mantle cell lymphoma prognosis | Lymphoma has ' cells of the mantle: standards and actualite´s theoretical treatment

Lymphoma has ' cells of the mantle:
standards and actualite´s theoretical treatment

Summary
A cells of the mantle (LCM) Lymphoma is a rare and aggressive form
Lymphoma non-Hodgkin, whose outcome is dark. A standard therapy
has been established in recent years, based on an association of
cytarabine and rituximab, followed by an increase and a transplant
autologous in young patients. The LCM is however still a disease
aggressive, marquee of many relapses. A new era is
However committed, with the development of therapies that could focus
change deeply therapeutic attitudes and the prognosis of the disease.
We present here the standards and what's new in era of treatment of the
LCM.
n key words: a mantle cell lymphoma
Abstract
Mantle cell lymphoma (MCL) is a rare and aggressive form of not Hodgkin's
Lymphoma with one of the worst outcomes. The last decades have established a
standard treatment based on the use of cytarabine combined with rituximab
followed by a therapeutic intensification and autologous transplant in
young patients. Despite this, LCM remains year aggressive entity with many
relapses. Currently, a new era is emerging with the development of new targeted
therapies that are coming to change our attitudes and therefore the prognosis of
This disease. This review presents the current standard treatment and therapeutic
developments in MCL.

Lymphoma's cells of the
Coat (LCM) is a lymphoma
Smart non Hodgkin which
the diagnosis is based on the identification
of a population of cells
CD20 + tumour
+ CD5
CD10-
,
CD23 - presenting a translocation
(11,14) (t(11;14)) qui induit une)
overexpression of cyclin protein
D1 deregulant the cell cycle.
Other genetic anomalies
then join a t (11,14) [1]
to form a genetic picture
complex related to the time cycle
cell phone, the regulation of apoptosis
or even the repair of DNA.
At the histological level, proliferation
tumor can ^ be nodular.
temoignant of the proliferation
the area of the mantle, or diffuse.
At the cytological level, the form
Classic (80%) is of
cells tumor tr're heterog enes, of
small size was average, with a core
irregular, a chromatin l ^ ache. Several
variants forms are directed.

It is recognized both variants has small cells (5%):
a Variant lymphocytoı¨de, mimicking leukaemia lymphoı¨de
Chronicle and a monocytoı¨de-like Variant
in the marginal area lymphomas. It is recognized by
elsewhere two variants blastoı¨des (5%): a form
Classic blastoı¨de, with cells similar to the
lymphoblasts, and one form blastoı¨de pleiomorphe, with
cells of larger sizes. The LCM is an entity
well characterized, however presenting variants
reflecting a certain heterogeneity [2].
The LCM has a prevalence of three cases per 100,000
inhabitants per year, with a median of ^ age at diagnosis
the order of 72 and a tr are marked predominance
male (sex ratio = 4/1). The LCM represents between 5 and
10% of malignant lymphomas not hodgkiniens.
During the last decade, many advances
therapies have significantly improved the survival of
patients:
-recognition of the LCM as an entity particularly era
Lymphoma, allowing therapeutic adjustment,
-addition of rituximab to the polychimiotherapies,
-determination of an intensive strategy, adapted to the
young subjects, allowing the achievement of remission
complete extended summers.
Recent studies have complete these advances. Since
a few years, the emergence of new therapies
We am ene has rethink therapeutic support
patients. What we see today
as the standard of treatment from the LCM won't
probably not for long, and many speak already has the
beginning of a new era of Therapeutics in the LCM.
What are these standards of treatments? What are these
new therapeutic agents and what changes
should he expect in the care of patients?
In this review, we will outline what can, or
could bring us a rethink the current paradigms
treatment.
In recent years, the prognosis of patients
has significantly improved. Thus, the Swedish registry
Lymphoma showed that patients taken in charge
for MCL between 2005 and 2010 had a survival
overall (SG) has three years of 62% against 47%
(p = 0.01) for patients diagnosed between 2000
and 2005 [3]. These progress are held has three breakthroughs in
therapeutic strategy: scaling up
therapy with autograft in first line, adding
the rituximab and, more recently, the introduction of
cytarabine high dose in the induction. The addition of rituximab
in post-autogreffe probably will complete
These advances.

Currently, the strategy of first therapeutic line
is essentially based on the age of the patient, and more ^
important, on its condition (figure 1).

Current recommendations
Theoretical subjects therapeutic support
Youth
For patients in good condition, the strategy of
first line is based on the use of chemotherapy
cytarabine-containing induction followed
consolidation with intensive chemotherapy and autologous transplant
(table 1). Prognostic indexes do not
not yet allow a stratification of treatment.
The contributions of the autologous transplant in first line to the subject
young is no longer a show in the LCM. It does so
part of the recommendations of the European Society of
Medical Oncology [4] and is included in the repositories
International [1, 5]. Autograft has won its place in
the LCM gr ^ ace to the results in a study of the MCL
network that shows a benefit, in terms of survival, of
autograft compared to maintenance therapy by
Interferon [6], with a median progression-free survival
(SSP) of thirty-nine months versus 17 months (p = 0.001).
After autograft, complete (CBR) response rate is
90% [6-8]. On the types of plans of
packaging, the retrospective of the SFGMTC study (500
patients autografts in first line) shows that 43%
patients have received a package of type BEAM
compared to 45 percent who received a package based on
irradiation body total (ICT) [9]. The study of the registry
of the EBMT [10] 418 patients seems to show that
the ICT would have an inter ^ and patients not reaching
not the RC (morphologically defined) before autograft.
However, this advantage of ICT is found either on the SG
three years ago nor on survival without relapse in other studies
[11]. If we can wonder infinity on the best
packaging, the reality on the ground shows us a tr are
sharp decline in packaging based on ICT for the benefit of
packaging by chemotherapy alone.
The use of rituximab (monoclonal antibody leads
against the CD20) a change management of
lymphomas diffuse large cell b and lymphomas
Follicular. The benefit of rituximab in the LCM has been
demonstrated later. In the first line, there are
the study of Lenz et al, which has compared chemotherapy
only one (CHOP) the Association of chemotherapy and
rituximab (CHOP-R). R-CHOP arm shows superior
in terms of overall response, with a rate of 75%
(p = 0.005); However, the quality of response in this
study of the German group remained poor, with a rate
RC at the end of the six cycles of only 37% in the
arm R-CHOP, against 4% in the single CHOP arm [12].
The study also confirmed the benefit of input from the
rituximab on the SSP. The positive impact of rituximab associated

has a combination chemotherapy in induction has also been
observed in retrospectives of registry studies. It is
now acquired (especially gr ^ ace to meta-analyses) that
rituximab Associates has a combination chemotherapy improved
the SSP and the percentage of answer, and probably the
Patients with MCL SG.
With a schema therapy based on a combination chemotherapy
associated with rituximab followed of an autologous transplant,
the treatment of first line of the LCM of the young subject
is quite similar to that of the diffuse malignant lymphoma
has large cells (DLBCL, for diffuse large B-cell
Lymphoma) of the beginning of the two thousand years. He is in
different nevertheless by the importance of cytarabine
d are the induction. The combination alternating R-CHOP and
R - DHAP was first reported by GELA it in a
prospective study. Apr are four cycles of CHOP, the rate
RC was 7% and increased 84% apr are four
R-DHAP cures [8]. A prospective trial randomize has
then summer realized by the European MCL network. This
test, reports the ASH 2012 by Olivier Hermine [13],
compared, before autograft, a sequence of three
cycles of R-CHOP followed by three cycles of R-DHAP has
six cycles of R-CHOP. The introduction of cytarabine
permit to increase the time before treatment failure
(TTF, for time to treatment failure), no impact
on the SG. Other Therapeutics, with patterns
not negligible toxicity, have also used a cytarabine,
like the R-hyper-CVAD schema, which allows a
rate of RC in the order of 85% in first era line
[14, 15], an 80% survival is three years old. However
highlight the significant toxicity of the hyper-CVAD schema
whose use is controversial: it is used by
some centers Americans, there's little use in Europe.In this therapeutic approach that can be described
of 'classic', combining rituximab with combination chemotherapy
then autologous transplant, advanced the most recent
could ^ being to wear to the credit of the Lyma study, which has studied
the benefit of a maintenance rituximab treatment
post-autogreffe following an induction by four
R-DHAP cures (partial response patients has
the outcome of these four beneficiaient four cures cures
R-chop extra) [16]. The first analysis
intent to treat confirms inter ^ and sequence
therapeutic: progression-free survival has three years of
75% for a SG has three years of 82.6%. Survival without
EV event (HSE) - that is to say without relapse, progression,
Dec are neither severe infection - from the randomization
shows a profit for rituximab maintenance
(88.7 versus 73.4%; p is 0,0057). This first analysis
intermediary planned shows a tr are strong signal that
application has ^ being confirmed in the final analysis, expected
to early 2016. Other analyses are expected,
as the impact of the level of disease (MRD) waste
or predictive of the TEP-scan value.
Support theoretical therapeutic of the subject aˆge´
In this population of patients, eight cures of R-CHOP21
followed by rituximab maintenance therapy
can ^ be regarded as the standard of treatment
and offer an SG has four years to 62 percent according to the study published
by the European MCL network [17]. It should be noted that
in this study, the contribution of rituximab in maintenance is
translated into the PHC but also in the SG compared to the arm
control (SG ^ four years of 87% compared to 63% for the)
arm interferon) (figure 1).
R-CHOP is provided the single chemotherapy of
first line in the LCM of the topic ^ age? We are entitled
the question in the light of the study by Rummel et al.
[18] published in 2013, and which compared R-CHOP (all
three weeks, with a maximum of six cycles) has
R - bendamustine. On 449 patients in the study.
Ninety-four were suffering from an LCM. Them
authors report an advantage in terms of SES in
favor of the R-bendamustine arm: 35.4 versus 22.1 months
in the R-CHOP (p = 0.0044) arm with a toxicity less
important. It is an analysis of one
subgroup of patients, which limits the scope, but which
offers a promising therapeutic option. Thus, on the
basis of a treatment by bendamustine, breadsticks introduced
during the last ASH a study of phase II student the
feasibility of a combination of rituximab, bendamustine,.
dexamethasone and bortezomib (RiBVD) in patients
^ over the age of 65. RC rate is 74% has two
years, and the SSE is a 69% - m ^ th 86% for the
patients in MRD undetectable at the end of the six cycles of
chemotherapy [19]. The median follow-up is still short but
This work demonstrated the effectiveness of the RiBVD, in addition to a
good tolerance. Other options are possible with the
bendamustine as the association with cytarabine
reported by Italians [20] (table 2). If it is possible
to improve Induction chemotherapy (do less
toxic than the R-CHOP, while getting a better
SG), it is also possible to work on the improvement of the
maintenance. In this spirit, the prospective trial randomize
and international MCLR2 Elderly tests at the same time a new
induction (R-HAD/R-CHOP versus CHOP-R) and a maintenance
combining rituximab and lenalidomide.
Theoretical treatment relapsed options:
clinical trials in progress
In the absence of standards established, the therapeutic decision
must, as much as possible, favor the inclusion of patients
in clinical research protocols. The treatment of
relapse is to ^ being adapted has the ^ age and the State general
the patient, but also the nature of the treatment
already a rec¸us, has the length of the response and the choice of the patient
-wait to be able to secure his choice according to the
more robust biomarkers.

Lymphoma's cells of the mantle: standards and Therapeutics news
Clinical trials open in France, include
include the Lysa group as the trial
RHAD-LYM006, which compares a rituximabcytarabine-dexamethasone treatment
bortezomib. The primary goal
This study is the duration of response before failure
of the treatment. As has the T3 test
, study of phase Ib,.
It evaluates the tolerance and feasibility feasibility of
the association of temsirolimus (inhibitor of mTor track)
with R-CHOP, R - CF and R - DHA [21]. Temsirolimus, one
the way mTor inhibitor, has already has authorization on
the market (AMM) monotherapy in lymphomas
cells of the mantle in relapse or refractories [22]. Finally,.
two protocols of research indicated for all lymphomas
B cells are also open to the inclusions:
-the Protocol Galen, phase Ib/II study that evaluated
obinutuzumab (GA101) combined with lenalidomide),
-test Biblos, study of phase Ib evaluating the ibrutinib
Associates has a type R-DHAP chemotherapy or
R DHAOX.
Other studies conducted by industry are also in
course testing several new molecules (see below).
Place of the Allograft
Despite all the progress you made in recent years in
therapeutic support and improving the rate
answer, SSE and SG, the LCM is still considered
as an incurable disease. As often in
This situation, the Allograft can be considered. To approach
the question of Allograft in the LCM, we must be
turn to studies always retrospectives, sometimes of
registers, sometimes monocentric, with all the limitations
This type of work. The study published in 2014 by the EBMT
[23] is interested in the fate of patients Allografts
(n = 80) with a (RICAllo) reduced intensity conditioning
in a situation of relapse (n = 360) postautogreffe. The
SG after Allograft was 46 and 34% two and five
years, respectively (32 months median follow-up).
No related mortality has relapse (TRM, for treatment
related mortality) was of 30% at two years. Results has
put in perspective with free post Allograft Survival-
failure of autograft of this m ^ th study: 37% has two
years. A similar retrospective study was conducted by
SFGM-TC, on a population of 105 patients [24],
the post-Allograft SG is the SSP and 57 months
Seventeen months, the price of an identical TRM of 30%.
The relapse rate in this study was about 20%.
Patients who seem the strongest benefit
the Allograft in relapse after are a first line of
treatment with autograft includes are those who had
a first remission superior has a year [23]. Others
[25] work also show that the Allograft in the
LCM must be considered on a case-by-case thinking well the
toxic risk which symbol higher than in other
lymphopathies mature B [26].

The new mole´ vehicles
In the LCM therapeutic arsenal is constantly
enriched in recent years, gr ^ ace has news
molecules: temsirolimus, bortezomib, lenalidomide and
more recently still the ibrutinib (table 3). A list has
which we can can-^ tomorrow be adding inhibitors
of the way of the phosphoinositide 3-kinase (PI - 3 K) such as
idelalisib or mimetiques as the ABT-199 BH3.
As monotherapy, bortezomib is not sufficient but
the association of bortezomib has chemotherapy regimes
proven, whether with bendamustine,
recently, or with R-HyperCVAD. The novelty
most of these months comes from the results of the study
R - CHOP versus VR - CAP (an R-CHOP without oncovin) in
the first line, which demonstrated the benefit of bortezomib in
Association and does so again falter R-CHOP [27].Efficacy of lenalidomide in the LCM has also been
confirmed by Trneny in the Sprint MCL002 study [32]. He
This is a study of phase III was aiming to record that
a compared lenalidomide has a treatment let choice
the investigator (gemcitabine monotherapy, rituximab,)
cytarabine, fludarabine, or chlorambucil). Lenalidomide
used at the usual doses (25 mg/day) demonstrated a
superiority on the comparator arm, reducing to
39% the risk of relapse in a population of 254
patients. The switch of the primary endpoint of the study, which
is the SSP, is 8.7 months in arm lenalidomide versus
5.2 months in the control arm (p = 0.004). Option ^.
lenalidomide which we knew she could ^ be effective
in the LCM is confirmed, m ^ even if the SSP is short for
these patients having a stage ahead in their illness. The
combination lenalidomide/rituximab (R2) is also a keep
in memory in the LCM, as shown in a study
Yet preliminary presented at the ASH. The association
R2 in first line displays a SSP has two years of 83.9%
with a rate of 52.6% RC. The R2 schema test is the
m ^ th than rated in in follicular Lymphoma
The Relevance test [33].
The ibrutinib is the last breakthrough Therapeutics
in the LCM. Indicates relapse or in forms
refractory was the dosage of 560 mg/d, the ibrutinib belongs
has a new class acting Therapeutics
blocking the Bruton tyrosine kinase kinase activity.
key of the track of BCR signaling protein.
The ibrutinib got an AMM following the study PCYC1104-CA
[28] (n = 111). In a population enough
heavily treated, the ibrutinib gave a response rate
67.6% with a median duration of
response of 17.5 months. More recently, has the 2014 ASH, the
first results from another test student association
to rituximab have been reported with RC rates of
38%, or about 10% more than in the study of
Wang and al. [29].
Idelalisib is another promising therapy that targets
the PI - 3 K track. A study of phase I has recently
published (n = 40) [30]. A response is comprehensive documented
observed in 40% of which 5% of RC but with a SSP
median of only 3.7 months. Idelalisib is underway
evaluation in Combinatorial approaches.
The ABT-199 is a molecule called "BH3 mimetique. He
This is a new class of drug that interacts
directly on the antiapoptotique protein BCl-2 that she
interrupts the binding with protein proapoptotiques.
By separating the form by Bcl - 2 and protein complex
antiapoptotique, ABT-199 restores the induction of apoptosis.
In Lymphoma extr ^ dependent gallons of
BCl-2 as the LCM, the ABT-199 is a molecule
Extr ^ fiield promising [31].

Disease maturity
The international prognostic index (MIPI, for mantle cell
Lymphoma prognosis index international) is based on
four independent factors: the ^ age, the performance
status ECOG, the rate of LDH and blood cells
whites in the blood. It is a relevant for index
evaluate the prognosis in patients pretherapeutique
with LCM of stadium advance [34]. However, the
settings for the early response assessment and/or
crit finer eras of individual risk are widely

Lymphoma's cells of the mantle: standards and Therapeutics news
default. The data in the literature show that the
quantification by PCR of the DSM is a powerful tool
to detect and predict relapse [35]. It remains a establishing
recommendations specific to that this technique
can ^ be used in routine, indispensable for step
consider clinical relapses preemptif treatment
based on the assessment of the DSM by PCR. If we
press already has that the MRD (PCR? flow cytometry?)
can quickly become a major tool to guide the
therapeutic strategy, the picture of what is happening in
acute leukemias € fiance, there are currently
no clear recommendations which would allow
a passage a clinical practice.

Conclusion
Advances in treatment of recent years have
allowed to set a clear therapeutic strategy, to the
less in first line. The recent advances, has the time
technological and therapeutic, will tr are certainly
come quickly modify these standards of treatment.
Current prognostic indexes such as the MIPI or the
Bio-MIPI cannot decide the treatment has
the scale of the patient, and it is reasonable to consider from here
a few years a medicine more "personalised."
a rational-based biological specific to the patient
and has its pathology, attitude all the more essential
in a rare disease like the LCM, or new
treatments are extremely ^ place expensive. In 2015, the ^.
the LCM is taking a new turn gr ^ ace to the
progress are that we have made in the knowledge
of the pathology, new molecules which we
have the MRD detection tools but also has
the mobilization of the Hematologists. Imagine that it will be a
possible day to treat a patient with a LCM ' has the '.
map' and without conventional chemotherapy is no longer
a r ^ eve, inaccessible.