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The therapy of relapsed or refractory (r/r) mantle cell lymphoma (MCL) patients remains a major clinical challenge to date. We conducted a randomized, open-label, parallel-group phase-III trial hypothesizing superior efficacy of rituximab, high-dose cytarabine and dexamethasone with bortezomib (R-HAD + B) versus without (R-HAD) in r/r MCL ineligible for or relapsed after autologous stem cell transplant (ASCT). Primary endpoint was time to treatment failure (TTF), secondary endpoints included response rates, progression free survival, overall survival, and safety. In total, 128 of 175 planned patients were randomized to R-HAD + B (n = 64) or R-HAD (n = 64). Median TTF was 12 vs. 2.6 months (p = 0.045, MIPI-adjusted HR 0.69; 95%CI 0.47-1.02). Overall and complete response rates were 63 vs. 45% (p = 0.049) and 42 vs. 19% (p = 0.0062). A significant treatment effect was seen in the subgroup of patients >65 years (aHR 0.48, 0.29-0.79) and without previous ASCT (aHR 0.52, 0.28-0.96). Toxicity was mostly hematological and attributable to the chemotherapeutic backbone. Grade ≥3 leukocytopenia and lymphocytopenia were more common in R-HAD + B without differences in severe infections between both arms. Bortezomib in combination with chemotherapy can be effective in r/r MCL and should be evaluated further as a therapeutic option, especially if therapy with BTK inhibitors is not an option. Trial registration: NCT01449344., (© 2024. The Author(s).)

One feature of the molecular pathology of myelodysplastic syndromes (MDS) is aberrant gene expression. Such aberrations may be related to patient survival, and may indicate to novel diagnostic and therapeutic targets. Therefore, we aimed at identifying aberrant gene expression that is associated with MDS and patient survival. Bone marrow-derived CD34+ hematopoietic progenitor cells from six healthy persons and 16 patients with MDS were analyzed on cDNA macroarrays comprising 1,185 genes. Thereafter, our patients were followed-up for 54 months. We found differential expression of genes that were hitherto unrecognized in the context of MDS. Differential expression of 10 genes was confirmed by quantitative real-time RT-PCR. Hierarchical cluster analysis facilitated the separation of CD34+ cells of normal donors from patients with MDS. More importantly, it also distinguished MDS-patients with short and long survival. Scrutinizing our cDNA macroarray data for genes that are associated with short survival, we found, among others, increased expression of six different genes that encode the proteasome subunits. On the other hand, the most differentially down-regulated gene was IEX-1, which encodes an anti-apoptotic protein. We confirmed its decreased expression on RNA and protein level in an independent validation set of patient samples. The presented data broadens our notion about the molecular pathology of MDS and may lend itself to better identify patients with short survival. Furthermore, our findings may help to define new molecular targets for drug development and therapeutic approaches for patients with poor prognosis.