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ASH 2019: CLL/Lymphomas
My Take on Key Studies in CLL and Lymphomas From ASH 2019

Released: January 23, 2020

Expiration: January 21, 2021

Jeffrey P. DONOTUSESharman
Jeffrey P. DONOTUSESharman, MD
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Treatment options for patients with chronic lymphocytic leukemia (CLL) and lymphomas have expanded rapidly in recent years with the introduction of new targeted therapies. At the ASH 2019 annual meeting, results from several exciting studies were presented on new treatment strategies in CLL and lymphomas. In this commentary, I discuss the clinical data and share my thoughts on practical implications of these findings.

Phase III ELEVATE-TN Trial
The first study I would like to discuss is ELEVATE‑TN, which I presented during an oral session at ASH 2019. This was a phase III trial of acalabrutinib with or without obinutuzumab vs chlorambucil plus obinutuzumab in previously untreated CLL including patients aged 65 years or older and those aged younger than 65 years with medical comorbidities. In total, 535 patients were randomized 1:1:1 to 3 different arms: acalabrutinib plus obinutuzumab, acalabrutinib alone, and a standard chemoimmunotherapy arm of chlorambucil plus obinutuzumab. The primary endpoint of the study was PFS with acalabrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab. Not surprisingly, a strong PFS benefit was observed with both acalabrutinib-containing arms compared with the chemoimmunotherapy arm. The 2‑year PFS rate was 93% with acalabrutinib plus obinutuzumab, 87% with acalabrutinib alone, and 47% with chlorambucil plus obinutuzumab. In addition, the PFS benefit of acalabrutinib was seen across patient subgroups, including those with high-risk disease and mutated IGHV.

In November 2019, the FDA approved acalabrutinib for the treatment of CLL or small lymphocytic lymphoma (SLL) based on results from ELEVATE-TN and the phase III ASCEND trial of acalabrutinib in relapsed/refractory CLL. Acalabrutinib is the second BTK inhibitor approved by the FDA for CLL, and it has a slightly different safety profile from ibrutinib, including fewer incidents of arthralgia and a lower rate of cardiac adverse events. However, acalabrutinib is associated with a higher rate of headache during the initial treatment phase, and it is too early to tell whether there are differences in bruising or bleeding between these 2 BTK inhibitors. ELEVATE-RR is a head‑to‑head phase III study comparing acalabrutinib with ibrutinib in previously treated high-risk CLL, and results from this trial should help tease out the differences in safety profile more clearly between these 2 BTK inhibitors. I think it would be reasonable for most practicing clinicians who treat CLL to become familiar with both agents, so that they can make the best choice for their patients.

Another interesting finding from ELEVATE-TN is the potential benefit of adding a CD20 antibody to a BTK inhibitor. Previously, it was believed that the addition of a CD20 antibody to a BTK inhibitor does not provide additional benefit, based on results from multiple studies, including the phase III Alliance trial comparing ibrutinib with or without rituximab with bendamustine plus rituximab. Therefore, it was a welcome surprise to see the PFS data from ELEVATE-TN, which showed an HR of 0.49 in favor of acalabrutinib plus obinutuzumab vs acalabrutinib, with a CI not crossing 1. However, this was a post hoc exploratory analysis for which a P value was not available. At this time, I think it would be reasonable to consider adding obinutuzumab to acalabrutinib for treating patients with CLL, although there is currently no established standard of care to delineate whether doing so is beneficial.

Phase II CAPTIVATE Trial
CAPTIVATE was a phase II study evaluating frontline ibrutinib plus venetoclax for the treatment of patients with CLL/SLL. Results from the measurable residual disease (MRD) cohort of CAPTIVATE were presented at ASH 2019. A total of 164 patients aged younger than 70 years with previously untreated CLL/SLL received 3 cycles of ibrutinib monotherapy as lead-in therapy, followed by 12 cycles of ibrutinib plus venetoclax. The purpose of ibrutinib lead-in was to eradicate a substantial volume of CLL cells, enabling patients to be effectively debulked prior to initiation of venetoclax with ramp-up dosing, thereby reducing the risk of tumor lysis syndrome (TLS). That is, in fact, exactly what was demonstrated in this study. Of patients with high TLS risk at baseline, 90% transitioned to medium or low risk with the ibrutinib lead-in, whereas no patients with low or medium TLS risk at baseline shifted to high risk. Two patients developed biochemical evidence of TLS, but no patients experienced clinical TLS.

This study also demonstrated that ibrutinib increases exposure to venetoclax, possibly by pharmacokinetic interaction. This drug–drug interaction might be the reason for the relatively high rate of grade 3/4 neutropenia in this study. Moving forward, hematologic toxicity appears to be the biggest concern for this combination. Regarding efficacy, the combination of ibrutinib plus venetoclax was quite effective, resulting in high rates of MRD negativity in both peripheral blood and bone marrow. Although this combination is not yet approved by the FDA, the phase III GLOW trial comparing ibrutinib plus venetoclax with obinutuzumab plus chlorambucil as frontline therapy for CLL/SLL is fully accrued. Positive results from this trial will likely lead to FDA approval of ibrutinib plus venetoclax, which would provide an appealing all-oral combination regimen to patients with previously untreated CLL/SLL.

Phase I/II TRANSCEND CLL 004 Trial
Despite initial signs of activity, an indication for CAR T-cell therapy in CLL has lagged behind some of the other hematologic malignancies. The approved CD19-directed CAR T-cell therapies have modest efficacy in CLL, possibly due to underlying T‑cell dysfunction from previous therapies or immunologic abnormalities caused by CLL itself.

Lisocabtagene maraleucel is a differentiated CD19-directed CAR T‑cell product in which CD4+ and CD8+ T-cells are expanded separately and infused at a prespecified ratio. At ASH 2019, Siddiqi and colleagues presented updated results from the phase I/II TRANSCEND CLL 004 study of lisocabtagene maraleucel in 23 patients with relapsed/refractory CLL/SLL who received previous ibrutinib. The ORR was 81.5%, and 75% of patients achieved MRD negativity in peripheral blood. Responses occurred early and deepened over time. Of the 15 patients who achieved undetectable MRD in blood, 12 maintained responses with a median follow-up of 11 months.

At least in some hematologic malignancies, we think there is the possibility that CAR T-cell therapy could be curative for some patients. At this point, it is premature to speculate whether that might also be true in CLL. The challenge in CLL is that there is already an abundance of effective treatment options, and the registration path toward FDA approval for lisocabtagene maraleucel is less clear, as much of the field is moving toward combination therapies. That is something we will look for in future clinical studies with this CAR T-cell product in CLL.

Phase I/Ib GO2971 Trial
Mosunetuzumab is a full-length bispecific antibody targeting both CD20 on B-cells and CD3 on T-cells, enabling elimination of malignant B-cells by T-cells. It has been evaluated in both indolent and aggressive lymphomas. Of importance, this agent is associated with possible cytokine-release syndrome as well as neurotoxicity and requires a step-up dosing strategy to reduce this risk.

At ASH 2019, Schuster and colleagues presented results from the phase I/Ib GO2971 study of mosunetuzumab in 270 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). The ORR in the subgroup of patients with indolent NHL was high at 63%, with a CR rate of 43%, and most patients achieving a CR had durable responses. In patients with aggressive NHL, the ORR was lower at 37%, with a CR rate of 19%. In addition, there was an indication that mosunetuzumab may have a role following CAR T-cell therapy, as the ORR in the 18 patients with previous CAR T-cell treatment was 39%, with a CR rate of 22%. This may be due to mosunetuzumab spurring expansion of the underlying CAR T‑cells that had previously failed to engage the target. Using a bispecific antibody might be a way to improve the efficacy of a failing CAR T‑cell therapy by providing additional T‑cell stimulation.

Mosunetuzumab is not yet approved by the FDA, and the path to registration is not exactly clear at this moment. Of note, another bispecific antibody targeting CD20 and CD3, odronextamab (formerly REGN1979), has also demonstrated promising activity in patients with relapsed/refractory B-cell NHL. Overall, this drug class needs to be watched in the future, and we anticipate robust clinical development in this space.

Phase I BRUIN Trial
Covalent BTK inhibitors such as ibrutinib and acalabrutinib bind to cysteine 481 on BTK, and an acquired resistance mutation can occur that converts cysteine 481 to serine. LOXO‑305 is an investigational, next-generation, noncovalent BTK inhibitor that has shown activity against both wild-type CLL cells and cells harboring the C481S mutation. At ASH 2019, Mato and colleagues presented results from the first-in-human phase I BRUIN trial of LOXO-305 in patients with previously treated CLL or B-cell NHL. Responses were observed at all dose levels, with an ORR of 77% in CLL and 50% in mantle cell lymphoma, respectively. LOXO-305 also demonstrated activity in patients who failed previous BTK inhibitors regardless of C481S mutation status. These results provide proof of concept that using noncovalent BTK inhibitors to treat CLL or B-cell NHL can yield clinical efficacy, and we anticipate further clinical development of these molecules, particularly in patients who either have intolerance or resistance to covalent BTK inhibitors.

Your Thoughts
What are your thoughts on the new data in CLL and lymphomas presented at ASH 2019? I encourage you to answer the polling question and join the conversation in the discussion box below.

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In your current clinical practice, do you test for BTK and PLCG2 resistance mutations in your patients with CLL who have progressed on a BTK inhibitor?
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