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Division of Hematology/Oncology
School of Medicine
University of California, Irvine
Susan M. O'Brien, MD, has disclosed that she has received consulting fees from AbbVie, Alexion, Amgen, Aptose Biosciences, Astellas, Celgene, Eisai, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Pfizer, Pharmacyclics, Sunesis, TG Therapeutics, and Verastem Oncology and funds for research support from Acerta, Gilead Sciences, Kite, Pfizer, Pharmacyclics, Regeneron, Sunesis, and TG Therapeutics.
New therapeutic approaches for patients with chronic lymphocytic leukemia (CLL) have the potential to improve efficacy and safety as well as expand treatment options in both the frontline setting and relapsed/refractory disease. At the ASCO 2019 annual meeting, we saw several exciting presentations on new treatment strategies in CLL. In this commentary, I briefly review the data and share my thoughts on a few of these studies that I found particularly interesting.
Results from the German phase III CLL14 trial were highly anticipated at the ASCO annual meeting this year after a press release late last year announced that the trial met its primary endpoint of PFS. Interestingly, the combination of venetoclax and obinutuzumab received FDA approval based on CLL14 data for patients with previously untreated CLL in May 2019, a few weeks before the ASCO presentation.
CLL14 was an open-label, randomized trial of venetoclax plus obinutuzumab vs chlorambucil plus obinutuzumab in patients with previously untreated CLL and coexisting medical conditions, including high comorbidity scores and/or reduced renal function. The study enrolled 432 patients, most of whom were older with a median age of 72. Notably, the treatment duration was fixed at 12 months in both arms. Not surprisingly, venetoclax plus obinutuzumab led to significantly longer PFS and higher rates of measurable residual disease (MRD) negativity in both peripheral blood and bone marrow. Moreover, MRD negativity in the venetoclax plus obinutuzumab arm occurred early and it was quite durable. This is likely to translate into very long remission with the added advantage of being a finite therapy. The PFS benefit was more prominent in patients with unmutated IGHV, and it was observed regardless of TP53 status, as seen with ibrutinib. IGHV mutation status is a strong predictor for outcomes with chemoimmunotherapy, but it might lose its significance as we move away from chemoimmunotherapy to targeted agents.
Now that it is approved in the United States, will oncologists begin using the combination of venetoclax and obinutuzumab? I think one issue that may slow the incorporation of this new regimen into clinical practice is the risk for tumor lysis syndrome and the associated monitoring requirement with venetoclax. The monitoring protocol is especially cumbersome, and I suspect that tends to deter physicians in the community from using venetoclax. However, if you want to prescribe a chemotherapy-free regimen, this combination provides a new option in addition to ibrutinib. Additionally, it offers a major advantage over ibrutinib in terms of the duration of treatment with the venetoclax plus obinutuzumab regimen being administered for a defined period of time while ibrutinib is a continuous treatment until either disease progression or intolerance. It will be interesting to see how clinicians incorporate this regimen as a frontline option for their CLL patients.
In my own practice, selecting first-line therapy for patients with CLL is becoming increasingly complex. I still use chemoimmunotherapy, specifically fludarabine/cyclophosphamide/rituximab (FCR), in younger, more fit patients with mutated IGHV. I like using FCR in select patients because we know from long‑term follow-up data, there is a plateau on the PFS curve suggestive of a possible cure for certain patients. For patients who are older or less fit, the discussions will revolve around the pros and cons of ibrutinib vs venetoclax plus obinutuzumab. With ibrutinib, we do not yet know the median PFS in the frontline setting, as none of the relevant clinical trials have reached median PFS. Based on data in the relapsed/refractory setting, I predict that ibrutinib will lead to approximately 7-8 years of remission in the frontline setting, which is an attractive outcome even without achieving MRD negativity. However, as mentioned, ibrutinib entails continuous therapy. Venetoclax plus obinutuzumab offers an attractive alternative in terms of being a fixed-duration therapy, which also translates to ultimately lower copays for patients. However, although the proportion of patients achieving and maintaining MRD negativity with venetoclax plus obinutuzumab is quite striking, we currently have limited long‑term data with this regimen.
Acalabrutinib is a second-generation Bruton tyrosine kinase (BTK) inhibitor that has demonstrated very high response rates (> 90%) as a single agent in both treatment-naive and relapsed/refractory CLL. We know that combining an anti-CD20 monoclonal antibody with a BTK inhibitor results in more rapid responses due to abrogation of lymphocytosis by the antibody. We have seen this approach in the phase III iLLUMINATE trial where obinutuzumab was combined with ibrutinib.
At the ASCO annual meeting this year, we saw 3-year follow-up results from the phase Ib/II ACE-CL-003 trial that paired acalabrutinib with obinutuzumab in patients with treatment-naive or relapsed/refractory CLL. Among 45 participants, the ORRs were quite high: 95% in the treatment-naive group and 92% in the relapsed/refractory group. These rates are comparable with what we have seen with acalabrutinib monotherapy, which begs the question: what is the relative contribution of obinutuzumab in this regimen? Looking at the CR rates, it is tempting to conclude that the antibody is bolstering CRs in the frontline setting. Among patients whose disease was treatment-naive, 32% achieved a CR. In contrast, in the phase I/II ACE-CL-001 study of acalabrutinib monotherapy, only 5% of treatment-naive patients had a CR with a median follow-up time of 42 months.
In the extended follow-up of ACE-CL-003, median PFS was not reached in either group. The 39-month PFS rate was 94% in treatment-naive patients, and the 42-month PFS rate was 73% in relapsed/refractory patients. These data are quite striking, particularly in the frontline setting. They are also quite similar to data from the ACE-CLL-001 study where 97% of treatment-naive patients remained progression free at 36 months. The rates of MRD negativity in bone marrow were also impressive. After 1 year on treatment, 26% of treatment-naive patients and 15% of patients with relapsed/refractory disease had a negative MRD test result, which is probably higher than what we would expect from acalabrutinib alone. The outstanding question is how the median PFS with acalabrutinib plus obinutuzumab will compare with acalabrutinib monotherapy.
Regarding the safety profile, a potential advantage of acalabrutinib is the reduced toxicity relative to ibrutinib, thanks to it being more selective with less off-target effects. Indeed, many of the toxicities associated with ibrutinib are likely from inhibition of kinases other than BTK. We know from earlier data and this trial that one of the most common adverse events with acalabrutinib is headache, which is manageable and does not tend to lead to treatment discontinuations. Overall, acalabrutinib plus obinutuzumab is well tolerated with manageable toxicities.
The current study had no control arm, but considering the data we have for acalabrutinib monotherapy, I think it suggests that obinutuzumab is a beneficial addition. To get more insights on the role of obinutuzumab, we will look forward to seeing results from the phase III ELEVATE-TN trial (NCT02475681) of acalabrutinib monotherapy vs acalabrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab in patients with treatment-naive CLL. A recent press release announced that this trial met its primary endpoint of PFS.
TRANSCEND CLL 004 Trial
The final study I will highlight is the TRANSCEND CLL 004 trial, a phase I/II study of lisocabtagene maraleucel (formerly JCAR017), a CD19-directed CAR T-cell therapy, in patients with relapsed/refractory CLL or small lymphocytic lymphoma who are ineligible for ibrutinib therapy or have progressed on ibrutinib. At ASCO 2019, the investigators presented results from the phase I dose-escalation portion of this trial in which 2 dose levels were evaluated in 23 patients. As we have seen in previous CAR T-cell therapy trials, these patients were heavily pretreated; all received prior ibrutinib therapy and over half received prior venetoclax therapy. An interesting facet of this particular CAR T-cell therapy is that CD4+ and CD8+ cells are separated to provide a defined composition of each T-cell subset. This strategy is based on preclinical data suggesting that each T-cell subset contributes a distinct but important function.
Overall, the results were encouraging. Cytokine release syndrome (CRS) is a common toxicity with CAR T-cell therapy, and indeed it was observed in 74% of patients. However, the incidence of grade 3 CRS was quite low at < 10%. Five patients (22%) had grade 3 or worse neurologic events, which is comparable with previous CAR T-cell therapy trials. The ORR was high at 82%, and nearly half of those were CR or CR with incomplete hematologic recovery. Although the median follow-up was relatively short at 9 months, the responses appeared to be durable. We know from other CAR T-cell therapy trials that relapse is common and tends to occur early, within the first year or so.
Overall, I find these results promising, as we do not have a commercially available CAR T-cell therapy for CLL yet. Remember, CLL presents a unique challenge for developing CAR T-cell therapy because the T-cells in these patients are dysfunctional, especially in those who are heavily pretreated. The trial is now open in the phase II stage, and I am eager to follow the phase II results, which could potentially lead to FDA approval if the trial results turn out to be positive.
What are your thoughts on new treatment strategies for patients with CLL? I encourage you to answer the polling question and join the conversation in the comments box below.