Role of PI3K Inhibition in Indolent Lymphomas

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As reported by Fowler et al in the Journal of Clinical Oncology1—and summarized in this issue of The ASCO Post—the international phase IIb UNITY-NHL trial of 208 patients with marginal zone lymphoma (MZL; n = 69), follicular lymphoma (FL; n = 117), and small lymphocytic lymphoma (SLL; n = 22) evaluated a new PI3K inhibitor, umbralisib. This agent is unique because it targets both the PI3K isoform, thereby theoretically limiting potential immune-associated adverse events,2-4 and CK1. Umbralisib has been shown in vitro to be highly selective for the  isoform of PI3K, and CK1 influences immunomodulatory effects on T cells by regulating elements of the Wnt signaling pathway.5

Median follow-up was almost 28 months for efficacy and 21 months for safety in the trial. The trial showed a modest overall response rate of 47% and some tumor reduction in as many as 86% of patients based on waterfall plots. This activity appeared to hold true for all of the indolent lymphoma subgroups.

Leo I. Gordon, MD

Leo I. Gordon, MD

Of note, the safety profile appeared somewhat better than in prior trials with other PI3K inhibitors, yet at least one grade ≥ 3 treatment-emergent adverse event occurred in 53% of patients. The incidence of what are thought to be immune-related adverse events (namely colitis and pneumonitis) was lower than that seen with other PI3K inhibitors.

Comparing Toxicity Among PI3K Inhibitors

There are several features to address as we try to find a place for PI3K inhibition in the treatment algorithm for indolent lymphomas.6,7 For the purposes of this discussion, we will focus on MZL and FL and exclude the 22 patients with SLL in the trial; those patients may fit better into a discussion of PI3K inhibitors in chronic lymphocytic leukemia (CLL), where there are more extensive and also promising data.8-11

The lower toxicity reported in this trial when compared with prior trials of other PI3K inhibitors is worth noting. This may be because of the limitation of immune effects, as noted previously, or because the number of prior treatments was lower in this trial than in other trials of PI3K inhibitors. For MZL, 50% of patients had just one line of prior treatment, and more than 85% had no more than three lines; for patients with FL, 14% had one line, and more than 63% had no more than three lines of prior treatment. 

However, in addition, these investigators were mindful of the infections that bedeviled prior clinical trials, possibly because of low CD4 counts or loss of immune function from prior therapy12; so, they recommended Pneumocystis jirovecii pneumonia and antiviral prophylaxis. The risk of serious and preventable infections in patients who have received prior therapy, especially bendamustine, has been documented in other trials.13 This observation, as well as the data across three GILEAD studies involving idelalisib and various combinations of bendamustine and rituximab in the first-line treatment of CLL and relapsed indolent non-Hodgkin lymphoma, led to U.S. Food and Drug Administration (FDA) mandates to use P jirovecii pneumonia prophylaxis and cytomegalovirus screening in patients receiving BCR inhibitors.

Where Do PI3K Inhibitors Fit in Treatment of Indolent Lymphomas?

The overall response rate in this trial was less than 50%, and complete response rates were quite low (single digits), so it appears that PI3K inhibitors as single agents may not have the horsepower or immunologic precision to achieve durable remissions, as the bar for the treatment of indolent lymphomas gets higher. In the era of chimeric antigen receptor (CAR) T-cell therapy and other more precise immunologic interventions, we are looking for shorter-duration therapy with higher complete response rates and lower toxicity, so the use of PI3K inhibitors as single-agent therapy in indolent lymphomas may not be the way forward, except in patients who are not candidates for CAR T-cell therapy or other immune-based approaches.

Further, the recent data on and subsequent approval of drugs targeting EZH2 (tazemetostat) and CD19 (tafasitamab-cxix) complicate the positioning of PI3K inhibitors in the treatment of indolent lymphomas. However, it appears that the safety profile and reasonable overall response rate will allow possible combination regimens, especially since other PI3K inhibitors have shown synergy with other agents14-16 (including radiation in solid-tumor models17) and may enhance CAR T-cell persistence, as shown in preclinical studies.18

PI3K Inhibitors: Bridge to Other Treatments?

Based on this study and phase I data with umbralisib as a single agent11 and together with the CD20 inhibitor ublituximab,19 the FDA approved this drug for second-line treatment of MZL and third-line or greater treatment for FL, providing some new options for these patients.20 Given the unfortunate lack of availability of radioimmunotherapy for FL, which has a much higher overall response rate and complete response rate than almost all of the newer therapeutics,21 clinicians need more options, and this agent provides a temporary treatment path that can be a bridge to other treatments. Further investigations should focus on intermittent-dosing schedules with PI3K inhibitors to limit toxicity and synergistic approaches with other agents or modalities to achieve deeper and more durable remissions using shorter-duration therapy. 

Dr. Gordon is the Abby and John Friend Professor of Cancer Research at Northwestern University Feinberg School of Medicine, Co-Director of the Hematologic Malignancies Program in the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, and Medical Director of the Mathews Center for Cellular Therapy.

DISCLOSURE: Dr. Gordon has served as a consultant or advisor to Bayer, Gilead Sciences, and Juno Therapeutics; and holds intellectual property in Zylem Biosciences.


1. Fowler NH, et al: Umbralisib, a dual PI3Kδ/CK1ε inhibitor in patients with relapsed or refractory indolent lymphoma. J Clin Oncol 39:1609-1618, 2021.

2. Fradera X, et al: Discovery of a new series of PI3K-δ inhibitors from virtual screening. Bioorg Med Chem Lett 42:128046, 2021.

3. Rodgers TD ,et al: Toxicity patterns of novel PI3K combinations in patients with non-Hodgkin lymphoma. Leuk Lymphoma 62:598-605, 2021.

4. Maharaj K, et al: The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells. Blood Adv 4:3072-3084, 2020.

5. Evangelisti C, et al: Targeting Wnt/β-catenin and PI3K/Akt/mTOR pathways in T-cell acute lymphoblastic leukemia. J Cell Physiol 235:5413-5428, 2020.

6. Berning P, Lenz G: The role of PI3K inhibitors in the treatment of malignant lymphomas. Leuk Lymphoma 62:517-527, 2021.

7. Flinn IW: PI3K inhibitors and the search for the Holy Grail. Blood 132:240-241, 2018.

8. Frustaci AM, et al: Duvelisib for the treatment of chronic lymphocytic leukemia. Expert Opin Pharmacother 21:1299-1309, 2020.

9. Lampson BL, et al: Efficacy results of a phase 2 trial of first-line idelalisib plus ofatumumab in chronic lymphocytic leukemia. Blood Adv 3:1167-1174, 2019.

10. Patel K, Pagel JM: Exploring a future for PI3K inhibitors in chronic lymphocytic leukemia. Curr Hematol Malig Rep 14:292-301, 2019.

11. Burris 3rd HA, et al: Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma. Lancet Oncol 19:486-496, 2018.

12. Hiddemann W, et al: Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone. Blood 106:3725-3732, 2005.

13. Zelenetz AD, et al: Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia. Lancet Oncol 18:297-311, 2017.

14. Bojarczuk K, et al: Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL. Blood 133:70-80, 2019.

15. Jiang H, et al: Venetoclax as a single agent and in combination with PI3K-MTOR1/2 kinase inhibitors against ibrutinib sensitive and resistant mantle cell lymphoma. Br J Haematol 184:298-302, 2019.

16. Tarantelli C, et al: Is there a role for dual PI3K/mTOR inhibitors for patients affected with lymphoma? Int J Mol Sci 21:1060, 2020.

17. Chuang FC, et al: PI3k inhibitors (BKM120 and BYL719) as radiosensitizers for head and neck squamous cell carcinoma during radiotherapy. PLoS One 16:e0245715, 2021.

18. Zheng W, et al: PI3K orchestration of the in vivo persistence of chimeric antigen receptor-modified T cells. Leukemia 32:1157-1167, 2018.

19. Lunning M, et al: Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 134:1811-1820, 2019.

20. Dhillon S, Keam SJ: Umbralisib: First approval. Drugs 81:857-866, 2021.

21. Gordon LI, et al: Durable responses after ibritumomab tiuxetan radioimmunotherapy for CD20+ B-cell lymphoma. Blood 103:4429-4431, 2004.

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