Chronic lymphocytic leukemia (CLL) is a common form of leukemia in the Western world, with an incidence rate of 5/100 000, and predominantly occurs in older people, with a median age at diagnosis of 70 years. This group of patients often does not qualify for intense combination chemotherapy, thereby stressing the need for alternative treatment options. CLL is mostly characterized by accumulation of malignant B-cells resistant to apoptosis. Two members of the tumor necrosis factor superfamily, B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), are involved in constitutively active survival-signaling pathways such as NFκB activation, and protect CLL cells from spontaneous apoptosis.1 BLyS and APRIL interact with the tumor necrosis factor receptor TACI (transmembrane activator and CAML-interactor) and with BCMA (B-cell maturation antigen). In addition, BLyS specifically binds to the BAFF-Receptor (BAFF-R). Whereas normal B-lymphocytes express little to no BLyS or APRIL, these proteins are highly expressed in CLL cells, and CLL patients with a low percentage of leukemic cells expressing BLyS or APRIL have a significant longer overall survival than patients with BlyS- or APRIL-positive leukemic cells.2 The blood level of soluble APRIL is elevated in patients with CLL and correlates with disease stage.3 Moreover, elevated serum BLyS levels are found in patients with familial CLL, and correlate with a single-nucleotide polymorphism (SNP) in the BLyS promoter region.4
Importantly, an allelic variation in the TNFRSF13B gene encoding for the TACI protein is associated with CLL susceptibility, suggesting a potential role for TACI in disease development.5 These genetic associations and the fact that BLyS and APRIL support in vitro CLL cell survival provide a strong rationale for targeting these proteins.
Atacicept is a soluble recombinant fusion protein containing the extracellular binding domain of the TACI receptor and a slightly modified version of the Fc region of human IgG. Atacicept selectively binds to BLyS and APRIL, and blocks activation of their receptors TACI, BCMA and BAFF-R. In this phase 1b clinical trial, we investigated the tolerability and biological activity of escalating doses of intravenously administered atacicept in patients with refractory or relapsed CLL. In all, 24 patients with refractory or relapsed CLL were enrolled. Of them, 21 patients completed at least one treatment cycle, whereas 3 patients had to be excluded and did not receive the first treatment cycle due to screening failure or adverse events that occurred before the first drug administration. Six patients (four in the 27 mg/kg group, one in the 20 mg/kg group and one in the 10 mg/kg group) continued to receive atacicept after the first cycle and completed four additional treatment cycles. Two patients in the intermediate dose group (10 mg/kg) withdrew from the trial after completing the first treatment cycle and did not participate in follow-up visits for response evaluation. All patients enrolled in this trial were fludarabine-refractory or had relapsed disease after fludarabine treatment. ‘Refractory to fludarabine’ was defined as a failure to achieve at least a partial remission or better with the last fludarabine-based treatment. ‘Relapsed disease after fludarabine’ was defined as progression within 6 months after the last fludarabine-based therapy. The median number of previous therapies was 4 (range 1–7). The patient demographics and clinical characteristics are summarized in Supplementary Table 1.
Dose levels of 1, 4, 10, 15, 20 and 27 mg/kg were tested. Three patients were treated at each of the first five dose levels and six patients were treated at the highest dose level. The primary end point of this study was to assess the maximum tolerated dose of atacicept and to report all adverse events attributed to the study drug. The maximum tolerated dose was not reached. Toxicity was graded using NCI Common Terminology Criteria for Adverse Events version 3.0. No dose-limiting toxicity was reported, and no serious adverse event related to the study drug was observed. Dose-limiting toxicity was defined as any adverse event greater than grade 2 that was possibly or probably related to the study drug. Notably, the dose levels reached in this study are the highest dose levels of atacicept administered in clinical trials. Dose escalation was stopped due to high protein load at 27 mg/kg. Seven subjects (two subjects in the 1 mg/kg group and five subjects in the 27 mg/kg group) experienced adverse events that were assessed as at least possibly related to the study drug. These events were either mild or moderate in intensity (Common Terminology Criteria for Adverse Events grade 1 or 2) and were for the most part classified as blood and lymphatic system disorders (three subjects, 12.5%) and infections (three subjects, 12.5%), respectively. All adverse events at least possibly related to treatment are listed in Table 1.
The PKs of free atacicept and atacicept-BLyS complex were assessed after the first, second, third and fifth dose in cycle 1. An approximately dose-proportional increase in Cmax and AUCτ was found for free atacicept. The Cmax of atacicept was reached primarily at the first sampling time point, probably due to the sampling times selected (Supplementary Figure 1a). The Cmax of atacicept–BLyS complex increased in a less-than-dose-proportional pattern (Supplementary Figure 1b). In the first week of treatment, the concentration of the complex did not decline before the next administration. Altogether, the maximum concentration of the complex was observed on average at or within 1–3 weeks after the fifth administration. In patients who received continuous weekly atacicept treatment, the concentration of the complex increased slightly until treatment cessation, indicating that complexes were continuously formed and that the clearance of the complex was slower than its formation.
For activity assessment, peripheral leukocyte counts, lymphocyte subpopulation counts (assessed by flow cytometry) and lymph node sizes (assessed by CT scan) were recorded. Clinical response to treatment was determined using the NCI-WG 96 criteria.6 To assess signs of biological activity other than clinical response, biological response was defined as a reduction or stabilization of previously increasing absolute leukocyte counts for at least 2 months (corresponding to stable disease by NCI-WG criteria). Of the 19 patients with available data for clinical response assessments, 1 (5.3%) had a partial response, 8 (42.1%) had stable disease and 10 (52.6%) had progressive disease. All patients treated with high dose levels (27 mg/kg) experienced stable disease or partial response. In contrast, patients treated with low dose levels (1 and 4 mg/kg) experienced progressive disease. Therefore, biological response seems to be dose dependent. At dose levels of 10–20 mg/kg, 43% of the patients had stable disease and 57% of the patients had progressive disease. The partial response was observed at the dose level of 27 mg/kg and lasted for 18 months. The median progression-free survival for patients with stable disease in this heavily pre-treated patient population ranged between 2.0 and 8.3 months (median 4.2 months). The median progression-free survival for patients at the highest dose level ranged between 2.0 and 18.0 months (median 6.7 months). The median follow-up time for the study population was 3.9 months and the median time to disease progression was 3.4 months.
The results of this phase 1 trial, showing that up to 27 mg/kg atacicept administered intravenously is well tolerated in heavily pretreated patients, will be of interest for future clinical trials with atacicept in a variety of B-cell disorders. Compared with most other antibodies in CLL treatment, atacicept has a different mechanism of action, as it binds to and neutralizes soluble survival factors instead of targeting the malignant cells directly. Potential combination treatments with agents having a different mechanism of action, such as cytotoxics or monoclonal antibodies, seem therefore promising and could result in additive effects without additive toxicity. The biological activity in CLL patients at higher dose levels supports the further investigation of atacicept in phase 2/3 trials.
The biological activity of atacicept did not correlate with ZAP-70 mutation status or chromosomal abnormalities, including 11q, 13q and 17p deletions. In addition to these prognostic parameters, allelic variations in the TACI, APRIL, BLyS, BAFF-R and BCMA genes were analyzed. Results from the sequencing studies provide preliminary evidence that SNPs in exon 2 of the APRIL gene (rs3803800GG, P=0.0090) and in exon 5 of the TACI gene (rs11078355TT, P=0.0130) are associated with biological response to atacicept (Table 2). Both genes are located on chromosome 17. The alleles associated with the biological activity of atacicept seem to be recessive as a single copy of these alleles did not affect the biological activity of atacicept. Given the small sample size of this phase 1 trial, the associations between the biological activity of atacicept and polymorphisms in the APRIL and TACI genes need to be confirmed in a larger population of CLL patients. In our patient population, 29.17% of individuals were homozygous for the rs11078355T allele in the TACI gene and 62.50% of individuals were homozygous for the rs3803800G allele in the APRIL gene.
It has been previously shown that a SNP (rs9514828T) in the BLyS promoter region is associated with elevated serum BLyS levels in CLL patients.4 This indicates that a single genetic variation might affect TACI activation by increasing BLyS levels. Whereas the rs3803800G SNP in the APRIL gene is non-synonymous and directly induces amino-acid changes (N96S), the rs11078355T SNP in the TACI gene is synonymous (S277S). However, it has been shown that synonymous SNPs can affect protein function.7 Moreover, rs11078355 is found in linkage disequilibrium with other SNPs in the TACI gene.8 Thus, TACI and APRIL polymorphisms might contribute to disease progression in a subset of CLL patients and removal of these proteins could be a potential strategy to prevent disease progression in patients homozygous for the respective alleles. This renders atacicept as a potential candidate for personalized treatment of patients with CLL.
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Bojarska-Junak A, Hus I, Chocholska S, Wasik-Szczepanek E, Sieklucka M, Dmoszyñska A et al. BAFF and APRIL expression in B-cell chronic lymphocytic leukemia: correlation with biological and clinical features. Leuk Res 2009; 33: 1319–1327.
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This trial was funded by Merck Serono SA. We thank Benoit Destenaves for genomic analysis; Giacomo Mordenti for the statistical analysis; Ralf Baumann, a medical writer and Merck Serono SA employee, for preparing the study report; and Ekaterine Asatiani and Stacey R Dillon for detailed review of the manuscript.
At the time the study was conducted, AGB was an employee of Merck Serono SA. The other authors declare no conflict of interest.
DMK, AGB, CMW and MH designed the research protocol; DMK, BBG, TE, CMW and MH were involved in treating patients and collecting data; DMK, CMW and MH wrote the paper, with contributions from the other authors. All authors approved the final version of the paper.
Supplementary Information accompanies the paper on the Leukemia website
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Kofler, D., Gawlik, B., Elter, T. et al. Phase 1b trial of atacicept, a recombinant protein binding BLyS and APRIL, in patients with chronic lymphocytic leukemia. Leukemia 26, 841–844 (2012) doi:10.1038/leu.2011.286
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