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Abstract Polatuzumab vedotin (Pola) is an approved therapy in combination with rituximab and bendamustine for relapsed or refractory diffuse large B‐cell lymphoma (RR‐DLBCL) based on positive results of the landmark phase II randomised G029365 trial. However, trial results for many approved novel therapies in RR‐DLBCL have not been replicated in routine care cohorts, as RR‐DLBCL patient populations are heterogeneous and trial eligibility is increasingly restrictive. We evaluated outcomes from pola ± bendamustine and rituximab in patients with RR‐DLBCL enrolled in a compassionate access program with no alternative treatment options identified via the Australasian Lymphoma and Related Diseases Registry according to their eligibility for the original phase II published study. Of 58 eligible patients, 74% met the criteria deeming them ineligible for the G029365 original study at the time of pola's commencement. Median progression‐free survival and overall survival in our cohort were 2.3 and 3.5 months, respectively. In contrast to the landmark trial cohort, more of our patients ceased therapy prior to completion, the majority due to progressive disease and only 8/58 received any subsequent treatment. Dismal outcomes in this Australian real‐world population demonstrate trial eligibility is challenging to meet, and newer treatments can be difficult to deliver in routine care. Clinically applicable results from therapeutic studies require trial cohorts to reflect representative clinical populations wherever possible, and more research is required to address the benefit of novel agents in the increasing majority who are ineligible for modern studies.

Abstract Chronic lymphocytic leukemia (CLL) predominantly affects older adults, characterized by a relapsing and remitting pattern with sequential treatments available for many patients. Identification of progressive/relapsed CLL should prompt close monitoring and early discussion about the next therapies when treatment indications are present. The intervening period represents an opportunity to optimize patient health, including establishing adequate vaccination and surveillance for second primary malignancies, and treating non-CLL-related comorbidities which may impact well-being and CLL therapy. We now see patients with relapsed/refractory (RR) CLL in the clinic who have been previously treated with chemoimmunotherapy (CIT) and/or one or more novel therapies. Continuous covalent inhibitors of Bruton’s tyrosine kinase (cBTKi) and fixed-duration venetoclax (Ven)-anti-CD20 monoclonal antibody (mAb) are preferred over CIT given the survival advantages associated with these therapies, although have never been evaluated head-to-head. While both classes are effective for RR CLL, potential side effects and the logistics of administration differ. Few randomized data demonstrate the sequential use of cBTKi and fixed-duration Ven-anti-CD20 mAb; however, they may be used in either sequence. Newer non-covalent BTKi, active against BTK C481 resistance mutations emerging with continuous cBTKi exposure, and novel approaches such as BTK degraders, bispecific antibodies, and chimeric antigen receptor T-cell therapies demonstrate impressive efficacy. In this review of RR CLL we explore relevant investigations, consideration of broader CLL- and non-CLL-related health needs, and evidence for efficacy and safety of B-cell receptor inhibitors and Ven, including available data to support drug sequencing or switching. We describe novel approaches to RR CLL, including rechallenging with fixed-duration therapies, allogeneic stem cell transplant indications in the novel therapy era, and highlight early data supporting the use of T-cell directing therapies and novel drug targets.

Abstract Background The treatment landscape for chronic lymphocytic leukemia (CLL) continues to undergo considerable evolution. Optimal selection of initial therapy from multiple effective options provides a major challenge for clinicians, who need to consider both disease and patient factors in conjunction with a view to sequencing available therapies in event of disease relapse. Review We explore the most topical clinically relevant unresolved questions through discussion of important available pertinent literature and propose expert opinion based on these data. (1) Shrinking role of chemoimmunotherapy (CIT); while novel therapies are generally superior, we highlight the utility of FCR for IGHV-mutated CLL. (2) Choosing between inhibitors of Bruton’s tyrosine kinase (BTKi); while efficacy between agents is likely similar there are important differences in toxicity profiles, including the incidence of cardiac arrhythmia and hypertension. (3) BTKi with or without anti-CD20 monoclonal antibodies (mAb); while obinutuzumab-acalabrutinib (AO) may confer superior progression-free survival to acalabrutinib (Acala), this is not true of rituximab (Ritux) to ibrutinib (Ib)—we highlight that potential for increased side effects should be carefully considered. (4) Continuous BTKi versus time-limited venetoclax-obinutuzumab (VenO); we propose that venetoclax (Ven)-based therapy is generally preferable to BTKi with exception of TP53 aberrant disease. (5) BTKi-Ven versus VenO as preferred time-limited therapy; we discuss comparable efficacies and the concerns about simultaneous 1L exposure to both BTKi and Ven drug classes. (6) Utility of triplet therapy (BTKi-Ven-antiCD20 mAb) versus VenO; similar rates of complete response are observed yet with greater potential for adverse events. (7) Optimal therapy for TP53 aberrant CLL; while limited data are available, there are likely effective novel therapy combinations for TP53 aberrant disease including BTKi, BTKi-Ven ± antiCD20 mAb. Conclusion Frontline therapy for CLL should be selected based on efficacy considering the patient specific biologic profile of their disease and potential toxicities, considering patient comorbidities and preferences. With the present paradigm of sequencing effective agents, 1L combinations of novel therapies should be used with caution in view of potential adverse events and theoretical resistance mechanism concerns in the absence of compelling randomized data to support augmented efficacy.