Phase 1b trial of atacicept, a recombinant protein binding BLyS and APRIL, in patients with chronic lymphocytic leukemia

Abstract

aberrations, altered drug metabolism, and enhanced cellular repair processes. In contrast, the median OS for the 14 patients undergoing an ASCT was not reached, suggesting perhaps continued response to alkylator-based therapy.Among the 74 patients, 31 had high-risk disease based on the presence of one or more of the following abnormalities (Del 13 by metaphase cytogenetics, hypodiploidy, del 17p, t(4;14) or t(14;16)). The median OS from the time of progression was 9.5 months for the high-risk group compared with 14.7 months for the rest; P ¼ 0.4. The higher than average proportion of patients with high-risk disease likely reflects a selection bias in favor of patients relapsing rapidly after currently available treatments.Our study represents a unique description of response to salvage therapies and outcome of patients progressing on pomalidomide, the latest IMiD to reach clinical trials. Several important conclusions can be derived from these clinical results. It confirms poor outcome of the patients relapsing after novel therapies. We also provide evidence of retained activity of lenalidomide in a proportion of patients relapsing on pomalidomide, suggesting that a trial of lenalidomide in these patients is justified. Finally, even in this relapsed and refractory population, ASCT when feasible is associated with high response rates.

Biology of Chronic Lymphocytic Leukemia in Different Microenvironments

“…By acting as a molecular decoy, it neutralizes the effects of BAFF and APRIL, blocking the activation of TACI, BCMA, and the BAFF-receptor. A phase Ib study of Atacicept demonstrated that intravenous doses of up to 27 mg/kg were well tolerated in 21 patients with refractory or relapsed CLL with one PR (ORR 5%) in the highest dose cohort [171]. …”

Polymorphisms in genes of the BAFF/APRIL system may constitute risk factors of B‐CLL – a preliminary study on a Polish population

“…The subjects with AA genotype had much higher risk of B-CLL (OR = 2.45; CI 95% = 1.10; 5.49; P = 0.025). Previously, this variant was reported in the preliminary study to be associated with biological response to atacicept in B-CLL patients (23). Rs3803800 had been also shown to be associated with the risk of SLE and higher serum level of APRIL (24,25).…”

High APRIL but not BAFF serum levels are associated with poor outcome in patients with follicular lymphoma

“…Two antihuman APRIL antibodies (hAPRIL.01A and hAPRIL.03A), which can effectively block the binding of APRIL to BCMA and TACI and prevent in vitro and in vivo APRIL-induced B cell activation, are currently being tested in B cell-derived diseases [30]. In addition, the efficacy and safety of atacicept (TACIIg), a recombinant fusion protein that inhibits BAFF and APRIL, have also been evaluated in two phase I studies in patients with relapsed and refractory B cell malignancies [31,32]. In these studies, atacicept demonstrated promising biological activity and slight toxicity [31,32].…”

“…In addition, the efficacy and safety of atacicept (TACIIg), a recombinant fusion protein that inhibits BAFF and APRIL, have also been evaluated in two phase I studies in patients with relapsed and refractory B cell malignancies [31,32]. In these studies, atacicept demonstrated promising biological activity and slight toxicity [31,32]. Thus, it is conceivable to speculate that the addition of novel anti-BAFF/ APRIL signaling system agents with conventional treatments may have a favorable impact on FL patient outcome.…”