FDA Withdraws Approvals for Umbralisib in MZL, Follicular Lymphoma Due to Safety Concerns

The FDA announced that it has withdrawn approval for umbralisib, an oral inhibitor of PI3K-δ and CK1-ε manufactured by TG Therapeutics.

The FDA announced that it has withdrawn approval for umbralisib (Ukoniq), an oral inhibitor of PI3K-δ and CK1-ε manufactured by TG Therapeutics.1 The agency began investigating the drug in February 2022 after findings from the phase 3 UNITY-CLL trial (NCT026112311) suggested that umbralisib might be associated with an increased risk of death.2

The agency issued umbralisib an accelerated approval in February 2021 for the treatment of adults with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based regimen and adults with relapsed or refractory follicular lymphoma (FL) who have received at least 3 prior lines of systemic therapy.3

The FDA said health care professionals should immediately stop prescribing the drug and shift patients to alternative treatments. Patients should return the drug to a take-back location such as a pharmacy or dispose of it safely.1

TG Therapeutics pulled umbralisib from the market and voluntarily withdrew a biologics license application and supplemental new drug application seeking approval for umbralisib plus ublituximab (TG-1101) in adults with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) in April 2022.4 The company plans to make umbralisib available in limited circumstances for patients who are deriving benefit under expanded access.

In UNITY-CLL, investigators analyzed umbralisib/ublituximab (U2) vs obinutuzumab (Gazyva)/chlorambucil in patients with treatment-naïve or relapsed/refractory CLL.5 Participants were randomly assigned to 1 of 4 arms: ublituximab monotherapy, umbralisib monotherapy, U2, or obinutuzumab/chlorambucil. Investigators examined the contribution of U2 in the combination arm for the prespecified interim analysis and permitted the termination of the single-agent arms.

A total of 421 patients were included in the primary analysis. U2 significantly improved progression-free survival (PFS) compared with the control regimen in those with this disease (31.9 vs 17.9 months, respectively; HR, 0.546; 95% CI, 0.413-0.720; P < .0001).

However, investigators also observed a potential increased risk for death in patients who received the U2 regimen. In February, the FDA determined that patients receiving the combination also experienced more serious adverse effects (AEs) than those in the control arm.2 Although this study examined patients with CLL, the agency was concerned that those findings could have implications for patients prescribed U2 for MZL or FL.1

Umbralisib is not the first PI3K inhibitor the FDA has flagged for safety concerns. In 2016, Gilead Sciences stopped 6 clinical trials evaluating idelalisib (Zydelig) for patients with CLL, SLL, and indolent non-Hodgkin lymphomas after the agency alerted physicians to an increased rate of AEs, including deaths.6 Idelalisib is currently approved to treat relapsed CLL in the United States and FL in the European Union, United Kingdom, Canada, Australia, New Zealand, and Switzerland.


  1. FDA approval of lymphoma medicine Ukoniq (umbralisib) is withdrawn due to safety concerns. News release. FDA. June 1, 2022. Accessed June 1, 2022. https://bit.ly/3zbuhnG
  2. FDA investigating possible increased risk of death with lymphoma medicine Ukoniq (umbralisib). News release. FDA. February 3, 2022. Accessed June 1, 2022. https://bit.ly/3L9QaHw
  3. FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma. News release. FDA. February 5, 2021. Accessed June 1, 2022. https://bit.ly/3t9AKvy
  4. TG Therapeutics announces voluntary withdrawal of the BLA/sNDA for U2 to treat patients with CLL and SLL. News release. TG Therapeutics, Inc.; April 15, 2022. Accessed June 1, 2022. https://bit.ly/36lqqZm
  5. Gribben JG, Jurczak W, Jacobs R, et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 Unity-CLL study. Blood. 2020;136(suppl 1):37-39. doi:10.1182/blood-2020-134783
  6. FDA alerts healthcare professionals about clinical trials with Zydelig (idelalisib) in combination with other cancer medicines. News release. FDA. March 14, 2016. Accessed June 1, 2022. https://bit.ly/3NmLoXO