Why MRD Falls Short as a Frontline CLL End Point—For Now

IN A DEBATE on whether minimal residual disease (MRD) is an important clinical end point in frontline therapy for chronic lymphocytic leukemia (CLL), a clear victor emerged, showing that it is not, at least not yet. Debaters Andres Chang, MD, PhD (pro); and Jean Louise Koff, MD, MS (against), led the verbal battle at the Debates and Didactics in Hematology and Oncology Conference held from July 25 to 28, 2024, in Sea Island, Georgia.¹

“Dr Chang is an accomplished physician-scientist who I collaborate with a lot…and that’s why it gives me no pleasure at all to absolutely crush him today in this debate,” Koff said. “Dr Chang focused on how MRD can be monitored [in] clinical trials. I’m going to focus on regimens that are currently approved for frontline management of CLL, because I read the assignment.”

Pro/Benefits

Chang, instructor in the Department of Hematology and Medical Oncology at Winship Cancer Institute of Emory University in Atlanta, Georgia, leading the side in favor of MRD as an important clinical end point, emphasized that MRD measures how sensitive a tumor is to any given treatment. “With the advent of newer therapies, we need something to guide us to formulate the best treatment and time-limited approaches for our patients,” he suggested. Outcomes have improved with novel treatments, demonstrating longer progression-free survival (PFS) rates, but CLL still has no cure. Chang argued that “for us to get that cure, we need to get undetected MRD [uMRD] first.”

The Data

Data from the randomized GCLLSG-CLL-8 trial (NCT00281918) during the chemoimmunotherapy era show that “patients who did best on chemoimmunotherapy were the patients who attained an undetectable MRD after treatment,” Chang said.² The median PFS for low MRD was 68.7 months, although it drops to 40.5 and 15.4 months for intermediate and high MRD levels, respectively. High MRD levels correlate with a median overall survival (OS) of 48.4 months, which is in stark contrast to the OS that was not reached for low MRD levels. The risk of disease progression is higher in patients with intermediate and high MRD levels, with an HR of 2.49 and 14.7, respectively.

Similarly, Chang highlighted retrospective data from the study by Kwok et al, in which investigators stated that the most significant benefit of achieving MRD-negative status was observed in patients undergoing initial treatment. For those with MRD-negative status, the 10-year PFS was 65%, significantly higher than the 10% for patients with MRD-positive status, and the 10-year OS was 70% vs just 30% for individuals with MRD-positive status.³

Regarding novel treatments, in the phase 3 CLL14 trial (NCT02242942) comparing obinutuzumab (Gazyva) plus chlorambucil (Leukeran) vs venetoclax (Venclexta) and obinutuzumab, “we see that if we stratify patients based on whether they attain MRD or uMRD after treatment, there’s a very nice separation of the curve for both PFS and OS,” Chang said.⁴ This was also elicited in the phase 3 GAIA/CLL13 trial (NCT02950051), which compared fludarabine/cyclophosphamide/rituximab (Rituxan) or bendamustine (Treanda) with venetoclax/rituximab, venetoclax/obinutuzumab, or venetoclax/ obinutuzumab/ibrutinib (Imbruvica). Here, Chang noted that the patients with the best outcomes were those who achieved uMRD.⁵

MRD’s importance grows as time-limited therapies develop, Chang explained. “[MRD] allows us to develop strategies for discontinuing therapies, which in turn reduces the risk of adverse effects [AEs], prevents the development of resistant mutations, lowers therapy costs, improves patient adherence, and minimizes the risk of relapse,” he said. This is exhibited in MRD-guided trials such as the phase 3 GLOW study (NCT03462719), which evaluated a fixed duration of ibrutinib/venetoclax or chlorambucil/obinutuzumab.⁶ Treatment was administered to all patients, regardless of MRD status, and when examining outcomes based on MRD status, approximately half the patients achieved uMRD and had better results vs those without it.

In contrast, the phase 3 FLAIR study (ISRCTN01844152), conducted in the United Kingdom, also evaluated fixed-duration therapy using the same 2 agents; however, this time, the duration of therapy was determined by the time it took patients to achieve MRD.7 Approximately 80% of patients were able to discontinue treatment at 60 months, Chang relayed, “but the [survival] curves are much flatter for this trial vs the GLOW trial.”

Considering the caveats when comparing trials, the phase 2 CAPTIVATE trial (NCT02910583) compared MRD-guided therapy with fixed-duration therapy with ibrutinib plus venetoclax.8 In the group receiving fixed-duration therapy, the PFS was 67% overall and the OS was 96%; however, “[for] the patients who achieve uMRD 3 months after therapy, the PFS increased to about 83%,” Chang said. For the group receiving treatment guided by MRD, the follow-up is shorter, but at 30 months, the PFS was 95% for those with uMRD receiving placebo.

“What’s interesting about this trial is that even patients who did not achieve uMRD still had very high rates of PFS, around 96%, if they received either ibrutinib or the combination therapy. This suggests that these treatments help overcome the limitation of not having uMRD after induction therapy,” Chang said.

Con/Limitations

There are 2 categories of approved frontline regimens for CLL: Venetoclax plus obinutuzumab is 1 category (5-year PFS, 62.6%), and the other is continuous therapy with Bruton tyrosine kinase (BTK) inhibitors with or without a CD20 monoclonal antibody (42-month PFS, 82.4%), according to Koff, associate professor of hematology and medical oncology at Emory University School of Medicine in Atlanta, Georgia. “Dr Chang showed data from CLL14,⁴ that MRD predicts PFS with venetoclax/obinutuzumab, but in continuous BTK therapy, you don’t need to get a complete response [CR] for durable disease control, let alone uMRD.” In the SEQUOIA trial [NCT03336333] data, which led to the use of this agent in frontline CLL with zanubrutinib, the investigators did not report the uMRD levels and the CR rate was only 17.4%, despite the robust PFS rates, she countered.⁹

This was also the case in the ELEVATE-TN study (NCT02475681; acalabrutinib/obinutuzumab), which reported relatively low CR rates despite long-term durable remissions and a low uMRD rate, even among patients who achieved a CR, Koff said.¹⁰ “Why weren’t investigators testing and reporting uMRD in continuous therapy?” Koff asked. This is because the BTK inhibitor ibrutinib paved the way, demonstrating that these agents don’t frequently induce uMRD as either single agents or with anti-CD20, she explained. Data from the E1912 study (NCT02048813) and the iLLUMINATE study (NCT02264574) demonstrated this.^11,12 In the E1912 study (ibrutinib/rituximab), uMRD rate at 12 months was 8.3% but the 5-year PFS rate was 78%, and in the iLLUMINATE study (obinutuzumab/ibrutinib), among patients who achieved a CR with uMRD, there was no difference in PFS, Koff noted.

Noting other fixed-duration regimens that are currently approved for CLL, Koff addressed fludarabine/cyclophosphamide/ rituximab (FCR) for patients who are younger and have IGHV-mutated CLL. “Dr Chang showed you FLARE study⁷ data that compared outcomes with patients receiving FCR in one of the arms,” Koff said. “He showed that in the all-comers ibrutinib plus venetoclax arm, there was better PFS vs FCR. But what he didn’t show you is that in the patient population [for whom] we would consider using FCR [ie, patients with IGHV-mutated CLL], the venetoclax/ obinutuzumab/ibrutinib [regimen] failed to outperform chemotherapy.”

Regarding novel fixed-duration regimens such as those evaluated in the CAPTIVATE trial, Koff acknowledged that MRD was associated with PFS rates in the fixed- duration arm.⁸ “I think this was a well-designed trial, answering questions about how MRD might guide treatment strategy,” she said. “But last time I checked, BTK inhibitors and venetoclax combination therapy have not been approved as a frontline approach.” Thus, it remains unclear whether this new approach will offer better long-term results and fewer AEs than current treatments.

“I would say that until we have evidence that the MRD-directed combination regimen outperforms currently available regimens without MRD [monitoring], we shouldn’t be using this approach just yet,” Koff said.