All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit the Lymphoma Coalition.
Join our
Treating classical Hodgkin lymphoma: Spotlight on targeted therapies
with Gilles Salles, Paul Bröckelmann, and Ann S. LaCasce
Saturday, November 2, 2024
8:50-9:50 CET
This independent educational activity is sponsored by Takeda. All content is developed independently by the faculty. Funders are allowed no direct influence on the content of this activity.
The Lymphoma Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the Lymphoma Hub cannot guarantee the accuracy of translated content. The Lymphoma Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.
The Lymphoma & CLL Hub is an independent medical education platform, sponsored by Beigene and Roche, and supported through educational grants from Bristol Myers Squibb, Ipsen Biopharmaceuticals, Pfizer, and Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC. View funders.
When analyzing patient outcomes in clinical trials, survival is often considered to be the gold standard of outcome measures; however, in many cancers, such as chronic lymphocytic leukemia (CLL), measuring outcomes by survival can be suboptimal. In practice, examining a survival endpoint can take many years, potentially delaying the acquisition of critical scientific data which is vital for clinical decision making and regulatory approvals. Surrogate endpoints, such as progression-free survival (PFS) and quality of life (QoL), are sometimes used in lieu of survival, although these can also have drawbacks and have been shown to be unreliable in practice.1
Another promising surrogate endpoint is the achievement of a negative measurable residual disease (MRD) test, with multiple clinical trials and regulatory approvals using such data in recent years. However, its acceptance is not ubiquitous; the European Medicines Agency (EMA) accepted MRD-test data from clinical trials for the approval of blinatumomab in acute myeloid leukemia, while the US Food and Drug Administration (FDA) did not.
This raises the question of whether MRD-negativity, or the achievement of unmeasurable MRD (uMRD) status, is an appropriate endpoint for clinical trials in CLL and a subsequent indicator for regulatory approval. Below, we summarize commentary from Yang et al. published in Leukemia in 2022.1
Overall, they suggest that use of MRD-test results to inform regulatory decision making may be premature at this time and that careful consideration is required before using MRD as a surrogate for PFS and survival.
An important consideration is whether PFS represents an acceptable surrogate for survival in CLL. Multiple studies of chemoimmunotherapy (CIT) in CLL indicate that it does not.
These discordances may reflect the hidden impact of subsequent therapies, insufficient follow-up, or fatal treatment-related adverse events.
International Workshop on Chronic Lymphocytic Leukemia (iwCLL) response criteria are based on laboratory evaluations of the blood and bone marrow alongside clinical evaluations of lymph nodes and the spleen. MRD-testing is typically performed using laboratory techniques, such as multi-parameter flow cytometry, quantitative real-time polymerase chain reaction, or next-generation sequencing technologies.
Further research is required to fully understand and address these discrepancies.
Treatment of CLL with CIT and/or venetoclax based regimens is more likely to achieve uMRD compared with Bruton’s tyrosine kinase inhibitors (BTKis) alone. However, BTKis prolong PFS and likely prolong survival.
The above examples further illustrate the lack of correlation between PFS and/or survival and MRD-testing.
There is much data to indicate that posttreatment concentration of residual leukemia cells correlates with PFS in CLL.
The above data suggests that there are increasing improvements in PFS at lower residual leukemia cell concentrations up to a certain point. However, it must be noted that the reliability of such estimates can depend on multiple covariates such as the sensitivity, specificity, accuracy, and precision of MRD-testing.
Residual leukemia cells can proliferate after therapy cessation, resulting in disease recurrence and progression despite previously achieving uMRD.
This suggests that while concentration of residual leukemia cells can correlate with PFS and survival, for patients with MRD <10-4 the rate at which residual leukemia cells proliferate could offer a better correlate of these endpoints, indicating the potential advantage of sequential MRD-testing.
Two issues regarding the predictive accuracy of uMRD are confounded:
Lymphocyte doubling rate correlates with outcomes in patients with CLL treated with chlorambucil and with modern CLL therapies. Additional confounding co-variates associated with the rate at which uMRD is lost include age and risk of tumour lysis syndrome. Taken together, these data indicate that the predictive accuracy of uMRD can depend on therapy context and individual patient characteristics.
Overall, the information presented above demonstrate the complexity of this topic, with many perplexing covariates and impacting factors. The authors conclude that while uMRD may be a suitable endpoint for informing clinical decisions regarding certain patients, it is oftentimes unsuitable for informing clinical decision making and regulatory approvals in the context of CLL. They also indicate that MRD-testing results of are a predictive rather than prognostic co-variate and suggest that sequential monitoring using an accurate and precise MRD-test in large scale phase III patient trials may be required to fully elucidate the relationship between uMRD and PFS/survival.
Understanding your specialty helps us to deliver the most relevant and engaging content.
Please spare a moment to share yours.
Please select or type your specialty
Your opinion matters
Subscribe to get the best content related to lymphoma & CLL delivered to your inbox