Finding the way among a multitude of targets and regimens

Stephen Opat, MD,  School of Clinical Sciences at Monash Health, Monash University, Melbourne, Australia

Stephen Opat, MD,  School of Clinical Sciences at Monash Health, Monash University, Melbourne, Australia

Under which conditions might patients with chronic lymphocytic leukemia achieve long-term treatment-free remission?

I would like to address two factors here. The first one relates to favorable disease biology. Patients who have mutated immunoglobulin genes or lack TP53 mutations or 17p loss are more likely to experience treatment-free remission. The other main factor is treatment capable of inducing deep remission, which is usually combination therapy. Historically, the fludarabine/cyclophosphamide/rituximab regimen was the gold standard with which patients could achieve deep remissions. However, we have several fixed-duration options. The CLL14 study investigated venetoclax plus obinutuzumab, while CAPTIVATE assessed ibrutinib plus venetoclax. Also, the combination of acalabrutinib, venetoclax and obinutuzumab was tested. These combinations achieved undetectable minimal residual disease in large proportions of patients [1-4], which correlates with long treatment-free remissions.

Where do you see BTK inhibition in the management of B-cell malignancies 3 years from now?

This is a very difficult question. If you look at the data, you see that in the RESONATE-2 trial investigating first-line ibrutinib in patients with CLL/SLL, 70 % of patients were progression-free at the time of the 5-year update that was recently published [5]. However, only 60 % were still receiving the study drug. The follow-up is still relatively short. I think single-agent BTK inhibitors will be a good option for several patients, particularly for those with comorbidities. It is being said that combinations tend to have more side effects; for instance, the rates of neutropenia are higher if you combine venetoclax with other drugs. Some of the newer BTK inhibitors have a favorable safety profile and might thus be more suited to long-term usage. A number of long-term toxicities have not been elucidated yet. There is a risk of infection, hypertension and arrhythmias, and there is also a question about second primary malignancies. Continuously administered BTK inhibitors are one option and combination time-limited therapy is another; it is really hard to say which one will win out. However, many patients have been on BTK in­hibitor therapy for several years and have achieved great disease control.

What are the strengths and limitations of immune checkpoint inhibition in B-cell malignancies from the current point of view?

This area is still emerging. We have seen very good responses in primary medi­astinal lymphoma and Hodgkin’s disease [6-8]. However, most studies to date have involved the PD-1 and PD-L1 checkpoints, although there are many other inhibitory receptors such as CTLA-4, TIM-3, TIGIT, and BTLA that can be explored. This also includes the agonist receptors 4-1BB, LAG-3, OX40 and CD27, the macrophage checkpoint CD47, and NK ligands. The main problem with these drugs is induction of autoimmunity, which can involve any organ system. Immune-related toxicities include rash, colitis, pneumonitis, or even endocrine insufficiency.

This entire area of immune checkpoint inhibition is a fantastic emerging area. However, our knowledge is early, and we still have a long way to go. Some patients are already deriving benefit, and I think there will be many more once we have worked out what the best combinations are and in which patients they should be used.


  1. Al-Sawaf O et al., Fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocyctic leukaemia: follow-up of efficacy and safety results from the multicenter, open-label, randomized phase 3 CLL14 trial. EHA 2020, abstract S155
  2. Wierda WG et al., Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia/small lymphocyctic lymphoma: 1-year disease-free survival results from the MRD cohort of the phase 2 CAPTIVATE study. ASH 2020, abstract 123
  3. Woyach JA et al., Acalabrutinib in combination with venetoclax and obinutuzumab or rituximab in patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia. ASH 2020, abstract 1312
  4. Davids MS et al., Updated safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab (AVO) for frontline treatment of chronic lymphocytic leukemia (CLL). ASH 2020, abstract 2216
  5. Burger JA 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: 787-798
  6. Zinzani PL et al., Nivolumab combined with brentuximab vedotin for relapsed/refractory primary mediastinal large B-cell lymphoma: efficacy and safety from the phase II CheckMate 436 Study. J Clin Oncol 2019; 37: 3081-3089
  7. Moskowitz AJ et al., Brentuximab vedotin and nivolumab for relapsed or refractory classic Hodgkin Lymphoma: long-term follow-up results from the single-arm phase 1/2 study. Blood 2019; 134 (Supplement_1): 238
  8. Kuruvilla J et al., Effect of pembrolizumab monotherapy compared with brentuximab vedotin on patients with relapsed/refractory classical Hodgkin lymphoma by prior lines of therapy: an exploratory analysis of the randomized phase 3 KEYNOTE-204 study. ASH 2020, abstract 1158

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