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Supplemental material, sj-docx-1-tah-10.1177_20406207221127550 for Coexisting conditions and concomitant medications do not affect venetoclax management and survival in chronic lymphocytic leukemia by Anna Maria Frustaci, Giovanni Del Poeta, Andrea Visentin, Paolo Sportoletti, Alberto Fresa, Candida Vitale, Roberta Murru, Annalisa Chiarenza, Alessandro Sanna, Francesca Romana Mauro, Gianluigi Reda, Massimo Gentile, Marzia Varettoni, Claudia Baratè, Chiara Borella, Antonino Greco, Marina Deodato, Giulia Zamprogna, Roberta Laureana, Alessandra Cipiciani, Andrea Galitzia, Angelo Curto Pelle, Francesca Morelli, Lucio Malvisi, Marta Coscia, Luca Laurenti, Livio Trentin, Marco Montillo, Roberto Cairoli and Alessandra Tedeschi in Therapeutic Advances in Hematology

Supplemental material, sj-docx-1-tah-10.1177_20406207221127550 for Coexisting conditions and concomitant medications do not affect venetoclax management and survival in chronic lymphocytic leukemia by Anna Maria Frustaci, Giovanni Del Poeta, Andrea Visentin, Paolo Sportoletti, Alberto Fresa, Candida Vitale, Roberta Murru, Annalisa Chiarenza, Alessandro Sanna, Francesca Romana Mauro, Gianluigi Reda, Massimo Gentile, Marzia Varettoni, Claudia Baratè, Chiara Borella, Antonino Greco, Marina Deodato, Giulia Zamprogna, Roberta Laureana, Alessandra Cipiciani, Andrea Galitzia, Angelo Curto Pelle, Francesca Morelli, Lucio Malvisi, Marta Coscia, Luca Laurenti, Livio Trentin, Marco Montillo, Roberto Cairoli and Alessandra Tedeschi in Therapeutic Advances in Hematology

According to the prognostic classifications of karyotypic abnormalities of AML (MRC and SWOG), the intermediate group includes patients either lacking good and poor karyotype or with normal karyotype. Therefore, it represents, by definition, a miscellaneous group for which the evaluation of the better treatment strategy is difficult due to its heterogeneity. Moreover, patients belonging to this intermediate group account for the large majority of AML cases enrolled into clinical trials. The aim of our study was to analyze the factors specifically affecting the outcome of patients bearing intermediate risk karyotypic abnormalities in a group of 94 AML cases entered into the EORTC/GIMEMA protocols AML10/AML12 (age 61 yrs), consisting in intensive induction and consolidation cycles. The clinico-biological variables evaluated in our model included age, FAB, WBC count, MDR1 phenotype, FLT3 mutations and level of post-consolidation bone marrow residual leukemic cells (BMRCL) assessed by multiparametric flow-cytometry (MPFC). In our experience, patients with 2.0x10−4 at the end of consolidation were considered MRDpos and showed a poor prognosis. However, the category of MRDpos patients could be divided into 2 subgroups depending on whether they had a reduction of BMRLC between induction and consolidation, even not reaching the threshold of MRD negativity. In fact, we identified patients whose BMRLC were reduced by at least 1-log between induction and consolidation, referred to as “chemosensitive MRDpos” with an intermediate prognosis, and those showing no reduction of MRD levels between induction and consolidation, referred to as “chemoresistant MRDpos” with the worst outcome. Using the MRC classification, 14/94 patients (15%) had a good-risk cytogenetics, 74/94 (79%) an intermediate-risk and 6/94 (6%) a poor-risk. When we restricted the analysis to cases with intermediate-risk karyotype we found that: 1) in multivariate model, MRD status after consolidation was the only variable significantly affecting relapse free survival (RFS)(P=0.001); 2) patients in the MRDneg, “chemosensitive MRDpos” and “chemoresistant MRDpos” group differed significantly in terms of relapse rate (25% vs. 50% vs. 78%, respectively, P Figure Figure

Tissino et al. demonstrate that in chronic lymphocytic leukemia, the VLA-4 (CD49d/CD29) integrin remains activable by B cell receptor stimulation also upon in vitro and in vivo ibrutinib exposure. Clinically, ibrutinib-treated CD49d-positive CLL patients experience reduced recirculation lymphocytosis and nodal response and inferior outcomes., The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.

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The B-cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). By global microRNA profiling of CLL cells stimulated or not stimulated by anti-IgM, significant up-regulation of microRNAs from the miR-132~212 cluster was observed both in IGHV gene unmutated (UM) and mutated (M) CLL cells. Parallel gene expression profiling identified SIRT1, a deacetylase targeting several proteins including TP53, among the top-ranked miR-132 target genes down-regulated upon anti-IgM exposure. The direct regulation of SIRT1 expression by miR-132 was demonstrated using luciferase assays. The reduction of SIRT1 mRNA and protein (P = 0.001) upon anti-IgM stimulation was associated with an increase in TP53 acetylation (P = 0.007), and the parallel up-regulation of the TP53 target gene CDKN1A. Consistently, miR-132 transfections of CLL-like cells resulted in down-regulation of SIRT1 and an induction of a TP53-dependent apoptosis. Finally, in a series of 134 CLL samples, miR-132, when expressed above the median value, associated with prolonged time-to-first-treatment in patients with M CLL (HR = 0.41; P = 0.02). Collectively, the miR-132/SIRT1/TP53 axis was identified as a novel pathway triggered by BCR engagement that further increases the complexity of the interactions between tumor microenvironments and CLL cells.