Is There Still a Role for Transplant for Patients with Mantle Cell Lymphoma (MCL) in the Era of CAR-T Cell Therapy?

OPINION STATEMENT: For years, upfront autologous hematopoietic cell transplant (auto-HCT) has been the standard of care for younger and physically fit mantle cell lymphoma (MCL) patients after chemoimmunotherapy (CIT) induction. Bruton's tyrosine kinase (BTK) inhibitors have proven to be excellent salvage therapies, but their durability remains a question, especially in high-risk (HR) MCL. Allogeneic HCT (allo-HCT) was the only option for long-term remission and possibly cure for MCL relapse after auto-HCT and sometime as upfront consolidation for a young patient with HR MCL (debatable). We have seen a paradigm shift since the FDA approval in July 2020 of the brexucabtagene autoleucel chimeric antigen receptor T (CAR-T) cell therapy for relapsed and refractory (R/R) MCL with an preliminary evidence suggesting CAR-T may overcome known biological risk factors in MCL. Given its safety profile and excellent efficacy, the role of CAR-T among other approved therapies and HCT may need to be better defined. Based on the current evidence, auto-HCT remains a standard frontline consolidation therapy. CAR-T therapy is a preferred option for patients with relapsed/refractory (R/R) MCL, particularly those who failed BTK inhibitors. In certain high-risk MCL patients (such as high ki 67, TP53 alterations, complex karyotype, blastoid morphology, early relapse after initial diagnosis), CAR-T cell therapy may be considered before BTK inhibitors (preferably on a clinical trial). The role of allo-HCT is unclear in the CAR-T era, but remains a viable option for eligible patients who have no access or who have failed CAR-T therapy. Our review discusses current standards and the shifting paradigms in the indications for HCT and the role of CAR-T cell therapy for MCL. Prospective studies tailored based on risk factors are needed to better define the optimal sequences of HCT and cellular therapy and other approved novel therapies.

Circulating Cell-Free Tumor DNA in Advanced Pancreatic Adenocarcinoma Identifies Patients With Worse Overall Survival.

BACKGROUND: Plasma-based circulating cell-free tumor DNA (ctDNA) genomic profiling by next-generation sequencing (NGS)is an emerging diagnostic tool for pancreatic cancer (PC). The impact of detected genomic alterations and variant allele fraction (VAF) in tumor response to systemic treatments and outcomes is under investigation. METHODS: Patients with advanced PC who had ctDNA profiled at time of initial diagnosis were retrospectively evaluated. We considered the somatic alteration with the highest VAF as the dominant clone allele frequency (DCAF). ctDNA NGS results were related to clinical demographics, progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 104 patients were evaluated. Somatic alterations were detected in 84.6% of the patients. Patients with ≥ 2 detectable genomic alterations had worse median PFS (p < 0.001) and worse median OS (p = 0.001). KRAS was associated with disease progression to systemic treatments (80.4% vs 19.6%, p = 0.006), worse median PFS (p < 0.001) and worse median OS (p = 0.002). TP53 was associated with worse median PFS (p = 0.02) and worse median OS (p = 0.001). The median DCAF was 0.45% (range 0-55%). DCAF >0.45% was associated with worse median PFS (p<0.0001) and median OS (p=0.0003). Patients that achieved clearance of KRAS had better PFS (p=0.047), while patients that achieved clearance of TP53 had better PFS (p=0.0056) and OS (p=0.037). CONCLUSIONS: Initial detection of ctDNA in advanced PC can identify somatic alterations that may help predict clinical outcomes. The dynamics of ctDNA are prognostic of outcomes and should be evaluated in prospective studies.