mantle cell lymphoma | Mantle lymphoma: Support 2011

Mantle lymphoma: Support 2011



Summary
Mantle lymphoma (LM) represents 6% of non-Hodgkin (NHL) lymphomas. The diagnosis is based on immunophenotyping and demonstration of the presence of translocation between chromosomes 11 and 14, with overexpression of Cyclin D1. The first line treatment of the young subject combines three alternating R-CHOP21 cures with three R-DHAP21 cures, followed by a autograft conditioned by total body irradiation, cyclophosphamide and Aracytine. The subject of over 65 years can benefit from eight cures of R-CHOP21. The value of maintenance treatment is being evaluated. The allograft of hematopoietic stem cells offers a chance of healing to patients in relapse in good general condition. The targeted treatments will improve the prognosis of this disease.

Introduction
Described as a clean entity since the publication of the Revised European American Lymphoma Classification (REAL) in 1994, Mantle lymphoma (LM) represents 6% of all non-Hodgkin (NHL) lymphomas and preferentially touches Individuals over 60 years old with a slight male predominance (ratio male/female: 3/1). It differs from other small cell lymphomas by the quasi-constant presence, within the tumor cells, the translocation between the long arms of chromosomes 11 and 14, T (11; 14) (q13; 32), responsible for the overexpression of Cyclin D1, one of molecules causing cell proliferation. 1 frequently diagnosed at an advanced stage, this disease usually requires systemic treatment. The comparison of the therapeutic results obtained in the years 70 and 80 with those obtained in the years 90 and following illustrates the therapeutic advances represented by the use of anthracyclines and monoclonal antibodies as well as the Use of bone marrow autografting and peripheral blood stem cells. 2 with median survival of five to seven years, LM is currently considered incurable with the exception of patients who can benefit from cellular immunotherapy obtained After allograft of stem cells. The improvement of diagnostic methods and the thorough understanding of the pathophysiology of this tumor will enable, in the coming years, better use of available therapeutic weapons with, as a result, an extension of the Survival. 3 This article describes the Anatomo-clinical characteristics of the disease, the additional examinations to be carried out during its management and the current treatment regimens.

Histological and PHYSIOPATHOGÉNIE Diagnosis
The LM is the result of tumor proliferation of small lymphocytes. Four cytological variants are currently described, namely the classical (small-cell) Form, the one resembling the lymphoma of the marginal zone, the Blastoïde variant, and the Pléiomorphe form. Differential diagnosis with other small cell lymphomas (chronic lymphoid leukemia, lymphocytic lymphoma, follicular lymphoma, hairy leukemia and marginal area lymphoma) is based on immunophenotyping (table 1) and analysis of cytogenetics and molecular biology. Tumor cells express the CD45, CD19, CD20, CD22, CD24, and CD79a. They present a surface immunoglobulin (IgM and/or IgD, more rarely IgG). The light chain λ is more often expressed than the κ chain. Lymphoma cells do not express CD23 and CD10 allowing differential diagnosis with chronic lymphoid leukemia and follicular lymphoma, respectively. Finally, tumor cells express CD5, an aberrant marker of the lymphocyte line T. 1 The diagnosis of certainty is based on the evidence, in cytogenetics, of translocation t (11; 14) (q13; 32). Following the latter, the gene encoding cyclin D1, kinase promoting the progression of cell division, is overexpressed because it is controlled by the gene promoter of the expression of genes encoding the heavy chains of immunoglobulins. 1.4 The Overexpression of the cyclin D1 can be sought in molecular biology. The diagnostic difficulty is based on the existence of rare LM cyclin D1 negatives, pathologies characterized by translocation t (2; 12) (P12; p13) responsible for an overexpression of the cyclin D 2.5 These latter cases can be distinguished from other Small cell lymphopathies by demonstrating the expression of transcription factor Sox 11.6, 7 other genetic anomalies disrupting the metabolic pathways involved in apoptosis, DNA repair mechanisms, expression Oncogenes and suppressive genes are necessary to allow the development of the disease. The number of abnormalities within the tumor is correlated with its aggression. 1, 8.9

Immunophenotyping of different small cell lymphomas

CD5 CD10 Bcl6 CD23 FMC7 LLC +--+-L to hairy----+ SMZL-----LF-+ +--LM +---+ NHL MALT----/+-LLC: chronic lymphocytic leukemia; L: leukemia; SMLZ: splenic lymphoma of the marginal zone (Splenic marginal zone Lymphoma); LF: follicular lymphoma; LM: Mantle lymphoma; NHL: Non-Hodgkin's lymphoma; MALT: lymphoid tissues associated with mucous membranes (Mucosa-associated Lymphoid tissues).

Prognostic factors

Many clinical, biological and histological criteria have been tested for their pretherapeutic prognostic impact. The Blastoïde and pleomorphic variants have a more aggressive evolution. 8,10 the LM in the form exclusively leukemia or Extraganglionnaire seem more indolent. 11 The application of the international prognostic indexes developed for the Management of diffuse large cell lymphomas (International prognostic Index – IPI) 12 and follicular (International prognostic Index of follicular lymphoma – FLIPI) 13 is less relevant in the presence of LM. The presence of mutations within the genes encoding the immunoglobulin heavy chains does not alter the natural history of the disease except for the VH3-21 mutation whose presence darkens the prognosis. 14,15 the International prognostic Index Mantle Cell Lymphoma International Prognostic Index – MIPI) takes into account the patient's age, serum white blood cell and lactate dehydrogenase (LDH) levels, and its Eastern-assessed performance Index Cooperative Oncology Group (ECOG) (table 2). 16 This index allows patients to be stratify in three different prognosis cohorts. The Ki67 cell division marker makes it possible to distinguish three subpopulations of LM from different evolution, whether patients are treated by chemotherapy or immunochimiothérapie. 17 incorporated into the MIPI (MIPI "biological"), it increases the power Discriminative. 16 Finally, the expression of SOX11 is associated with shorter survival. 7

International prognostic Index of Mantle lymphomas (MIPI)

Points Age (years) ECOG LDH * GB (109/L) 0 < 50 0-1 < 0.67 < 6700 1 50-59-0.67-0.99 6700-9999 2 60-69 2-4 1.00-1,49 10 000-14 999 3 ≥ 70-≥ 1.50 ≥ 15 000 ECOG: Eastern Cooperative Oncology Group; LDH: lactate dehydrogenase; GB: white blood cells. * ratio of patient LDH rate to higher normal value.

INITIAL Balance Sheet

After the diagnosis of LM in a ganglionic biopsy with cytological examination, immunophenotyping, cytogenetic analysis and molecular biology, the initial assessment involves a rigorous clinical examination in search of adenopathies and/or Hepatosplenomegaly. Laboratory tests include CBC, coagulation balance, ionogram, renal function, measurement of blood glucose and uric acid levels, hepatic enzymology with measurement of LDH, protéinogramme with immuno-electrophoresis. The additional tests are used to determine the number of sites affected and include a double bone biopsy and thoraco-abdominal and cervical scanners of soft tissues. In case of neurological symptomatology or in the presence of the Blastoïde variant, an exploratory lumbar puncture and a brain scan are indicated. 18 A systematic ENT examination is recommended. A high and low GI endoscopic exploration should be performed in any patient with digestive symptoms. 19 Although LM cells are avid for 18-fluoro-deoxy-glucose (18FDG), to date, positron emission tomography ( TEP) is not part of the initial balance sheet except for patients participating in a clinical trial whose main objective is the evaluation of the therapeutic response rate. 20,21 Finally, a pre-therapeutic cardiac assessment (ECG and ultrasound TRANSTHORACIC) is recommended prior to the administration of chemotherapy.

Treatment

Therapeutic modalities

Historically, the first-line treatment of LM uses polychemotherapy. 2 The addition of rituximab (Mabthéra) to it allows a significant improvement in response and non-progression survival rates. On the other hand, the overall survival gain is not significant so that the benefit of this therapeutic association is less pronounced than in the treatment of diffuse B lymphomas with large cells or folliculars. 22-25 The intensity of treatment depends on the Age and takes into account the comorbidities of the patient. In patients under 65 years of age, after anthracycline-based chemotherapy, a therapeutic intensification followed by autografting of peripheral blood stem cells allows a significant improvement in response and survival rates without Progression and overall survival. 26,27 older patients benefit from an association of Immunochimiothérapie without autografting. 28 for these patients, the interest of a maintenance treatment is being evaluated. The allograft of peripheral blood stem cells, due to its anti-tumor immunological action, is the only therapeutic modality that can cure the disease. 18 many molecules, aiming to correct the malfunctions of the different pathways Metabolics involved in division, cell differentiation and death are currently under study. 1

Therapeutic Indications

Some LM patients seem to be able to benefit from a simple surveillance. 29 to date, the various prognostic indexes and biological markers intended to select these patients must be validated prospectively before such Attitude can be recommended in the clinic. Only patients with a leukemia phase LM, with no other lymphomateuse impairment except for a possible splenomegaly with a low score according to the MIPI, can benefit from simple monitoring.

First line treatment

Anthracyclines-based Polychimiothérapies (CHOP: cyclophosphamide, Adriamycin, vincristine, and prednisone),30 fludarabine (FCM: Fludarabine, cyclophosphamide, mitoxantrone) 30 or Bendamustine (BOP: Bendamustine, vincristine, prednisone) 31 Provide therapeutic response rates greater than 70%. These are higher than 90% when adding rituximab. 31 the use of Aracytine clearly provides an additional benefit in the quality of the therapeutic response. 32 The R-HyperCVAD-HDMTX scheme (rituximab, vincristine, doxorubicin, Dexamethasone, methotrexate and Aracytine), developed in the United States, provides 97% response rates but is accompanied by a prohibitoire toxic death rate. 33-35 immuno-chemotherapy type R-DHAP21 (rituximab, dexamethasone, Aracytine High dose and cisplatin) is less toxic than the previous diagram. Alternating with the R-CHOP21 diagram and followed by an intensification by autografting of peripheral blood stem cells (conditioned by radiotherapy, aracytine and Melphalan), this scheme constitutes in Europe the reference for treatment of patients under 65 Years in good general condition (table 3). This scheme offers a therapeutic response rate of 97%. During the last update of this protocol, the median time for non-relapse survival was not reached. 27 older patients and those not eligible for therapeutic intensification are treated, on the front line, by eight cures for R-CHOP21, Regimen of chemotherapy higher than that comprising Fludarabine and cyclophosphamide (R-FC28) (table 3). 28 where the general condition of the patient is precarious, symptomatic treatment with chlorambucil and prednisone or cytarabine is Proposed. 36

Chemotherapy regimens used in first line treatment of mantle lymphoma

Drugs dosages routes and durations day (s) of administration R-CHOP21 * Rituximab 375 mg/m2 IV,-hours J1 Cyclophosphamide 750 mg/m2 IV, 1 hour J1 Adriamycin 50 mg/m2 IV, 30 minutes J1 Vincristine 1.4 mg/m2 * * IV, 15 minutes J1 Prednisone 80 mg/m2 PO or IV J1 to J5 R-DHAP21 * Rituximab 375 mg/m2, day IV,-hours J1 dexamethasone 40 mg DT, Day IV, 15 minutes J1 to J4 cisplatin 100 mg/m2, day IV, 24 hours J1 Aracytine 2 x 2000 mg/m2 IV, 2 hours J2 R-CHOP: Rituximab-cyclophosphamide, Adriamycin, vincristine, prednisone; R-Ptwi: rituximab-dexamethasone, Aracytine, cisplatin. IV: intravenous; MG: milligram; PO: Per OS; DT: Total dose. * A cure every 21 days; * * Maximum 2 mg.

Revaluation at the end of treatment

All abnormal examinations in the initial balance sheet are repeated at the end of the first line treatment to define the therapeutic response. The importance of the quality of the response is demonstrated and requires a medullary or blood research of the molecular markers of the disease. 37 Although pet is not recommended in this indication, the negativity of this test can be used to affirm the response Complete metabolic. 21

Maintenance

After first-line treatment, in order to prolong the response or improve the quality, maintenance could be offered to the patients. Rituximab, Interferon, lenalidomide (Revlimid) are potential candidates. Different studies are underway to determine which patients can benefit, which molecules to use and in what modalities. To date, maintenance is not yet part of the daily clinical practice.

Followed

After the first-line treatment, the patient is clinically and biologically monitored every three months. It benefits semi-annually from scannographiques controls. A second-line treatment is initiated in any young patient in partial or progression remission, even asymptomatic. On the other hand, patients over 65 years of age with low clinically silent residual masses or asymptomatic relapse can benefit from close surveillance. In this case, the second line treatment is initiated during the progression of the tumor masses or during the recurrence of the symptoms.

Second line processing

After the first-line treatment, the relapse remains sooner or later inevitable. 18 second-line treatment includes chemotherapy agents not yet used in first-line treatment with generally platinum derivatives (R-ICE: Rituximab, VP16, Carbopatine and ifosphamide; R-ESHAP: Rituximab, Prednisolone, VP16, cisplatin, Aracytine) or Bendamustine (R-B: Rituximab, Bendamustine; R-VB: rituximab, bortezomib, bendamustine; R-BOP: rituximab, Bendamustine, vincristine, prednisone) (table 4). Each scheme can be used as is or adapted according to the clinical circumstances (comorbidities, general condition of the patient...). If an HLA-compatible donor is available and the general condition of the patient permits, a allograft of stem cells should be proposed, usually after non-myéloablateur conditioning, to patients with a good response to this treatment of Second line. 18

Table 4

Chemotherapy regimens used in the second line treatment of mantle lymphoma

Drugs dosages routes and durations day (s) of administration R-ICE21 * Rituximab 375 mg/m2 IV,-hours J1 VP16 100 mg/m2 IV, 1 hour j1 to J3 carboplatin AUC 5 IV, 1 hour J2 Ifosphamide 5000 mg/m2 iv, 24 hours J2 R-BOP21 * Rituximab 375 mg/m2 iv ,-hours J1 Bendamustine 60 mg/m2 IV, 30 minutes J1 to J5 Vincristine 2 mg DT IV, 15 minutes J1 prednisone 100 mg/m2 IV, 15 minutes J1 to J5 R-FC28 * * Rituximab 375 mg/m2 iv,-hours J1 Fludarabine 25 mg/m2 IV, 30 minutes J1 to J3 250 mg/m2 iv , 4 hours J1 to J3 R-ESHAP28 * * Rituximab 375 mg/m2 IV,-hours J1 Prednisolone 250 mg DT IV, 15 minutes J1 to J5 VP16 40 mg/m2 IV, 1 hour j1 to J4 cisplatin 15 mg/m2 IV, 24 hours J1 to J4 Aracytine 2 x 500 mg/m2 IV , 2 hours J5 R-ICE: rituximab-Ifosphamide, carboplatin, etoposide; R-BOP: rituximab-Bendamustine, vincristine, prednisone; R-FC: rituximab-Fludarabine, cyclophosphamide; R-ESHAP: rituximab-Prednisolone, etoposide, cisplatin, Aracytine; IV: intravenous; MG: milligram; PO: Per OS; AUC: Area under the curve. * A cure every 21 days; * * A cure every 28 days.

Other therapeutic weapons

Radiotherapy finds its place during the Pregraft conditioning or in combination with immunotherapy (radioimmunotherapy – RIT) 38 and can be saving during the palliative management of a compressive mass.

Many new molecules, targeting different metabolic pathways, are currently under study and, for some of them, available in phase I or II clinical studies. Among the latter, Temsirolimus (Torisel, M-TOR inhibitor), Flavopiridol (Alvocidib, cell cycle inhibitor), bortezomib (Velcade, proteasome inhibitor), Vorinostat (Zolinza, histone inhibitor deacetylases – HDAC), and Lenalidomide (Revlimid, immunomodulator) seem promising. 3, 39,40

CONCLUSIONS and therapeutic algorithms

Although long-term therapeutic outcomes remain disappointing, many progress has been made in taking care of LM patients. The role of rituximab, aracytine and stem cell autografting is currently well established. The platinum derivatives, the Fludarabine and, more recently, the Bendamustine find their place in case of relapse. The targeted treatments, by correcting the dysfunctions of metabolic pathways regulating the cell cycle, give hope for a future improvement of the therapeutic results (figures 1 and 2).

MCL: Mantle cell lymphoma, mantle lymphoma; CI: contra-indication; R-CHOP: rituximab-cyclophosphamide, Adriamycin, vincristine, prednisone; R-DHACarboplatine: rituximab-dexamethasone, Aracytine, carboplatin; R-Ptwi: rituximab-dexamethasone, Aracytine, cisplatin; Bit: Total body irradiation; Gy: Grays; Ara C: aracytine; R-ICE: rituximab-Ifosphamide, carboplatin, etoposide; R-BOP: rituximab-Bendamustine, vincristine, prednisone; RC: Complete Remission; RP: Partial Remission.

MCL: Mantle cell lymphoma, mantle lymphoma; PS: Performance index (performance status); Fit: Patient in good general condition; Unfit: Patient in poor general condition; R-CHOP: rituximab-cyclophosphamide, Adriamycin, vincristine, prednisone; RC: Complete Remission; RP: Partial remission; R-ESHAP: rituximab-Prednisolone, etoposide, cisplatin, Aracytine.

Practical IMPLICATIONS

Consisting of small cells, mantle lymphoma represents 6% of all lymphomas and remains incurable except for patients who may benefit from a allograft of stem cells

> The diagnosis of certainty is based on the immunophenotyping of tumor cells and the demonstration of the presence of translocation between the long arms of chromosomes 11 and 14, T (11; 14) (q13; 32), resulting in an overexpression of cyclin D1

> first-line treatment of the young subject combines three alternating R-CHOP21 cures with three R-DHAP21 cures and followed by an autograft conditioned by total body irradiation (bit), cyclophosphamide and Aracytine

> The recommended first-line treatment for over 65 years includes eight cures for R-CHOP21

> The value of maintenance treatment is being evaluated

Many targeted treatments are currently being studied and will likely soon improve the prognosis of this disease