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ASH Studies Show Predictive Power of Undetectable MRD in Fixed-Duration CLL Regimens

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NEW YORK – At the Association for Hematology's annual meeting, undetectable minimal residual disease (uMRD) continued to gain attention as a biomarker for predicting which leukemia patients receiving fixed-duration, chemotherapy-free treatment regimens are likely to derive a sustained benefit and can go off treatment for a time.

In the Phase II CAPTIVATE trial, for example, researchers reported that 95 percent of previously untreated chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) patients, who achieved uMRD in blood and bone marrow samples after 12 cycles of ibrutinib (Janssen/AbbVie's Imbruvica) and venetoclax (Genentech/AbbVie's Venclexta), were disease free at one-year follow-up.

Similarly, longer-term follow-up data from the Phase III MURANO trial confirmed that relapsed or refractory CLL patients who received two years of venetoclax plus rituximab (Genentech/Biogen's Rituxan) and achieved uMRD at the end of the fixed-duration treatment, experienced better progression-free survival outcomes than those on rituximab and the chemotherapy bendamustine. In new analysis presented at the meeting, researchers explored patients' outcomes according to how quickly they went from uMRD to MRD-positive status to progressive disease and explored a clonal growth rate model as a way to measure the depth of remission patients had to the fixed-duration regimen.

Studies have shown that uMRD is associated with improved long-term outcomes in patients with hematologic malignancies. The US Food and Drug Administration earlier this year finalized guidance on how to incorporate MRD measurements into drug trials to predict which patients will respond to treatment or identify those at risk of future relapse. As such, uMRD as a biomarker is of particular interest in studies of fixed-duration CLL treatments, where the goal is to get patients to remission so they can get off treatment. 

In CAPTIVATE, researchers assessed MRD status in bone marrow and peripheral blood samples using flow cytometry, while in MURANO, researchers conducted central analysis of peripheral blood samples using allele-specific oligonucleotide PCR and flow cytometry. In both studies, uMRD was defined as less than one cancer cell in 10,000 leukocytes.

For a long time, the treatment for CLL involved the antibody rituximab or chemo-immunotherapy regimens, such as bendamustine plus rituximab. Then, with increasing understanding of cancer biology, targeted therapies, such as the BTK inhibitor ibrutinib, the PI3K inhibitor idelalisib (Gilead's Zydelig), and the BCL-2 inhibitor venetoclax, entered the market and improved patients' outcomes.

However, these newer targeted drugs are expensive and require continuous treatment to stave off disease progression. As such, researchers began exploring combination targeted treatment strategies given in a time-limited manner, hoping that these fixed-duration regimens would allow some patients to achieve remission, get off treatment for a time, and reduce costs.

For relapsed or refractory CLL patients, the FDA in 2018 approved venetoclax-rituximab as the first fixed-duration regimen based on the MURANO trial data. Last year, the FDA approved fixed-duration venetoclax plus obinutuzumab (Gazyva) as a front-line CLL treatment, based on data from the CLL14 trial. In that study, when researchers looked at MRD status, they found that around 50 percent of patients had no detectable disease on venetoclax-obinutuzumab compared to those receiving fixed-duration chlorambucil-obinutuzumab.

At the ASH annual meeting, researchers presented data further exploring patients' outcomes on fixed-duration CLL treatment strategies involving venetoclax and ibrutinib, focusing particularly on the role of uMRD as a biomarker to determine which patients might achieve sustained benefit and be able to stop treatment.

uMRD in CAPTIVATE

In the CAPTIVATE study, "the clinical question explored … is whether deep remissions can be achieved with one-year, fixed duration, combined ibrutinib and venetoclax to allow treatment discontinuation and reasonable duration off treatment," William Wierda from the MD Anderson Cancer Center who led the trial said in a presentation at the meeting.

The study enrolled 164 previously untreated CLL/SLL patients younger than 70 years old who received treatment with ibrutinib for three cycles, and then ibrutinib plus venetoclax for 12 cycles. Patients were tested over at least three cycles of treatment by flow cytometry for MRD and were deemed to have confirmed uMRD only if they had undetectable disease in blood and bone marrow samples. Patients were deemed to have unconfirmed uMRD if they became MRD-positive during the course of treatment, or didn't have uMRD confirmed in both types of samples.

Patients with confirmed uMRD were randomized to receive placebo or ibrutinib, while those with unconfirmed uMRD were randomized to ibrutinib or ibrutinib-venetoclax. The primary endpoint was to compare the one-year disease-free survival of patients in these cohorts. The design of the study allowed Wierda and colleagues to specifically evaluate how patients with confirmed uMRD after fixed-duration ibrutinib-venetoclax fared when they went completely off treatment.

After 12 cycles of ibrutinib-venetoclax, 93 percent of patients achieved confirmed uMRD in both blood and bone marrow samples. Ultimately, 58 percent of 149 patients eligible for randomization had confirmed uMRD and received placebo or ibrutinib. At a median follow-up of nearly 17 months, the one-year disease-free survival rate was 95 percent in patients receiving placebo and 100 percent for those on ibrutinib. The difference between the two arms was not statistically significant, which according to Wierda, supports a fixed-duration treatment strategy of ibrutinib-venetoclax in the first-line setting, followed by treatment discontinuation for CLL and SLL patients who achieve confirmed uMRD.

Meanwhile, among patients with uMRD not confirmed, those randomized to receive ibrutinib-venetoclax again were more likely to achieve uMRD compared to patients receiving just ibrutinib.

In the study overall, the fixed-duration combination regimen provided deep MRD remission in 72 percent of patients based on bone marrow assessments and 75 percent of patients based on blood assessments. More than 95 percent of patients across all cohorts were alive without disease progression at 30-month follow-up. Overall survival data were not mature at the time of the presentation.

There were few dose adjustments and drug discontinuations in the study, and common adverse events, such as diarrhea, arthralgia, and hypertension were more frequent during the fixed-duration treatment period than in the follow-on treatment period.

Despite the positive efficacy and safety data seen in CAPTIVATE, Weirda said at the meeting that additional studies are needed before fixed-duration ibrutinib-venetoclax can be used in front-line CLL. The study "clearly shows the efficacy in terms of the depth of remission with this combination," he said. "This supports the concept of fixed-duration treatment, particularly for those patients who achieve an undetectable MRD status."

However, he acknowledged that there is still uncertainty around whether 12 cycles of the combination regimen will achieve optimal patient outcomes. "It's a question we all struggle with and that I struggle with," he said. "This study I don't think really answers that question." Some CLL patients remain MRD-positive at MD Anderson after 24 cycles of ibrutinib-venetoclax, he noted, adding this question will have to be addressed within other MRD-directed studies.

Long-term MURANO data

Data reported in the Journal of Clinical Oncology from the MURANO trial last year suggested that at 36-month follow-up, relapsed or refractory CLL patients on fixed-duration venetoclax-rituximab had better survival outcomes than those on rituximab-bendamustine. Moreover, blood-based uMRD status appeared to be predictive of longer progression-free survival, and of those who achieved uMRD at the end of treatment, 70 percent maintained uMRD status and 98 percent were without disease progression. 

Based on five-year follow-up data within MURANO, Arnon Kater from Cancer Center Amsterdam reported at the ASH annual meeting that median progression-free survival was 53.6 months on venetoclax-rituximab versus 17 months on rituximab-chemo. Median overall survival had not been reached in either arm and no new safety signals were reported.

Additionally, Kater reported that of the 130 patients who received venetoclax-rituximab for two years without progressive disease, those who achieved uMRD had better outcomes than those who didn't. For example, three years after end of treatment, 61 percent of patients on venetoclax-rituximab were alive without their disease progressing in the uMRD group. In comparison, 41 percent of those with low MRD-positive status were not progressing three years after end of treatment, while in the high MRD-positive cohort all but one patient had progressive disease.

Although a significant portion of CLL patients who achieved uMRD after two years of treatment remained so at longer follow-up, some patients converted to MRD positive status, and in this group, the median time to covert from uMRD to MRD-positive status was 19 months, and median time from MRD-positive to having progressive disease was another 25 months.

Sustained uMRD, progression-free survival, and overall survival benefits seen in these long-term follow-up data "provide further support for the use of fixed duration [venetoclax-rituximab] in patients with relapsed or refractory CLL," Kater concluded. Particularly, the data showing the long timeframe between patients converting from uMRD to MRD-positive status and then to progressive disease suggests that MRD status can be informative for guiding treatment, he added.

Noting that some patients converted to MRD-positivity but still didn't experience disease progression, researchers wanted to further study how quickly patients' cancer cells were growing. Using data from around 200 patients in the MURANO trial, researchers developed a clonal growth rate model and showed that MRD levels increased slower in patients receiving venetoclax-rituximab than in those getting rituximab-bendamustine.

There is growing interest in using clonal growth rate, in addition to MRD status, as a way to guide duration of treatment in CLL patients. In the Phase III CLL14 trial, which led to the approval of fixed-duration venetoclax and obinutuzumab in previously untreated CLL last year, researchers used Adaptive Biotechnologies' next-generation sequencing-based Adaptive clonoSEQ Assay to explore the impact of clonal dynamics on treatment response.

Using this test researchers developed a model for assessing clonal growth rates and showed that a lower clonal growth rate after venetoclax-obinutuzumab was indicative of more effective eradication of residual disease. Based on clonal growth-rate assessments, the majority of patients with uMRD on venetoclax-obinutuzumab had more stable responses and were more likely to stay in remission longer. Comparatively, patients on obinutuzumab-chlorambucil, even if they achieved uMRD, tended to have unstable responses and weren't able to stay in remission for long.

In a subset of 20 patients with uMRD, there was no clonal growth on venetoclax-obinutuzumab, indicating that these patients had the deepest responses. In these patients, no clonal growth translated to a sustained PFS lasting several years after finishing fixed-duration venetoclax-obinutuzumab treatment.

Adaptive's test was the first NGS platform to receive FDA authorization in 2018 for assessing MRD in acute lymphoblastic leukemia and multiple myeloma patients and determining their response to treatment or the extent of their remission. The test is able to establish uMRD using very low cutoffs. Earlier this year, the FDA expanded the test's authorization to the CLL setting. 

The company is collaborating with various pharmaceutical companies to use its test in their therapeutic programs for hematologic malignancies. Notably, earlier this year, Adaptive inked a deal with Genentech to use the ClonoSeq assay to assess MRD in studies of venetoclax in newly diagnosed CLL patients, as well as in drug trials where MRD status is a primary efficacy endpoint.