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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

Kolstad, Arne; Pedersen, Lone Bredo; Eskelund, Christian W.; Husby, Simon; Grønbæk, Kirsten; Jerkeman, Mats LU ; Laurell, Anna LU ; Räty, Riikka; Elonen, Erkki and Andersen, Niels Smedegaard, et al. (2017) In Biology of Blood and Marrow Transplantation 23(3). p.428-435
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... (More)

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.

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keywords
Autologous stem cell transplantation, Mantle cell lymphoma, Minimal residual disease, Preemptive rituximab
in
Biology of Blood and Marrow Transplantation
volume
23
issue
3
pages
428 - 435
publisher
Elsevier
external identifiers
  • scopus:85009455648
  • wos:000395367300009
ISSN
1083-8791
DOI
10.1016/j.bbmt.2016.12.634
language
English
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yes
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d70232ac-cf9d-457b-b290-0dcef083f33a
date added to LUP
2017-02-01 11:00:33
date last changed
2018-04-08 04:53:19
@article{d70232ac-cf9d-457b-b290-0dcef083f33a,
  abstract     = {<p>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 &lt; .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 &lt; .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.</p>},
  author       = {Kolstad, Arne and Pedersen, Lone Bredo and Eskelund, Christian W. and Husby, Simon and Grønbæk, Kirsten and Jerkeman, Mats and Laurell, Anna and Räty, Riikka and Elonen, Erkki and Andersen, Niels Smedegaard and Brown, Peter De Nully and Kimby, Eva and Bentzen, Hans and Sundström, Christer and Ehinger, Mats and Karjalainen-Lindsberg, Marja-Liisa and Delabie, Jan and Ralfkiær, Elisabeth and Fagerli, Unn-Merete and Nilsson-Ehle, Herman and Lauritzsen, Grete Fossum and Kuittinen, Outi and Niemann, Carsten and Geisler, Christian Hartman},
  issn         = {1083-8791},
  keyword      = {Autologous stem cell transplantation,Mantle cell lymphoma,Minimal residual disease,Preemptive rituximab},
  language     = {eng},
  number       = {3},
  pages        = {428--435},
  publisher    = {Elsevier},
  series       = {Biology of Blood and Marrow Transplantation},
  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},
  url          = {http://dx.doi.org/10.1016/j.bbmt.2016.12.634},
  volume       = {23},
  year         = {2017},
}