Abstract
Background: CALiBRe trial was designed as a single arm, multi-centre, feasibility study with two cohorts of patients. Patients had either CLL requiring therapy according to IWCLL criteria or relapsed or refractory CLL; 40 patients were intended to be recruited into two cohorts of 20 patients, treatment naïve (TN) and relapsed refractory(RR). The recruitment was temporarily halted in April 2016 due to the idelalisib safety alert from other trials. 23 patients have been recruited to date, 11 TN and 12 RR. Majority of patients were male. The (TN) cohort had a median age of 68y(56-87) and RR cohort had a median age of 71y(53-82). Across both cohorts, 12% were Binet Stage C, 20% were Stage B with remainder being progressive stage A. In the RR cohort, the median number of prior therapies was 2, with FCR(84%) and BR(10%) being the most frequent. All patients received continuous oral therapy with idelalisib(150mg BD) from registration until disease progression. IGVH was mutated in 7 patients and unmutated in 11 patients; 5 patients had inconclusive results. Most common cytogenetic abnormality was 13q deletion(8/23) followed by 11q deletion(4/23) and trisomy 12(2/23).There was only one patient with 17p deletion in TN cohort.
Methods:
23 of 40 participants with CLL requiring treatment received idelalisib until either achievement of<0.01% residual disease in bone marrow(BM) or disease progression. A large panel of markers were assessed on PB & BM taken at screening, 1 & 6 months with additional PB at 0 (baseline), 4 hours, 1, 2, 7, & 14 days and 3, 9, & 12 months. Outcomes are analysed by descriptive statistics only.
Phosphorylation of SyK pY348, ERK 1/2, AkT S473, AkT T308 was assessed in four different conditions: Unstimulated with or without idelalisib/Stimulated with IgM and IgD with or without idelalisib at each time point. Phosphorylation of various kinases were assessed based on the changes in MFI using Diva software and FlowJo software.
Results:
B-cell counts increased after the first dose, peaked at 4 weeks, and reduced substantially compared to baseline by month 3. CLL cells Ki67 expression in the BM at baseline was 3.2%. There was minimal median reduction in the bone marrow infiltration at 6 months in both TN(3% reduction) and RR(7% reduction) cohorts.
CLL levels decreased continuously during months 3 to 12 of treatment. The rate of decrease showed no apparent correlation with baseline biological or clinical features. There was a substantial decrease in the B-cell count between month 3 and 12 in responding patients.
Helper T-cells (CD4+) and cytotoxic T-cells (CD8+) peaked at day 1 after idelalisib and continue to decline over later time points. NK cells(CD56+) peaked at 4 hours and continue to decline at later time points. Patients developing autoimmune side effects related to idelalisib had either stable or increased number of T and NK cells at various time points following the initial decline. The changes were visible prior to development of side effects.
Phosphorylation of AKT S743 and AKT T308 in both unstimulated and stimulated condition decreased over time in patients responding to idelalisib. There was no major effect on phosphorylation of ERK1/2. Patients with drug interruption/disease exhibited baseline or enhanced phosphorylation of the kinases. Substantial drop in phosphorylation of AKT T308 and AKT S473 at 1 and 3 months translated into continued response at later time points. SyK pY348 continued to be phosphorylated suggestive of no impact of idelalisib on this upstream kinase. These results are different to the changes we have reported with ibrutinib previously. The predominant changes are in the AKT arm of BCR pathways.
Conclusions:
Results of the biological changes in CLL cells with idelalisib are presented. Redistribution of CLL cells during idelalisib happens rapidly few hours after initiation followed by decline especially after 3 months of therapy. Helper, cytotoxic T cells and NK cells continue to decline with continuing idelalisib therapy and this may be the explanation for increased risk of infective complications. However, baseline or increased T-cell counts were evident in patients experiencing autoimmune complications in our cohort. Decreased Phosphorylation of AkT at 1 and 3 months of therapy with idelalisib correlated with continuing response. Idelalisib results in interesting biological changes which may have correlative clinical implications both in terms of efficacy and toxicity.
Munir: Janssen: Honoraria; AbbVie: Honoraria; Roche: Honoraria; Gilled: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria. Hillmen: Gilead: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Celgene: Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Rawstron: Roche: Consultancy, Honoraria; BD biosciences: Patents & Royalties; Gilead: Research Funding; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Brock: Merck: Other: travel expenses; Astra-Zeneca: Equity Ownership; Roche: Honoraria, Other: travel expenses; GlaxoSmithKline: Equity Ownership. Fox: Roche: Consultancy, Honoraria, Other: Travel Sponsorship, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Sponsorship, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Travel Sponsorship, Research Funding. Fegan: Janssen: Honoraria; Napp: Honoraria; Roche: Honoraria; Gilead: Honoraria. Bloor: AbbVie: Honoraria, Other: travel expenses; Janssen: Other: travel expenses, Speakers Bureau; Roche: Honoraria; Gilead: Consultancy, Other: travel expenses. Schuh: Novartis: Honoraria; Novartis: Honoraria; Roche: Honoraria; Abbvie: Honoraria; Abbvie: Honoraria; Celgene: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Roche: Honoraria; Gilead: Consultancy; Janssen: Honoraria; Gilead: Honoraria, Research Funding.
Author notes
Asterisk with author names denotes non-ASH members.
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