Ofatumumab Added To Dexamethasone In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia. Results From a Phase II Study Of The Czech Leukemia Study Group For Life
Authors: Doubek Michael , Brychtova Yvona , Panovska Anna , Trizuljak Jakub , Sebejova Ludmila , Stehlikova Olga , Chovancova Jana , Malcikova Jitka , Smardova Jana , Plevova Karla , Volfova Pavlina , Trbusek Martin , Mraz Marek , Majercakova Denisa , Obrtlikova Petra , Karban Josef , Smolej Lukas , Lindtnerova Michaela , Oltova Alexandra , Jelinkova Eva , Pospisilova Sarka , Mayer Jiri 
Published: October 2019

Abstract
The treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical issue despite remarkable improvements in prognostication and therapy. One emerging treatment option for relapsed/refractory CLL is the use of high-dose corticosteroids. High-dose methylprednisolone or dexamethasone combined with rituximab are active in relapsed/refractory CLL, but serious infections are frequent and progression-free survival (PFS) is short. The purpose of this clinical trial was to determine the efficacy and toxicity of ofatumumab-dexamethason (O-dex) combination in relapsed or refractory CLL population.
The trial was an open-label, multi-center, non-randomized, phase II study. The O-dex regimen consisted of intravenous ofatumumab (Cycle 1: 300mg on day 1, 2000mg on days 8, 15, 22; Cycles 2-6: 1000mg on days 1, 8, 15, 22) and oral dexamethasone (40mg on days 1-4 and 15-18; Cycles 1-6). Premedication consisted of glucocorticoid, paracetamol, and antihistamine before each ofatumumab infusion. All patients received allopurinol, omeprazol, co-trimoxazole, and fluconazole for prophylaxis of tumor lysis syndrome and infections. The O-dex regimen was given for a minimum of 3 cycles, until best response, or a maximum of 6 cycles.
Between July 2010 and December 2012, 32 patients (pts.) were recruited at 3 centers. Basic patient characteristics at the start of O-dex therapy were as follows: median age 66 years (range, 50-77); 24 males, 8 females; median CIRS score 7 (0-15); median previous treatment lines 3 (1-10); 30 (94%) pts. were pretreated with fludarabine and 12 (38%) with alemtuzumab; Rai III/IV stage was present in 20 (63%) pts.; 6 (19%) pts. had bulky lymphadenopathy; IgVH genes were unmutated in 30 (94%) pts.; del 11q was present in 6 (19%) and p53 defects (del 17p and/or TP53 mutation) in 8 (25%) pts.
The median number of O-dex cycles administered was 6 (1-6). Twenty two (69%) pts. completed at least 3 cycles of therapy. The remaining 9 patients were prematurely discontinued due to CTCAE grade 3/4 infections (7 pts.), disease progression (1 pt.), or uncontrollable diabetes mellitus (1 pt.). Overall responses/complete remissions (ORR/CR) were achieved in 22/5 pts. (69/16%). One patient achieved minimal residual disease negativity (measured by 4-color flow cytometry) at the end of therapy. Median PFS was 10 months. In patients with p53 defects, ORR/CR were achieved in 5/2 pts. (63/25%). The Median PFS was 10.5 months for this subgroup. Median overall survival (OS) has not yet been reached.
During therapy, CTCAE grade 3/4 toxicity consisted of bacterial infections (25%), ofatumumab infusion-related side-effects (9%), neutropenia (9%), hyperglycemia (6%), and anemia (3%). No reactivation of herpetic viral infection was observed during the course of therapy. Nine patients died during the follow-up as a result of disease progression (6 pts.), infections (2 pts.), or complications after allogeneic stem cell transplantation (1 relapsed pt.).
The median CD20 antigen density in CLL cells was 4766 (881-18515) MESF (molecules of equivalent soluble fluorochrome) units at baseline. At the end of therapy, CD20 density had significantly decreased (median 821 MESF; 443-2637); nevertheless, it was high once more at relapse (median 6619 MESF; 628-21359).
In vitro testing of malignant pts. cells sensitivity to dexamethasone and ofatumumab did not show synergistic or additive effect of these compounds in majority of patients. Also, in vitro testing did not clearly predict the outcome of O-dex therapy.

Conclusions
The O-dex regimen shows relatively high ORR and CR, with promising findings for PFS and OS (including pts. harboring p53 defects), as compared to published data on rituximab plus dexamethasone regimen or ofatumumab in monotherapy. The infectious toxicity in 1/4 of pts. represents the most frequent side effect for this regimen.
The study was registered at www.clinicaltrials.gov (NCT01310101).

Disclosures:
Doubek: GlaxoSmithKline: Research Funding. Mayer:Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding.