Primary refractory plasmablastic lymphoma: A precision oncology approach

Abstract

Introduction: Hematologic malignancies are currently underrepresented in multidisciplinary molecular-tumor-boards (MTB). This study assesses the potential of precision-oncology in primary-refractory plasmablastic-lymphoma (prPBL), a highly lethal blood cancer.

Methods: We evaluated clinicopathological and molecular-genetic data of 14 clinically annotated prPBL-patients from initial diagnosis. For this proof-of-concept study, we employed our certified institutional MTB-pipeline (University-Cancer-Center-Schleswig-Holstein, UCCSH) to annotate a comprehensive dataset within the scope of a virtual MTB-setting, ultimately recommending molecularly stratified therapies. Evidence-levels for MTB-recommendations were defined in accordance with the NCT/DKTK and ESCAT criteria.

Results: Median age in the cohort was 76.5 years (range 56-91), 78.6% of patients were male, 50% were HIV-positive and clinical outcome was dismal. Comprehensive genomic/transcriptomic analysis revealed potential recommendations of a molecularly stratified treatment option with evidence-levels according to NCT/DKTK of at least m2B/ESCAT of at least IIIA were detected for all 14 prPBL-cases. In addition, immunohistochemical-assessment (CD19/CD30/CD38/CD79B) revealed targeted treatment-recommendations in all 14 cases. Genetic alterations were classified by treatment-baskets proposed by Horak et al. Hereby, we identified tyrosine-kinases (TK; n=4), PI3K-MTOR-AKT-pathway (PAM; n=3), cell-cycle-alterations (CC; n=2), RAF-MEK-ERK-cascade (RME; n=2), immune-evasion (IE; n=2), B-cell-targets (BCT; n=25) and others (OTH; n=4) for targeted treatment-recommendations. The minimum requirement for consideration of a drug within the scope of the study was FDA-fast-track development.

Discussion: The presented proof-of-concept study demonstrates the clinical potential of precision-oncology, even in prPBL-patients. Due to the aggressive course of the disease, there is an urgent medical-need for personalized treatment approaches, and this population should be considered for MTB inclusion at the earliest time.

Keywords: molecular tumor board; plasmablastic lymphoma; recurrent aberrations; targeted therapy; whole exome sequencing; whole transcriptome sequencing.

Figure 1

Virtual UCCSH molecular tumor board workflow for primary refractory plasmablastic lymphomas (prPBL). (A) After institutional PBL selection, academic WES and RNA-seq were performed in 33 and 20 cases, respectively. (B) Consecutively, 14 prPBL cases were identified and underwent UCCSH MTB pipeline evaluation. (C) Afterwards, manual database research annotation was conducted for each relevant variant. (D) In a virtual MTB setting, each prPBL case was discussed. Potential therapeutic vulnerabilities were allocated to molecular evidence levels and to treatment baskets. (E) Multifactorial treatment prioritization process revealed (F) MTB treatment recommendations.

Figure 2

Clinical and genomic features in prPBL. (A) The swimmer plot illustrates the clinical course of the disease for each prPBL case. (B) Kaplan Meier survival analysis (PFS and OS) comparing prPBL cases and the comparison cohort which were not associated with primary refractory disease. (C) Pie charts outlining functionality, the mutational subtype and the mechanism of detected mutations. (D) Comparative median TMB calculation between prPBL and the comparison group.

Figure 3

Results from manual database research and annotation of relevant genomic alterations. (A) Oncoplot summarizes relevant driver mutations and immunohistochemical targets detected upon MIRACUM pipeline analysis and potential therapeutic options. (B) Additional therapeutic vulnerabilities resulting from manual annotation procedure. (C) Bar plot visualizing the status of approval for annotated therapeutic options. (D) Sankey plot assigning molecular evidence levels to treatment baskets.

Figure 4

Therapeutic targets und treatment recommendations. (A) Case-related summary of MTB recommendations and associated molecular evidence levels. (B) Evaluation of RNA expression, gene set enrichment analysis and variant allele frequency (VAF) for each mutation serving as a therapeutic vulnerability. (C) Sankey plot allocating patients dependent on HIV status and age. The plot shows the best response of prPBL patients after standard chemotherapy. Moreover, the Sankey plot illustrates therapeutic vulnerabilities beyond standard chemotherapy based on genomic alterations and immunohistochemical targets. (D) Both chord plots demonstrate the relationships between cases and potential therapeutic targets, drugs and related evidence levels.