U2 Plus Pembrolizumab Shows Continued Efficacy at 5 Years in CLL and Richter’s Transformation


The triplet combination of umbralisib, ublituximab, and pembrolizumab demonstrated durable responses with a tolerable safety profile in patients with relapsed/refractory chronic lymphocytic leukemia and Richter’s transformation.

Lindsey Roeker, MD

Lindsey Roeker, MD

The triplet combination of umbralisib (Ukoniq), ublituximab (U2), and pembrolizumab (Keytruda) demonstrated durable responses with a tolerable safety profile in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and Richter’s transformation, according to findings from the 5-year updated analysis of a phase 1/2 study (NCT02535286) that were presented in a poster during the 2021 International Workshop on CLL (iwCLL).1

In patients with CLL (n = 11), the overall response rate (ORR) was 91% (n = 10), which comprised 1 (9%) complete response (CR) and 9 (82%) partial responses (PRs). An additional patient (9%) achieved stable disease (SD). The ORR was 83% in patients with BTK inhibitor–refractory CLL (n = 6), and 80% of BTK inhibitor–refractory responders achieved a response following U2 induction prior to the addition of pembrolizumab.

In patients with Richter’s transformation (n = 9), the ORR was 25% (n = 2), which comprised 2 CRs (25%). An additional 3 (38%) patients achieved SD. Additionally, patients with heavily refractory Richter’s transformation achieved durable responses.

“Although there are preclinical data to support a role for inhibiting the PD-1/PD-L1 axis in CLL, clinical experience with checkpoint inhibitor monotherapy has been disappointing, with a 0% ORR in CLL and limited durability in Richter’s transformation,” lead study author Lindsey Roeker, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, said in a presentation of the data.

“Given that there is a known interaction between the PI3K signaling pathway and immune checkpoint surveillance it was thought that PI3K inhibition and checkpoint blockade may act synergistically,” Roeker added.

Umbralisib is an oral PI3Kδ and CK1ε inhibitor that has demonstrated encouraging activity in CLL in combination with ublituximab, a glycoengineered CD20-directed monoclonal antibody.

On May 25, 2021, the FDA accepted a biologics license application for the U2 regimen for the treatment of patients with CLL and small lymphocytic lymphoma. The acceptance was based on findings from the phase 3 UNITY-CLL trial (NCT026112311), in which the doublet improved progression-free survival (PFS) vs obinutuzumab (Gazyva) plus chlorambucil in patients with CLL.

To evaluate U2 in combination with pembrolizumab, the multicenter phase 1/2 study utilized a dose-escalation, 3+3 design to evaluate the safety of the triplet in patients with CLL and Richter’s transformation.

Cohort 1 (n = 5 patients with CLL; n = 4 patients with Richter’s transformation) received 100 mg of pembrolizumab and cohort 2 (n = 6 patients with CLL; n = 5 patients with Richter’s transformation) received 200 mg of pembrolizumab. Peripheral blood and/or bone marrow samples were collected at screening, as well as during cycles 2 and 6 for correlative study.

Safety served as the primary end point of the study, with efficacy (ORR and PFS) and the characterization of immunophenotypic profiles of B and T cells as key secondary end points.

Patients with CLL who progressed on at least 1 prior therapy were eligible for enrollment. A mid-study amendment required all patients with CLL to be refractory to a BTK inhibitor, defined as disease progression within 6 months of prior BTK inhibitor therapy.

Patients with Richter’s transformation were refractory to chemoimmunotherapy or ineligible for high-dose chemotherapy.

Notably, patients with prior PD-1 inhibitor or PI3K inhibitor exposure were not excluded from the study.

Patients with CLL were a median age of 70 years (range, 60-81) and most patients were male (n = 7). Five patients had an ECOG performance status (PS) of 0, and 6 patients had an ECOG PS of 1. The median number of prior therapy regimens was 1 (range, 1-4); 64% (n = 7) of patients received prior BTK inhibitors (ibrutinib [Imbruvica] or acalabrutinib [Calquence]) and 86% (n = 6) were refractory to their prior BTK inhibitor. Additionally, 73% of patients (n = 8) were refractory to their immediate prior therapy.

Most patients (n = 8; 73%) had at least 1 high-risk feature and 55% (n = 6) had 2 or more high-risk features. High-risk features included 17p deletions/TP53 mutations (n = 3; 27%), complex karyotype (n = 5; 45%), NOTCH1, ATM, or SF3B1 mutations (n = 5; 45%), unmutated IGHV (n = 4; 57%), and bulky disease (n = 7; 64%).

In the Richter’s transformation cohort, the median age was 66 years (range, 53-73), and 6 patients were male. An ECOG PS of 0, 1, and 2 was observed in 3, 5, and 1 patient, respectively. The median number of prior therapies was 5 (range, 1-9); 89% (n = 8) of patients received prior ibrutinib and 100% were refractory to the BTK inhibitor. Prior regimens included chemotherapy (n = 9; 100%), idelalisib (Zydelig) plus rituximab (Rituxan; n = 2; 22%), venetoclax (Venclexta; n = 3; 33%), and CAR T-cell therapy or allogeneic transplant (n = 3; 33%). Most patients (n = 8; 89%) were refractory to their immediate prior treatment and had bulky disease.

The median follow-up was 48 months for all patients and 54 months for patients with CLL.

Additional results showed that circulating FoxP3+ CD4+ T-cell levels did not change significantly among patients with CLL.

“The maintenance of T regs throughout therapy may explain the limited autoimmune sequelae that were seen in this study,” Roeker said.

Regarding safety in both cohorts, all-causality, all-grade adverse effects (AEs) included neutropenia (n = 12; 60%), pyrexia (n = 10; 50%), diarrhea (n = 10; 50%), nausea (n = 9; 45%), chills (n = 9; 45%), cough (n = 9; 45%), fatigue (n = 9; 45%), thrombocytopenia (n = 8; 40%), decreased appetite (n = 8; 40%), headache (n = 8; 40%), infusion-related reactions (n = 7; 35%), peripheral edema (n = 6; 30%), increased alkaline phosphatase (n = 6; 30%), leukopenia (n = 6; 30%), dizziness (n = 6; 30%), nasal congestion (n = 6; 30%), contusion (n = 5; 25%), myalgia (n = 5; 25%), oral candidiasis (n = 5; 25%), anemia (n = 5; 25%), pruritus (n = 5; 25%), increased alanine aminotransferase (ALT; n = 5; 25%), insomnia (n = 5; 25%), and vomiting (n = 5; 25%).

Grade 3 or higher AEs included neutropenia (n = 9; 45%), nausea (n = 1; 5%), fatigue (n = 1; 5%), thrombocytopenia (n = 3; 15%), leukopenia (n = 2; 10%), anemia (n = 1; 5%), and increased ALT (n = 3; 15%).

One dose-limiting toxicity of transient elevated liver function test (LFT) was observed with 200 mg of pembrolizumab and was subsequently resolved. The maximum-tolerated dose was not reached.

Grade 3 or 4 elevated LFT was observed in 20% (n = 4) of patients, but no grade 3 or 4 diarrhea was reported. One patient developed grade 5 colitis secondary to Clostridium difficile.

No dose reductions were required with pembrolizumab, but 4 patients required dose reductions with umbralisib because of grade 3 asthenia/fatigue, grade 3 neutrophil count decrease, grade 2 ALT increase, and grade 2 headache.

“Notably, immune-mediated toxicities were not increased above what would be expected with umbralisib or pembrolizumab alone,” Roeker concluded.


  1. Roeker LE, Shadman M, Svoboda J, et al. Phase I/II study of umbralisib, ublituximab, and pembrolizumab in patients with relapsed or refractory chronic lymphocytic leukemia and Richter’s transformation: 5-year follow-up. Presented at: 2021 International Workshop on CLL; September 17-20, 2021; virtual. Poster 1083523. https://bit.ly/39mpYYA

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