In this issue of Blood, Al-Sawaf et al1 report no significant outcome differences for unfit vs fit patients with chronic lymphocytic leukemia (CLL) without TP53 aberrations treated front line with standard fixed duration venetoclax plus obinutuzumab (ven-obi) in the randomized CLL14 and CLL13 trials. Fitness was a key trial inclusion determinant considering their respective chemoimmunotherapy (CIT) comparators; the CLL14 study focusing on older, unfit patients (“slow go”) and randomizing to ven-obi or chlorambucil-obi, and the CLL13 study examining younger, fit patients (“go go”) and randomizing to ven-regimens or fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab. At the time these trials started enrolling (2015-2016), the paradigm shift away from an age-centric selection of frontline CLL treatment had begun, and exploratory analyses from the CLL11 trial identified creatinine clearance (<70 mL/min) and the cumulative illness rating scale (CIRS > 6) score to reflect unfit.1 These fitness definitions were subsequently incorporated into pivotal trials.
As the authors acknowledge, lack of outcome differences (including progression-free survival [PFS], overall survival [OS], and complete response) for unfit vs fit with frontline ven-obi does not imply that fitness, age, or comorbidities no longer deserve attention in CLL—rather the contrary. These and other findings underscore the unmet needs in the contemporary era for (A) more relevant and comprehensive definitions of fitness, particularly definitions that inform individualized approaches among a growing list of therapeutic options; and (B) feasible methods to dynamically assess for intervenable measures of fitness with a chronic malignancy that may span decades.
Significant gaps remain for patients with CLL vs their similarly aged peers including the impact of comorbidities on mortality.2 Patients with comorbidities were more likely to have BTKi treatment–related toxicities and early discontinuation, which concerningly impacts on long-term disease control.3 Thus importantly, Al-Sawaf et al performed outcome analyses on total ven-obi dose intensity received and early treatment discontinuations. Dose intensity was defined by the percentage of cumulative total dose received vs planned total dose (12 cycles of ven, 8000 mg total of obi); dose intensity was examined at or below cutoffs of 80%, 70%, 60%, and 50%. Although no difference in PFS was seen around 80% intensity, shortened PFS was observed at 70% or less, and a greater percentage of unfit patients received a lower dose intensity. Furthermore, unfit patients were more likely to have permanent early treatment discontinuations (15.8% vs 5.0%), and among the early discontinuations, unfit patients had a notably shorter ven exposure (4.7 months vs 7.8 months). Early treatment discontinuation for both unfit and fit patients was associated with a significantly shorter PFS and OS, and most early treatment discontinuations were due to adverse events [AEs].
The ven dose intensity widely varied across age groups with median dose intensity of 98.6% for patients 65 years and younger, vs 80% for patients 75 to 80 years, and 67.3% for patients >80 years. The most common hematologic AE was neutropenia (62.7% unfit vs 56.9% fit), and blood and lymphatic disorders (mostly neutropenia) was the most frequent AE (59.1% of AEs) that led to early treatment discontinuation. Not surprisingly, neutropenia was higher in unfit and older patients, particularly in patients >75 years. Interestingly, granulocyte colony-stimulating factor (GCSF) support was administered less in unfit compared to fit patients (46.5% vs 51.9%). It was beyond the scope of this analysis to know if early dose modifications were effective with frontline ibrutinib,4 or mandatory growth factor support, could have prevented some of the early therapy discontinuations. However, it raises consideration for future protocols to have a mandated vs permitted approach for early modifications and/or GCSF support to help answer this question.
The call to improve upon capturing individual fitness, function, and comorbidity burden in patients with CLL, is not new. The Eastern Cooperative Oncology Group (ECOG) score is often nonspecific; in this analysis from CLL13 and CLL14 the median ECOG score was 0 and 1, respectively. Comprehensive geriatric assessments identify specific domains of dysfunction, and are proven feasible and prognostic within BTKi- and venetoclax-containing frontline trials.5,6 However, the resource support to complete comprehensive assessments makes it impractical within most clinics. Even the CIRS calculation, helpful in quantifying the comorbidity burden, requires substantial time and data elements that may be unknown. Therefore, an optimal method for measuring fitness and function must somehow fulfill the goldilocks paradox of complete enough to inform patient-level management, yet succinct enough to be practically implemented. Studies undertaken to identify focused assessments most relevant to both CLL and the treatment at hand, have started to move the needle including limited CIRS scores7 and selective physical function tests,8 but ongoing work is imperative.
Finally, although well received to read headlines that 80 is the new 60, and a hopeful aspiration to identify modifiable aspects to fitness in hematologic malignancies,9 we must assure that our anti-aging enthusiasm does not ignore the scientific advancements uncovering the age-related functional impacts to the hematopoietic and immune systems. Interestingly in this analysis, unfit patients (median age, 72 years) had less obi-infusion related reactions vs fit (median age, 58 years), hypothesized to reflect differentiated cytokine and immune phenotypes in older populations, as also observed in patients receiving immunotherapies for solid tumors.10 This empowered awareness over denial on age-related changes occurring independent of fitness has the potential to positivity impact on management approaches; for example, in optimizing preventive strategies. And encouragingly, although age may raise risk for infections and other AEs, improving fitness up front may meaningfully impact on recovery, that is, resilience.
In summary, the work of Al-Sawaf et al and others reassures that being unfit by current definitions does not undermine frontline treatment advances, but it does call to action on refitting the ways we integrate fitness in CLL. Patients require individualized treatment approaches that still maintain a planned cumulative amount of therapy. However, it may be irrelevant to reach the finish line in one intense uninterrupted motion vs acceptance of a strategy that tolerates a slower pace or even stopping for a little, with permission for longer time on the course or additional support along the way. Perhaps we will be moving from the “no go,” “slow go,” or “go go” standards of fitness in CLL to a personalized approach and reaching one’s finish line goals by building the resilience to be “still going.”
Conflict-of-interest disclosure: D.M.B. reports consulting/advisory roles for AbbVie, Pharmacyclics, BeOne Medicine, Bristol Myers Squibb (BMS), and Nurix and received grants (paid to institution/site principal investigator clinical trials [effort may support part of principal investigator salary, variable support over course of the trial]) from AbbVie, ArQule/Merck, BeOne Medicine, BMS (former Juno/Celgene), Carna Biosciences, Catapult, Genentech, NeWave, Nurix, and Pharmacyclics.
