Does MRD Predict PFS in Patients With CLL on Indefinite Ibrutinib-Based Therapy?

According to research published in Blood, measurable residual disease (MRD) was not associated with improved progression-free survival (PFS) in patients with chronic lymphocytic leukemia (CLL) who were on indefinite ibrutinib-based therapy or who received six cycles of fludarabine, cyclophosphamide, and rituximab (FCR). However, PFS was significantly longer in patients with undetectable MRD.

The study also found that ibrutinib-treated patients with CLL who have detectable MRD levels lower than 10-1 have longer PFS. “We have established in this large cooperative group study for upfront therapy of CLL that sequential MRD done with sensitive flow cytometry approaches can be highly informative for the practitioner in predicting clinical outcomes for patients on novel agent-based approaches,” study author Neil Kay, MD, of Mayo Clinic, told ASH Clinical News.

Lead study author Victoria Wang, PhD, of Dana-Farber Cancer Institute, explained that the utilization of MRD assessment in B-cell CLL has been a source of controversy for some time. Issues with MRD assessment in this condition include finding optimal ways to measure MRD, timing of MRD measurements, and its use as a surrogate for clinical outcomes in CLL.

While MRD status is associated with the survival outcomes of patients with CLL, “with the advent of novel agents either alone or in combination, the value of MRD testing as a surrogate of outcome has been less obvious most likely because of more infrequent complete remissions,” said Dr. Wang. There is also limited data on the value of MRD status in patients who receive ibrutinib-based therapies.

The phase III study by Drs. Kay and Wang evaluated the association of PFS and MRD status in patients with CLL. Patients were randomized to the IR treatment group (indefinite ibrutinib plus six cycles of rituximab) or the FCR treatment group (six cycles of fludarabine, cyclophosphamide, and rituximab).

The MRD levels in peripheral blood were measured using eight-color flow cytometry with a sensitivity of one CLL cell per 104 leukocytes. MRD was estimated by dividing the number of monotypic events by the total number of leukocytes. Samples with an MRD level of <10-4 (<1 CLL cell/104 leukocytes) had undetectable MRD.

A total of 529 patients were randomized to receive either IR (n=354) or FCR (n=175). The undetectable MRD rates for patients in the IR group were significantly lower than those in the FCR group (p<0.001). Undetectable MRD was associated with longer PFS for patients in the FCR group than in the IR group.

Patients with undetectable MRD in the FCR group had significantly better PFS than those who had detectable MRD at three, 12, and 24 months. In contrast, patients with MRD in the IR group did not have significantly worse PFS than those with undetectable MRD.

In the IR arm, undetectable MRD was associated with mutated immunoglobin heavy chain (IGHV, p=0.001), as well as lower CD19+CD5+ cell counts (p=0.020) and higher CD49d+ cell counts (p=0.001) at baseline. For the FCR group, undetectable MRD was associated with higher hemoglobin levels (p=0.011), mutated IGHV (p=0.009), and higher CD49d+ (p=0.042) cell counts.

While patients in the FCR group with unmutated IGHV at baseline had significantly shorter PFS than those with mutated IGHV, there was no association between IGHV mutation and PFS in the IR group.

Given the small number of deaths in this study (n=23), the researchers were unable to perform an analysis focused on MRD status and overall survival. The researchers added that future studies are needed to validate these findings, particularly those observed in the continuous IR arm.

“These findings need to be further assessed with longer follow up and validated in future large phase III trials,” concluded Dr. Kay. “However, they set the stage for further use of MRD studies as an important surrogate laboratory tool in assessing responses to novel agents for CLL patients.”

Study authors report relationships with AstraZeneca, the manufacturer of ibrutinib.


Wang VX, Hanson CA, Tschumper RC, et al. Measurable residual disease does not preclude prolonged progression-free survival in CLL treated with ibrutinib [published online ahead of print, 2021 Aug 18]. Blood. doi: 10.1182/blood.2020010146.