CAR T cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: the phase 2 TARMAC study.

ABSTRACT: 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.

Analysis of molecular cytogenetic changes in metastatic renal cell carcinoma in the setting of everolimus treatment: a pilot project.

BACKGROUND: The mTOR inhibitors have improved outcomes for patients with metastatic renal cell carcinoma (mRCC) but the duration of benefit is variable. Currently there are no predictive biomarkers for preselecting patients who are more likely to benefit from these agents. We undertook an exploratory translational study evaluating molecular cytogenetic changes in the context of outcomes from treatment with everolimus. PATIENTS AND METHODS: Ten patients with clear cell mRCC treated with everolimus were enrolled. Pretreatment tissue specimens were analyzed for molecular cytogenetic changes using fluorescence in situ hybridization and progression-free survival (PFS) data were obtained. Gene probes chosen for this analysis were: Von Hippel Lindau, fragile histidine triad, fibroblast growth factor receptor (FGFR) 1, FGFR3, PDGFß, PDGFRß, epidermal growth factor receptor, and myelocytomatosis viral oncogene. RESULTS: Median PFS was 8.75 months. Two patients with the longest PFS (28 months and 23 months) had gain of PDGFß and PDGFRß. This was also observed in 3 other patients who had a PFS of 11.5 months, 8 months, and 5.5 months, respectively. Cytogenetic evolution was observed between primary and metastatic specimens. CONCLUSION: PDGFß and PDGFRß gene status might be of relevance to everolimus therapy. Further research evaluating the utility of these potential biomarkers is required.

How long do acute coronary syndrome patients wait for reperfusion, diagnostic coronary angiography and surgical revascularisation?

AIM: To describe the components of in-hospital waiting time to investigation and management in patients with acute coronary syndromes (ACS) admitted to the Middlemore Hospital (MMH) Coronary Care Unit. METHOD: We examined the time to (1) reperfusion therapy in ST-elevation myocardial infarction (STEMI), (2) coronary angiography in ACS, and (3) surgical revascularisation. Data was collected prospectively for consecutive patients via the Acute PREDICT ACS registry. RESULTS: Of 280 STEMI admissions in 2009 and 2010, 101 underwent primary percutaneous coronary intervention. The median door-to-balloon time when performed on site at MMH was 83 minutes (IQR 69-101 minutes) compared with 135 minutes (IQR 112-165 minutes) for those transferred after hours to Auckland City Hospital (ACH). Of 2115 ACS admissions between 2007 and 2010 84% underwent inpatient coronary angiography and 69% of these underwent this within 3 days. The strongest predictors of a >3 day delay were advanced chronic kidney disease (odds ratio 3.68, 95% CI 2.08-6.51) and presenting late in the week (odds ratio 2.85, 95% CI 2.30-3.54). 329 patients (16%) underwent coronary artery bypass graft surgery (CABG). The median time from admission to inpatient CABG was 13 days and from discharge to outpatient CABG was 155 days. Of ACS patients referred for outpatient surgery in the public sector 38% were readmitted with further ACS whilst waiting. CONCLUSION: Important delays were identified across the spectrum of post-admission care for ACS patients potentially impacting on both patient outcomes and the cost of care. Active quality improvement programmes to reduce delays are required.