In the past decade, there have been exponential improvements in the understanding of chronic lymphocytic leukemia (CLL), which has led to novel treatment approaches and increased overall survival – however, patients often ask how long treatment will be required and if their disease will ever be cured. The current frontline options of indefinite BTKi versus time limited therapy with obinutuzumab-venetoclax (GVe) have led to debates regarding the best treatment approach, without a true head to head comparison. These novel therapies have also left oncologists questioning the role for chemoimmunotherapy (CIT), which was the standard of care for many years. In recent years CIT has been used less, but is still considered for select younger, fit patients, with mutated IgVH and without TP53 mutation or deletion(17p), as this is a finite treatment with the goal of a long remission (or even cure) without the need for ongoing treatment.
Dr. Susan O’Brien moderated Sunday’s Education Program session on CLL (available on demand) and described the combination small molecules (with or without antibody) as “the wave of the future.” Several abstracts presented this year examine such combinations. The use of GVe in the frontline setting was previously reported in patients with CLL with comorbidities (CLL14); however, data in a more fit population had not yet been reported. The International Intergroup GAIA trial (CLL13; abstract 71) addressed frontline use of anti-CD20+venetoclax combination therapy compared to CIT in fit patients without TP53 mutation/deletion. The study had four arms: CIT (fludarabine, cyclophosphamide, rituximab [FCR] for those ≤ 65 years old or bendamustine-rituximab [BR] for those older than 65 years), rituximab-venetoclax (RV), GVe, and obinutuzumab-venetoclax-ibrutinib (GIVe). The time-limited therapies of GVe and GIVe provided superior undetectable minimal residual disease (uMRD) rates in peripheral blood at 15 months compared to CIT (86.5% and 92.2 vs. 52.0% with CIT; p<0.0001). The RV arm was not superior to CIT in uMRD rates. This may challenge whether CIT has a role even in the younger patient population described above, since higher uMRD rates were seen with GVe and GIVe. In a similar fashion, the 2-year update of the phase 2 Captivate study of ibrutinib + venetoclax in treatment naïve CLL was presented with the 2-year DFS rate in the MRD-guided placebo arm remaining at 95%. This may support the use of fixed duration ibrutinib/venetoclax for upfront therapy of CLL.
We continue to see data suggesting that MRD testing may also be useful to guide when to stop or restart treatments. Dr. Carsten Utoft Niemann presented data examining use of MRD to guide therapy after venetoclax-ibrutinib in the relapsed and refractory setting. Patients who had undetectable MRD in blood and bone marrow after 15 cycles of therapy were randomized 1:2 to ibrutinib maintenance or treatment cessation; patients who became MRD positive re-initiated combination therapy. Similar outcomes were seen in patients on ibrutinib maintenance compared to observation (abstract 69). Patients who developed detectable MRD were successfully reinitiated on therapy, suggesting that MRD-guided treatment could prove to be a strategy to help prevent acquired resistance to therapies. Dr. Alessandra Tedeschi presented data on another BTKi-venetoclax combination, zanubrutinib-venetoclax therapy in patients with treatment naïve CLL with deletion 17p, arm D of the phase III SEQUOIA trial (abstract 67). There was an overall response rate of 96.8 percent in this high-risk group.
For the patients who don’t mind adding another pill to the box, what happens when the clock runs out? Second-generation covalent BTKis acalabrutinib and zanubrutinib have helped mitigate some of the off-target side effects of ibrutinib, but Dr. O’Brien reminded us that these second-generation BTKis have mechanisms of resistance similar to ibrutinib, namely BTK mutations. Updates on two non-covalent inhibitors, pirtabrutinib and MK-1026 (nemtabrutinib), were presented at this year’s meeting (abstracts 391 and 392). Both drugs show promising efficacy in heavily pretreated patients with CLL/small lymphocytic lymphoma (SLL) who had prior resistance to other BTKi with a manageable side effect profile. However, a limitation of these drugs is that they do not usually clear MRD; therefore, continuous therapy is required.
So, what is the answer for frontline treatment? Fixed-duration small molecule/antibody combinations? Indefinite single agent BTKi? Is the answer more complicated? Dr. Constantine Tam also presented during the Education Program session “CLL: Extending Survival,” making the argument that a “BTKi is logistically easier and provides better coverage against poor prognostic groups, at the price of indefinite therapy.” He discussed how GVe has lower progression-free survival in patients with deletion(17p) or TP53 mutations and those with unmutated IGVH, whereas BTKis appear to be generally effective across subgroups. Dr. Tam reviewed important logistic challenges with venetoclax-based regimens including the ramp-up involved and monitoring for tumor lysis syndrome, renal function, and urgent electrolyte management.
Also in this CLL session, Dr. Deborah Stephens addressed the role of anti-CD20 antibody therapy in CLL. She recommended using anti-CD20 antibody therapy in numerous situations: with FCR, with venetoclax-based therapy (obinatuzumab in frontline and rituximab in subsequent lines), and with PI3K inhibitors (idelalisib+rituximab in relapsed setting, emerging data for ublituximab+umbralisib in frontline or relapsed settings). She did not recommend use of anti-CD20 antibodies with BTKi unless there is need for urgent disease control or uncontrolled autoimmune cytopenias; neither does she recommend anti-CD20 antibody maintenance therapy. When we asked her opinion on time-limited compared to continuous therapy, Dr. Stephens answered, “I feel very fortunate to have so many great weapons to fight CLL and so many different ways to use them. I think it will come down to tailoring the therapy for each individual patient. Younger patients in particular are well-suited for time-limited therapies, which will limit the overall years of their life that they would have to maintain indefinite therapy. Select high-risk patients, such as those with TP53 mutation or del(17p) will likely benefit from continuous therapy until relapse.”
During the live Q&A for the education session (available on demand), many questions were asked of the panelists. When asked about the combination of venetoclax with ibrutinib, the panelists endorsed enthusiasm for the combination, but shared concerns about cost, the uncertainty about what to do at relapse in that setting, and tolerability, particularly in older patients. The panelists were asked if they currently use MRD to guide duration of therapy. Dr. Stephens pointed out that she does check for MRD at the end of-time limited therapy, but that currently this does not affect what she does therapeutically. Multiple presenters pointed out the limited availability of MRD tests as well as the heterogeneity of the methods used, making it hard to form universal conclusions. There was also a question about whether we should consider treating at the point of MRD positivity versus waiting for frank relapse. Dr. Stephens pointed out that studies are looking at this question, and we will need to take note of both PFS and tolerability when we evaluate these trials. For now, there does not appear that there is any data to suggest re-initiating therapy at the time of MRD positivity versus waiting for clinical relapse. The panelists note that they often do follow MRD in peripheral blood, but currently at most that information helps them determine how often to monitor the patient.
So, in the end, the answer is complicated, but we are fortunate to have an ever-expanding toolkit in terms of not only novel therapies, but tools to monitor response and guide therapy (MRD testing).
Dr. Blackmon and Dr. Brem indicated no relevant conflicts of interest.