Indolente Lymphome/CLL/Hodgkin-Lymphome II

V484 Wirksamkeit und Sicherheit von Tisagenleceucel (Tisa-cel) bei erwachsenen Patienten (Pts) mit rezidiviertem / refraktärem follikulärem Lymphom (r/r FL): Primäranalyse der Phase-2 ELARA-Studie
Martin Dreyling, München, D

Introduction: Tisa-cel has demonstrated durable responses and manageable safety in adult pts with r/r DLBCL. Here we report the primary analysis results of ELARA, a single arm phase 2 trial of tisa-cel in adult pts with r/r FL.

Methods: Eligible pts (≥18y) had r/r FL (grades [Gr] 1-3A) after ≥2 lines of therapy or had failed auto- SCT. Bridging therapy was permitted followed by disease assessment prior to tisa-cel infusion. Pts received tisa-cel (0.6-6×108 CAR+ viable T-cells) after lymphodepletion. The primary endpoint was complete response rate (CRR) by central review-Lugano 2014 criteria. Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and cellular kinetics. Predefined primary analysis occurred when ≥90 treated pts had ≥6mo of follow-up.

Results: As of September 28, 2020, 97 of 98 pts received tisa-cel (median follow-up, 10.6mo). At study entry, median age among treated pts was 57y (range, 29-73), 85% had stage III-IV disease, 60% had a FLIPI score ≥3, 65% had bulky disease, and 42% had LDH > upper limit of normal. The median number of prior therapies was 4 (range, 2-13); 78% pts were refractory to the last treatment and 60% progressed within 2y of initial anti-CD20-containing treatment. In 94 pts evaluable for efficacy, the CRR was 66% (95% CI, 56-75) and the ORR was 86% (95% CI, 78-92). CRRs/ORRs were comparable among key high-risk subgroups. Estimated DOR (CR) and PFS rates at 6mo were 94% (95% CI, 82-98) and 76% (95% CI, 65-84), respectively. Of 97 pts evaluable for safety, 65% experienced Gr ≥3 adverse events within 8 weeks post-infusion, most commonly neutropenia (28%) and anemia (13%). Any-grade cytokine release syndrome (Lee scale) occurred in 49% of pts (Gr ≥3, 0%). Any-grade neurological events (CTCAE v4.03) occurred in 9% of pts (Gr 3, 0%; Gr 4, 1 pt and recovered). Three pts died from progressive disease.

Cmax and AUC0-28d were similar between responders (CR or partial response) and non-responders (stable or progressive disease). Maximum transgene levels (by qPCR) reached by a median of 10d in responders and 12.9d in non-responders; transgene persistence was detected up to 370d and 187d, respectively.

Conclusions: These data demonstrate the efficacy and acceptable safety of tisa-cel in pts with r/r FL, including high-risk pts after multiple lines of prior therapy, and suggest that tisa-cel may be a promising therapy for pts with r/r FL.

V419 Erste Ergebnisse einer Head-to-Head Studie von Acalabrutinib versus Ibrutinib bei vorbehandelter chronischer lymphatischer Leukämie
Stephan Stilgenbauer, Ulm, D

Background: Increased selectivity of the Bruton tyrosine kinase inhibitor (BTKi) acalabrutinib (Aca) vs ibrutinib (Ib) may improve tolerability. We conducted an open-label, randomized, noninferiority, phase 3 trial to compare Aca vs Ib in patients (pts) with chronic lymphocytic leukemia (CLL).
Methods: Previously treated CLL pts with del(17p) or del(11q) by central lab were randomized to receive oral Aca 100 mg BID or Ib 420 mg QD (stratified by del(17p) status, ECOG PS [2 vs ≤1], and number of prior therapies [1-3 vs ≥4]) until progression or unacceptable toxicity. Primary endpoint was progression-free survival (PFS) as assessed by IRC; secondary endpoints of all grade atrial fibrillation (AF), grade ≥3 infection, Richter transformation, and overall survival (OS) were assessed in hierarchical order.

Results: 533 pts (Aca, n=268; Ib, n=265) were randomized (median age 66 y; median 2 prior therapies; del(17p) 45.2%; del(11q) 64.2%). At a median follow-up of 40.9 mo (range 0.0-59.1), Aca was noninferior to Ib with a median PFS of 38.4 mo in both arms (HR 1.00; 95% CI 0.79-1.27). Aca was statistically superior to Ib in all-grade AF incidence (9.4% vs 16.0%; P=0.023). Among the other secondary endpoints, incidences of grade ≥3 infection (Aca: 30.8%, Ib: 30.0%) and Richter transformation (Aca: 3.8%, Ib: 4.9%) were comparable between arms. Median OS was not reached in either arm (HR 0.82 [95% CI 0.59-1.15]), with 63 (23.5%) deaths in the Aca arm and 73 (27.5%) in the Ib arm. Among any-grade AEs in ≥20% of pts in either arm, Aca was associated with a lower incidence of hypertension (9.4%, 23.2%), arthralgia (15.8%, 22.8%), and diarrhea (34.6%, 46.0%) but a higher incidence of headache (34.6%, 20.2%) and cough (28.9%, 21.3%). AEs led to treatment discontinuation in 14.7% of Aca- vs 21.3% of Ib-treated pts. Among any-grade events of clinical interest, cardiac, hypertension, and bleeding events were less frequent with Aca (Table).

Conclusions: In this first head-to-head trial of BTKis in CLL, Aca demonstrated non-inferior PFS with less cardiotoxicity and fewer discontinuations due to AEs vs Ib.
Sponsor: Acerta Pharma References: ASCO Meeting Library, Byrd J.C. et al. 2021


V51 Acalabrutinib ± Obinutuzumab vs. Obinutuzumab + Chlorambucil bei therapienaiver chronischer lymphatischer Leukämie: ELEVATE-TN 4-Jahres Follow-up
Uwe Martens, Heilbronn, D

Background: Early results from ELEVATE-TN (NCT02475681) at a median follow-up of 28.3 mo demonstrated superior efficacy of acalabrutinib (A) ± obinutuzumab (O) compared with O + chlorambucil (Clb) in patients (pts) with treatment-naïve (TN) chronic lymphocytic leukemia (CLL). Results from a 4-year update are reported here.

Methods: Pts received A±O or O+Clb; crossover to A was permitted. Investigator-assessed (INV) progression-free survival (PFS), INV overall response rate (ORR), overall survival (OS), and safety were evaluated.

Results: 535 pts (A+O, n=179; A, n=179; O+Clb, n=177) were randomized (median age was 70 y; 63% had unmutated IGHV and 9% had del(17p). At a median follow-up of 46.9 mo (range, 0.0-59.4;), the median PFS was not reached (NR) for A+O and A pts vs 27.8 mo for O+Clb pts (both P< 0.0001). In pts with unmutated IGHV, the median PFS was NR (A+O and A) vs 22.2 mo among O+Clb pts (both P < 0.0001). In pts with del(17p), the median PFS was NR (A+O and A) vs 17.7 mo for O+Clb (P< 0.005). Estimated 48-mo PFS rates were 87% for A+O, 78% for A, and 25% for O+Clb. Median OS was NR in any treatment arm with a trend towards significance in the A+O group (A+O vs O+Clb, P=0.0604); estimated 48-mo OS rates were 93% (A+O), 88% (A), and 88% (O+Clb). ORR was significantly higher with A+O (96.1%; 95% CI 92.1-98.1) vs O+Clb (82.5%; 95% CI 76.2-87.4; P< 0.0001); ORR with A was 89.9% (95% CI 84.7-93.5; P=0.035 vs O+Clb). CR/CRi rates were higher with A+O (26.8%/3.9%) vs O+Clb (12.4%/0.6%); 10.6%/0.6% had CR/CRi with A. Common adverse events (AEs) and AEs of interest are shown in the Table. Overall treatment discontinuation rates were 25.1% (A+O), 30.7% (A), and 22.6% (O+Clb); the most common reasons were AEs (12.8%, 12.3%, 14.7%, respectively) and progressive disease (4.5%, 7.8%, 1.7%).

Conclusions: With a median follow-up of 46.9 mo (~4y), the efficacy and safety of A+O and A monotherapy was maintained, with an increase in CR since the interim analysis (from 21% to 27% [A+O] and from 7% to 11% [A]) and low rates of discontinuation.

Sponsor: Acerta Pharma References: ASCO Meeting Library, Sharman J.P. et al. 2021


V99 CHRONOS-3: randomisierte Phase III-Studie mit Copanlisib plus Rituximab vs. Rituximab/Placebo bei rezidivierten indolenten Non-Hodgkin- Lymphomen (iNHL)
Martin Dreyling, München, D

Introduction: Rituximab (R)-based therapies are standard for patients (pts) with relapsed iNHL. Copanlisib (C) is a PI3K inhibitor approved as monotherapy for relapsed follicular lymphoma (FL) in pts who have had ≥2 prior systemic therapies. We report primary data from the Phase III CHRONOS-3 study of treatment with C+R vs placebo (P)+R in relapsed iNHL (NCT02367040).

Method: Pts with relapsed iNHL who were progression-free and treatment-free for ≥12 months (mo) after last R-based therapy or unwilling/unfit to receive chemotherapy were randomized 2:1 to receive C+R or P+R. C 60 mg/P was given i.v. on days 1, 8, and 15 (28-day cycle); R 375 mg/m2 was given i.v. on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint: centrally assessed progression-free survival (PFS). Secondary endpoints: objective response rate (ORR), duration of response, complete response rate (CRR), overall survival (OS), and treatment-emergent adverse events (TEAEs). Data cut-off: August 2020.

Result: 307 pts were randomized to C+R and 151 to P+R. FL was the most common lymphoma histology subtype (60.0%), followed by marginal zone (MZL, 20.7%), small lymphocytic (SLL, 10.9%), and lymphoplasmacytic/Waldenström macroglobulinemia (LPL/WM, 8.3%). Median age was 63 years. C+R significantly reduced the risk of disease progression/death vs P+R (hazard ratio [HR] 0.52 [95% CI 0.39, 0.69]; 1-sided p=0.000002); median PFS was 21.5 mo (95% CI 17.8, 33.0) vs 13.8 mo (95% CI 10.2, 17.5), respectively. Higher ORRs were seen across all subtypes with C+R. Median OS was not estimable. Most common TEAEs (all grades [G]/G3+) in pts receiving C+R were hyperglycemia (69.4%/56.4%), hypertension (49.2%/39.7% [all G3]), and diarrhea (33.6%/4.9% [all G3]). For pts receiving P+R, hyperglycemia (23.3%/8.2% [all G3]), hypertension (19.2%/8.9% [all G3]), neutropenia (16.4%/12.3%), and upper respiratory tract infection (16.4%/0%) were the most common TEAEs. Serious adverse events were higher with C+R (47.2%) vs P+R (18.5%). G5 TEAEs occurred in 6 pts (2.0%) receiving C+R (1 [0.3%] deemed treatment-related; pneumonitis) and 1 (0.7%) receiving P+R.

Conclusion: C+R demonstrated broad and superior efficacy vs P+R in pts with relapsed iNHL. The safety profile of C+R was manageable and consistent with C and R as monotherapy. Copanlisib is the first PI3K inhibitor to be safely combined with R in relapsed iNHL, representing a potential new option for relapsed iNHL across all subtypes.


V274 ASPEN: Ergebnisse einer randomisierten Phase 3 Studie mit Zanubrutinib versus ibrutinib bei Patienten mit Morbus Waldenström (WM)
Christian Buske, Ulm, D

Introduction: Bruton's tyrosine kinase (BTK) inhibition is an emerging standard of care for WM. The ASPEN trial (NCT03053440) is a randomized phase 3 study comparing zanubrutinib, a potent and selective BTK inhibitor, versus ibrutinib, a first generation BTK inhibitor, in patients with WM.
Methods: Patients with MYD88 mutation-positive (MYD88mut+) WM were randomly assigned 1:1 to receive zanubrutinib (160 mg twice daily) or ibrutinib (420 mg once daily). Patients without MYD88 mutations were assigned to a separate cohort, received zanubrutinib, and are reported separately. Randomization was stratified by CXCR4 mutational status and the number of lines of prior therapy (0 vs 1-3 vs >3). The primary end point was the proportion of patients achieving a complete response or very good partial response (CR+VGPR). Sample size was calculated to provide 81% power to detect a difference in CR+VGPR rate of 35% vs 15% in the subset of patients with relapsed or refractory WM. Primary analysis was planned to occur at ~12 months after the last patient enrolled.

Results: In total, 201 patients were randomized from Jan 2017 to Jul 2018. The treatment groups were well balanced for important baseline factors, with the exception of more elderly patients (aged >75 years, 33.3% vs 22.2%) and more anemia (hemoglobin ≤110 g/L, 65.7% vs 53.5%) in the zanubrutinib arm. At a median follow-up of 19.4 months, the rate of VGPR (no CRs were observed) was 28.4% vs 19.2% with zanubrutinib vs ibrutinib, respectively (2-sided P=0.09). Rates of atrial fibrillation, contusion, diarrhea, edema peripheral, hemorrhage, muscle spasms, pneumonia, and adverse events leading to discontinuation or death were lower with zanubrutinib. The rate of neutropenia was higher with zanubrutinib (Table), but grade ≥3 infection rates were similar (17.8% vs 19.4%).

Conclusions: ASPEN is the largest phase 3 trial of BTK inhibitors in WM and the first head-to-head comparison of BTK inhibitors in any disease. Although not statistically significant, zanubrutinib was associated with a numerically higher VGPR response rate and demonstrated clinically meaningful advantages in safety and tolerability compared with ibrutinib.