Targeting MRD as a Potential Therapy Guide in Hematologic Malignancies

William G. Wierda, MD, PhD

Cancer treatment is undergoing a reformation because of novel therapeutics that provide dramatic responses, including complete radiographic or pathologic remission. However, minimal residual disease (MRD) is often retained, resulting in relapse. Early evidence indicates that iterative detection, profiling, and targeting of MRD could improve outcomes and even lead to a cure.¹

Current Uses and Limitations of MRD

Complete remission (CR) generally requires more than 99% reduction in tumor burden, and remaining tumor cells have been referred to as MRD. Treating a patient when only MRD is present is preferable to waiting for clinical relapse because the smaller number of tumor cells in MRD increases the chance of eradication of all tumor cells and is associated with a lower likelihood of the following cancer-promoting factors: resistance due to clonal complexity, microenvironment remodeling, reprogramming of infiltrative hematopoietic cells, and development of chemoprotective niches. As a result, certain drugs may have greater efficacy against MRD than against the same cancer at the time of relapse. Additionally, patients may tolerate drugs better when only MRD is present.¹

Tailoring consolidation therapy based on MRD load is already standard practice for the treatment of children with acute lymphoblastic leukemia (ALL). If such a patient tests positive for MRD (exceeding a defined threshold), this can suggest a change in doses but does not yet guide the selection of therapies targeted specifically at eradicating MRD. Looking ahead, precise targeting of MRD through genetic, transcriptional, functional, and other predictive biomarkers is the next step toward improving outcomes for patients.¹

“MRD results correlate with PFS [progression-free survival], so it is prognostic for how patients do with finite-duration treatment. [Patients] get a course of treatment, they [achieve] remission, and [when] they come off treatment, their MRD status clearly correlates with PFS and overall survival [OS]. [This has] given us a prognostic tool for outcomes for our patients with fixed-duration treatment,” William G. Wierda, MD, PhD, professor, section chief of chronic lymphocytic leukemia (CLL) and executive medical director at The University of Texas MD Anderson Cancer Center, stated in an interview with Targeted Therapies in Oncology™.

MRD assessment does have limitations, such as reliance on measuring disease within bone marrow without taking into account the bone marrow microenvironment, lack of uniform bone marrow involvement, and the possibility of extramedullary disease.² The clearest limitation is the need to perform a bone marrow aspirate for MRD assessment. This has led to interest in liquid biopsy or analyzing circulating cell-free tumor DNA (ctDNA) in the peripheral blood for MRD. However, using optimal methodologies for bone marrow to test on peripheral blood may result in lower sensitivity.³ In a multiple myeloma (MM) study, approximately 40% of patients with MRD-positive bone marrow were deemed MRD negative when ctDNA was assessed with a deep sequencing technique designed for bone marrow samples.4 Because of this, other ctDNA assays are under development, including targeted mutation detection and low-pass whole-genome sequencing.²

The clinical application of MRD testing is variable. There are no prospective, randomized data to guide treatment decisions. Recent studies incorporating the use of MRD hope to shed more light on how MRD can help guide therapeutic decisions, and several studies were presented at the recent 2021 American Society of Hematology (ASH) Annual Meeting.

ASH 2021 Studies

Dara-KRd in Multiple Myeloma

A recent study incorporating MRD by nextgeneration sequencing with the combination of daratumumab (Darzalex), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Dara-KRd) revealed MRD response–adapted consolidation therapy leads to the highest rate of MRD negativity reported in patients with newly diagnosed MM (NDMM). A total of 123 patients with NDMM were enrolled in the phase 2 MASTER trial (NCT03224507), 53 (43%) patients had no high-risk cytogenetic abnormalities (HRCAs), 46 (37%) had 1, and 24 (20%) had 2 or more HRCAs. Patients received 4 cycles of Dara-KRd as induction therapy, autologous hematopoietic cell transplantation (AHCT), and 0, 4, or 8 cycles of Dara-KRd as consolidation therapy, according to MRD status. The primary end point was MRD negativity below 10-5, and patients continued therapy until 2 consecutive MRD assessments of less than 10-5, at which point patients entered treatment-free observation (TFO) and MRD surveillance.^5,6

At a median follow-up of 25.1 months, disease was trackable by MRD in 118 (95.9%) patients, with 4 (3.2%) remaining on protocol treatment, 20 (16.3%) on maintenance lenalidomide, and 84 (71.2%) reaching confirmed MRD negativity and entering treatment-free MRD surveillance. The depth of response improved with each phase of therapy, and similar responses were observed in patients with 0, 1, or 2 or more HRCA abnormalities assessed post-AHCT and with MRD-guided consolidation. Overall, 80% reached MRD negativity at 10-5 and 66% achieved MRD levels below 10-6 by the consolidation phase. Rates of MRD negativity below 10-5 were similar per HRCAs. Best response post MRD-adapted consolidation was CR or stringent CR (sCR) in 86% of patients. The 2-year PFS rate was 87% and the OS rate was 94%. Cumulative incidence of MRD resurgence or International Myeloma Working Group progression 12 months after cessation of therapy was 4%, 0%, and 27% for patients with 0, 1, or 2 or more HRCA abnormalities, respectively. This strategy suggests MRD surveillance could be an alternative to indefinite maintenance, although patients with ultra-high–risk MM will likely need novel consolidative strategies.^5,6

Ibrutinib, Ublituximab, and Umbralisib in CLL

High overall response rates and durable responses have been observed in patients with CLL treated with time-limited novel agent combinations, but high rates of adverse events occur. Additionally, patients on chronic ibrutinib monotherapy have a risk of developing cumulative toxicity and acquired resistance.

In a recent phase 2 study (NCT04016805), patients with CLL treated with a combination of ibrutinib (a Bruton tyrosine kinase [BTK] inhibitor; Imbruvica), umbralisib (a PI3K inhibitor; Ukoniq), and ublituximab (an anti-CD20 monoclonal antibody) achieved deep remissions and a tailored, time-limited therapy and sustained TFO using an MRD-driven approach. Patients with CLL with detectable MRD were treated with monotherapy ibrutinib, then umbralisib and ublituximab. The open-label study enrolled patients with CLL already taking ibrutinib for a minimum duration of 6 months, with detectable residual CLL in the peripheral blood via MRD assay. Umbralisib and ublituximab were added, and patients were serially monitored for MRD starting on day 1 of cycle 3. Patients entered a period of TFO once undetectable MRD (uMRD) was achieved and confirmed 4 weeks later. If uMRD was not attained, patients completed 24 cycles followed by TFO.⁷

Ublituximab and umbralisib were added for 26 patients receiving ibrutinib. MRD was assessed in 24 patients, with 17 (71%) having uMRD in at least 1 assessment. A total of 16 patients (67%), 15 achieving 2 consecutive uMRD assessments and 1 completing 24 cycles with detectable MRD, entered TFO. A median of 242 days (range, 5-538) of TFO was achieved as of the cutoff date and 73% remain uMRD as of the most recent follow-up. The median time to first uMRD was 7.4 months (95% CI, 4.6-10.2). No patient has progressed or required retreatment per International Workshop on Chronic Lymphocytic Leukemia criteria. In the study, the use of MRD assessment appeared promising in helping reduce continued exposure to medications preventing possible resistance and increased adverse events.⁷

Ibrutinib Plus Venetoclax in CLL

Results from the phase 2 CAPTIVATE trial (NCT02910583) further support the use of MRD for achieving treatment-free remission with fixed-duration treatment. CAPTIVATE evaluated the use of ibrutinib in combination with venetoclax (Venclexta), an oral BCL-2 inhibitor. First-line ibrutinib and venetoclax were evaluated in fixed duration and MRD cohorts. Patients first received 3 cycles of ibrutinib followed by ibrutinib and venetoclax for 12 cycles. Then patients with uMRD for at least 2 assessments spaced at least 3 months apart in both the peripheral blood and bone marrow were randomized 1:1 to receive double-blind treatment with placebo or single-agent ibrutinib. Those not achieving uMRD were randomized 1:1 to receive single-agent ibrutinib or ibrutinib in combination with venetoclax.⁸

After 12 cycles of ibrutinib and venetoclax, 149 patients were randomized; 86 patients with confirmed uMRD were randomized equally to placebo and ibrutinib; 63 patients without confirmed uMRD were randomized to ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Post randomization 2-year disease-free survival rates in patients who achieved confirmed uMRD were 95.3% for patients receiving placebo and 100% for patients receiving ibrutinib (log-rank P = .1573). These results were consistent in patients deemed high risk, including those with unmutated IGHV, del(17p)/TP53 mutation, complex karyotype, and del(11q) without del(17p). In those with not confirmed uMRD, 36-month PFS rates were 96.7% with ibrutinib monotherapy and with ibrutinib plus venetoclax. These results are promising for an all-oral, once-daily, chemotherapy-free regimen and support high efficacy with an MRD-based approach.⁸

“In our program, most of us are thinking about fixed-duration treatment as an avenue to developing curative therapy,” Wierda said. “This is a large, international, multicenter trial [that] demonstrates the feasibility and activity of a combination of targeted therapy and of chemotherapy-free treatment.”

Future of MRD

As a surrogate marker for survival, MRD is increasingly employed as an end point in clinical trials because of the improved PFS and OS results associated with MRD negativity. Patients who achieve uMRD at a more stringent threshold (10-6 vs 10-5) have better outcomes (longer PFS).9,10 Questions remain regarding MRD and its relationship to high risks associated with unfavorable cytogenetic abnormalities. Achievement of uMRD by high-risk patients is less frequent than for standard patients, although highrisk patients who achieve uMRD appear to have survival rates similar to those of standard-risk patients.

In one study, time to progression (TTP) was similar for uMRD patients regardless of fluorescence in situ hybridization (FISH) status, whereas FISH status still impacted TTP for MRDpositive patients (median TTP, 15 months for standard-risk patients vs 12 months for highrisk patients; P =.02).¹¹

The use of MRD status to decide between autologous stem cell transplant treatment (ASCT) or nontransplant-based treatment is one area of interest. ASCT provides a PFS advantage for many patients, although inconsistent OS results have been reported. In the IFM 2009 trial (NCT01191060) evaluating the addition of ASCT to treatment with bortezomib (Velcade), lenalidomide, and dexamethasone (VRd) in patients with NDMM, MRD status had a greater effect on outcome (PFS) than did treatment group. MRD-negative patients did better than MRD-positive ones.9 Data from several recent studies evaluating Dara-KRd and ASCT indicate patients who are able to achieve MRD negativity with induction therapy may not need ASCT.¹¹

The need for maintenance therapy in MRD-negative patients after induction therapy and ASCT is also of interest. In one trial, best PFS rates for patients with MM was associated with lenalidomide maintenance despite MRD-negative status.

The current data are insufficient to recommend that patients who achieve uMRD either before or during maintenance should forego or discontinue maintenance therapy, respectively. Ongoing clinical trials, such as EMN17Perseus (NCT03710603) and SWOG S1803 (NCT04071457), hope to address this question.¹¹

The predictive value of MRD status for relapse is another area of interest. MRD-negative patients can become MRD positive over time. One study indicated MRD reappearance from previous uMRD occurred 9 months before clinical relapse,¹² although 30% of MRD-positive patients in the same study did not experience relapse.

These data encourage further trials evaluating serial monitoring of MRD and its potential for relapse prediction.

MRD-positive status indicating a need for treatment change is another question.11 A recent phase 1/2 study (NCT02937571) for patients with NDMM used an MRD-guided approach to therapy. Patients received cycles of KRd. Patients who achieved MRD-negative status received 2 cycles from conversion time, then ceased further therapy, whereas patients not achieving MRD-negative status continued a full 12 cycles of therapy. An average of 8 cycles (range 2-12) was needed to achieve MRD-negative status. PFS was similar between MRD-negative and MRD-positive groups, but follow-up was short overall and lack of consistency in post trial therapies was a concern. MRD-negative status was achieved by 5 of 7 high-risk patients but durability was only observed in 2.

The MRD response–adapted approach produced 36-month PFS rates at 77% (95% CI, 60%-97%) for combined dosing cohorts. Median PFS was not reached, and approximately 85% remained in CR/sCR and/or MRD negative at the post-12–month MRD follow-up. Further studies are needed to validate the MRD response–adapted approach and sustainability for clinical practice.¹³

Final Thoughts

Wierda said there are 2 main strategies for targeted therapy: One is continuous treatment with a maintenance therapy, and the other is a fixed-duration or finite-duration treatment to achieve deep remission with undetectable MRD status.

"We need to develop strategies and clinical trials that utilize MRD status to direct treatment. That may be directing treatment in terms of duration or switching treatment if we have not achieved an MRD undetectable status at a time point we feel is necessary. Moving forward, I look forward to using MRD to direct therapy in our patients with CLL, and ultimately, as a tool to help develop curative therapies for our patients,” he said.

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