How We Developed a Curative Therapy for CLL and Stopped Using It (SOHO 2023)
Recent radical changes in the therapeutic landscape for CLL have led to current global treatment guidelines recommending the use of various highly effective targeted agents as frontline therapy,1,2 displacing previous chemoimmunotherapy (CIT) regimens such as fludarabine/ cyclophosphamide/rituximab (FCR)...In the late 1980's, three functionally similar agents related to purine nucleoside analogues entered clinical development; deoxycoformycin (DCF), 2-chlorodeoxy-adenosine (cladribine; 2-CdA) and 2-F-ara-adenosinemonophosphate (fludarabine; F). The first major report of F in relapsed/refractory CLL by Keating was truly remarkable in describing a 13% CR rate (overall response rate 57%).3 Cheson summarized this period as a "therapeutic beauty contest" among the three agents, that F ultimately emerged from victorious and became the foundational agent for subsequent combination development.4 As a single agent in frontline CLL, F improved PFS compared to chlorambucil (20 vs 14 months) and attained a CR rate of 20%.5 Elegant work in Plunkett's lab at MD Anderson established the synergy between F and DNA-damaging agents such as cyclophosphamide via inhibition of DNA repair,6 and at least 3 frontline trials have shown the superiority of the FC combination over single agent F, with CR rates as high as 39%, but modest overall survival impact.7 The new century brought the first therapeutic monoclonal antibody in cancer (rituximab; antiCD20) to be bravely applied in CLL by Byrd and O'Brien showing modest single agent activity, developing a safe infusion schedule to mitigate reactions, and establishing a dose response curve above the standard 375 mg/m2 lymphoma dose.8 Further laboratory studies showed bi-directional synergistic cytotoxicity with FC and R, both directly and through reduction in levels of surface complement defense proteins by F, and reduction in anti-apoptotic BCL2 protein levels by R.9 The resultant FCR regimen was pioneered at MD Anderson10 and subsequently shown in randomized trials in both frontline and relapse settings to deliver improved overall survival compared to FC and attain CR rates of up to 72% and the unprecedented attainment of uMRD (<10–4 by flow cytometry) in 68% of evaluable patients.11 Such deep remissions were associated with prolonged remission and improved OS.11 Although having little benefit in patients with disease harboring TP53 dysfunction, those patients with favorable disease biology (intact TP53 and mutated IGVH status) had high rates of sustained uMRD and a plateau at ~50% in their PFS curve stable beyond 10 years and with latest follow-up out to 20 years.10,12 These data together with long-term follow-up from both randomized trials and multiple real-world and registry cohorts are congruent in establishing the curative capacity of FCR...These newer targeted agent regimens have been S101 accepted for all biological subsets, despite the absence of robust superiority in the IGVH mutated group relative to FCR and, as yet, no evidence for truly curative potential although acknowledging the exceptionally high uMRD rate with venetoclax-obinutuzumab.15 Conclusions The history of the development of FCR illustrates the important lessons of understanding the mechanism of action of new agents, the critical role of laboratory translational studies, and the interplay between disease biology and therapy. Depth of remission, as assessed by various MRD assays, remains critical for the rapid evaluation of the efficacy of newer time-limited regimens in CLL and FCR first established that this is a necessary, but not in itself sufficient, step in the now achievable quest for better tolerated and more widely deliverable curative regimens in CLL.
