Current treatment of follicular Lymphoma
Summary
The most common Lymphoma after the B-cell lymphoma diffuse large cell, follicular Lymphoma of advanced stage remains incurable. Advanced forms must be dealt with in the presence of clinical or biological signs signing the aggressiveness of the disease. First-line treatment Associates rituximab (MabThera) with the combination chemotherapy to base of cyclophosphamide, vincristine and prednisone. After this treatment, the benefit of rituximab maintenance must be validated. Autograft of bone marrow is reserved for the treatment of relapses of young patients. The allogeneic bone marrow transplant is an interesting option for eligible patients. Other treatment options available in case of relapse include immuno-radiotherapy by 90Y-ibritumomab (Zevalin) quality and, more recently, bortezomib (Velcade).
INTRODUCTION
Second most common Lymphoma after the B-cell lymphoma diffuse large cell (LBDGC), follicular Lymphoma (LF) is 22% of non Hodgkin (NHL) lymphomas. With the exception of localized radiation curable diseases, this disease remains incurable. His diagnosis is based on the ganglionic biopsy. The opening balance allows to stage the disease, but also to determine if there are therapeutic indication. This lymphoma is sensitive to administered Therapeutics, but relapse is inevitable. It occurs in a shorter delay when previous therapies are numerous. The currently available therapeutic options are reviewed and their indications discussed according to the stage of the disease, the symptoms, the age of the patient, his general condition, its history as well as, in case of relapse, treatments previously received .
HISTOLOGY
The diagnosis of LF is based on a pathological lymph node biopsy. Typically, follicular Lymphoma takes the form of a proliferation which the pattern is mostly follicular. Neoplastic follicles, underpinned by a network of follicular dendritic cells, contain a tumor population to a mixture of (usually majority) centrocytes and centroblasts. A diffuse component devoid of dendritic network is exceptionally exclusive sometimes present, often minority, sometimes predominant. The histologic grade, important prognostic factor, is defined by the number of centroblasts evaluated by counting on a dozen of microscopic fields at the high magnification (table 1). When the average count is less than 5 centroblasts by field, it is a grade I; the tumors containing 5-15 centroblasts by field are grade II and those containing more than 15 centroblasts by grade III field. Grade III PMQS are categorized in IIIa and IIIb depending on whether there is still a contingent of centrocytes (IIIa) or that the tumor is formed exclusively by blast (IIIb) cells. Grades I and II, usually associated with some progressive diseases, tend to be grouped together. In the case of the LF of grade III, the presence of diffuse areas is considered to diffuse large B cell lymphoma.
Table 1
Histologic grades of follicular Lymphoma
Centrocytes Centroblasts Grade histological changes +++ / ++ 0 to 15/field I - II indolent + > 15 / IIIa aggressive field 0 > 15/field IIIb aggressive
The immunophenotyping allows the differential diagnosis of LF with other NHL of phenotype B small cells. The cells have surface antigens that are conventionally associated with the B-line: CD 19 +, CD20 +, CD22 +, + CD79a; they are typically negative for CD5 and are often positive for surface immunoglobulins (sIgM ± EMIS, less often sIgG, rarely sIgA). In the majority of cases the lymphoma cells Express CD 10 and BCL6 differentiation markers that are normally associated with germinal centers B cells. The overexpression of BCL2, accordingly him more often of translocation t (14; 18) (q32; q21), is observed in 85-90% of tumors of grade I - II and less frequently in the tumors of grade III (about 50% of cases). This translocation is not usually found in primitive skin PMQS. Rearrangements of BCL6, less frequent, meet especially in the LF of grade III. Cytogenetic, very many other abnormalities, can be found. Among these, anomalies of the 6q, 17 p and the 9 p deletion regions sign an aggressive transformation.
In molecular biology, a monoclonalite for the IgH (V-D-J) locus can be highlighted.
INITIAL BALANCE
The initial assessment includes a rigorous clinical review looking for Lymphadenopathy or a hepato-splenomegaly. Laboratory tests include the blood stock of coagulation, the electrolytes, renal function, the enzymology liver with measure of lactates dehy-drogenases (LDH), the proteinogramme with immuno-electrophoresis, the β2-microglobulin, a test of Coombs and autoimmune stock, an immunophenotyping, a red typing and HLA. A double bone puncture biopsy should be performed (immunophenotyping, caryo-type, cytology and molecular biology). The realization of cervical, thoracic and abdominal-pelvic scanners used to describe deep ganglion damage not accessible to clinical examination. The PET scan allows to discover sites invaded further, but is currently not part of the initial balance sheet outside of clinical studies whose primary goal is assessment of responses therapeutiques.1 the Ann Arbor staging to determine the extent of the disease. Post-treatment assessment requires the repetition of abnormal examinations during the initial assessment. Subsequently, the same exams are made at intervals of three to six months depending on the clinical course.
PROGNOSTIC FACTORS
Fruit of the retrospective analysis of survival over 4000 patients carry a PMQ and included in tests of large cooperative groups between 1985 and 1992, the Index predicts international follicular lymphomas or Follicular lymphoma International prognosis index (FLIPI, table 2) takes into account the age of the patient, its hemoglobin and lactate dehydrogenase (LDH), the stage of the disease and the number of affected lymph node areas (figure 1).2 it allows a stratification of patients in cohorts of homogeneous prognosis, making easier the comparison of published trials. Currently, it does not, unlike the international Prognostic Index (IPI) used during the processing of the LBDGC, the choice of more or less aggressive treatment strategies.
Table 2
International prognostic index in follicular lymphomas (FLIPI) 2
Settings factors • unfavourable Age ≥ 60 years • stage III • LDH ≥ > normal • hemoglobin < 120 g / l number of sites • ganglion ≥ 4 risk groups number of factors unfavourable • low 0-1 • intermediate 2 • student 3-5
THERAPEUTIC MODALITIES
The PMQS can be treated using many modalities, therapeutic, alone or in association. In the past, only chemotherapy and radiotherapy were available. Immunotherapy, radio-immunotherapy, interferon and hematological stem cell transplantation were added to the therapeutic arsenal. New therapeutic modalities, such as bortezomib, and new monoclonal antibodies are promising. In some situations, the therapeutic abstention can also be retained.
THERAPEUTIC INDICATIONS
The decision to treat a patient suffering from a LF and the choice of treatment depend on the stage of the disease, the symptoms of biological criteria, the status of the disease (untreated vs. relapsed), of the chimiosensibilite of the lymphoma and criteria tumour as described by the task force of the follicular lymphomas (CETF) and West-East group study of acute leukemia and other diseases of the blood (GOELAMS) (table 3).3 many guidelines have been established as a result of studies in a time when rituximab (MabThera) was not yet available and must be validated in the era of monoclonal antibodies. It should, therefore, to distinguish Therapeutics used in routine as part of clinical research protocols.
Table 3
Criteria characterize the large tumour masses 3
Big tumor mass defined by: • tumor diameter ≥ 7 cm • splenomegaly (large diameter ≥ 20 cm) • more than three lymph nodes with a diameter of more than 3 cm in three areas ganglion different • pleural effusion / ascites Syndrome • compressive symptoms B index performance (ECOG) > 1 LDH > normal β2-microglobulin > 3 mg/l.
TREATMENT
Follicular Lymphoma localized (stage I, small II)
PMQS located can be cured by radiation involved field applied to the conventional dose of 40 Gy. After this type of treatment, four large cooperative groups related without relapse and overall survivals to ten years ranging from 40 to 55 percent and 60 to 80 percent, respectively, carrying sick of LF of stages I or II (table 4).4 Haas et al. answered glo Basel 92% and 61% in a population of 109 patients with localized LF treated by double exposure of 2 grays complete. Median time to progression is 25 months for the 67 patients in remission complete.5 Finally, in the series of Advani et al., 43 patients in stages I or II received a wait and see attitude, providing an overall survival at 10 years of 85%.6 therefore are best treatment modalities for patients of a localized stage of low tumor mass, the therapeutic abstention or the involved field radiation. For these patients, the radio-immunotherapy is a treatment option under evaluation.
Table 4
Results of representative studies of radiotherapy alone as treatment of lymphomas of low grade localises4
Center Patients (n) stages survival without relapse survival overall Princess Margaret Hospital 190 I and II 53% to 12 years 58% at 12 BNLI 208 I 49% at 10 years 64% at 10 years Stanford 177 I and II 44% at 10 years 64% at 10 years Royal Marsden Hospital 58 I and II 43% at 10 years 79% in 10 years
Indolent follicular Lymphoma (stage > I, no tumor test)
CETF 86 compares therapeutic abstention to treatment by interferon or predmustine as treatment of patients of a PMQS without tumor test. With a median follow-up of some four years, no difference in overall survival is observed between the three arms of therapeutiques.7 studies of the National Cancer Institute and the British National Lymphoma Investigation compare the therapeutic abstention to one treatment by ProMACE-MOPP (prednisone, methotrexate, leucovorin, doxorubicin, cyclophosphamide, etoposide and mechlorethamine, vincristine, procarbazine, prednisone) or chlorambucile, respectivement.8, 9 provides therapeutic abstention as well as those offered by chemotherapy and is the recommended treatment for these patients. Since these historical studies, new protocols using rituximab have emerged. That of Hainsworth et al. demonstrates a survival without progression to five years of 40% for stage II to IV, without 'tumour' criteria, patients treated with rituximab alone. In this essay, the monoclonal antibody is administered at the dose of 375 mg/m2, at the rate of a weekly treatment for a total of four courses. Patients benefit from a maintenance treatment at the rate of a treatment every six months for a total of four cures.10 test, still currently under way, within the National Cancer Research Institute-led D. Linch, compares the use rituximab, with and without consolidation, to the therapeutic abstention and will verify the validity of the approach for these patients. The immuno-radiotherapy using 90Y-ibritumomab (Zevalin) quality or 131Iodine-tositumo-mab (Bexxar) offers results encourageants.11, 12 in Belgium in 2009, however, nor the radio-immunotherapy and rituximab are reimbursed in this indication of whether although, in this case of figure, the therapeutic standard therapeutic abstention.
Symptomatic follicular Lymphoma (stage > I, tumor present criteria)
Four randomised studies show the striking superiority of the immuno-chemotherapy compared with chemotherapy for patients with lymphoma unlocated and presenting tumor criteria (table 5).3, 13-15 in all four studies, the addition of rituximab with chemotherapy significantly improves the rate of overall therapeutic responses and complete as well as progression-free survival. Also, the addition of rituximab improves overall survival except in the FL2000 study. The immuno-chemotherapy is the treatment of choice for these patients. After chemotherapy with CVP (cyclophosphamide, vincristine, prednisone), rituximab maintenance can improve survival without progression.16 the role of this maintenance after immuno-chemotherapy treatment must be validated. The study PRIMA (PRimary RItuximab MAintenance), conducted by him GELA and the GOELAMS, which assesses the impact of rituximab maintenance after immuno-chemotherapy (R-CHOP (rituximab, cyclophosphamide, Adriamycin, vincristine, prednisone) or R - FCM ()) rituximab, fludarabine, mitoxantrone) or R - CVP (rituximab, cyclophosphamide, vincristine, prednisone)) will address this issue. In addition, this test will determine the possible superiority of one of the three treatments of induction. After such treatment, the radio-immunotherapy appears promising, particularly through the conversion of partial remissions in complete remissions, State necessary to improve chances of survival prolongee.17, 18 three studies evaluating the role of consolidation by autograft after first line chemotherapy are not managed to demonstrate a benefit in overall survival for patients greffes.19, 20 in addition, the question of the usefulness of the consolidation by autograft after immuno-chemotherapy remains, to this day, unanswered.
Table 5
Randomised studies of patients with follicular Lymphoma treated with chemotherapy and rituximab3
Treatment allocation FLIPI scoring * (%) Age (years) median PFS for the experimental arm (%) PFS median (months) arms control arm experimental overall survival (%) Arms control experimental arms (R-) CVP 19/41/40 52 50 (3 years) 15 34 77 (at 4 years) 83 * (for 4 years) (R-) CHOP * 14/41/45 55 80 (-2 years) 31 not reached 90 (2 years) 95 * (in 2 years) (R-) MCP * 7/37/56 59 71 (for 4 years) 26. not reached 74 (under 4 years) 87 * (for 4 years) (R-) CHVP + Inf.* * 19/35/46 61 53 (at 5 years) 35 unfulfilled (at 5 years) 79 84 (to 5 years) - R: rituximab; CVP: cyclophosphamide, vincristine, prednisone; CHOP: cyclophosphamide, Adriamycin, vincristine, prednisone; MCP: mitoxantrone, chlorambucil and prednisone; CHVP: cyclophosphamide, Adriamycin, etoposide, prednisone, Inf: interferon; FLIPI: foliculaires Lymphoma international prognostic index. PFS: progression free survival (survival without progression); *: low/middle/high; *: significant difference between the two treatment arms. : (R-) CHOP was followed by an autograft or interferon; : (R) - MCP was followed by interferon. : twelve priests in the R - vs arm six cures in the arm R +.
Refractory or relapsed follicular Lymphoma
During a relapse, the criteria for treatments described in the first line treatment continue to apply. The choice of one or other of the therapeutic modalities depends on the stage of the disease when a relapse, the previous treatments, the sensitivity of lymphoma and the age of the patient. Localized relapses can be cured by a dose limited radiotherapie.5 during LF treatment relapsed or refractory, the addition of rituximab to re-Induction chemotherapy improves overall response rates and complete. Maintenance by this monoclonal antibody significantly prolongs progression-free survivals and globales.15 spinal cord transplantation is the therapeutic option of choice for young patients due to the intensification of the doses of chemotherapy delivered and, if transplant allogeneic, the Antitumor effect of the graft. This immunological aspect of the treatment can be offered to patients of advanced age since the advent of transplant allogeneic with conditioning no myeloablateurs (mini-greffes). The Zevalin provides better response rates and survival without treatment more prolonged than rituximab in case of relapse after treatment by this last administered in larger dose anticorps.21, this last molecule can also be associated with the packaging used in the peripherique.22 blood stem cells autologous transplantation Finally, bortezomib (Velcade), whose effectiveness is still being investigated currently seems to be a promising molecule in this pathology.
CONCLUSION
Current treatment options (table 6)
Table 6
First-line treatments
Follicular Lymphoma (LF) localized (stage I, small II) • therapeutic Abstention • radiation involved field of 40 Gy or 2 x 2 Gy LF indolent (stage > I, no tumor test) • therapeutic Abstention symptomatic LF (stage > I, tumor criteria) present) • Six to eight treatments of R-CHOP21 or R-CVP21 and R-FM21 + eight courses of rituximab 375 mg/m2 relapsed or refractory LF depending on age, stage and symptomatology: several options • therapeutic Abstention • involved field radiotherapy (4 Gy vs 40 Gy) • Six R-CHOP21 cures or four courses of R-DHAP21 or four courses of R-ICE21 + rituximab 375 mg/m2, 1 priest/3 months, for a maximum period of 2 years • autograft conditioned by Cytoxan-TBI or Z-Beam • Mini-allogeneic • Zevalin 0.4 mCI/kg • four weekly treatments rituximab 375 mg/m2 R-CHOP21: rituximab, cyclophosphamide, Adriamycin, vincristine, prednisone, one treatment every three weeks; R - CVP21: rituximab, cyclophosphamide, vincristine, prednisone, one treatment every three weeks; R - FM21: rituximab, fludarabine, mitoxantrone, a cure tou - your three weeks; R - DHAP21: rituximab, dexamethasone, aracytine high dose cisplatin, one treatment every three weeks; R - ICE21: rituximab, ifosfamide, carboplatin, etoposide, one treatment every three weeks; TBI: total body irradiation (total body irradiation); Z - Beam: Zevalin, BCNU, aracytine, etoposide, melphalan.
Major advances have made in recent years in therapy of the LF. Localized forms can be cured by irradiation involved fied. A wait and see attitude can be adopted for asymptomatic advanced forms. For forms clinically by herbs, the immuno-chemotherapy improves responses and survival rates. During a relapse, the stem cell transplant keeps his place in young patients. Other treatment options should be discussed according to the patient's age, general condition, extent of relapse and treatments previously received. New therapeutic weapons fight tumor cells by distinct mechanisms devoid of resis tance crossroads and keep efficiency in heavily pretreated patients.
PRACTICE IMPLICATIONS
> Follicular Lymphoma remains incurable except by radiation curable localized forms
> Asymptomatic carriers patients of advanced disease must have a wait and see attitude
> First line of symptomatic advanced forms processing appeals to the immuno-chemotherapy
> During a relapse, the autologous transplant of peripheral blood stem cells should be offered to young patients
> The immuno-radiotherapy, Allograft and bortezomib are interesting therapeutic options in case of relapse
0 komentar:
Posting Komentar