What management in relapsed patients after inhibitors of Bruton's tyrosine kinase and B-cell lymphoma 2?

BCR inhibitors (BCRi) have revolutionized the management of CLL relapse. Treatment after chemoimmunotherapy (CIT) is now mainly based on ibrutinib allowing a median progression-free survival (PFS) of at least 50 months, which is shorter if patients are multi-treated, have TP53 alteration or a complex karyotype. In case of relapse after ibrutinib, venetoclax alone or in combination with rituximab allows again a high response rate but with a shorter median PFS. These new agents have logically postponed the use of allogeneic transplantation, which in high-risk CLL can produce a PFS of 40 to 60 %, is potentially curative but with a risk of toxic death of 10 to 30 % and chronic graft-versus-host reaction. Relapses are also a problem, but their prevention through better pre-transplant control of CLL and post-transplant pre-emptive treatment for persistent minimal residual disease (MRD) improves outcomes. More recently, chimeric receptor T-cells (CAR-T) have been developed that can achieve, also in high-risk patients including those relapsing after ibrutinib and/or venetoclax, 60-80 % response and 60 % negative marrow MRD with potentially severe but transient acute toxicity, including 20-30 % neurotoxicity and 75-95 % cytokine release syndrome. CAR-T exert slower and partial control of lymph node tumor mass, and their long-term efficacy is still hypothetical, although very prolonged responses are described. Indications for allogeneic transplantation, and as an alternative for CAR-T redefined in 2018 by the EBMT and the ERIC, include level 1 (TP53 alteration and relapse after TBI and response to BCRi or BCL2i) for which allografting is suggested if HLA 10/10 donor and no comorbidity, and level 2 (relapse after TBI and relapse after BCRi or BCL2i) for which allograft is indicated even with a non HLA 10/10 donor and even if comorbidities. In the therapeutic sequence of CLL relapses, which today is mostly based on the sequence ibrutinib followed by venetoclax, it is important to determine early on the risk factors for early progression under venetoclax. These may be pre-therapeutic factors such as the notion of prior resistance (not intolerance) to ibrutinib, a large tumor mass, an alteration in TP53 and complex karyotype, or post-therapeutic factors such as the absence of a complete response (CR/RCi) at 9 months or a remaining or regaining positive blood MRD. These should prompt consideration cellular therapy before the patient relapses and becomes doubly refractory.