Sequencing-based analysis of clonal evolution of 25 mantle cell lymphoma patients at diagnosis and after failure of standard immunochemotherapy.

Our knowledge of genetic aberrations, that is, variants and copy number variations (CNVs), associated with mantle cell lymphoma (MCL) relapse remains limited. A cohort of 25 patients with MCL at diagnosis and the first relapse after the failure of standard immunochemotherapy was analyzed using whole-exome sequencing. The most frequent variants at diagnosis and at relapse comprised six genes: TP53, ATM, KMT2D, CCND1, SP140, and LRP1B. The most frequent CNVs at diagnosis and at relapse included TP53 and CDKN2A/B deletions, and PIK3CA amplifications. The mean count of mutations per patient significantly increased at relapse (n = 34) compared to diagnosis (n = 27). The most frequent newly detected variants at relapse, LRP1B gene mutations, correlated with a higher mutational burden. Variant allele frequencies of TP53 variants increased from 0.35 to 0.76 at relapse. The frequency and length of predicted CNVs significantly increased at relapse with CDKN2A/B deletions being the most frequent. Our data suggest, that the resistant MCL clones detected at relapse were already present at diagnosis and were selected by therapy. We observed enrichment of genetic aberrations of DNA damage response pathway (TP53 and CDKN2A/B), and a significant increase in MCL heterogeneity. We identified LRP1B inactivation as a new potential driver of MCL relapse.

Anti-CD38 Therapy with Daratumumab for Relapsed/Refractory CD20-Negative Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common and one of the most aggressive subtypes of non-Hodgkin's lymphomas. Front-line therapy consists of chemotherapy in combination with anti-CD20 monoclonal antibody rituximab. Relapses after rituximab-based regimen have poor prognosis and call for new treatment options. Immunohistochemistry analysis of relapsed DLBCL often reveal CD20-negative lymphoma, which limits repeated use of rituximab in combination with salvage chemotherapy. CD38 is a surface antigen that binds to CD38, CD31/PECAM-1 and hyaluronic acid. CD38 is an important mediator of signal transmission from the microenvironment into the cell. Anti-CD38 monoclonal antibody daratumumab has been approved for the treatment of multiple myeloma. Expression of CD38 on the surface of DLBCL is highly variable (compared to strong expression on myeloma cells), but can be easily assessed by flow cytometry or immunohistochemistry. A patient-derived xenograft (PDX) model of CD20-negative, CD38-positive DLBCL derived from a patient with rituximab-refractory DLBCL was used for in vivo experiments. We demonstrated that daratumumab suppressed growth of subcutaneous PDX tumours significantly more effectively than rituximab. Analysis of tumours obtained from mice treated with daratumumab revealed down-regulation of surface CD38, suggesting endocytosis of CD38-daratumumab complexes. The results suggest a potential clinical use of daratumumab in combination with salvage chemotherapy in patients with relapses of CD20-negative DLBCL. In addition, daratumumab might potentially serve as a suitable antibody moiety for derivation of antibodydrug conjugates for the targeted delivery of toxic payloads to the lymphoma cells.

[Successful Therapy of Czech Patients with ROS1 Translocation by Crizotinib]. / Úspesná terapie ceské pacientky s ROS1 translokací crizotinibem.

Targeted therapy of lung cancer has brought significant improvement in prognosis for a lot of patients with EGFR-sensitive mutations and ALK translocations. Other clinical studies have shown ROS1 translocation as another potential target. Our case report brings probably the first successful use of crizotininib in a patient with ROS1 translocation in the Czech Republic. Treatment was well-tolerated and persists continually. During the control PET/ CT scans, partial regression of the disease was observed. ROS1 translocation becomes another promising target for our patients. Therefore, in our opinion, serious discussion about its inclusion among the basic genetic testing in lung adenocarcinomas should occur.

Current two EGFR mutations in lung adenocarcinoma -  case report.

Nowadays, EGFR TKIs (epidermal growth factor receptor-tyrosine kinase inhibitors) targeted therapy is well established treatment for patients with the so-called EGFR common mutations with advanced or metastatic nonsmall cell lung cancer. The efficacy for the so-called rare and especially for the very rare complex EGFR mutations is not clear. We describe a case of a 63- year-old female with metastatic nonsmall cell lung cancer with complex EGFR mutation (G719X + S768I) who had been treated by gefitinib. She achieved progression free survival within eight months. Then, we discuss our case with other literature case reports. Together, it seems that described complex EGFR mutation has a relatively good sensitivity for EGFR TKIs treatment.Key words: nonsmall cell lung cancer -  EGFR gene -  EGFR protein -  complex mutations -  rare EGFR mutations -  EGFR TKIs.

Targeted therapy of non-small cell lung cancer.

The review article presents the current state and development of the treatment with tyrosine kinase inhibitors in advanced non-small cell lung cancer. It focuses on the therapeutic progress of traditionally targeted gene mutations EGFR, ALK and ROS1, as well as new established or promising targets. Mutations in the BRAF, NTRK, RET, cMET, HER2 and KRAS genes are discussed in this regard. In EGFR mutations, it focuses mainly on possible combination therapy and treatment for mutations in exon 20. In ALK translocation, it points to a new generation of tyrosine kinase inhibitors. In ROS1, the article mentions possible treatment in addition to the usual krizotinib, including the treatment after disease progression. For other genes, the author lists newly approved molecules, or molecules in the promising phase of their development.