Ending endless follow-up for low-risk CLL?

In this issue of Blood Advances, Brieghel et al¹ have demonstrated the successful implementation of a health care model where low-risk, asymptomatic patients with chronic lymphocytic leukemia (CLL) are discharged from specialist follow-up (sFU). This builds upon earlier work undertaken by the same group to refine prognostication for patients with early-stage CLL, with a particular focus on identifying low-risk patients who are very unlikely to ever require therapy, culminating in the development of the aptly named CLL-WONT score. This score utilizes routinely available laboratory markers (lactate dehydrogenase, beta-2-microglobulin, absolute lymphocyte count), clinical markers (age and Binet stage) and specialized genomic evaluation (fluorescence in situ hybridization for del(11q) and del(17p) and immunoglobulin heavy chain variable region [IGHV] mutation status) to risk-stratify patients according to the likelihood of requiring therapy for their CLL. This model has been trained on a very large data set and externally validated.² It contains several similarities to the widely used CLL-international prognostic index (IPI), which utilizes beta-2 microglobulin, clinical stage, IGHV mutation status, and TP53 status (deletion and/or mutation).³ 

Developed countries throughout the world are faced with challenges associated with caring for a rapidly aging population within resource-constrained health care systems. CLL is a disease that affects older people,⁴ with increasing incidence due to aging population and frequent analysis of hematologic parameters in routine care.⁵ Most patients are diagnosed with early-stage disease and the majority of these, especially when diagnosed at an older age, will never need treatment.⁶ The current paradigm of indefinite follow-up of increasing numbers of patients with early stage, asymptomatic CLL, will place added strain on already stretched health care systems.

Prognostic models in early-stage CLL have been utilized to identify very high-risk populations, in whom early therapeutic intervention has been initiated, such as in the GCLLSG CLL12 study,⁷ without demonstrating benefit for such patients, thus entrenching “watch and wait” as the standard of care for management of early stage, asymptomatic CLL. Arguably, however, a more important use of these models is the identification of a low-risk group of patients, for whom intensity of sFU could be attenuated, thus freeing up scarce resources for patients with more pressing health care needs.

Clearly, demonstration of a robust model to reduce pressure on specialist health care systems would be of great interest to health policy markers worldwide. The Danish system, with its superb central data collection tools and universal health care coverage of the population, is an ideal test case. Brieghel et al evaluated patients with CLL and determined risk category utilizing both CLL-WONT and CLL-IPI.¹ Low/intermediate risk patients were discharged from sFU to primary care. However, it is important to note that before discharge, manual review of electronic health records was undertaken by CLL specialists, to identify additional features, not captured by CLL-WONT or CLL-IPI, that might warrant ongoing sFU. These included B-symptoms, short lymphocyte doubling time, autoimmune cytopenias, immune dysfunction and need for immunoglobulin replacement therapy. Such patients continued sFU. The results presented in the accompanying article need to be viewed with this in mind; the art of medicine remains and there was discretion exercised by highly-regarded CLL clinicians/researchers in whom to discharge. Replicating these decisions, which requires nuanced interpretation that is difficult to standardize, could prove challenging in a less specialized practice group. With this caveat, it was nevertheless notable that the implementation of this model appeared successful.

Key findings after a median of 3.7 years of follow-up were: 3-year survival was similar for those continuing sFU vs those discharged to primary care, when stratified for CLL-WONT low vs intermediate risk; health care utilization was considerably lower among those patients discharged from sFU (0.7 vs 4.3 hospital visits per year); re-referral in patients who were discharged from sFU only occurred in 19 (16%) patients, of whom only 4 required treatment initiation in the short term. Additional findings presented included a lower risk of infection (based on in-hospital antimicrobial use) and lower risk of COVID-19 infection in patients discharged from sFU, but, in my view, this relationship is unlikely to be causative; as noted above, there was major selection bias in which patients continued sFU, including continued follow-up in those with perceived higher risk CLL (eg, rapid lymphocyte doubling time) or higher risk of infection (eg, those with hypogammaglobulinemia).

In summary, the authors should be congratulated on a well-implemented project many years in the making. On a macro level, this has major potential health policy implications, and this work could serve as a model for use in other diseases to better allocate scare resources. On a micro level, those of us who care for many patients with low-risk CLL (the majority of whom are older and thus, frequently have comorbidities), know that this could improve clinic workflow, where much time is often devoted to discussing non–CLL-associated issues. Nevertheless, implementation risk remains. First, the prognostic models used require analysis of genomic data (fluorescence in situ hybridization and IGHV somatic hypermutation analysis) that are not always readily available, with CLL-IPI particularly heavily weighted toward these 2 parameters. Secondly, as discussed, there are numerous factors not contained within these models which were considered by the study team before discharging patients and this may be difficult to replicate by general hematologists who see fewer patients with CLL. Third, prospective communication with the patient’s primary health care provider (PCP) in such a system is surely critical to its success. This provider-to-provider communication is important to ensure the PCP is adequately educated regarding both findings that should prompt re-referral, as well as the unique preventive health care needs of patients with CLL, given that even early-stage CLL is associated with increased risk of infection and other cancers, particularly skin.⁸ This underscores the need for coordinated health maintenance activities, which would need to be implemented by the PCP, including vaccination (eg, pneumococcal pneumonia, COVID-19, influenza) and other cancer screening (especially skin). Finally, when implementing such a practice, patient and other stakeholder satisfaction should be monitored and considered. Regarding this, one wonders whether a shared-care arrangement, where some more limited sFU, rather than complete discharge from sFU, may provide greater patient and PCP satisfaction.

Conflict-of-interest disclosure: P.A.T. has served as a paid consultant for AbbVie, Adaptive Biotechnologies, Ascentage, AstraZeneca, BeiGene, Genentech, Genmab, Janssen, Lilly, and Merck; received honoraria from AbbVie, Adaptive Biotechnologies, AstraZeneca, Janssen, and Merck; and receives research funding (to institution) from Sana Biotechnologies, AbbVie, and Genmab.