title: Molecular Monitoring after Autologous Stem Cell Transplantation and Preemptive Rituximab Treatment of Molecular Relapse; Results from the Nordic Mantle Cell Lymphoma Studies (MCL2 and MCL3) with Median Follow-Up of 8.5 Years.
abstract: The main objectives of the present study were to monitor minimal residual disease (MRD) in the bone marrow of patients with mantle cell lymphoma (MCL) to predict clinical relapse and guide preemptive treatment with rituximab. Among the patients enrolled in 2 prospective trials by the Nordic Lymphoma Group, 183 who had completed autologous stem cell transplantation (ASCT) and in whom an MRD marker had been obtained were included in our analysis. Fresh samples of bone marrow were analyzed for MRD by a combined standard nested and quantitative real-time PCR assay for Bcl-1/immunoglobulin heavy chain gene (IgH) and clonal IgH rearrangements. Significantly shorter progression-free survival (PFS) and overall survival (OS) was demonstrated for patients who were MRD positive pre-ASCT (54 patients) or in the first analysis post-ASCT (23 patients). The median PFS was only 20 months in those who were MRD-positive in the first sample post-ASCT, compared with 142 months in the MRD-negative group (P < .0001). OS was 75% at 10 years and median not reached in the MRD-negative group, compared with only 35 months in the MRD-positive group (P < .0001). Of the 86 patients (47%) who remained in continuous molecular remission, 73% were still in clinical remission after 10 years. For all patients, the median time from ASCT to first molecular relapse was 55 months, with a continuous occurrence of late molecular relapses. Fifty-eight patients who experienced MRD relapse received rituximab as preemptive treatment on 1 or more occasions, and in this group, the median time from first molecular relapse to clinical relapse was 55 months. In most cases, rituximab converted patients to MRD negativity (87%), but many patients became MRD-positive again later during follow-up (69%). By multivariate analysis, high-risk Mantle Cell Lymphoma International Prognostic Index score and positive MRD status pre-ASCT predicted early molecular relapse. In conclusion, preemptive rituximab treatment converts patients to MRD negativity and likely postpones clinical relapse. Molecular monitoring offers an opportunity to select some patients for therapeutic intervention and to avoid unnecessary treatment in others. MRD-positive patients in the first analysis post-ASCT have a dismal prognosis and thus are in need of novel strategies.
authors.affiliation: Department of Oncology, Oslo University Hospital, Radiumhospitalet, Oslo, Norway. Electronic address: arnek@ous-hf.no.
authors.forename: Arne
authors.initials: A
authors.lastname: Kolstad
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Lone Bredo
authors.initials: LB
authors.lastname: Pedersen
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Eskelund
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Husby
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Grønbæk
authors.affiliation: Department of Oncology, Skåne University Hospital, Lund, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Jerkeman
authors.affiliation: Department of Oncology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Laurell
authors.affiliation: Department of Hematology and Oncology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Räty
authors.affiliation: Department of Hematology and Oncology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Erkki
authors.initials: E
authors.lastname: Elonen
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Niels Smedegaard
authors.initials: NS
authors.lastname: Andersen
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Peter deNully
authors.initials: PD
authors.lastname: Brown
authors.affiliation: Department of Hematology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Kimby
authors.affiliation: Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Hans
authors.initials: H
authors.lastname: Bentzen
authors.affiliation: Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Sundström
authors.affiliation: Department of Pathology, Skåne University Hospital, Lund, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Ehinger
authors.affiliation: Department of Pathology, Helsinki Central University Hospital, Helsinki, Finland.
authors.forename: Marja-Liisa
authors.initials: ML
authors.lastname: Karjalainen-Lindsberg
authors.affiliation: Department of Pathology, Oslo University Hospital, Oslo, Norway.
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.affiliation: Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ralfkiær
authors.affiliation: Department of Oncology, St Olavs University Hospital, Trondheim, Norway.
authors.forename: Unn-Merete
authors.initials: UM
authors.lastname: Fagerli
authors.affiliation: Department of Hematology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Herman
authors.initials: H
authors.lastname: Nilsson-Ehle
authors.affiliation: Department of Oncology, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.
authors.forename: Grete Fossum
authors.initials: GF
authors.lastname: Lauritzsen
authors.affiliation: Department of Oncology, Oulu University Hospital, Oulu, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Kuittinen
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Carsten
authors.initials: C
authors.lastname: Niemann
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Christian Hartman
authors.initials: CH
authors.lastname: Geisler
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual / Q000175:diagnosis / Q000188:drug therapy / Q000517:prevention & control*; D012008:Recurrence; D000069283:Rituximab / Q000627:therapeutic use*; D012537:Scandinavian and Nordic Countries; D016019:Survival Analysis; D014182:Transplantation, Autologous; D016896:Treatment Outcome
chemical_list: D000069283:Rituximab
keywords: Autologous stem cell transplantation; Mantle cell lymphoma; Minimal residual disease; Preemptive rituximab