Mantle cell lymphoma strategies in primary treatment

University dissertation from Lund University, Faculty of Medicine

Abstract: Mantle cell lymphoma (MCL) is associated with poor prognosis due to an aggressive clinical course. Being a raredisease, there are few randomized trials in MCL and there is no defined golden standard in primary treatment.This works aimed to (I) investigate outcome in relation to primary treatment in MCL based on population-basedregistry data, (II) to evaluate tolerability and efficacy of lenalidomide-rituximab-bendamustine (LBR) in newlydiagnosed MCL patients within a phase I/II trial (MCL4) including (III) outcome in relation to genetic alterations,and (IV) to study how novel agents interfere with response to anti-CD20 antibodies.Our results showed that survival in MCL patients improved during 2000-2011, which partly could be explained bythe introduction of rituximab and intensified treatment with high dose chemotherapy consolidation. We also foundthat treatment with radiotherapy to limited-stage disease and observation in non-symptomatic MCL wereassociated with long-term survival. In paper II and III, LBR was found to be an active combination in untreatedMCL patients, except for cases harboring TP53 mutations, but associated with significant toxicity including secondprimary malignancies. In paper IV, we showed that the BTK-inhibitor ibrutinib, negatively affected the immunemediated cell death induced by a type I or II anti-CD20 antibody in MCL cell lines, not restored by addition oflenalidomide, a potential sensitizer to anti-CD20 ab.This work has provided data on important factors for outcome in MCL that may be taken into clinical use, such asactive observation in non-symptomatic patients and rituximab and intensified approaches in primary treatment.Moreover, the addition of lenalidomide to BR could not be recommended as first-line treatment in MCL due toexcessive toxicity and novel combinations with activity in elderly patients as well as in TP53 mutated MCL arehighly warranted. Future studies, including in vitro models on drug interaction will clarify how novel agents shouldbe combined for optimal use in MCL.

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