The future of minimal residual disease testing in chronic lymphocytic leukemia may be applicable for patients being treated with venetoclax in combination with Bruton’s tyrosine kinase inhibitors.
In chronic lymphocytic leukemia (CLL), detection of minimal residual disease (MRD) can be prognostic of patient outcomes on chemoimmunotherapy and the combination of venetoclax (Venclexta) and antibody therapies, according to Jennifer A. Woyach, MD.1
During a presentation at the NCCN 2021 Virtual Congress: Hematologic Malignancies, Woyach, hematologist-oncologist, and associate professor, Division of Hematology, The Ohio State University explained that in the future of MRD testing in CLL would be applicable for patients being treated with venetoclax in combination with Bruton’s tyrosine kinase inhibitors.
In standard practice, MRD in CLL is defined as < 1 CLL cell in 10,000 leukocytes (0.01%; <104). When MRD is undetectable in these patients, research has shown that progression-free survival (PFS) is prolonged.
“The first demonstration of the utility of minimal residual disease testing and CLL came from studies of fludarabine, cyclophosphamide, and rituximab [Rituxan] or FCR,” Woyach stated. The research Woyach refers to single-intuition assessment at the University of Texas MD Anderson Cancer Center1 and a prospective assessment of MRD in patients with CLL from 3 multicenter, randomized, open-label, phase 3 clinical trials (NCT00281918, NCT00769522, and NCT02053610).2
In the MD Anderson cohorts of these 3 studies, there were 170 patients with IGHV mutated/unmutated CLL who were either MRD-positive or MRD-negative who were followed for roughly 15 years. Survival results show that of the 35 patients who had IGHV-mutated, MRD-negative CLL, 28 were progression-free at data cutoff, and of the 34 patients with IGHV-mutated, MRD-positive disease, only 14 were progression-free. Further, in the 35 patients with IGHV-unmutated, MRD-negative CLL, 6 were progression-free by data cutoff, and 4 of the 66 patients with IGHV-unmutated, MRD-positive CLL were progression-free.1,3
The probability of PFS improvement was also highlighted in the CLL8 study. A total of 184 patients in the study were treated with fludarabine plus cyclophosphamide (FC), and 209 were treated with FCR. The cohort was observed for a median period of 55 months. In the FC arm, 31% of patients with MRD-negative. In the FCR arm, 68% of patients were MRD negative for an absolute difference of 37 and MRD relative risk of 2.20. Sixty-five percent of the FC arm had a PFS event compared with 51% of the FCR arm (HR, 0.63, 0.48-0.82).2
Combing the FC arm and FCR and comparing patients who were MRD-negative to those who were MRD-positive, the Kaplan-Meier analysis shows a separation of the survival curves in which patients with MRD positivity have shorter PFS.1,2
“Importantly, when you have these patients with very long follow-up, some patients that are treated with FCR have a very prolonged disease-free survival on the order of 10 to 15 plus years. Essentially, we think [these patients are] being cured of their CLL, Woyach said. “It was first demonstrated that about 60% of patients who were IGHV-mutated and were treated with FCR would be cured by the regimen. You can see [in this research], that when you look at patients by MRD status at the end of therapy, you can really refine that risk and those patients that are IGHV-mutated and are MRD-negative at the end of treatment have about an 80% chance of being cured with this 1 therapy, and that's really phenomenal I think for a disease that was widely considered incurable.”
Another question about MRD status in patients with CLL Woyach addressed is how the efficacy benefit observed is sustained over time based on MRD positivity or negativity.
An analysis of the multicenter, phase 3, open-label, randomized MURANO clinical trial (NCT02005471) of venetoclax plus rituximab compared with bendamustine in patients with relapsed or refractory CLL showed that efficacy the fixed-duration combination was sustained, especially among patients with undetectable MRD.4
In the group of patients with undetectable MRD, the landmark PFS rate at 18 months was 90.3% (95% CI, 83.5%-97.3%) compared with 64.4% (95% CI, 42.1%-86.6%) in the low MRD positivity group and 8.33% (95% CI, 0.0%-24/0%) in the high MRD positivity group.
“Interestingly, it looks like there are patients who are becoming positive for MRD or even going from low to high MRD even during the course of therapy. Then, we start to see that loss of MRD status, fairly quickly after the end of treatment for some patients,” Woyach commented about the MURANO analysis.
Another study showed similar findings of how MRD impacts continued benefit in patients with newly-diagnosed CLL (CLL14, NCT02242942). In the prospective, open-label, multicenter randomized phase 3 CLL14 study, 432 were assigned in a 1:1 fashion. Two hundred sixteen patients in 1 treatment arm to receive venetoclax plus obinutuzumab (Gazyva) and the remaining 216 patients received chlorambucil plus obinutuzumab.1,5 The overall finding of the study was that 2 years following treatment venetoclax plus obinutuzumab improved PFS compared with chemotherapy and obinutuzumab, but an exploratory analysis of the PFS based on MRD status showed that this was not the case for all patients treated with venetoclax/obinutuzumab.5
With the combination of venetoclax/obinutuzumab, exploratory analysis results showed that there were initially 163 PFS events among patients with undetectable MRD compared with the 76 in the chlorambucil plus obinutuzumab. Those with low MRD positivity treated with venetoclax/obinutuzumab had only 11 events, while those treated with chlorambucil plus obinutuzumab experienced 47 events. Finally, among patients with MRD high CLL, only 9 patients treated with venetoclax and obinutuzumab had PFS events compared with 56 in the chemotherapy and obinutuzumab arm.
Based on this collection of studies, Woyach concluded that MRD testing is useful for predicting PFS to certain therapies for patients with CLL.1 She said: “It's clear that undetectable MRD predicts progression-free survival for patients who are treated with chemoimmunotherapy, as well as those who are created with venetoclax plus anti-CD20 and platinum. Measurements of MRD following therapy reliably predict progression events, though with a delay, and it's been shown, I think from the MURANO study that from the time that a patient became detectable with MRD it was still about 2 years before they needed additional therapy. So, [there’s] certainly no rush to start treatment if you know that somebody who has undetectable MRD becomes detectable without clinical disease.”
An outstanding question about the utility of MRD in CLL management is whether sensitivity >1/10,000 leukocytes is a vital factor and how it will impact remission rates in CLL.
1. Woyach J. Minimal residual disease assessment in chronic lymphocytic leukemia/ small lymphocytic lymphoma: is it ready for routine clinical practice? Presented at: NCCN 2021Virtual Congress: Hematologic Maligancies; October 14-16, 2021.
2 Dimier N, Delmar P, Ward C, et al. A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL. Blood. 2018;131(9):955-962. doi: 10.1182/blood-2017-06-792333
3. Thompson, PA. MRD negativity as a surrogate for PFS in CLL? Blood. 2018; 131 (9): 943–944. doi: 10.1182/blood-2018-01-824177
4. Kater AP, Wu JQ, Kipps T, et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study. J Clin Oncol. 2020;38 (34):4042-4054. doi: 10.1200/JCO.20.00948
5. Al-Sawaf O, Zhang C, Tandom M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9): 1188-1200. doi: /10.1016/S1470-2045(20)30443-5