Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study

Abstract

IntroductionIncorporation of CD20 monoclonal antibody (mAb) has significantly advanced treatment for patients with chronic lymphocytic leukemia (CLL). Improved outcomes were demonstrated with the addition of the CD20 mAb rituximab to fludarabine-based therapy, both in frontline and relapsed settings, 1-5 including improved overall survival (OS) in the frontline setting with combined fludarabine, cyclophosphamide, and rituximab (FCR). 5 Monotherapy with standard dose and schedule of rituximab has limited efficacy, especially in relapsed/refractory CLL. 6,7 A large number of patients in the United States receive rituximab either as monotherapy or in combination with fludarabine-based chemotherapy in both frontline and relapsed/refractory settings 8 ; refractoriness to CD20 mAb in CLL is poorly defined. Moreover, no data are currently available regarding treatment outcomes with other CD20 mAbs in CLL patients previously treated with rituximab or refractory to their last rituximab-containing regimen.Refractoriness to fludarabine or alemtuzumab was defined as failure to achieve at least partial remission to the last regimen or relapse within 6 months of treatment, including combinations. The prognosis for patients with fludarabine-refractory CLL was poor, with low response rates and short progression-free survival (PFS) and OS. 9,10 Outcomes were worse for patients also refractory to alemtuzumab, the CD52 mAb approved for fludarabine-refractory CLL. 9,10

Ofatumumab Is More Efficient than Rituximab in Lysing B Chronic Lymphocytic Leukemia Cells in Whole Blood and in Combination with Chemotherapy

“…Overall response rates as a single agent in relapsed or refractory B-CLL are 44-58% and 73-77% in previously untreated B-CLL (17)(18)(19), which compares favorably with the response previously observed for this subgroup of patients subjected to RTX monotherapy (20).…”

“…Furthermore, overall response to OFA is ∼43% in B-CLL patients relapsed or refractory to RTX treatment (18). These data suggest an improved clinical activity of OFA in B-CLL with respect to the gold standard anti-CD20 Ab RTX.…”

“…OFA is currently under evaluation in phase II-III clinical trials in B-NHL and B-CLL, as a single agent or in combination with chemotherapy (http://www.clinicaltrials.gov) (15)(16)(17)(18). Overall response rates as a single agent in relapsed or refractory B-CLL are 44-58% and 73-77% in previously untreated B-CLL (17)(18)(19), which compares favorably with the response previously observed for this subgroup of patients subjected to RTX monotherapy (20).…”

Effector mechanisms of anti-CD20 monoclonal antibodies in B cell malignancies

“…Recently, ofatumumab was shown to exert clinical responses in rituximab -refractory NHL patients patients 54 as well as in fludarabine / alemtuzumab -refratory CLL 55 . Similarly, some of the clinically tested anti-CD20 mAbs were engineered to enhance ADCC 56,57 but these modifications and their effects could not distinguish either CDC or ADCC as a crucial effector mechanism for the parental compound.…”

Relationship between Progression-Free Survival and Overall Survival in Chronic Lymphocytic Leukemia: A Literature-Based Analysis

“…Of those studies, seventeen were nonrandomized [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] and six were randomized [33][34][35][36][37][38] . The studies included a total of 27 treatment arms and a mean of 118 patients (minimum 30, maximum 724).…”