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Measurable Residual Disease Kinetics: A Potential New Tool in CLL


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Achieving undetectable measurable residual disease (MRD) is an important milestone in the treatment of patients with chronic lymphocytic leukemia (CLL) as well as those with other hematologic malignancies undergoing treatment. Now a small phase II study, presented at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition, goes a step farther. The findings suggest that MRD kinetics might be a useful tool for guiding therapy in CLL, identifying newly diagnosed patients with CLL who might require a longer duration of therapy or additional agents to achieve more durable undetectable MRD remissions, and determining those who may safely stop therapy early.1 Another important finding of this study is that the triplet combination of zanubrutinib, obinutuzumab, and venetoclax achieved high rates of undetectable MRD in the blood and bone marrow of patients with CLL.2

Both findings—the utility of MRD kinetics and the efficacy of the triplet regimen—need to be replicated in larger phase III studies in CLL. 

However, this phase II study provides reason for optimism.

The triplet combination of zanubrutinib, obinutuzumab, and venetoclax met the primary endpoint of the study, with 89% of patients reaching undetectable MRD by flow cytometry in both peripheral blood and bone marrow, all of whom met the prespecified criterion for stopping therapy after a median of 10 months of treatment. Undetectable MRD responses appear to be durable; 94% of patients have achieved ongoing undetectable MRD, with a median of 15.8 months from the end of therapy. These data were published concurrently in The Lancet Haematology.2


This is the first published study to use MRD as the principal tool to guide treatment duration and discontinuation.
— Andrew D. Zelenetz, MD, PhD

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“This is the first study to test the triplet combination of zanubrutinib, obinutuzumab, and venetoclax in newly diagnosed CLL and the first published study to use MRD as the principal tool to guide treatment duration and discontinuation,” said senior author Andrew D. Zelenetz, MD, PhD, Professor at Memorial Sloan Kettering Cancer Center and Cornell Medical School, New York. “We observed high rates of undetectable MRD and a favorable safety profile, notably with a low rate of grade 3 or 4 neutropenia.”

The investigators identified delta MRD400 and proposed this measure of MRD kinetics as a potential biomarker for guiding treatment duration. (Delta MRD400 represents a 400-fold reduction in peripheral blood MRD from pretreatment to cycle 5 on day 1 with the ClonoSEQ assay.)

The investigators of the triplet regimen built on prior data from the CLARITY trial of venetoclax and ibrutinib in relapsed or refractory CLL, which showed that rapid MRD kinetics predicted longer progression-free survival.3 The triplet regimen investigators found that the delta MRD may identify patients who reach early bone marrow undetectable MRD and maintain durable posttreatment undetectable MRD remissions as well as others who have high-risk disease at increased risk for MRD recurrence after treatment is stopped.

“The fact that early MRD kinetics measured in the blood is so predictive of early bone marrow undetectable MRD and more durable undetectable MRD responses after treatment is stopped is an important finding,” said lead author Jacob D. Soumerai, MD, Assistant Professor at Massachusetts General Hospital and Harvard Medical School. “We identified a defined group of delta MRD400 achievers with rapid bone marrow undetectable MRD who stopped therapy after a median of eight cycles. We also identified another group of patients who failed to achieve delta MRD400 and had delayed bone marrow undetectable MRD; these patients may require a longer treatment duration or additional agents and should be the subject of further study into mechanisms underlying this high-risk biology.”

“Delta MRD400 kinetics and other measures of early MRD kinetics appear to be strongly prognostic for early bone marrow undetectable MRD, so they have the potential to obviate the need for a bone marrow biopsy. However, I am most excited by its potential to be used as a predictive tool to guide treatment. These data are early and require validation. We plan to test prospectively whether delta MRD400–directed therapy duration improves outcomes for patients with unfavorable kinetics,” Dr. Soumerai commented.

Jacob D. Soumerai, MD

Jacob D. Soumerai, MD

Background

Based on study findings from 2019, 1 year of fixed-duration venetoclax/obinutuzumab induced undetectable MRD and durable remissions in treatment-naive patients with CLL.4 In an analysis of the CLARITY trial of venetoclax/ibrutinib in relapsed or refractory CLL, early MRD kinetics predicted bone marrow undetectable MRD and were associated with progression-free survival.5 The present study explored MRD kinetics (specifically, delta MRD400 measured in the peripheral blood) as a biomarker in newly diagnosed patients with CLL treated with a more potentially powerful regimen: the addition of venetoclax to zanubrutinib (Bruton’s tyrosine kinase inhibitor) and obinutuzumab (anti-CD20 monoclonal antibody).

Study Details and Key Findings

The study, conducted at Massachusetts General Hospital and Cancer Center and Memorial Sloan Kettering Cancer Center, enrolled 39 previously untreated patients with CLL requiring treatment. The primary endpoint was the frequency of undetectable MRD confirmed both in peripheral blood and bone marrow. Secondary endpoints included the time on therapy to achieve undetectable MRD in blood and bone marrow as well as safety and tolerability.

Zanubrutinib and obinutuzumab were started on day 1 of cycle 1, and venetoclax was started on day 1 of cycle 3. Obinutuzumab was stopped after 8 months, and zanubrutinib and venetoclax were stopped after 8 to 24 months, once prespecified undetectable MRD criteria were met in peripheral blood and bone marrow. After stopping therapy, patients could resume treatment if prespecified MRD retreatment criteria were met.

The median age of patients was 62. ­Participants were mostly male: 30 men and 9 women. A total of 72% had high- or very high–risk CLL International Prognostic Index scores, and 13% had del(17p) and/or TP53 mutations—both associated with poor outcomes.

The median follow-up was 26 months, including median posttreatment surveillance of 16 months. At best response, 95% achieved undetectable MRD in peripheral blood and 89%, in both bone marrow and peripheral blood. The median time to bone marrow undetectable MRD was 8 months, and the median treatment duration was 10 months.

KEY POINTS

  • MRD kinetics might be a useful tool for guiding therapy in CLL, identifying newly diagnosed patients with CLL who might require a longer duration of therapy or additional agents to achieve more durable undetectable MRD remissions, and determining those who may safely stop therapy early.
  • The triplet combination of zanubrutinib, obinutuzumab, and venetoclax achieved high rates of undetectable MRD in the blood and bone marrow of patients with CLL.

All-cause adverse events included decreased platelet counts in 59% (grade 3, 8%); fatigue in 54% (grade 3, 3%); and decreased neutrophil count in 51% (grade 3, 5%; grade 4, 13%). Other adverse events were mainly grade 1 or 2. Grade 3 rash was observed in 8%, grade 3 alkaline phosphatase increase was seen in 3%, and grade 3 lung infection was reported in 8%.

MRD Kinetics

Using the ClonoSEQ immunosequencing MRD test (which has a limit of detection of 10-6), a 400-fold reduction in the peripheral blood MRD level measured at day 1 cycle 5 was identified as the optimal cutoff for predicting bone marrow undetectable MRD by 8 months. 

Of 35 evaluable patients for this analysis, 21 (60%) achieved delta MRD400, and all went on to achieve bone marrow undetectable MRD within 8 months of therapy and stopped therapy after a median of 8 months of treatment. A total of 14 patients (40%) failed to achieve delta MRD400; these patients required a longer duration of therapy to achieve undetectable MRD, with 3 (21%) achieving bone marrow undetectable MRD within 8 months. Of note, 19% of those who achieved delta MRD400 had del(17p)/TP53 mutations. 

“Delta MRD400 predicted posttreatment undetectable MRD outcomes,” Dr. Soumerai stated.

Posttreatment surveillance was 15.8 months. The median time to recurrent MRD was significantly longer among those who achieved delta MRD400 (P < .001). A total of 31 patients had ClonoSEQ data available after treatment discontinuation for this analysis. Among 20 patients who achieved delta MRD400, the 1-year rate of recurrent MRD at 10-5 was 5% vs 75% among 11 patients who did not reach delta MRD400.

Further Thoughts

In an interview with The ASCO Post, Dr. Soumerai explained that most CLL therapies in clinical development require that treatment be stopped after a defined period or based on achievement of a static MRD measurement assessed at more than 1 year. “If your goal is to identify high-risk patients and improve their outcomes, earlier actionable biomarkers are needed. These data suggest that early dynamic MRD response assessment has potential as a predictive tool for guiding therapy.”

These data suggest that early dynamic MRD response assessment has potential as a predictive tool for guiding therapy.
— Jacob D. Soumerai, MD

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Dr. Soumerai continued: “It is compelling that all of the patients stopped therapy. MRD recurrence was much longer in patients who achieved MRD400. What is remarkable is that patients who achieved MRD400 by 8 months received less therapy than those who did not. They appear to have favorable MRD outcomes despite having received less therapy.” 

“All of the patients in this analysis did achieve undetectable MRD eventually. Thus, it’s not just achieving undetectable MRD but the MRD kinetics that appear to be prognostic for posttreatment outcomes and may have a role in guiding treatment duration,” he continued.

“We observed more durable undetectable MRD at < 10-5 among delta MRD400 achievers. This is especially remarkable in the context of our undetectable MRD–driven treatment discontinuation design; patients who achieved delta MRD400 had more durable undetectable MRD remissions despite receiving less therapy than those who did not achieve this landmark. This suggests that delta MRD400 stratifies patients based on biologic risk,” Dr. Soumerai explained.

Dr. Soumerai, Dr. Zelenetz, and colleagues are planning to prospectively evaluate delta MRD400 and advocate that MRD kinetics should be explored as a potential predictive tool in other CLL therapies.

A separate companion study6 presented at the 2021 ASH meeting explored the triplet regimen of zanubrutinib, obinutuzumab, and venetoclax in TP53-mutated mantle cell lymphoma, which represents an unmet need. “These data, presented by Anita Kumar, MD, of Memorial Sloan Kettering Cancer Center, are very encouraging in this very high–risk population,” Dr. Soumerai added. 

DISCLOSURE: Dr. Zelenetz holds stock or other ownership interests in Adaptive Biotechnologies; has received honoraria from Clinical Care Options, National Comprehensive Cancer Network, Oncology Information Group, and PER; has served as a consultant or advisor to Amgen, AstraZeneca, BeiGene, Cancer Support Community, Celgene, Dava Oncology, Genentech/Roche, Gilead Sciences, Janssen, Karyopharm Therapeutics, Medscape, MEI Pharma, MorphoSys, Novartis, Pfizer, Pharmacyclics, Prime Education, TRM Oncology, Vaniam Group, and Verastem; and has received research funding from BeiGene, Genentech/Roche, Gilead Sciences, and MEI Pharma. Dr. Soumerai has received institutional research funding from Adaptive, BeiGene, BostonGene, Genentech (Roche), GSK, Moderna, and TG Therapeutics and has served as a consultant to AbbVie, AstraZeneca, BeiGene, BMS, TG Therapeutics, and Verastem.

REFERENCES

1. Soumerai JD, Mato AR, Dogan A, et al: Zanubrutinib, obinutuzumab, and venetoclax in chronic lymphocytic leukemia: Early MRD kinetics define a high-risk patient cohort with delayed bone marrow undetectable MRD and earlier post-treatment MRD recurrence. 2021 ASH Annual Meeting & Exposition. Abstract 3753. Presented December 13, 2021.

2. Soumerai JD, Mato AR, Dogen A, et al: Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: A multicentre, single-arm, phase 2 trial. Lancet Haematol 8:e879-e890, 2021.

3. Hillmen P, Rawstron AC, Brock K, et al: Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: The CLARITY Study. J Clin Oncol 37:2722-2729, 2019.

4. Fischer K, Al-Sawaf O, Bahlo J, et al: Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 380:2225-2236, 2019.

5. Rawstron A, Webster N, Dalal S, et al: Kinetics of response in the peripheral blood predicts long-term responses to ibrutinib + venetoclax treatment for relapsed/refractory CLL in the Bloodwise TAP CLARITY trial. 2020 EHA Annual Congress. Abstract S164. Presented June 12, 2020.

6. Kumar A, Soumerai JD, Abramson JS, et al: Preliminary safety and efficacy from a multicenter, investigator-initiated phase II study in untreated TP53 mutant mantle cell lymphoma with zanubrutinib, obinutuzumab, and venetoclax (BOVen). 2021 ASH Annual Meeting & Exposition. Abstract 3540. Presented December 13, 2021.


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