MRD-Guided Combination Treatment Appears Feasible in Patients With a Form of Relapsed/Refractory Leukemia

The use of the presence of minimal residual disease, which is a small percentage of cancer cells left in the body after treatment, as a guide to direct treatment with Imbruvica (ibrutinib) plus Venclexta (venetoclax) in patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) appears to be a feasible treatment approach, according to recent study results.

Moreover, the data showed that restarting treatment was feasible in patients who initially had undetectable minimal residual disease (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 Dr. Carsten Utoft Niemann, head of the CLL Laboratory at Rigshospitalet, Copenhagen University Hospital in Denmark, said during a presentation of the data at the 2021 ASH Annual Meeting. “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 to 87) received two 28-day cycles of 420 milligrams (mg) of Imbruvica daily. After which, 216 patients received Venclexta during the third cycle of treatment to get them acclimated to the therapy. The Venclexta dose then reached 400 mg per day at cycle 4 and patients continued receiving the combination from cycles four to 15.

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 maintenance Imbruvica. Patients who achieved at least partial remission (PR) and undetectable MRD in both blood and bone marrow samples at cycle 15 were randomized to either continue receiving maintenance Imbruvica (24 patients) or observation (48 patients). MRD-positive patients at cycle 15 remained on Imbruvica until progression.

Here, Niemann and colleagues presented progression-free survival (length of time during and after treatment a patient lives without disease progression) data from the group who received observation treatment at month 27.

Measuring the progression-free survival rate at 12 months after MRD-guided Venclexta and Imbruvica treatment had stopped in the group who was randomized to observation was the main goal of the study. To ensure if MRD returned, those individuals received tests every three months and started treatment again if they were deemed to be MRD-positive.

At 27 months, 71% of the patients in the observation group had undetectable MRD in blood samples and 54% had undetectable MRD in their bone marrow, compared with 75% and 63% in the Imbruvica maintenance group, respectively.

Moreover at 27 months, 29% of patients in the non-randomized, Imbruvica group achieved undetectable MRD in their 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 nine patients actually were allocated here even though they had undetectable MRD levels in bone marrow,” Niemann said.

“This includes two patients by mistake not randomized by the local investigators and seven 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 (Imbruvica). 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 (Imbruvica), keep the MRD level with a low degree of progressions.”

The study results demonstrated that the main goal of the study was met and that progression-free survival at 27 months (12 months after stopping treatment) was 98% in the observation group. Of note, this was above the predefined limit of 60%, according to Niemann.

Only seven patients in the observation group needed to restart Imbruvica and Venclexta because of a detectable MRD. Six of those patients achieved a complete response to treatment within the first three cycles and the seventh patient awaits evaluation.

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

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

After cycle 15, patients in the observation group experienced fewer side effects than either of the other Imbruvica maintenance groups.

“We can conclude that MRD-guided (Imbruvica) with (Venclexta) 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) (Imbruvica) 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 (Imbruvica) and (Venclexta) in relapsed refractory CLL is feasible and can be recommended similar to what has been seen for CML.”

A version of this article originally appeared on OncLive as, “MRD-Guided Ibrutinib Plus Venetoclax Demonstrates Feasibility in Relapsed/Refractory CLL.”

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