Effects of lenalidomide on the bone marrow microenvironment in acute myeloid leukemia: Translational analysis of the HOVON103 AML/SAKK30/10 Swiss trial cohort.

This translational study aimed at gaining insight into the effects of lenalidomide in acute myeloid leukemia (AML). Forty-one AML patients aged 66 or older of the Swiss cohort of the HOVON-103 AML/SAKK30/10 study were included. After randomization, they received standard induction chemotherapy with or without lenalidomide. Bone marrow biopsies at diagnosis and before the 2nd induction cycle were obtained to assess the therapeutic impact on leukemic blasts and microenvironment. Increased bone marrow angiogenesis, as assessed by microvessel density (MVD), was found at AML diagnosis and differed significantly between the WHO categories. Morphological analysis revealed a higher initial MVD in AML with myelodysplasia-related changes (AML-MRC) and a more substantial decrease of microvascularization after lenalidomide exposure. A slight increase of T-bet-positive TH1-equivalents was identifiable under lenalidomide. In the subgroup of patients with AML-MRC, the progression-free survival differed between the two treatment regimens, showing a potential but not significant benefit of lenalidomide. We found no correlation between the cereblon genotype (the target of lenalidomide) and treatment response or prognosis. In conclusion, addition of lenalidomide may be beneficial to elderly patients suffering from AML-MRC, where it leads to a reduction of microvascularization and, probably, to an intensified specific T cell-driven anti-leukemic response

Analysis of the Mutational Landscape of Marginal Zone B-Cell Lymphomas by High Throughput Sequencing Techniques

Marginal zone lymphoma (MZL) is a rare tumor that accounts for only 7%-8% of all lymphoid neoplasms; however, the incidence rate has increased in recent years.1 The median age at disease onset is 60 years, with a 5-year overall survival (OS) rate of 85%. Depending on the MZL subtype, different treatment options are available. New personalized therapy is a promising approach to increase the effectiveness of anti-tumor treatments in MZL lymphomas. However, the heterogeneity of MZL subtypes makes it challenging to have a single treatment approach for patients with MZL. These challenges are also due to an unexplored genetic landscape and a lack of understanding of the molecular pathogenesis of MZL tumor development. In my doctoral thesis, I characterized the genetic landscape of two marginal zone lymphoma subtypes in two independent patient cohorts. The first cohort consisted of 34 patients with ocular adnexal marginal zone lymphomas (OMZL) and the second comprised 28 patients with primary pulmonary marginal zone lymphomas (PMZL). We used a customized high-throughput sequencing gene panel covering 146 genes to study the most common nucleotide-level alterations in both study cohorts. In OMZL, we frequently saw mutations in genes related to the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway like TNFAIP3 were; on the other hand, in PMZL, we detected higher frequencies of chromatin modifier-encoding gene mutations, like KMT2D. We compared the mutational profiles with other lymphomas as well as lymphoproliferative and reactive lesions from the same anatomic region. We detected a different mutational composition of pulmonary diffuse large B-cell lymphoma (DLBCL) compared to PMZL, suggesting that there is no transformation from PMZL to DLBCL. Further, we found recurrent PTEN mutations in reactive lesions, these might play an important role in diagnostics. In addition, we performed pathway analyses of the three main affected pathways, namely chromatin modifiers, the NF-κB pathway and the NOTCH pathway, to identify cluster patterns. We did not find any association between Chlamydia spp. infections and OMZL in the Basel cohort. Furthermore, we studied genetic evolution patterns in relapsing OMZL. To get a complete picture of the mutational landscape across all MZL, we performed a comparative meta-analysis of reported genetic variants in various MZL subtypes

Effects of lenalidomide on the bone marrow microenvironment in acute myeloid leukemia: Translational analysis of the HOVON103 AML/SAKK30/10 Swiss trial cohort

This translational study aimed at gaining insight into the effects of lenalidomide in acute myeloid leukemia (AML). Forty-one AML patients aged 66 or older of the Swiss cohort of the HOVON-103 AML/SAKK30/10 study were included. After randomization, they received standard induction chemotherapy with or without lenalidomide. Bone marrow biopsies at diagnosis and before the 2nd induction cycle were obtained to assess the therapeutic impact on leukemic blasts and microenvironment. Increased bone marrow angiogenesis, as assessed by microvessel density (MVD), was found at AML diagnosis and differed significantly between the WHO categories. Morphological analysis revealed a higher initial MVD in AML with myelodysplasia-related changes (AML-MRC) and a more substantial decrease of microvascularization after lenalidomide exposure. A slight increase of T-bet-positive TH1-equivalents was identifiable under lenalidomide. In the subgroup of patients with AML-MRC, the progression-free survival differed between the two treatment regimens, showing a potential but not significant benefit of lenalidomide. We found no correlation between the cereblon genotype (the target of lenalidomide) and treatment response or prognosis. In conclusion, addition of lenalidomide may be beneficial to elderly patients suffering from AML-MRC, where it leads to a reduction of microvascularization and, probably, to an intensified specific T cell-driven anti-leukemic response