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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 2020 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 II CAPTIVATE Trial
The combination of ibrutinib and venetoclax is currently being explored in several clinical trials in both treatment-naive and relapsed/refractory (R/R) patients with CLL/small lymphocytic lymphoma (SLL). This investigational combination has the advantage of inducing deep responses with undetectable measurable residual disease (MRD) in the majority of patients, allowing for a fixed-duration treatment regimen. At ASH 2020, Wierda 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, 58% of the patients had undetectable MRD (uMRD) and were randomized to ibrutinib vs placebo while those 42% of patients with detectable MRD were assigned to ibrutinib or ibrutinib plus venetoclax. The primary endpoint was 1-year disease-free survival, defined as freedom from MRD relapse and without disease progression or death. With a median follow-up of 16.6 months after randomization, the 1-year disease-free survival in the uMRD group was similar regardless of randomization assignment (95% on placebo vs 100% on ibrutinib). Patients with detectable MRD at randomization reached a higher uMRD rate by continuing treatment, with this improvement being greater in those receiving ibrutinib plus venetoclax vs ibrutinib alone. The 30-month PFS from treatment initiation in the uMRD and detectable MRD groups was > 95%. In terms of safety, very few patients required dose adjustments or drug discontinuation, and no new safety signals were reported.
The results compare favorably with other recently presented first-line trials in CLL, with > 95% of patients experiencing a 30-month PFS in all subgroups. From the European standpoint, deep and durable responses with this combination, along with the fixed-duration treatment strategies allow for drug holidays and 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 R/R CLL with a fixed-duration regimen of venetoclax plus rituximab that showed superior PFS and OS compared with bendamustine plus rituximab. At ASH 2020, Kater and colleagues reported the 5-year results from a subset of patients with R/R CLL in the MURANO trial. Previous updates have already documented the superiority of venetoclax plus rituximab vs bendamustine plus rituximab. uMRD at the end of treatment was associated with the longest 3-year PFS of 61.3%. In the 83 patients who completed treatment with venetoclax plus rituximab and achieved uMRD, median time to MRD conversion was 19 months and median time from MRD conversion to disease progression was 25 months. Patients without del(17p), without genomic complexity and with mutated IGHV were more likely to maintain uMRD and had a lower chance to progress after experiencing MRD conversion, in line with the longer MRD doubling time. With this longer follow-up, no new safety concerns were reported, and of note, no increased risk of other malignancies was documented in the venetoclax plus rituximab arm. Sixteen patients were retreated with venetoclax plus rituximab upon disease progression in the amended study, and 5 of these patients obtained uMRD. These data suggest prolonged disease control in those obtaining uMRD at the end of treatment. MRD kinetics highlight that patients with high genomic complexity—including those with del(17p)—have a more rapid MRD doubling time and are at higher risk of relapse. Retreatment with venetoclax plus rituximab was able to induce uMRD in approximately one third of cases. This regimen is already approved and widely available in the United States and Europe, and these long-term results further confirm the benefit of fixed-duration venetoclax plus rituximab in patients with R/R CLL, with 50% of patients being progression free approximately 3 years after discontinuing treatment.
Phase I/II BRUIN Trial
Disease progression on ibrutinib represents an ongoing clinical challenge in CLL and other B-cell malignancies. Currently 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 2020, Mato and colleagues presented updated results from the CLL/SLL-specific cohort from the phase I/II BRUIN trial. The CLL/SLL group included heavily pretreated patients with a median of 3 previous therapies. Eighty-six percent of the patients were previously exposed to a covalent BTK inhibitor, and of those, two thirds of cases were discontinued because of disease progression; 34% of the patients had previously received venetoclax. In this patient population with very difficult-to-treat disease, LOXO-305 was able to obtain an ORR of 63%, with responses deepening over time and reaching up to 86% in patients followed for at least 10 months.
Of note, the ORR was the same regardless of previous BTK inhibitor exposure, BTK inhibitor discontinuation, and BTK/PLCG2 mutation status. LOXO-305 was generally well tolerated with very few grade 3/4 adverse events (AEs), and only 5 of the 323 patients in the cohort discontinued the drug due to treatment-related AEs. Covalent BTK inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib, have shown great efficacy in patients with CLL, but with prolonged follow-up, treatment discontinuation due to disease progression or intolerance is generating an unmet clinical need. Third-generation, noncovalent BTK inhibitors have shown very promising activity in patients with R/R CLL, and LOXO-305, with longer follow-up and more treated patients, confirms the favorable results previously presented at ASH 2019. Of significance, LOXO-305 also was effective in patients carrying BTK and/or PLCG2 mutations that are associated with resistance to covalent BTK inhibitor.
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 I/II Transcend CLL 004 Trial
Lisocabtagene maraleucel (liso-cel) 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 2020, Wierda and colleagues presented results from the phase I cohort of liso-cel in combination with ibrutinib for patients with R/R CLL/SLL. The combination of a BTK inhibitor with anti-CD19 CAR T-cell therapy has previously been shown to improve response rates and reduce toxicities in preclinical models and small clinical experiences in patients with CLL. In this cohort, patients were eligible if they were progressing on ibrutinib at enrollment or showed high-risk features (less than CR on ibrutinib or BTK/PLCG2 mutations or previous treatment with ibrutinib and no contraindication to resume it). A total of 19 patients with heavily pretreated CLL and a median of 4 previous therapies and showing unfavorable disease features (42% carrying 17p deletion, 32% TP53 mutation, 42% complex karyotype) were treated. The most common grade 3/4 AEs were represented by cytopenias and febrile neutropenia; cytokine-release syndrome occurred in 74% of patients, but grade 3 cytokine-release syndrome was uncommon (only 5%), and 16% of patients presented with grade 3 neurologic events. However, ibrutinib discontinuation because of AEs was rare. After a median follow-up of 10 months, ORR reached 95% with 63% CR, up to 89% of patients achieved uMRD in peripheral blood by flow cytometry, and up to 75% achieved uMRD in bone marrow by next-generation sequencing. Sixteen of 18 patients with at least 6 months of follow-up maintained or improved their responses over time. The efficacy of initial CAR T-cell strategies have been disappointing in CLL. This could be linked to the profound immune dysregulation associated with the disease and in particular the impaired T-cell function leading to suboptimal CAR T-cell activity. Transcend CLL 004 is demonstrating improved efficacy and tolerability of CAR T-cell therapy in combination with ibrutinib therapy and may indicate a widely applicable and safe strategy to achieve deep and durable responses and reduce toxicity.
Transcend NHL 001 Trial
Liso-cel, the anti-CD19 4-1BB CAR T-cell therapy, is characterized by a 1:1 ratio between CD4+ and CD8+ CAR T-cells administered separately at equal target doses. At ASH 2020, Palomba and colleagues presented safety and preliminary efficacy data with liso-cel in patients with R/R mantle cell lymphoma from the Transcend NHL 001 Trial. The study enrolled patients with heavily pretreated R/R mantle cell lymphoma, previously exposed to BTK inhibitors, alkylating agents, and anti-CD20 monoclonal antibodies. Forty-one percent of the patients were of blastoid morphology and 22% carried TP53 mutations; of note, patients with secondary central nervous system lymphoma were also eligible. ORR was 84%, with 66% CR without differences in terms of response in patients with blastoid morphology and/or ibrutinib resistance. Median follow-up was only 3.9 months, so the durability of such responses needs to be confirmed with longer observation. TLS and cytopenias were dose-limiting toxicities, but the risk of severe (grade ≥ 3) cytokine-release syndrome or neurologic events was only 3% and 10%, respectively. Two deaths (1 due to TLS and 1 to cryptococcal meningoencephalitis) were deemed related to study treatment, whereas the frequency of long-term AEs including prolonged grade ≥ 3 cytopenias and hypogammaglobulinemia compares favorably with previous studies. Patients with R/R mantle cell lymphoma relapsing after BTK inhibitor treatment remain a largely unmet clinical need, as well as those with unfavorable biologic disease features including blastoid variant, TP53 aberrations, and high Ki67. These patients could benefit the most from CAR T-cell strategies whose wide application is currently hampered by the risk of toxicities. If the very favorable safety profile of this CAR T-cell product is confirmed, and considering the very high ORR and CR rate, it is worth considering administration at an earlier stage, in particular in patients with disease features known to be associated with poor response to standard treatments.
Pooled Analysis of Cardiovascular Events From Clinical Trials Evaluating Acalabrutinib Monotherapy in Patients With CLL
Cardiovascular toxicities are known AEs associated with the first-in-class BTK inhibitor ibrutinib and are thought to be related to off-target effects of the drug. Acalabrutinib, a second-generation covalent BTK inhibitor, more selectively targets BTK and off-target effects should be reduced with its use. This pooled analysis presents the cardiovascular AEs occurring in 762 patients with CLL treated with acalabrutinib monotherapy in 4 phase I-III clinical trials. After a median follow-up of 25.9 months, 72% of patients remained on acalabrutinib. Seventeen percent of patients experienced cardiovascular AEs of any grade but < 1% discontinued treatment with acalabrutinib because of cardiovascular toxicities. The most frequent cardiovascular AEs were atrial fibrillation, palpitations, and tachycardia, but only 5% of patients experienced grade ≥ 3 cardiovascular AEs. Median time to cardiac event was 10.1 months, and median cardiac event duration was 0.2 months. Hypertension occurred earlier (median time to event: 6.5 months) and lasted longer (1 month), whereas atrial fibrillation manifested later (17.1 months) and resolved quickly (0.1 month). The majority (91%) of patients who experienced cardiovascular AEs had preexisting risk factors. The results of this pooled analysis are relevant to better understand how to optimize the use of novel BTK inhibitors. As cardiovascular AEs are difficult to manage in a subgroup of patients receiving ibrutinib, if this low cardiovascular toxicity rate with acalabrutinib is confirmed with longer follow-up and in randomized phase III studies comparing acalabrutinib and ibrutinib, then this may support the preferential use of acalabrutinib in patients with cardiovascular risk factors.
What are your thoughts on the new data in CLL and lymphomas presented at ASH 2020? I encourage you to answer the polling question and join the conversation in the discussion box below.