Mantle cell lymphoma
resume
Therapeutic trials in mantle cell lymphoma (S. The Gouill) results of clinical studies closed to inclusionsRiBVDPlusieurs work demonstrated the interest of bendamustine [1, 2] and bortezomib [3] in monotherapy with prolonged responses of more than six months in mantle cell lymphoma (LCM ) in Relapse. The interest of the RiBVD trial is to test the association Bendamustine and bortezomib in elderly patients with LCM in diagnosis. The [...]
Therapeutic trials in mantle cell lymphoma
(S. Le Gouill)
Results of clinical studies closed to inclusions
RiBVD
Several studies have demonstrated the interest of bendamustine [1, 2] and bortezomib [3] in monotherapy with prolonged responses of more than six months in relapsing mantle cell lymphoma (LCM).
The interest of the RiBVD trial is to test the association Bendamustine and bortezomib in elderly patients with LCM in diagnosis.
The final results were presented at ASH in December 2014 and show a complete response rate (CR) of 75% at the end of treatment and an increase in the CR/CRu rate to 57% after four cycles at 74% after six cycles. These results are higher than those of the R-CHOP21 [4] and R-Bendamustine [5] very good results are obtained in terms of complete molecular response: 83% at the blood level and 75% at the medullary level after four cycles of treatment, which will allow for more "proactive" molecular follow-up. Finally, although the median follow-up is only twenty-four months, the surviving data are encouraging with progression-free survival (PFS) and overall survival (OS) medians of 70% and 80%, respectively.
LyMa
The randomized phase III study LyMa evaluated the rituximab's interest in maintenance every two months for three years. Patients were induced by four cycles of R-Ptwi and a autograft conditioned by R-BEAM and Préautogreffe refractory patients were caught by R-CHOP. The analyses show a three-year PFS of 75% overall stackable at rates obtained with protocols using anthracyclines and the bit in pre-autograft conditioning. The interim analysis presented at ASH in 2014 showed interesting results with a two-year EFS of 93% for the rituximab arm in maintenance versus 83% for the observational arm [6] with identical bones between the two arms, in the order of 94%.
Clinical studies still open to inclusions
MCL-R2 ederly
Lenalidomide allows for prolonged responses alone or in association with rituximab in maintenance [7] and it has been shown that cytarabine plays a major role in induction treatment. An international work has been put in place with the MCL-R2 protocol comparing in the elderly, in the first line, a pattern by R-Chop/R-HAD (at age-appropriate doses) versus R-Chop alone followed by a randomized maintenance treatment by rituximab + lenalidomide Versus rituximab alone for two years.
Study T3
The T3 study was presented at ASH 2014. It evaluates the association of Temsirolimus at different polychimiothérapies (R-CHOP, R-HAD and R-FC) and the main objective is to determine the maximum tolerated dose (dose escalation from 25 to 75 mg).
The first results show a marked hematologic toxicity with, among others, labelled thrombocytopenia requiring a decrease in doses and making the regimen of Temsirolimus to J2-J8 and J15 difficult to meet. The complete response rates appear favorable for Cytarabine-based association and the assay continues with a reduction in doses of temsirolimus to 25 mg.
R-DHA-V (MCL 2005-01)
A randomized phase III study, in collaboration with the European MCL Network, compares R-HAD alone or with bortezomib in relapsed or refractory patients and is intended to assess the response time before treatment failure.
Treatment Outlook
The rational
The European MCL Network protocol for subjects under 65 years comparing a pattern by six R-Chop/R-Ptwi versus six R-Chop cycles followed by therapeutic intensification, showed an improvement in the median PFS in the cytarabine arm. Without improvement of the bone with a median follow-up of 5.3 years. This study confirmed the prognostic nature of the DSU. In addition, the LYMA study objectively rituximab the benefit of Postautogreffe maintenance on survival. However, the prognosis of relapse patients remains very unfavourable despite the intensification by autografting. All these data tend to reconsider the position of the autograft in case of negative DSU and associated maintenance treatment.
On the pathophysiological plane, the LCM is dependent on BCR signaling, which allows the activation of the ft3 kinase and NFKB pathways which leads to the activation of Bcl2. Among the many molecules being tested are BTK, Bcl2, and ft3 kinase inhibitors that show significant effects in relapsing or refractory LCM.
In this context, the next two trials in front-line patients under 65 years will attempt to answer the following questions:
What is the place of autografting in patients in negative bn before autografting?
What is the place of autografting in these patients when maintenance by rituximab improves survival with or without autografting?
How can ibrutinib be associated with R-CHOP/R-Ptwi?
Topics < 65 years; First line
The European randomized TRIANGLE protocol was set up for subjects in the front line of less than 65 years in order to evaluate the efficacy of ibrutinib in induction and maintenance, as well as the interest of autograft in this context. This trial has three randomized arms:
One arm R-CHOP/R-Ptwi + Autograft,
One arm R-CHOP/R-Ptwi and ibrutinib + autograft and maintenance by ibrutinib ± rituximab for two years,
An R-CHOP/R-Ptwi and ibrutinib arm without autografting with maintenance by ibrutinib ± rituximab for two years.
However, it remains to await the results of the feasibility of the Association of Ibrutinib and R-Ptwi/Ox.
Bcl2 inhibitors are promising because of the resistances described with BTK inhibitors via activation of the alternating pathway that leads to the activation of Bcl2. In this context, the study LyMa 101, Phase I/II, will evaluate the interest of an anti-Bcl2, ABT-199 within a scheme associating it with GA-101 + ptwi/Ox and then autograft and maintenance treatment by GA-101, systematic or preemptive according to the DSU.
The IDÉLALISIB, a ft3 kinase inhibitor, will be associated with RiBVD for a total of four cures. According to the therapeutic response, the general condition of the patients and the DSU; It may be proposed:
A allograft for fit patients,
An autograft for the primary refractory fit, followed by four cures of rituximab according to the DSU
Treatment with IDÉLALISIB for six months for patients who could not benefit from a transplant, followed by four cures of rituximab according to the DSU.
In conclusion, the therapeutic strategies of the future will aim to assess the interest and feasibility of the association of targeted therapies with conventional cytarabine-based chemotherapy as well as maintenance treatment.
Biomarkers in mantle lymphoma
(A. Martin, a. Traverse-Glehen, A. Moreau, B. Burroni, D. Cadenyi)
The work projects presented concerned five subjects of interest in the LCM and are based on the study of the impact of certain signalling pathways which may be biomarkers of interest or even therapeutic targets for the future.
Transferrin Receiver
Original work carried out by the Necker Hospital team emphasizes the potential interest of the expression of the membrane transferrin receptor (TfR) by tumor cells. In follicular lymphomas, an expression greater than 25% would be associated with an adverse prognosis in a retrospective cohort. These data are being validated in the cohort of prospective protocol patients and could be explored in the LCM. Indeed, in addition to its potential prognostic impact, TfR is a potential therapeutic target since anti-TfR antibodies are in development and could be tested in patients with LCM.
LCM microenvironment
Recent data have highlighted the importance of microenvironment in LCM, including parameters such as the number and subtype of macrophages (M1 or M2) [8] subtypes lymphocyte T or microvascularization as well as the distribution Stromal cells in the tumor tissue. The group therefore proposes to explore some of these aspects on a anatomopathologic side which has not been achieved to date.
The proliferation index evaluated by the percentage of cells expressing the Ki67 protein showed a prognostic interest in LCM with the establishment of mixed prognostic scores combining the clinical score MIPI and Ki67 [9]. The thresholds of expression to be considered remain controversial and standardized evaluation is often difficult to achieve. Work is currently being carried out on the cohort of patients included in the LYMA protocol according to standardized methods [10] and preliminary results report an excellent correlation between the high rate of cells expressing the Ki67 and a Aggressive presentation Since 90% of these aggressive forms have a Ki67 greater than 30%.
SOX11 TRANSCRIPTION Factor
The SOX11 protein is a neural transcription factor absent from normal B lymphocytes. It is currently recognized as a useful marker for diagnosis in CCDN1-negative LCM and has a pejorative prognostic value due to its correlation with a more aggressive initial presentation [11]. It could, moreover, be a therapeutic target of interest because its expression promotes tumor angiogenesis through the transcriptional regulation of PDGFA [12]. Therefore, it seems interesting to study the prognostic impact of SOX11 expression in LCM in prospective cohorts and to compare it with Ki67 expression or alterations in C-MYC found in immunohistochemistry, cytogenetics, or biology Molecular.
ACTIVATION of the WNT/Β-catenin pathway by the LCM microenvironment
Activation of the Wnt/β-catenin signalling pathway in LCM is common [11] and depends on the activation of the BCR pathway. The group proposes a work to identify the mechanisms of this activation, a possible relationship with the mutational status of immunoglobulin genes or its impact on transcriptional activity (CCND1, C-MYC). Finally, this work can be pursued by studying a possible impact of activating this signalling pathway in prognostic and therapeutic terms.
Biological ASPECT
(Mr. Callanan)
Residual disease
The prognostic impact of the DSU at different treatment times or during post-treatment monitoring is being prospectively evaluated within the LYSA protocols and the EU MCL network on LCM. A prospective follow-up of the estimated DSU in molecular biology (current gold standard), EURO-BN [13, 14], was foreseen in the Protocols LYMA and RiBVD with a central analysis of the samples in the biology centers of the CHU of Grenoble, of Créteil and Necker .
For the record, the evaluation of the DSU requires diagnostic sampling to allow further follow-up after determination of the specific VDJ rearrangements of the tumor. This evaluation is carried out by QPCR Clonospécifique of the specific V (D) J rearrangements of the tumor after extraction of genomic DNA from blood and medullary samples or more rarely tissue.
The purpose of this work is to determine whether the response to the treatment estimated by the DSU has a prognostic impact in patients with LCM and whether appropriate maintenance or emptive therapy strategies could be proposed based on the profiles Response to the treatment of patients.
Despite the excellent sensitivity of molecular biology, which allows detection at a threshold of 10-5 and a robust quantification threshold of 10-4, other techniques might be interesting, such as high-throughput sequencing by NGS method or Cytometry In flux (CMF). Indeed, a retrospective work carried out by the hospital team Necker on Sixty-four cases of LCM shows that half of the samples with a positive DSU in QPCR method are below the threshold of quantification and are therefore of delicate interpretation. The results show that the eight-colour CMF has an excellent rate of concordance with QPCR for the quantification of the DSU when it exceeds 0.1% and is informative in more than 60% of cases where the DSU is valued at between 0.1 and 0.01%. This work also highlights the existence of an average period of five months between the recurrence of a positive DSU at 10-4 and the clinical relapse, which leaves a potential place for preemptive treatments. In total, it seems necessary to assess prospectively both the concordance between the CMF and the QPCR for the follow-up of the DSU and the place of the preemptive treatments.
New biomarkers
Dr. Callanan has detailed the interest of the study of new biomarkers and the understanding of the mechanisms of lymphomagénèse in the LCM [15]. Several programmes are being developed, with the Relysis project, which focuses on the mutational spectrum within tumor cells, and on the other hand a project that will study the landscape of changes epigenetic to diagnosis. Indeed, there is a strong rationale for the impact of epigenetic changes in the emergence and evolution of LCM, and thus of transcriptional regulation of genes, genomic stability and control of cell fate, particularly via the Regulation of histone methylation-dependent heterochromatin. Dr. Callanan reported a particular "heterochromatic mark" in about one-third of the samples from a series of fifty patients. This heterochromatic disturbance is related to a specific transcriptional profile, enriched in functional signatures of major, pathological and in fine therapeutic interest, in LCM
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