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Università Vita-Salute San Raffaele
Strategic Research Program on CLL
Lydia Scarfò, MD, has disclosed that she has received consulting fees from AbbVie, AstraZeneca, Gilead Sciences, and Janssen.
At the 2019 ASH annual meeting, exciting data were presented from several studies that were relevant to clinicians involved in caring for patients with chronic lymphocytic leukemia (CLL) and lymphomas. Novel agents to address unmet clinical needs and new data on previously established drugs are bringing innovative and effective treatment strategies closer to the clinic. In this commentary, I discuss the clinical data and share my thoughts on practical implications of these findings from a European perspective.
Phase III ELEVATE-TN Trial
New frontline treatment options for patients with CLL including ibrutinib monotherapy and venetoclax plus obinutuzumab have become available in recent years. Although previous studies in CLL reported no significant benefits by adding rituximab to ibrutinib, high response rates and prolonged PFS have been observed with the combination of a BTK inhibitor and obinutuzumab, but a direct comparison with single-agent BTK inhibitor was lacking.
At ASH 2019, Sharman and colleagues presented results from the phase III ELEVATE-TN study of acalabrutinib with or without obinutuzumab vs chlorambucil plus obinutuzumab in previously untreated CLL. This trial included patients aged 65 years or older and younger patients with comorbidities. At a median follow-up of 28 months, the study met its primary endpoint of PFS favoring acalabrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab (24-month PFS rate: 93% vs 47%; HR: 0.10; P < .0001) with a significant PFS benefit also seen in patients receiving acalabrutinib monotherapy vs the control arm (24-month PFS rate: 87% vs 47%; HR: 0.20; P < .0001). Of interest, the HR was 0.49 in favor of acalabrutinib plus obinutuzumab vs acalabrutinib, although no P value was reported. The safety profile was in line with the expected acalabrutinib-related toxicities, including grade 1/2 headache and grade 3/4 infection. Although a higher rate of grade 3/4 neutropenia was documented with the addition obinutuzumab to acalabrutinib, it was comparable to the control arm of chlorambucil plus obinutuzumab. Infusion-related reaction and grade 5 adverse events occurred less frequently in the acalabrutinib-containing arms.
These positive results from ELEVATE-TN along with those from the phase III ASCEND trial of acalabrutinib in relapsed/refractory CLL led to the recent FDA approval of acalabrutinib for treating CLL or small lymphocytic lymphoma (SLL). Although acalabrutinib is not yet approved in Europe for patients with CLL/SLL, the results from ELEVATE-TN suggest that acalabrutinib with or without obinutuzumab could be a very relevant addition to our therapeutic armamentarium in the near future. This is particularly true considering its favorable safely profile with low rates of atrial fibrillation and major bleeding coupled with prolonged PFS and high response rates.
Phase II CAPTIVATE Trial
The combination of ibrutinib and venetoclax is currently being explored in several clinical trials in both treatment-naive and relapsed/refractory patients with CLL/SLL. This investigational combination has the advantage of inducing deep responses with undetectable measurable residual disease (MRD) in the majority of patients, thus allowing for a fixed-duration treatment regimen. At ASH 2019, Tam and colleagues presented results from the MRD cohort of the phase II CAPTIVATE study of frontline ibrutinib plus venetoclax in patients with CLL/SLL. In this study, venetoclax was added after 3 cycles of ibrutinib lead-in with the goal of reducing the risk for tumor lysis syndrome (TLS). After 12 cycles of the combination therapy, patients with undetectable MRD were randomized to ibrutinib vs placebo and those with detectable MRD were assigned to ibrutinib or ibrutinib plus venetoclax. With 12 cycles of ibrutinib plus venetoclax, the undetectable MRD rate was 74% in peripheral blood and 72% in bone marrow. No clinical TLS occurred in the trial with 76% of patients with a high baseline TLS risk downgraded to lower risk after ibrutinib lead-in. Although the concomitant administration of ibrutinib and venetoclax nearly doubled the plasma concentration of venetoclax, no new safety signals were reported, and the most frequent grade 3/4 toxicities included neutropenia, hypertension, thrombocytopenia, and diarrhea. Longer follow-up is needed to understand if this combination can lead to sustained deep remission after treatment interruption and to identify patients who will most likely benefit from this approach. From the European standpoint, fixed-duration treatment strategies allowing for drug holiday are worth pursuing to gain long-term disease control, minimize toxicities, and reduce financial cost.
Phase III MURANO Trial
Results from the phase III MURANO trial set a standard of care in relapsed/refractory CLL with a fixed-duration regimen of venetoclax plus rituximab showing superior PFS and OS compared with bendamustine plus rituximab. At ASH 2019, Seymour and colleagues reported results from an updated analysis of MURANO with a median follow-up of 48 months. Sustained PFS and OS benefits were observed with venetoclax plus rituximab vs bendamustine plus rituximab with a 24-month PFS rate of 68%. Undetectable MRD at the end of treatment was associated with the longest PFS followed by low MRD positivity and high MRD positivity. Of note, patients with high MRD positivity at the end of treatment had rising MRD levels in peripheral blood before venetoclax cessation, suggesting that prolonged venetoclax treatment is unlikely to provide much benefit. In patients who progressed after venetoclax discontinuation, treatment with ibrutinib produced responses in all of the 10 evaluable patients, whereas retreatment with venetoclax led to a PR in 6 of 11 evaluable patients. Regarding toxicities, no new safety signals with venetoclax were observed during the extended follow-up.
These updated results from MURANO further support the use of venetoclax plus rituximab as salvage therapy in patients with relapsed/refractory CLL, and this combination regimen is approved in both the United State and Europe. Further investigation is needed to better identify and manage those patients with detectable MRD at the end of treatment who are likely to relapse quickly based on the available data.
Phase I BRUIN Trial
Disease progression on ibrutinib represents an ongoing clinical challenge in CLL and other B-cell malignancies. Current available evidence suggests that patients who have developed resistance to ibrutinib commonly acquire the BTK C481S mutation, leading to suboptimal BTK inhibition by ibrutinib. Novel agents targeting BTK are being developed including LOXO-305, a highly potent noncovalent BTK inhibitor that has activity against both wild-type BTK and mutated BTK with the C481S mutation. At ASH 2019, Mato and colleagues presented results from the first-in-human, dose-escalation phase I BRUIN trial of LOXO-305 in 28 patients with CLL or B-cell non-Hodgkin lymphoma who received at least 2 previous therapies. No dose-limiting toxicities were reported and the maximum tolerated dose was not reached. LOXO-305 was generally well tolerated with a favorable safety profile. Even more impressive were the responses obtained, with 77% of patients with CLL and 50% with mantle cell lymphoma (MCL) responding. LOXO-305 demonstrated antitumor activity at all dose levels and also in patients with acquired resistance to ibrutinib regardless of the C481S mutation status.
Although the median follow-up of this study is relatively short, if confirmed with prolonged observation, LOXO-305 may represent a very effective therapy for patients progressing on ibrutinib who have very limited treatment options. Since its approval in 2014, ibrutinib has been widely adopted in Europe based on its favorable efficacy and safety profiles, but its use is limited by resistance and intolerance. New agents with improved tolerability and the potential for activity in ibrutinib-resistant or ibrutinib-intolerant patients will play an important role in the future management of patients with CLL or other B-cell malignancies.
Phase II ZUMA-2 Trial
Patients with MCL who progress on BTK inhibitors have poor outcomes with a median OS of just 6-10 months, and new treatment options are urgently needed. At ASH 2019, Wang and colleagues presented results from the pivotal phase II ZUMA-2 trial of the CD19-targeted CAR T-cell therapy KTE-X19 in 68 patients with relapsed/refractory MCL including those who failed previous BTK inhibitor. The study population included 25% of patients with blastoid morphology and 17% with TP53 mutations. Among 60 evaluable patients, ORR was very impressive at 93% with a CR rate of 67%. At a median follow-up of 12.3 months, 78% of patients with a CR remained in remission without further treatment. Treatment-emergent adverse events were as expected and the safety profile was consistent with previous studies of CD19-directed CAR T-cells in aggressive non-Hodgkin lymphoma. Although 91% of patients experienced cytokine-release syndrome (CRS) of any grade, only 15% were grade ≥ 3 and all events resolved. No grade 5 CRS or neurologic events were observed in the study. Patients with the most robust CAR T-cell expansion were at higher risk of grade ≥ 3 neurologic events and CRS.
If the favorable efficacy and safety profile of CAR T-cells in MCL is confirmed, it will expand the therapeutic armamentarium for this disease with a treatment strategy that is effective even in patients progressing on BTK inhibitors. To this end, since EMA market authorization of the first CAR T-cell therapy in 2018, many European medical centers have spent much effort in developing the necessary structures to provide essential support for using CAR T-cell therapies to treat aggressive B-cell lymphomas and acute lymphoblastic leukemia.
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.