MRD-Guided Ibrutinib Plus Venetoclax Demonstrates Feasibility in Relapsed/Refractory CLL

The minimal residual disease (MRD)–guided combination of ibrutinib (Imbruvica) plus venetoclax (Venclexta) was found to be a feasible treatment regimen for patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to findings from the primary analysis of the phase 2 VISION HOH141 trial (NCT03226301) that were presented during the 2021 ASH Annual Meeting & Exposition.

Moreover, the data showed that restarting treatment was feasible in patients who initially had undetectable MRD after 15 cycles of treatment but then developed detectable MRD at later assessments.

“The rationale for this trial is based on wanting to come up with a time-limited treatment for relapsed/refractory CLL,” lead study author Carsten Utoft Niemann, MD, PhD, Department of Hematology, Rigshospitalet, Copenhagen University Hospital, said during a presentation of the data. “Furthermore, we wanted to test the potential for MRD-guided therapy in CLL.”

Niemann also said that the researchers took inspiration from prior trials in the chronic myeloid leukemia (CML) space where study authors stopped and reinitiated treatment. As a result, Niemann noted, patients who had stopped treatment but had to be reinitiated on therapy upon future positive MRD results would not be considered a progression event.

To start, 225 patients (median age, 68 years; range, 36-87) received 2, 28-day cycles of ibrutinib lead-in at 420 mg daily. Then, 216 patients received venetoclax ramp-up during the third cycle. The dose of venetoclax reached 400 mg per day at cycle 4 and patients continued receiving the combination from cycles 4-15.

Of note, Niemann explained that the baseline characteristics patient population in the VISION HO141 trial reflected what has been seen in most other R/R CLL populations, with only 14% being Binet stage A and 24% having del(17p) and/or TP53 mutations.

After the first 15 cycles of treatment, in which several patients were lost due to death or leaving the study, 72 patients reached an undetectable MRD and 125 did not.

Of those patients who did not achieve undetectable MRD, 116 were administered ibrutinib maintenance. Patients who achieved at least partial remission (PR) and undetectable MRD in both peripheral blood and bone marrow samples at cycle 15 were randomized 1:2 between continuing ibrutinib maintenance (arm A; n = 24)) or observation (arm B; n = 48). MRD-positive patients at cycle 15 remained on ibrutinib until progression.

Here, Niemann and colleagues presented progression-free survival (PFS) data from the observation arm at month 27.

The primary endpoint of this analysis was to assess PFS rates among patients in arm B 12 months after MRD-guided venetoclax and ibrutinib treatment had stopped. Those individuals received an MRD test every 3 months and started treatment again if they were MRD-positive.

At 27 months, 71% of the patients in the observation arm (arm B) had undetectable MRD in peripheral blood samples and 54% had undetectable MRD in their bone marrow, compared with 75% and 63% in the ibrutinib maintenance (arm A) group, respectively.

Moreover at 27 months, 29% of patients in the non-randomized, ibrutinib arm achieved undetectable MRD in peripheral blood and 13% in their bone marrow.

“If we follow up in the group of patients who did not achieve undetectable MRD level[s], you will realize that 9 patients actually were allocated here even though they had undetectable MRD levels in bone marrow,” Niemann said. “This includes 2 patients by mistake not randomized by the local investigators and 7 patients who were included prior to an amendment. Before this amendment, it was required that patients should also have undetectable MRD levels at cycle 12. What is important here is that the MRD levels seem to stay stable for this patient group, continuing Ibrutinib. So if you have a patient in the relapsed refractory CLL setting being MRD positive at cycle 12 to cycle 15, it seems that you can, by continuing ibrutinib, keep the MRD level with a low degree of progressions.”

The study results demonstrated that the primary endpoint was met and that PFS at 27 months, 12 months after stopping treatment was 98% in the observation arm (arm B). Of note, this was above the predefined limit of 60%, according to Niemann.

Only 7 patients in the observation arm (arm B) needed to restart ibrutinib and venetoclax because of a detectable MRD. Six of those patients achieved de novo CR within the first 3 cycles and the seventh patient awaits evaluation.

For patients who achieved undetectable MRD at cycle 15 and remained on ibrutinib maintenance, no disease progression was reported (OS at month 27, 100%). Although there were some progressions in the group that did not achieve undetectable MRD and continued ibrutinib, the OS rate at 27 months was 92%.

The adverse event profile during the first 15 cycles of treatment was representative of what has been seen with single agent ibrutinib or single agent venetoclax as well as what has been reported for the combination thus far, according to Niemann.

A quarter of patients (25%) experienced a grade 2 AE during the first 15 cycles; 40% experienced a grade 3 AE and 25% experienced a grade 4 AE.

After cycle 15, patients in the observation arm experienced less adverse events than either of the other ibrutinib maintenance arms.

“We can conclude that MRD-guided ibrutinib with venetoclax for relapsed refractory CLL is feasible, [and] that the primary endpoint of the trial was met with 98% progression-free survival of patients in the observation arm being followed by MRD assessment every three months,” Niemann concluded.

“[And the fact] that MRD levels remained stable for the MRD-positive patients who continue[d] ibrutinib maintenance and that all patients that were evaluated after reinitiating therapy upon becoming MRD-positive, actually successfully reinitiated therapy and went into complete remission and thus MRD-guided stop/start treatment with ibrutinib and venetoclax in relapsed refractory CLL is feasible and can be recommended similar to what has been seen for CML.”

Reference

1. Niemann CU, Dubois J, Brieghel C, et al. Time-Limited Venetoclax and Ibrutinib for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Who Have Undetectable MRD – Primary Analysis from the Randomized Phase II Vision HO141 Trial. Paper presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 69.