Measurable Residual Disease With Time-limited Venetoclax-based Regimens: Clinical Standards, Nuances

A 59-year-old woman with CLL with no abnormalities by FISH, mutated IGHV, and wildtype TP53 status who received frontline therapy with 1-year fixed duration of venetoclax plus obinutuzumab per the CLL14¹ is in your office for her 2-month post-therapy follow-up.    

You perform a physical examination, which demonstrates no significant lymphadenopathy, splenomegaly, or hepatomegaly. Laboratory evaluation including complete blood cell count and comprehensive metabolic panel is unremarkable. CT scans of the chest, abdomen, abdomen, and pelvis demonstrate resolution of previously noted adenopathy with no lymph nodes measuring > 1.5cm.   

Results from measurable residual disease (MRD) evaluation by four-color flow cytometry (10-⁴) in peripheral blood demonstrate undetectable MRD (uMRD).  How do you counsel her on her expected length of remission given all of these results?   

Discussion

Due to the development and approval of highly effective frontline therapeutic combinations that elicit complete clinical responses for many patients, MRD has become a common clinical trial endpoint in addition to progression-free survival (PFS) and overall survival. MRD is defined as the number of leukemic cells detectable in peripheral blood (PB) or bone marrow (BM) post-therapy. “Measurable residual disease” has replaced “minimal residual disease” and “undetectable MRD” (uMRD) has replaced “MRD negative” as terms, as the latter is more accurate in situations where the MRD threshold has not been specified.² Currently, the most commonly used definition of uMRD is the presence of <1 CLL cell in 10,000 leukocytes (< 10-⁴), though studies vary.^2,3  MRD detection is performed after therapy, as standard cytology-based staging methods can only detect one CLL in up to 100 leukocytes. Although uMRD now represents an important predictor of PFS and correlates with longer PFS in analyses of time-limited venetoclax-based regimens,⁴ clinical use has been somewhat limited due to lack of availability and high cost.⁵ NCCN guidelines do recommend obtaining MRD analysis at the end of treatment.⁶ Importantly, MRD appears to play less of a role in patients on indefinite therapy with BTK inhibitors such as ibrutinib; in fact, MRD positivity does not in fact preclude prolonged PFS in these patients.⁷

The current regulatory standard and NCCN recommendation for method of MRD detection in PB is 4-color flow cytometry, which has a sensitivity of 10-⁴.⁶ More recent studies have are also assessing the role and value of more deeper levels of MRD including 10-⁵ and 10-⁴ in time limited venetoclax-based regimens.^8,9 Although 10-⁴ is the NCCN-recommended threshold, next-generation sequencing-based assays have demonstrated increased sensitivity, allowing for detection of MRD at the 10-⁶ or 10-⁸levels, but these are costly and not as widely used.¹⁰ Most clinical trials use the 10-⁴ threshold, and the typical timing of MRD assessment is at least 2 months after the completion of the last treatment cycle, so as to correlate with PFS and overall survival data.²

In general, peripheral blood is often used to determine MRD status. However, a compartment effect has been noted, leading to different MRD levels in the marrow and requiring an aspirate to verify.³ Although bone marrow sampling site and timing, as well as the patient’s treatment status, have been shown to cause discordance, it has been estimated that concordance between PB and BM MRD status is approximately 85% at the 10-⁴ threshold.⁵ However, the iwCLL guidelines explicitly state that “there are therapies that preferentially clear the blood but not the marrow (such as monoclonal antibodies); therefore, it may be important to confirm that the marrow aspirate also is MRD-neg when the blood is found to be MRD-neg.”¹¹

Specific to this patient’s case, the 5-year results from the CLL14 study showed that 75% of patients demonstrated uMRD by PB at the threshold of 10-⁴. Our patient is among the majority of patients with CLL who demonstrate uMRD by PB at the level of 10-⁴ data-fontsize="8">-4 at the end of treatment with venetoclax plus obinutuzumab in the frontline setting. Fewer patients demonstrated deeper levels of uMRD at the end of treatment; 66% demonstrated uMRD at the level of 10-⁵, and 40% demonstrating uMRD at the level of 10-⁶.  For patients who demonstrated uMRD at the level of 10-⁴, which is the most common threshold used in both clinical practice and most currently published clinical trials, the 4-year PFS was approximately 67%. For all-comers treated with venetoclax plus obinutuzumab in the frontline setting, the estimated 5-year PFS is 62.6% at a median follow-up of 65.4 months regardless of MRD status at the end of treatment.⁸

References

1. Fischer K, Al-Sawaf O, Bahlo A-M, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225-2236.  
2. Wierda WG, Rawstron A, Cymbalista F, et al. Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations. Leukemia. 2021;35:3059-3072.  
3. Fürstenau M, De Silva N, Eichorst B, Hallek M. Minimal residual disease assessment in CLL: Ready for use in clinical routine? Hemasphere. 2019;3:e287.   
4. Al-Sawaf O, Zhang C, Lu T, et al. Minimal residual disease dynamics after venetoclax-obinutuzumab treatment: extended off-treatment follow-up from the randomized CLL14 study. J Clin Oncol. 2021;39:4049-4060.  
5. Benintende G, Pozzo F, Innocenti I, et al. Measurable residual disease in chronic lymphocytic leukemia. Front Oncol. 2023;13. Accessed June 7, 2023.  
6. National Comprehensive Cancer Network. NCCN Guidelines, Version 3.2023, Chronic lymphocytic leukemia/small lymphocytic lymphoma. June 12, 2023. Accessed September 6, 2023. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf   
7. Wang XV, Hanson CA, Tschumper RC, et al. Measurable residual disease does not preclude prolonged progression-free survival in CLL treated with ibrutinib. Blood. 2021;138:2810-2827.   
8. Al-Sawaf O, Zhang C, Jin HJ, et al. Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia. Nat Comm. 2023;14:2147.  
9. Al-Sawaf O, Hallek M, Fischer K. The role of minimal residual disease in chronic lymphocytic leukemia. Clinical Advances in Hematology & Oncology. 2022;20:97-103.    
10. National Comprehensive Cancer Network. NCCN Guidelines Insights: Chronic lymphocytic leukemia/small lymphocytic lymphoma, Version 3.2022. JNNCN. 2022;20:https://doi.org/10.6004/jnccn.2022.0031.    
11. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131:2745-2760.