PI3K Inhibitors Safe and Effective in CLL Patients

Updated data on the safety and effectiveness of three different phosphoinositide 3-kinase inhibitors (PI3K inhibitors) presented at the European Hematology Association (EHA) Congress show that these agents are safe and effective for patients with chronic lymphocytic leukemia (CLL).

The PI3K inhibitors target one or more of the phosphoinositide 3-kinase enzymes, which are part of an important signaling pathway for many cellular functions, including growth control, metabolism, and translation initiation. Idelalisib, TGR-1202, and duvelisib demonstrated high response rates that were durable – offering a promising treatment option for patients with CLL, particularly those with relapsed/refractory disease.


Two presentations at this year’s EHA Congress characterized the impact of idelalisib treatment on patient safety and quality-of-life (QoL). Idelalisib was recently approved by the U.S. Food and Drug Administration for the treatment of relapsed CLL in combination with rituximab.

The first study, presented by Rodolphe Perard, MD, of Merck Serono Ltd. in the United Kingdom, examined the drug’s impact on health-related QoL, analyzing data from the phase III randomized controlled trial comparing idelalisib plus rituximab with rituximab-alone in patients with previously-treated CLL unsuitable for cytotoxic therapy.1 Dr. Perard and colleagues administered the EQ-5D questionnaire to 220 patients (110 in each treatment arm) at baseline and at regular intervals throughout the trial until disease progression.

Overall, there were 1,667 observations over both treatments arms; compliance rates for questionnaire completion were good (>70%) across all time points. A generalized estimation equation (GEE) regression was designed to determine absolute health-related QoL scores across treatment arms and whether there was a difference in QoL between rituximab monotherapy or idelalisib-rituximab combination therapy.

“Estimated utility was high across treatment arms, and a significant treatment effect was found,” Dr. Perard and colleagues wrote, “with patients receiving idelalisib with rituximab having a better quality of life than those receiving rituximab monotherapy (0.8127 for combination vs. 0.7475 for rituximab alone), for an absolute difference of 0.0652 (p=0.031).”

“The tolerability and efficacy profile of idelalisib with rituximab may provide previously treated CLL patients with high quality of life,” the authors concluded, “both in absolute terms and in relation to treatment with rituximab monotherapy.”

Pier Zinzani, MD, of University of Bologna in Italy, and colleagues looked at idelalisib’s safety and efficacy in treating follicular lymphoma (FL) – particularly for heavily pretreated, high-risk patients refractory to anti-CD20 and chemotherapy.2 These patients generally have few promising treatment options, Dr. Zinzani noted, but in this study, “idelalisib demonstrated rapid, durable responses that were substantially longer than those with the previous regimen with acceptable safety in these patients.”

The study included 72 histologically confirmed patients with indolent non-Hodgkin lymphoma (iNHL) who were refractory to both rituximab and an alkylating agent, who received oral idelalisib 150 mg twice-daily until disease progression or unacceptable tolerability. Fifty-four percent of patients had a high-risk follicular lymphoma International Prognostic Index (FLIPI) score, 22 percent had bulky disease, and 17 percent had grade 3a FL.

The median number of prior treatments was four (range, 2-12), and 86 percent of patients were refractory to their last therapy. The most common prior treatment was bendamustine. At data cutoff, median treatment duration was 6.5 months, with 65 patients (90%) off treatment due to progressive disease (38 patients), treatment-emergent adverse events (AEs) (15 patients), investigator decision (7 patients), and death (5 patients).

Estimated median time to response was 2.6 months (range, 1.6-11.0 months), while median response duration was 11 months (27 months in patients with complete response). These findings, Dr. Zinzani and colleagues concluded, demonstrate that idelalisib is a promising option for high-risk relapsed/refractory FL patients with limited treatment options.


In a presentation by Matthew Lunning, DO, of the University of Nebraska Medical Center and colleagues, results were reported from a phase I trial evaluating the combination of the anti-CD20 monoclonal antibody ublituximab with TGR-1202, a combination that has shown strong synergistic activity in previous studies.3 TGR-1202 is a novel once-daily oral PI3K inhibitor with demonstrated clinical activity in B-cell lymphoma, and – importantly – without the hepatotoxicity typically associated with similar agents, Dr. Lunning noted.

Subjects were heavily pre-treated relapsed/refractory patients with NHL or CLL who were refractory to prior PI3K or Bruton tyrosine kinase inhibitors. The median number of prior treatment regimens was three (range, 1-9). Ublituximab was administered on days 1, 8, and 15 of cycles 1 and 2, and then day 1 of cycles 4, 6, 9, and 12. TGR-1202 was administered orally once-daily.

Thirty-seven patients were evaluable for safety: 13 patients with CLL/small lymphocytic lymphoma, 12 with FL, nine with diffuse large B-cell lymphoma, two with marginal zone lymphoma, and one with Richter’s transformation. Grade 3 or 4 adverse events included day 1 infusion reactions (3%), neutropenia (32%), and diarrhea (3%). There was one instance of dose-limiting toxicity: a patient with grade 3 neutropenia at study entry worsened. Of note, there was no observed TGR-1202–related hepatotoxicity.

Of the 29 patients evaluable for response, 13 of the 15 patients in the higher-dose cohorts (treated with 900 mg and 1,200 mg; 87%) remained progression-free compared with six of 14 patients in the lower-dose cohorts (450 mg and 600 mg; 43%). All but one of the CLL patients remained progression-free with a median follow-up time of 9 months. The data suggested that the chemotherapy-free combination of ublitixumab and TGR-1202 was active and well-tolerated in both iNHL and CLL, Dr. Lunning reported.


Finally, in a phase I study of duvelisib monotherapy in 18 treatment-naïve CLL patients presented by Susan O’Brien MD, from University of California: Irvine, an overall response rate of 82 percent was seen. Duvelisib is an oral dual inhibitor of the PI3K-delta and PI3K-gamma isoforms currently in clinical development for iNHL and CLL.4 According to Dr. O’Brien and co-authors, because duvelisib inhibits both the PI3K-delta and PI3K-gamma isoforms, it may be uniquely positioned to inhibit key signals important in the pathogenesis of B-cell malignancies.

In the study, patients received duvelisib 25 mg twice-daily and took the drug for a median of 53 weeks (range, 8-69 weeks). Ten patients remained on treatment, while eight patients discontinued – including six due to AEs. Most of these AEs were grade 1 or 2, Dr. O’Brien noted. The most common grade ≥3 AEs were neutropenia (7 patients) and ALT/AST increase (3 patients).

Evaluation of the pharmacodynamics data showed that duvelisib had early clinical activity in these patients, including the inhibition of pAKT and Ki67 in CLL cells and reductions in serum chemokines, cytokines, and T-cell proliferation, as well. “These data support the further development of duvelisib in treatment-naïve CLL,” Dr. O’Brien concluded, “including combinations with other targeted therapies.”


  1. Sullivan, W; Lee, D; Perard, R, et al. Quality of life benefits of idelalisib with rituximab for patients with previously treated chronic lymphocytic leukaemia. Abstract #P214. Presented at the 2015 European Hematology Association, Vienna, Austria, June 12, 2015.
  2. Zinzani P, Salles G, Schuster S, et al. Idelalisib efficacy and safety in follicular lymphoma patients from a phase 2 study. Abstract #P689. Presented at the 2015 European Hematology Association, Vienna, Austria, June 13, 2015.
  3. Lunning M, Vose J, Fowler N, et al. Ublituximab + TGR-1202 demonstrates activity and favorable safety profile in relapsed/refractory B-cell NHL and high-risk CLL. Abstract #P327. Presented at the 2015 European Hematology Association, Vienna, Austria, June 12, 2015.
  4. O’Brien S, Faia K, White K, et al. Early clinical activity and pharmacodynamics effects of duvelisib, a PI3K-delta, gamma inhibitor, in patients with treatment-naïve CLL. Abstract #S434. Presented at the 2015 European Hematology Association, Vienna, Austria, June 12, 2015.