts.