Page 9 - Haematologica Vol. 110 - January 2025

LANDMARK PAPER IN HEMATOLOGY
L. Ysebaert
The CLL hunters: finally, BTK got arrested
Loic Ysebaert
Service d’Hématologie, IUCT-Oncopole, Toulouse, France E-mail: Ysebaert.Loic@iuct-oncopole.fr
https://doi.org/10.3324/haematol.2024.286469
©2025 Ferrata Storti Foundation Published under a CC BY-NC license
The Mindhunters Netflix series shows how two FBI agents study and interview imprisoned serial killers, to better understand them, and hunt down one of the most dread- ful American psychopaths of the seventies, called BTK (a name he gave himself, referring to his modus operandi “Bind-Torture-Kill”). Back to 1952, in the Pediatrics journal, Dr O. Bruton reported his cases of agammaglobulinemia in several children (later described as Bruton’s syndrome). The gene defect, mapped to the Xq21.3 locus, would be published in 1993 in the Science journal and code-named: BTK (Bruton-Tyrosine-Kinase, this time).
The hunt for BTK inhibitors started in the mind of a chemist at Celera Genomics, which developed (but did not patent) the first covalent inhibitor (“not ideal for a drug”, accord- ing to the chemist’s assumptions) as a “tool compound” (for rheumatoid arthritis). The drug was soon acquired by Pharmacyclics, a small company co-founded by a chemist (who experienced chemotherapy himself as a lymphoma survivor) and his oncologist, but they rapidly needed bigger investors in order to enter the clinical evaluation phase. When a successful businessman took the position of Chief Executive Office, and saved the company from bankrupt- cy, he also allowed and funded with his own money the first human trial of PCI-32765. Because access to cancer cells was important to monitor drug covalent binding, and despite it being unusual to include them in a lymphoma development plan, some patients with chronic lymphocytic leukemia (CLL) were allowed among the different lympho- ma patients...It rapidly turned out that they were the ones who benefited most from the therapy.1
CLL lacks a single genetic target (like BCR-ABL in chronic myeloid leukemia), but “Chronic activation of BCR” is what actually best defines the pathophysiology behind the “de- viancy of B cells” (together with “improved resistance to apoptosis”: but that is a different story).
Promising preliminary results prompted the initiation of a phase Ib/II trial.2 Eight US centers and 85 patients par- ticipated in the study (around Dr J. Byrd and Dr S. O’Brien as principal investigators) to assess the safety, efficacy, pharmacokinetics and pharmacodynamics of ibrutinib: 51 patients received 420 mg and 34 received 840 mg. The overall response rate was 71% in both dose groups, and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis (a brand new response criterion had to be created). Of note, the overall response rate was consistent across groups with different clinical and genomic risk factors, including dis- ease-refractoriness to chemotherapy and the 17p deletion. At 26 months, the estimated progression-free survival and overall survival rates were 75% and 83%, respectively. To put this result in the context of relapsed/refractory CLL back in 2012, registered monoclonal antibodies yielded a median progression-free survival of 11 months and a me- dian overall survival of 16 months. These ground-breaking results led to the first accelerated approval by the Food and Drug Administration of a BTK inhibitor for this indi- cation. The drug was also registered for other B-cell lym- phomas, alone or in combination. Since the introduction of antiCD20 monoclonal antibodies 15 years previously, no single agent had improved overall and progression-free survival as ibrutinib did.
After up to 8 years of follow-up of the PCYC-1102 study (including high-risk patients treated with frontline ibruti- nib in the extension study), sustained responses were still reported, confirming that the chemists at Celera had done a really nice job 20 years earlier. The overall response rate was 89% with complete response rates of 10% (in the re- lapsed/refractory setting) to 35% (as first-line treatment), the 7-year progression-free survival rates were 34% (in the relapsed/refractory setting) to 83% (as first-line treatment),
TITLE
Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.
AUTHORS
Byrd JC, Furman RR, Coutre SE, et al.
JOURNAL
The New England Journal of Medicine. 2013;369(1):32-42. doi: 10.1056/NEJMoa1215637.
Haematologica | 110 January 2025
1