CLL Research: Ublituximab plus Ibrutinib vs. Ibrutinib Alone in Chronic Lymphocytic Leukemia (CLL)
This post summarizes and explains a peer-reviewed article published on February 22, 2021, by The Lancet, a renowned medical journal. The title of the article is “Ublituximab plus Ibrutinib versus Ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukemia (GENUINE): a phase 3, multicenter, open-label, randomized trial.” Dr. Jeff P. Sharman (photo to the right or below on mobile) of Willamette Valley Cancer Institute in Eugene, Oregon, served as chairman of this study at 119 sites in the United States and Isreal.
Background – Ublituximab plus Ibrutinib (GENUINE) Study
The Genuine Trial design occurred in early 2014. At that time, ibrutinib, the first-in-class Bruton’s tyrosine kinase (BTK) inhibitor, research had demonstrated both safety and effectiveness in CLL. The introduction of ibrutinib represented a landmark shift in CLL treatment. Early studies of ibrutinib showed that the same markers associated with poorer prognosis in patients treated with CIT also impacted prognosis negatively for patients treated with ibrutinib. Since the GENUINE implementation, other research has shown that del(11q) is no longer considered to influence patients’ prognosis with ibrutinib.
This study aimed to determine the benefit of combining ublituximab and ibrutinib in a high-risk population. In early 2014, no randomized studies had reached publication comparing a BTK inhibitor combined with anti-CD20 therapy, to monotherapy with a BTKi.
Ublituximab is a next-generation, glycoengineered type I, an anti-CD20 monoclonal antibody (MAB). Ublituximab is not like rituximab, ofatumumab, or obinutuzumab because it binds to the CD20 protein found on the surface of b-cells at a unique location. Ublituximab plus ibrutinib produced an overall response rate (ORR) of 88% in all patients, and 95% in patients with high-risk cytogenetics, in an earlier Phase II study. This success lead to the Phase III GENUINE trial.
Methods – Ublituximab plus Ibrutinib (GENUINE) Study
GENUINE was a fixed-dose, phase III clinical trial conducted at 119 sites in the US and Isreal. This trial compared ublituximab plus ibrutinib to ibrutinib alone. The cutoff date for this final analysis was September 1, 2019. There were several eligibility requirements for patients to enter this study, including:
• age of 18 or greater,
• in need of treatment, as defined by the International Workshop on chronic lymphocytic leukemia (iwCLL) criteria,
• have at least one confirmed high-risk cytogenetic abnormality (del [17p], del [11q], or TP53 mutation) by fluorescence in-situ hybridization (FISH) and next-generation sequencing,
• have previously received at least two 28-day cycles of at least one standard therapy regimen,
• have an Eastern Cooperative Oncology Group (ECOG) status of two or lower, and
• have at least one measurable lymphadeno-pathy (swollen lymph node) that measures at least 2 centimeters by 1 centimeter as assessed by CT or MRI scan.
Patients received treatment in an outpatient setting in 28-day cycles. Trial participants took Ibrutinib orally once daily (420mg.) Patients were required to obtain their supply of ibrutinib, billed to their insurance. Study subjects received Ublituximab intravenously as follows:
• Cycle 1 – Day 1 – up to 150mg over 4 hours,
• Cycle 1 – Day 2 – 750mg over 4 hours,
• Cycle 1 – Day 8 and Day 15 – 900mg over 3 hours,
• Cycles 2-6 – Day 1 – 900mg over 3 hours, and
• Every 3rd Cycle After Cycle 6 – Day 1 – 900mg over 90 minutes.
Both ublituximab and ibrutinib were given continuously until disease progression, unacceptable side effects, or withdrawal of consent by the patient. Patients received diphenhydramine (Benadryl®) 50mg and dexamethasone (10-20mg, or equivalent) before each ublituximab infusion during cycles 1-6. These two drugs lessen the infusion reactions associated with monoclonal antibodies. Dosage reductions of ublituximab were not permitted. Patients could have Ibrutinib doses lowered if they experienced any grade 3 or higher side effects at the investigating physician’s discretion.
An independent review committee (IRC) evaluated radiographic and clinical data on an ongoing basis.The IRC used the 2008 iwCLL criteria to assess patient responses.
This clinical trial’s primary endpoint or goal was IRC overall response rate, which was defined a the proportion of patients who had a partial response, complete response, or complete response with incomplete bone marrow recovery. The IRC assessed patients at the end of cycles 2, 4, and 6. Further assessments occurred every three cycles for those who remained in treatment or every three months for those who ended therapy and were in the follow-up group.
Secondary endpoints were:
• progression-free survival (PFS), defined as time from starting treatment to disease progression, or death from any cause,
• minimal residual disease (MRD) negativity, defined as less than one chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes,
• complete response rate,
• time to response, defined as the interval between entering treatment and the first complete or partial response,
• duration of response, defined as the time between first response and PFS or death, and
• safety assessment.
Results – Ublituximab plus Ibrutinib (GENUINE) Study
Patients had a median age of 66 (range, 62-74) in the ublituximab plus ibrutinib group and a median age of 67 (range, 62-74) in the ibrutinib monotherapy group. Patients in both groups had a median of one prior treatment (range, 1-2) before entering this study. The two treatment groups were generally well balanced except for an imbalance of patients with bulky disease in the ublituximab plus ibrutinib group vs. the ibrutinib-only group. (48% vs. 28%) The bulky disease definition was patients having at least one lymph node larger than 5 centimeters (2 inches).
The median follow-up for patients in the ublituximab plus ibrutinib group was 31.5 months (range, 12.4-39.5). The median follow-up for ibrutinib monotherapy patients was 17.0 months (range, 5.2-35.3).
The proportion of treated patients who attained complete response (with or without incomplete bone marrow recovery) was 20% in the ublituximab plus ibrutinib cohort. In the ibrutinib alone group, only 5% attained complete response.
In both groups, the median duration of response was not reached. (fewer than 50% of patients in that group had disease progression or died).
The median time to first partial response was 2.0 months (range, 1.9-3.7) for the ublituximab plus ibrutinib group and 4.4 months (range 2.0-9.8) for those treated with ibrutinib alone. Similarly, the median time to first complete response was 22.1 months (range 15.5-28.8) in the U+I group and 24.8 months (23.6-31.4) in the monotherapy group.
The median PFS in the ublituximab plus ibrutinib group was not reached, but the PFS for the ibrutinib alone group was 35.9 months. (at 35.9 months, more than 50% percent of patients had experienced disease progression)
A higher proportion of patients treated with ublituximab plus ibrutinib attained MRD negativity. (42% vs. 6%)
The overall response rate (ORR) for patients treated with ublituximab plus ibrutinib was 86%, while the rate for patients who received ibrutinib alone experienced an ORR of 73%.
Among the 27 patients treated with ublituximab plus ibrutinib who reached undetectable MRD, fifty-nine (59%) did so by 18 months of treatment compared to none in the ibrutinib group in the same time interval.
All patients experienced at least one adverse effect of any grade. Seventy-Six (76) percent of patients in the ublituximab plus ibrutinib group experienced an adverse effect of grade 3 or higher. In the ibrutinib alone cohort, 83% of patients experienced an adverse effect ≥ grade 3.
Eight (8) patients (14%) had doses of ublituximab delayed, while six patients (10%) had ublituximab stopped possibly due to adverse effects of ublituximab or ibrutinib. A similar number of patients had doses of ibrutinib reduced in each cohort (15% - UI vs. 14% - I).
Conclusions
The Phase III GENUINE trial met the primary endpoint of significantly improved overall response rate (ORR) assessed by the independent review committee (IRC). The ORR of 83% of patients treated with ublituximab plus ibrutinib supports the findings of the earlier Phase II multicenter study of this combination.
Marrow-confirmed complete responses (19% vs. 5%) and MRD negativity (42% vs. 6%) occurred more frequently in the combination ublituximab plus ibrutinib patients. These findings suggest that the addition of ublituximab increased the depth of response. Improved progression-free survival (PFS), both in the total population and in patients with deletion (17p), could translate to improved outcomes.
Increased depth of response appeared to translate to prolonged durability of response, with improved PFS in patients who reached MRD negativity has shown to a PFS benefit with chemoimmunotherapy (CIT) and the novel BCL-2 inhibitor, venetoclax. Unfortunately, patients receiving the BTK inhibitors ibrutinib or acalabrutinib rarely attain negative MRD.
This clinical trial’s findings suggest that ublituximab maintenance therapy, given every three months, may improve the long-term response depth.
The GENUINE study’s findings indicate that combination therapy with the next-generation anti-CD20 antibody ublituximab plus ibrutinib suggests the benefit of combination therapy in relapsed or refractory high-risk chronic lymphocytic leukemia (CLL).
Historically, since the advent of targeted therapies to treat CLL, these agents have been used in sequence rather than combinations. Today combinations that are NCCN preferred regimens include venetoclax and obinutuzumab, venetoclax and rituximab, acalabrutinib with or without obinutuzumab, and idelalisib plus rituximab.
Previously we covered one study on the combination of ibrutinib plus venetoclax. We also covered a more recent clinical trial of ibrutinib + venetoclax + obinutuzumab (IVO.) You may recall that I took the combination of ibrutinib and venetoclax, which brought me to undetectable disease seven months after adding venetoclax to the ibrutinib I had been on 3+ years.