Back from (BTKi) holiday

In this issue of Blood Advances, Shanafelt et al¹ present additional follow-up of the pivotal frontline E1912 trial randomizing young, fit patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) to covalent BTK inhibitor (cBTKi) ibrutinib plus rituximab (IR) vs fludarabine, cyclophosphamide, and rituximab (FCR). In demonstrating superior progression-free survival (PFS) and overall survival (OS) for patients receiving IR, the E1912 trial is credited with paving the way for frontline BTKi-targeted therapy over chemoimmunotherapy in which FCR was the gold standard. Despite these significant outcomes, reservations have emerged about continuous treatments especially in the frontline setting involving years of exposure to toxicities and potential for treatment resistance. Shanafelt et al’s analyses from E1912 are highly relevant to these important ongoing conversations regarding BTKi management: what factors contribute to PFS after frontline ibrutinib discontinuation when stopped for reasons other than progressive disease (PD) or death and, in turn, who is best served by continuous treatment and who possibly can enjoy a BTKi drug holiday (wouldn’t it be, be so nice)?

With 8.2 years of median follow-up for the 354 patients randomized to the ibrutinib arm of E1912, 149 (42%) remained on ibrutinib, and 145 discontinued for reason other than PD or death after a median of ∼4 years on ibrutinib (47.7 months). As suspected, time on therapy before the discontinuation of ibrutinib affected PFS; those on ibrutinib <12 months had much shorter PFS once off therapy, and those able to remain on treatment for at least 4 years had longer PFS vs those on 12 to 47 months.

Further insight is gained from E1912 on CLL markers associated with PFS off ibrutinib therapy in the non-PD/death setting; complementary to this is how the same markers on therapy are associated with outcomes. Specifically, Shanafelt et al noted important observations for patients with unmutated immunoglobulin heavy chain variable region (UM-IGHV) vs mutated IGHV (M-IGHV). Nearly 25 years ago, 2 concurrent landmark Blood publications brought attention to IGHV mutation status and CLL/SLL outcomes.^2,3 Higher-risk UM-IGHV is present in nearly 60% of patients at frontline treatment. Fortunately, UM-IGHV outcomes are significantly improved with novel agents vs the initial publications reflecting treatment in the chemoimmunotherapy era; Hamblin et al reported strikingly shorter median OS of ∼8 years in UM-IGHV vs 24 years in M-IGHV, and Damle demonstrated similar OS discrepancies.

Aligned with other cBTKi studies, Shanafelt et al herein present nearly identical PFS in patients on ibrutinib independent of IGHV mutation status (8-year PFS, 75% in UM-IGHV vs 79% in M-IGHV; P = .63). However, UM-IGHV had a significantly shorter PFS off ibrutinib after discontinuation for non-PD: median PFS was 2.5 years in UM-IGHV relative to 3.9 years in M-IGHV (P = .02). Interestingly, although venetoclax regimens are differentiated from BTKi in current fixed treatment paradigms, IGHV mutation status also appears to play a role in PFS off therapy in the frontline CLL14 trial (PFS estimate of 76 months for venetoclax-obinutuzumab arm compared with 65 months in the UM-IGHV subset of venetoclax-obinutuzumab).⁴ 

Similarly, in E1912, the adverse fluorescence in situ hybridization (FISH) marker del11q shows comparable PFS to lower-risk FISH on ibrutinib therapy vs shorter PFS than lower-risk FISH off therapy. Even though in smaller subsets, these findings are encouraging for novel therapies closing the outcome gaps of high-risk FISH if patients are managed on treatment.⁵ Unfortunately, FISH and IGHV testing remain disappointingly low despite awareness of differing outcomes in the era of BTKi and venetoclax. Recent studies demonstrating a decline in testing rates is especially concerning given the number of patients receiving frontline chemoimmunotherapy.⁶ 

This E1912 follow-up suggests that strategies to maintain on BTKi, such as dose reductions,⁷ could preserve PFS in high-risk patients (UM-IGHV and/or del11q) to match those with lower-risk disease. Additionally, although not designed to address the question of the population appropriate for a holiday from frontline BTKi, it elevates this question, also receiving attention in other prospective studies: can certain patients receive time limited BTKi without combining it with B-cell lymphoma 2 inhibitor (adding more costs and toxicities)? Rawstron et al recently presented encouraging results from the FLAIR trial of disease control 1 year off ibrutinib after 6 years of frontline ibrutinib,⁸ and ongoing prospective data are anticipated from the STATIC trial randomizing to continuous vs intermittent BTKi management.

Holidays from continuous BTKi may provide multiple benefits: avoiding cumulative toxicities and cost, as well as preventing selective resistance mechanisms. Even in young and fit patients, continuous treatment with first generation cBTKi ibrutinib was associated with toxicities, and interestingly E1912 toxicity rates matched that of the much older RESONATE-2 patient population.⁹ Clinically significant cardiovascular side effects including arrythmias and new onset or worsening hypertension, vary in incidence among agents but appear to be a BTK class effect even in later years on treatment.⁹ BTKi treatment increases hypertension eight fold to 12.9-fold, and this and/or other cardiovascular toxicities’ impact on patients’ long-term health remains unclear. Furthermore, even low-grade or minor toxicities on BTKi (fatigue, peripheral edema, diarrhea, and arthralgias) can significantly affect quality of life and lead to discontinuation when no end date is available to patients.⁹ Other considerations including atypical infections, secondary cancers, and financial toxicity¹⁰ are important in a treatment that can last for years. Finally, although the incidence of BTKi acquired resistance mutations was not presented in this study, it raises the ongoing issue of finding the right drug(s) for the right length of time to maximize PFS/OS in the immediate treatment while mitigating risk for resistance; BTKi resistance is concerning in current treatment options, as well as potential for suboptimal responses in the future of a generally incurable disease.

If BTKi drug holidays become an option for some, it does not mean they will never go down the road of BTKi again. Sometimes, however, time away not only permits recovery but also clarity on the next best direction to take for balancing risks and quality of life in a still chronic malignancy. IGHV and FISH, among other biomarkers, are likely to remain important directional signs for each patient’s journey, and we should not drive blind regardless of the point in the journey or the agents in the changing landscape along the way.

Conflict-of-interest disclosure: D.M.B. reports (2 years) consulting/advisory fees from AbbVie, Pharmacyclics, BeiGene, and grants paid to institution/site principal investigator clinical trials from AbbVie, ArQule/Merck, AstraZeneca, BeiGene, Catapult, DTRM, Genentech, Juno/Celgene/Bristol Myers Squibb, NeWave, Novartis, Nurix, Pharmacyclics, and TG Therapeutics. A.S. reports grants paid to institution/site PI clinical trials from BeiGene, Loxo, and Genmab.