FDA Investigates Possible Increased Risk of Death Associated With Umbralisib in Lymphoma


Umbralisib is potentially linked to an increased risk of death in patients with lymphomas, according to an alert for clinical and patients announced by the FDA.

Umbralisib (Ukoniq) is potentially linked to an increased risk of death in patients with lymphomas, according to an alert for clinical and patients announced by the FDA. The oral inhibitor of PI3K-delta and CK1-epsilon is currently approved for patients with marginal zone lymphoma (MZL) and follicular lymphoma (FL).1

Findings from a phase 3 UNITY-CLL trial (NCT026112311) which evaluated umbralisib, revealed the possibility of an increase of death in patients being treated with the medication.

According to the drug safety communication issued by the regulatory agency, “[b]ecause of the seriousness of this safety concern and the similarities between the two types of cancer for which this drug is approved and the type of cancer that was studied in the clinical trial, we are alerting patients and health care professionals that we are re-evaluating this risk against the benefits of [umbralisib] for its approved uses.”

The randomized and controlled clinical trial, UNITY, investigated umbralisib in combination with ublituximab (U2) vs the active control regimen of obinutuzumab (Gazyva; O) and chlorambucil (Chl) in patients aged 18 and older with treatment-naïve or relapsed/ refractory (r/r) chronic lymphocytic leukemia (CLL).2 Participants were randomized to 1 or 4 arms: U2, O plus Chl, umbralisib monotherapy, or ublituximab monotherapy. Patients were then randomized 1:1 to U2 of O plus Chl following the establishment of contribution which compared U2 to the single agents.

The primary analysis of the trial included 421 patients. Umbralisib was given once a day at 800 mg until progression or discontinuation from treatment to those on the investigative arm. Ublituximab was administered intravenously (IV) at 900 mg on days 1 and 2 (150 on day 1 followed by 750 mg on day 2) as well as 900 mg on days 8 and 15 of cycle 1; day 1 of cycles 2 to 6, and on day 1 every 3 cycles following cycle 6. Those in the control arm were given obinutuzumab IV at a dose of 1000 mg on days 1 and 2 (100 mg on day 1 followed by 900 mg on day 2), 8, and 15 of cycle 1; and day 1 of cycles 2 to 6. Chl was given at a dose of 0.5 mg/kg orally on days 1 and 15 of cycles 1 to 6. Each treatment cycle was 28 days.

The trial’s primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS) of U2 vs O plus Chl with key secondary endpoints consisting overall response rate (ORR), complete response (CR), undetectable minimal residual disease (uMRD), duration of response (DOR), and safety which was examined between the first dose of treatment and 30 days after the last dose was administered.

Results from the study showed U2 to be well-tolerated and to significantly improve PFS over the control regimen in those with TV and r/r CLL. The median PFS with U2 was 31.9 months vs 17.9 months for O plus Chl with the control (HR, 0.546; 95% CI, 0.413-0.720; P < .0001). The estimated 24-month PFS rates in the investigative and control arms were 60.8% and 40.4%.

Other findings included U2 having an ORR of 83.3% (n = 210) vs 68.7% (n = 211) with O plusChl (P < .001). Among those, 26 (6%) of patients were previously treated and received prior ibrutinib (14 on U2 and 12 on O plus Chl). The ORR to U2 was 57% vs the 25% ORR to O plus Chl.

During this time, enrollment of new patients in other ongoing clinical trials of umbralisib has been suspended. The FDA plans to continue evaluating the results from UNITY and says they will communicate their findings and conclusions when more information is uncovered.

Health care professionals are being advised to review patients' progress on umbralisib and to discuss continuing on it in the context of other treatments which may be available to them. Additionally, patients should make sure to talk to their health care professionals regarding the risks and benefits of continuing umbralisib as well as discussing other possible treatment plans.

Back in February 2021, the FDA granted accelerated approval to umbralisib, the first and only oral inhibitor of phosphoinositide 3 kinase (PI3K) delta and casein kinase 1 (CK1) epsilon.3 Eligible patients either had r/r MZL and received at least 1 prior anti-CD20–based regimen or have were adults with r/r follicular lymphoma who received at least 3 prior lines of systemic treatment.

PI3K-delta assists in supporting cell proliferation and survival, cell differentiation, intercellular trafficking and immunity and is expressed in normal and malignant B-cells, while CK1-epsilon is a regulator of oncoprotein translation and has been implicated in the pathogenesis of cancer cells, including lymphoid malignancies.4

This decision was based on two single-arm cohorts of the trial, UTX-TGR-205 (NCT02793583) which used 69 patients with MZL who received at least one prior therapy, including an anti-CD20 containing regimen, as well as in 117 patients with FL after at least 2 prior systemic therapies. Patients were given 800 mg of umbralisib orally once daily until disease progression or unacceptable toxicity. ORR and DOR were used to determine efficacy.

Findings showed the ORR for patients with MZL to be 49% (95% CI: 37.0, 61.6) with 16% achieving CR vs the ORR for patients with FL to be 43% (95% CI: 33.6, 52.2) with 3% achieving CR. Median DOR 11/1 months in patients with FL but was not reached in patients with MZL.

In regard to safety, the most common adverse reactions included increased blood creatinine, diarrhea-colitis, fatigue, nausea, neutropenia, transaminase elevation, musculoskeletal pain, anemia, thrombocytopenia, upper respiratory tract infection, vomiting, abdominal pain, decreased appetite, and rash. In 18% of patients, serious adverse reactions led to dose modifications most often resulting from diarrhea-colitis and infection.


  1. FDA investigating possible increased risk of death with lymphoma medicine Ukoniq (umbralisib). News release. FDA; February 3, 2022. Accessed February 4, 2022. https://bit.ly/3L9QaHw
  2. 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
  3. 3. FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma. News release. FDA; February 5, 2021. Accessed February 4, 2022. http://bit.ly/3aCBqQa
  4. TG Therapeutics provides regulatory update. TG Therapeutics. News release. TG Therapeutics; November 30, 2021. Accessed February 4, 2022. https://bit.ly/3d6biPa

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