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Editorials
whom 86% had received prior treatment with a BTK inhibitor, with 33% discontinuing the prior BTK inhibitor due to reasons other than progressive CLL.8 Furthermore, LOXO-305 had promising efficacy in this heavily pre- treated population with an overall response rate of 62% in 121 efficacy-evaluable patients with CLL/small lym- phocytic leukemia who had previously been treated with a BTK inhibitor.8
Taken together, these studies challenge the traditional sequencing paradigm of switching drug classes in the set- ting of CLL therapy discontinuation for intolerance. In Figure 1, we propose a sequencing algorithm incorporat- ing the new data from Rogers et al. While venetoclax is an acceptable option in the setting of intolerance to BTK inhiitors,9 CLL remains an incurable, chronic disease and there is a strong scientific rationale for maximizing clini- cal benefit from each drug class prior to exposing patients to the selective pressures of another therapeutic class. In the case of the common problem of intolerance to ibruti- nib it is best to keep the solution “all in the (BTK inhibitor) family.”
Disclosures
The authors have no disclosures to make regarding this edito- rial. With regard to work outside this publication, MCT has received honoraria from MJH Life Sciences, VJHemOnc, and Curio Science. LER has received research funding from the American Society of Hematology and Pfizer; has minority own- ership interest in Abbott Laboratories; provides consultancy serv- ices for AbbVie, AstraZeneca, Pharmacyclics, the Vaniam group and, uncompensated, for Verastem. ARM has received grants and personal fees from and is a data safety monitoring board member for TG Therapeutics; has received grants and personal fees from Loxo Oncology (a wholly owned subsidiary of Eli Lilly), Genentech, AbbVie, AstraZeneca, Adaptive,
Pharmacyclics, and Curio Sciences; has received grants from Sunesis, Regeneron, Pfizer, Aprea, Aptose, and DTRM; has received non-financial support from the NCCN, CLL society, and Lymphoma Research Foundation; and has received grants from and sat on a steering committee for Verastem.
Contributions
MCT and ARM drafted the manuscript. MCT, LER and ARM provided feedback and edited the manuscript.
References
1. Rogers KA, Thompson PA, Allan JN, et al. Phase II study of acalabru- tinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia. Haematologica. 2021;106(9):2364-2373.
2. Mato AR, Nabhan C, Thompson MC, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103(5):874-879.
3. UK CLL Forum. Ibrutinib for relapsed/refractory chronic lymphocyt- ic leukemia: a UK and Ireland analysis of outcomes in 315 patients. Haematologica. 2016;101(12):1563-1572.
4. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798.
5. Coutre SE, Byrd JC, Hillmen P, et al. Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies. Blood Adv. 2019;3(12):1799-1807.
6. Awan FT, Schuh A, Brown JR, et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 2019;3(9):1553-1562.
7. Mato AR, Ghosh N, Schuster SJ, et al. Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy. BBlood. 2021;137(20):2817-2826.
8. Mato AR, Shah NN, Jurczak W. Pirtobrutinib in relapsed or refracto- ry B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901.
9. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lympho- cytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018;19(1):65-75.
Do we need more genome wide association studies?
Stephan Menzel
Red Cell Research Unit, King's College London, London, UK E-mail: STEPHAN MENZEL - stephan.menzel@kcl.ac.uk
doi:10.3324/haematol.2021.278642
Much of the individual biological traits we have, of what we look like, of our physical and men- tal abilities, of our risk to suffer from the non- communicable diseases that will ultimately end our lives, is encoded in the genetic ‘background’, consisting of millions of single-nucleotide polymorphisms (SNP) and other common sequence variants that each have minute functional effects on regulatory sequences with- in our genome.
Genome-wide association studies (GWAS) are the tool of choice to make the connection between common- variant genotype data, collected either through genome sequencing or with genotyping arrays (‘chips’), and human phenotype. In its simplest form, GWAS compare the frequency for each of of thousands or millions of
common genetic variants between groups of patients and controls, thus identifying genetic risk factors for the diseases studied this way.
There are limits to what the traditional GWAS approach can achieve. Suffocating type-I error rates aris- ing from the analysis of millions of genetic variants make it necessary to assemble very large groups of patients and controls, but even then, only the strongest genetic risk factors can be identified with meaningful certainty. Even so, finding this initial set of genetic fac- tors has significantly enhanced our understanding of pathways leading to common disease or shaping health- relevant physiological traits. With the majority of dis- ease risk factors still hidden, however, it is presently impossible to assemble enough genetic information to
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