S100 EXABS-210-CLL How a Curative Therapy for CLL Was Developed and Why We Have Stopped Using It John F Seymour, MBBS, FRACP, PhD1,2,*, Philip A Thompson, MB, BS1,2, and Constantine S Tam, MBBS, MD3,4 1Peter MacCallum Cancer Centre & Royal Melbourne Hospital, Melbourne, 3000 Australia 2University of Melbourne, Parkville, 3052, Australia 3Alfred Hospital, Prahran, 3181, Australia 4Monash University, Clayton 3145, Australia *Corresponding author: john.seymour@petermac.org Keywords Fludarabine, pre-clinical synergy, DHA repair, IGVH mutational status, treatment-related myelodysplasia / acute myeloid leukemia Introduction Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western World and is consistently described in standard textbooks as being “incurable”. 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). Perhaps ironically over this same period there has been increasingly robust data accumulating that FCR has truly curative capacity in a subset of patients with CLL and yet its frontline use has now virtually vanished. Material and Methods We present a summary of the pre-clinical and clinical development history of the FCR regimen, its efficacy particularly in certain favorable biological subsets, short- and long-term toxicity and reflect on the concept of “cure” for chronic diseases such as CLL in the targeted therapy era. Results and Discussion For many decades, alkylating agents had been the only drugs with clinical utility in CLL, but they had modest activity and no complete remissions (CRs) were attained. 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. However the regimen has major burdens and toxicities, having poor tolerability in patients aged >65 or with significant co-morbidities, requiring adequate renal function for F clearance, causing significant and prolonged immunosuppression and myelosuppression, with the most feared complication being development of therapy-related myelodysplasia or acute myeloid leukemia see in 2–6% of patients and being nearly universally fatal.10,13 Given these issues with FCR, it had always struggled for widespread acceptability and recent comparative trials of either BTK inhibitors14 or venetoclax-combinations15 showing shortterm superiority and better tolerability have lead to its rapid displacement. These newer targeted agent regimens have been
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