Stephen Lade

Oral ibrutinib and venetoclax (I+V) demonstrate activity as monotherapy in marginal zone lymphoma (MZL), with low complete response (CR) rates. I+V has shown good clinical activity with acceptable tolerability in other malignancies. We conducted a single-site, phase 2 trial of daily I+V in patients with MZL. Ibrutinib commenced at 560 mg daily; after 4 weeks, venetoclax commenced with weekly dose escalation to 400 mg daily. Combination therapy continued until disease progression or toxicity. The primary end point was week 16 CR. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and peripheral blood. Patients achieving eradication of MRD could enter elective treatment interruption (ETI). Fifteen patients with MZL were treated; 14 are included in efficacy analysis, and 15 were evaluable for safety. Overall response was 79% (95% confidence interval [CI], 49-95) by F-fluorodeoxyglucose–positron-emission tomography (CR rate, 43%; 95% CI, 18-71). By computed tomography, 16-week CR rate was 29% (95% CI, 8-58). Best response within 56 weeks was 57% CR (95% CI, 37-80), which is higher than historic ibrutinib-monotherapy control (3% CR; P< .001). MRD clearance at week 56 was 40%. Six MRD-negative CR patients entered ETI, with 4 remaining disease-free at a median of 4 years. With a median follow-up of 5.5 years for the whole cohort, the 5-year progression-free survival estimate was 56% (95% CI, 27-78). I+V is safe and effective for MZL, with higher CR than with ibrutinib. Durable, ongoing CR was observed in MRD-negative patients. This trial was registered at www.clinicaltrials.gov as #NCT02471391.

In the phase 2 clinical trial (AIM) of venetoclax-ibrutinib, 24 patients with mantle cell lymphoma (MCL; 23 with relapsed/refractory [R/R] disease) received ibrutinib 560 mg and venetoclax 400 mg both once daily. High complete remission (CR) and measurable residual disease negative (MRD-negative) CR rates were previously reported. With median survivor follow-up now exceeding 7 years, we report long-term results. Treatment was initially continuous, with elective treatment interruption (ETI) allowed after protocol amendment for patients in MRD-negative CR. For R/R MCL, the estimated 7-year progression-free survival (PFS) was 30% (95% confidence interval [CI], 14-49; median, 28 months; 95% CI, 13-82) and overall survival (OS) was 43% (95% CI, 23-62; median, 32 months; 95% CI, 15 to not evaluable). Eight patients in MRD-negative CR entered ETI for a median of 58 months (95% CI, 37-79), with 4 experiencing disease recurrence. Two of 3 reattained CR on retreatment. Time-to-treatment failure (TTF), which excluded progression in ETI for those reattaining response, was 39% overall and 68% at 7 years for responders. Beyond 56 weeks, grade ≥3 and serious adverse events were uncommon. Newly emergent or increasing cardiovascular toxicity were not observed beyond 56 weeks. We demonstrate long-term durable responses and acceptable toxicity profile of venetoclax-ibrutinib in R/R MCL and show feasibility of treatment interruption while maintaining ongoing disease control. This trial was registered at www.clinicaltrials.gov as #NCT02471391.

CD19-directed chimeric antigen receptor T cells (CAR-T) achieve high response rates in patients with relapsed/refractory mantle cell lymphoma (MCL). However, their use is associated with significant toxicity, relapse concern, and unclear broad tractability. Preclinical and clinical data support a beneficial synergistic effect of ibrutinib on apheresis product fitness, CAR-T expansion, and toxicity. We evaluated the combination of time-limited ibrutinib and CTL019 CAR-T in 20 patients with MCL in the phase 2 TARMAC study. Ibrutinib commenced before leukapheresis and continued through CAR-T manufacture for a minimum of 6 months after CAR-T administration. The median prior lines of therapy was 2; 50% of patients were previously exposed to a Bruton tyrosine kinase inhibitor (BTKi). The primary end point was 4-month postinfusion complete response (CR) rate, and secondary end points included safety and subgroup analysis based on TP53 aberrancy. The primary end point was met; 80% of patients demonstrated CR, with 70% and 40% demonstrating measurable residual disease negativity by flow cytometry and molecular methods, respectively. At 13-month median follow-up, the estimated 12-month progression-free survival was 75% and overall survival 100%. Fifteen patients (75%) developed cytokine release syndrome; 12 (55%) with grade 1 to 2 and 3 (20%) with grade 3. Reversible grade 1 to 2 neurotoxicity was observed in 2 patients (10%). Efficacy was preserved irrespective of prior BTKi exposure or TP53 mutation. Deep responses correlated with robust CAR-T expansion and a less exhausted baseline T-cell phenotype. Overall, the safety and efficacy of the combination of BTKi and T-cell redirecting immunotherapy appears promising and merits further exploration. This trial was registered at www.ClinicalTrials.gov as #NCT04234061.

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (also called double-hit [or triple-hit] diffuse large B-cell lymphoma [DLBCL]) is a dist

Gao et al report that early use of extracorporeal photopheresis improves time to next treatment and survival in patients with Sézary syndrome.