Combination therapy guided by MRD appears feasible in patients with relapsed / refractory form of leukemia

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

In addition, the data showed that resuming treatment was possible in patients who initially had undetectable minimal residual disease (MRD) after 15 cycles of treatment, but who developed detectable MRD on subsequent assessments.

“The rationale for this trial is based on the desire to provide a time-limited treatment for relapsed / refractory CLL,” said lead author of the study, Dr. Carsten Utoft Niemann, head of the laboratory at the LLC at Rigshospitalet, University Hospital Copenhagen, Denmark. during a data presentation at the 2021 ASH annual meeting. “Additionally, we wanted to test the potential of MRD-guided therapy in CLL.”

Niemann also said the researchers were inspired by previous trials in the area of ​​chronic myelogenous leukemia (CML) where the study authors stopped and restarted treatment. As a result, Niemann noted, patients who had stopped treatment but were to resume treatment after future positive MRD results would not be considered a progression event.

To begin with, 225 patients (median age, 68; range, 36 to 87) received two 28-day cycles of 420 milligrams (mg) of Imbruvica per day. After that, 216 patients received Venclexta in the third cycle of treatment to accustom them to the therapy. The dose of Venclexta then reached 400 mg per day in cycle 4 and patients continued to receive the combination of cycles 4 to 15.

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

Of the patients who did not achieve undetectable MRD, 116 received maintenance Imbruvica. Patients with at least partial remission (PR) and undetectable MRM in blood and bone marrow samples at cycle 15 were randomized to continue receiving Imbruvica (24 patients) or observed (48 patients). MRD-positive Cycle 15 patients remained on Imbruvica until progression.

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

The primary objective of the study was to measure the 12-month progression-free survival rate after discontinuation of treatment with Venclexta and Imbruvica guided by MRD in the randomized observation group. To ensure that MRD returned, these people were tested every three months and restarted treatment if they were found to be positive for MRD.

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

In addition, 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 the group of patients who did not achieve undetectable MRD levels, you will realize that nine patients were affected here even though they had undetectable levels of MRD in the bone marrow,” Niemann said. .

“This includes two patients who were mistakenly not randomized by local investigators and seven patients who were included before an amendment. Prior to this amendment, it was required that patients also have undetectable MRD levels in cycle 12. What is important here is that MRD levels appear to remain stable for this group of patients, continuing (Imbruvica). So if you have a relapsed refractory CLL patient who is MRD positive at Cycle 12 to Cycle 15, it appears that you can, by continuing (Imbruvica), maintain the level of MRD with a low degree of progression. .

The results of the study demonstrated that the primary objective of the study was achieved and that the progression-free survival at 27 months (12 months after stopping treatment) was 98% in the observation group. It should be noted that this figure was above the preset limit of 60%, according to Niemann.

Only seven patients in the observation group had to re-start Imbruvica and Venclexta due to detectable MRD. Six of these patients have achieved a complete response to treatment within the first three cycles and the seventh patient is awaiting evaluation.

For patients who achieved undetectable MRM in cycle 15 and who remained on maintenance treatment with Imbruvica, no disease progression was reported. Although there were some disease progressions in the group that did not achieve undetectable MRD and continued maintenance of Imbruvica, 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 observed with the single agent Imbruvica or single agent Venclexta as well as what has been reported for the combination so far, according to Niemann.

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

“We can conclude that guided (Imbruvica) with (Venclexta) MRD for relapsed refractory CLL is feasible, (and) the primary endpoint of the trial was met with 98% progression-free survival of patients in the observation group followed by MRD assessment every three months, ”Niemann concluded. “(And the fact) that MRD levels have remained stable for MRD-positive patients who continue (d) maintenance (Imbruvica) and that all patients who were assessed after resuming treatment when they became MRD -positive, have in fact successfully resumed treatment and entered remission and therefore MRD-guided stop / start treatment with (Imbruvica) and (Venclexta) in relapsed refractory CLL is feasible and may be recommended from the same way as what has been observed 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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