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Mantle cell lymphoma strategies in primary treatment

Albertsson Lindblad, Alexandra LU (2018) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2018(28).
Abstract
Mantle cell lymphoma (MCL) is associated with poor prognosis due to an aggressive clinical course. Being a rare disease, 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-based registry data, (II) to evaluate tolerability and efficacy of lenalidomide-rituximab-bendamustine (LBR) in newly diagnosed 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... (More)
Mantle cell lymphoma (MCL) is associated with poor prognosis due to an aggressive clinical course. Being a rare disease, 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-based registry data, (II) to evaluate tolerability and efficacy of lenalidomide-rituximab-bendamustine (LBR) in newly diagnosed 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 by the introduction of rituximab and intensified treatment with high dose chemotherapy consolidation. We also found that treatment with radiotherapy to limited-stage disease and observation in non-symptomatic MCL were associated with long-term survival. In paper II and III, LBR was found to be an active combination in untreated MCL patients, except for cases harboring TP53 mutations, but associated with significant toxicity including second primary malignancies. In paper IV, we showed that the BTK-inhibitor ibrutinib, negatively affected the immune mediated cell death induced by a type I or II anti-CD20 antibody in MCL cell lines, not restored by addition of lenalidomide, 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 as active 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 to excessive toxicity and novel combinations with activity in elderly patients as well as in TP53 mutated MCL are highly warranted. Future studies, including in vitro models on drug interaction will clarify how novel agents should be combined for optimal use in MCL.
(Less)
Abstract (Swedish)
Mantle cell lymphoma (MCL) is associated with poor prognosis due to an aggressive clinical course. Being a rare
disease, 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-based
registry data, (II) to evaluate tolerability and efficacy of lenalidomide-rituximab-bendamustine (LBR) in newly
diagnosed 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... (More)
Mantle cell lymphoma (MCL) is associated with poor prognosis due to an aggressive clinical course. Being a rare
disease, 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-based
registry data, (II) to evaluate tolerability and efficacy of lenalidomide-rituximab-bendamustine (LBR) in newly
diagnosed 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 by
the introduction of rituximab and intensified treatment with high dose chemotherapy consolidation. We also found
that treatment with radiotherapy to limited-stage disease and observation in non-symptomatic MCL were
associated with long-term survival. In paper II and III, LBR was found to be an active combination in untreated
MCL patients, except for cases harboring TP53 mutations, but associated with significant toxicity including second
primary malignancies. In paper IV, we showed that the BTK-inhibitor ibrutinib, negatively affected the immune
mediated cell death induced by a type I or II anti-CD20 antibody in MCL cell lines, not restored by addition of
lenalidomide, 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 as
active 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 to
excessive toxicity and novel combinations with activity in elderly patients as well as in TP53 mutated MCL are
highly warranted. Future studies, including in vitro models on drug interaction will clarify how novel agents should
be combined for optimal use in MCL. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • professor Kluin-Nelemans, Hanneke, University of Groningen, Netherlands
organization
alternative title
Mantelcellslymfom : strategier i primärbehandling
publishing date
type
Thesis
publication status
published
subject
keywords
mantle cell lymphoma, registry data, Clinical Trial, Phase I, Clinical Trial, Phase II, rituximab, bendamustine, lenalidomid, ibrutinib, ADCC, in vitro model, TP53 mutations, watchful waiting, mantle cell lymphoma, real-world data, lenalidomide, rituximab, bendamustin, ibrutinib, ADCC, TP53 mutation, CDKN2A, NGS, MIPI, Watchful waiting
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2018
issue
28
pages
130 pages
publisher
Lund University: Faculty of Medicine
defense location
Föreläsningssalen, Onkologikliniken, Universitetssjukhuset i Lund
defense date
2018-04-19 09:00:00
ISSN
1652-8220
ISBN
978-91-7619-595-6
language
English
LU publication?
yes
additional info
ISSN: 1652-8220 Lund University, Faculty of Medicine Doctoral Dissertation Series 2018:28
id
efd53312-9b59-4e37-99b5-e97ff8591faa
date added to LUP
2018-03-22 09:21:43
date last changed
2019-11-19 13:49:34
@phdthesis{efd53312-9b59-4e37-99b5-e97ff8591faa,
  abstract     = {Mantle cell lymphoma (MCL) is associated with poor prognosis due to an aggressive clinical course. Being a rare disease, there are few randomized trials in MCL and there is no defined golden standard in primary treatment. <br/><br/>This works aimed to (I) investigate outcome in relation to primary treatment in MCL based on population-based registry data, (II) to evaluate tolerability and efficacy of lenalidomide-rituximab-bendamustine (LBR) in newly diagnosed 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. <br/><br/>Our results showed that survival in MCL patients improved during 2000-2011, which partly could be explained by the introduction of rituximab and intensified treatment with high dose chemotherapy consolidation. We also found that treatment with radiotherapy to limited-stage disease and observation in non-symptomatic MCL were associated with long-term survival. In paper II and III, LBR was found to be an active combination in untreated MCL patients, except for cases harboring TP53 mutations, but associated with significant toxicity including second primary malignancies. In paper IV, we showed that the BTK-inhibitor ibrutinib, negatively affected the immune mediated cell death induced by a type I or II anti-CD20 antibody in MCL cell lines, not restored by addition of lenalidomide, a potential sensitizer to anti-CD20 ab. <br/><br/>This work has provided data on important factors for outcome in MCL that may be taken into clinical use, such as active 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 to excessive toxicity and novel combinations with activity in elderly patients as well as in TP53 mutated MCL are highly warranted. Future studies, including in vitro models on drug interaction will clarify how novel agents should be combined for optimal use in MCL.	<br/>},
  author       = {Albertsson Lindblad, Alexandra},
  isbn         = {978-91-7619-595-6},
  issn         = {1652-8220},
  language     = {eng},
  number       = {28},
  publisher    = {Lund University: Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Mantle cell lymphoma strategies in primary treatment},
  url          = {https://lup.lub.lu.se/search/ws/files/42063963/Mantle_cell_lymphoma_strategies_in_primary_treatment_thesis_for_Lucris247510_2_G5_Alexandra_A.pdf},
  volume       = {2018},
  year         = {2018},
}