Sequential Therapy with Ofatumumab, High Dose Methylprednisolone and Lenalidomide Is a Safe and Effective Regimen for the Treatment of Previously Treated and Untreated CLL/SLL: The Hilo Trial

Background: With the introduction of new targeted drugs for the treatment of CLL, a new therapeutic paradigm is emerging where chemo-immunotherapy is being replaced by newer non-chemotherapy containing regimens with the goal to maintain long term responses while an oral drug is being administered. Based on demonstrated activity of ofatumumab (Ofa) and lenalidomide (len) as monotherapy, here we present the results of a sequential combination regimen consisting of high-dose methylprednisolone (HDMP) combined with Ofa, followed by consolidative therapy with Len in combination with Ofa.

Methods: This is a Phase II, single institution, study involving pts with previously treated with relapse or refractory (R/R) disease or treatment naive (TN) CLL/SLL. During the first stage (cycles 1-3) patients (pts) were treated with a combination of HDMP 1000mg/m2 IV and Ofa 2000mg (300mg given week 1 then 2000mg for a total of 12 doses) IV infusion weekly x 4 doses in cycle 1 of a 28 day cycle, then every 2 weeks in cycle 2 and 3. During the second stage (cycles 4-12) pts were given Len 5-10mg daily (adjusted to CrCl) and Ofa 2000mg IV once every 8 weeks. Growth factor support was permitted at the discretion of the treating physician. Pts were assessed for response by iwCLL 2008 criteria (including CT assessment) after cycle 3 and 12 and allowed to continue on Len if they achieved CR, PR or SD. Primary end points were efficacy, adverse events (AEs) profile, and time-to-treatment failure (TTF)

Results: Between 01/2012 and 05/2015, 73 pts (44 TN and 29 R/R) were enrolled in this study. Sixty-seven and 32 pts were evaluable at 3 months (40 TN and 27 R/R) and 12 months (22 TN and 10 R/R), respectively including response assessment. The median age was 63 (49 - 86) years and 67 (36-87) years for TN and R/R, respectively. For TN and R/R groups pts, 7 and 5 pts had 17pdel/TP53; and 31 and 20 pts were IgVH unmutated, respectively. Median number of prior treatments in the R/R cohort was 2(1-4). The median duration of treatment (DOT) was 14 (2 - 40) and 6 (1 - 40) months, respectively in the TN and R/R pts. Response rates are shown in table 1. With a median F/U for survivors of 18 and 35 months in the TN and R/R cohorts, respectively, 35 pts remain in the trial (31 TN and 4 R/R). The median TTF was 15 and 5.8 months in the TN and R/R cohort, respectively. Treatment was well tolerated in both arms with no grade 3/4 infusion reactions. Grade 3/4 treatment related hematological AEs were: neutropenia 50% and 82.8%, thrombocytopenia 9% and 20.7% and anemia 2.3% and 10.3% in the TN and R/R cohort, respectively. Grade 3 infections occurred in 6.8% and 41.4% pts in the TN and R/R cohorts, respectively. Three pts developed thromboembolism (2 PE and 1 DVT), all in the R/R cohort. None developed grade 3/4 tumor lysis syndrome or tumor flare. Three pts in each cohort underwent allo HSCT after a median of 3 cycles of therapy.

Conclusion: Combination of ofatumumab, methylprednisolone and lenalidomide is an effective and well tolerated regimen in untreated or R/r CLL, including those with poor prognostic genetic features. This therapy may be used as salvage prior to allo-HSCT.