Page 18 - Haematologica Vol. 107 - September 2022

EDITORIAL
A.R. Mato and L.E. Roeker
relative contribution of each component will not be poss- ible. A major unanswered question in the treatment of CLL is which patients require monotherapy, which require doublet therapy and which require triplet therapy.6 Active phase III studies, with the notable exception of CLL17 (NCT04608318), are not designed to answer this question. The issue of relative contribution is ubiquitous in oncol- ogy, as recently highlighted in an excellent review by Brewer et al., which focused on regulatory considerations for the contribution of effects of drugs used in combina- tion regimens.7 The authors concluded that for the appro- val of combination regimens, “it is necessary to demonstrate the contribution of effect of each monother- apy to the overall combination.” These authors further as- sessed the strengths and weaknesses of various methods we can use to assess relative contribution of effect. Per- haps the most applicable solution to the issue at hand in CLL is a multi-arm adaptive trial design in which patients can be randomized to trial arms performing at a “pre- specified level of efficacy.” Such an approach can yield data on the contribution of novel agent monotherapy con- trol arms with the ability to drop such controls if they are underperforming. This adaptive approach was employed in UNITY-CLL, a front-line clinical trial in CLL which suc- cessfully assessed the relative contributions of umbralisib and ublituximab monotherapies to the combination of umbralisib and ublituximab.8
In their article, Moreno et al.1 eloquently discuss the issue of relative contribution. Most notably, the authors com-
pare the 48-month PFS of ibrutinib monotherapy from the RESONATE-2 trial to the 48-month PFS of the ibrutinib plus obinutuzumab iLLUMINATE regimen demonstrating nearly identical PFS (~75%) at that time point. As we aim to understand the role of novel agent doublet and triplet therapy in CLL, iLLUMINATE shines a light on an ever-im- portant issue to be considered in the next generation of clinical trials: the law of relative contributions.
Disclosures
ARM has received research support from TG Therapeutics, Pharmacyclics, Abbvie, Adaptive Biotechnologies, Johnson and Johnson, Acerta / AstraZeneca, DTRM BioPharma, Sunesis, BeiGene, Genentech, Genmab, Janssen and Loxo Oncology, Nurix; and has provided advisory, consultancy or data safety and monitoring board services for TG Therapeutics, Pharmacyclics, Adaptive Biotechnologies, Abbvie, Johnson and Johnson, Acerta / AstraZeneca, DTRM BioPharma, Sunesis, AstraZeneca, BeiGene, Genentech, Janssen and Loxo Oncology. LER has received research support from Pfizer, Loxo Oncology, and Aptose Biosciences; has served as a consultant for AbbVie, AstraZeneca, Beigene, Janssen, Loxo Oncology, Pharmacyclics, Pfizer, TG Therapeutics, and Vaniam group; and holds minority ownership interest in Abbott Laboratories.
Contributions
Both authors contributed equally.
References
1. Moreno C, Greil R, Demirkan F, et al. First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase III iLLUMINATE trial. Haematologica. 2022;107(9):2108-2120.
2. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528.
3. Burger JA, Sivina M, Jain N, et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019;133(10):1011-1019.
4. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291.
5. Kater A, Owen C, Moreno C, et al. Fixed duration ibrutinib and venetoclax (I+V) versus chlorambucil plus obinutuzumab (CLB+O)
for first-line (1L) chronic lymphocytic leukemia (CLL): primary analysis of the phase 3 GLOW study. HemaSphere. 2021;5(S2):LB1902.
6. Sarraf Yazdy M, Mato AR, Cheson BD. Combinations or sequences of targeted agents in CLL: is the whole greater than the sum of its parts (Aristotle, 360 BC)? Blood.
2019;133(2):121-129.
7. Brewer JR, Chang E, Agrawal S, et al. Regulatory considerations for contribution of effect of drugs used in combination regimens: renal cell cancer case studies. Clin Cancer Res. 2020;26(24):6406- 6411.
8. Gribben JG, Jurczak W, Jacobs RW, et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 Unity-CLL study. Blood. 2020;136:37-39.
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