Mature peripheral T/Natural killer (NK)-cell neoplasms represent 10–15% of non-Hodgkin's lymphoma (NHL) in adults. T/NK-NHL have a worst prognosis compared with B-cell lymphomas. Allogeneic stem cell ...transplantation (allo-SCT) is an attractive option for these patients. On behalf of the SFGM-TC group, we conducted a retrospective analysis and included seventy-seven T/NK-cell lymphoma patients. Diagnosis were: ALCL (n=27), Peripheral T-cell Lymphoma Not-Otherwise Specified (PTCL-NOS) (n=27), Angioimmunoblastic T-cell Lymphoma (AITL) (n= 11), Hepatosplenic g/d lymphoma (HSL) (n=3), T-cell granular lymphocytic leukemia (T-GLL) (n=1), nasal NK/T-cell lymphoma (nasal-NK/L) (n=3) case or non-nasal NK/T-cell lymphoma (non nasal-NK/L) (n=2), enteropathy-Type T-cell (n=1) and HTLV-1 lymphoma (n=2). Fifty-seven patients received myeloablative conditioning regimen prior allo-SCT. Donors were HLA-matched in 70 cases and related in 60 cases. Patients status at the time of allo-SCT was CR in 31 cases, PR in 26 cases and SD/PD in other cases. Five-year toxicity-related mortality (TRM) rate was 34%. Major cause of death was infection. Five-year OS and EFS rates were 57% and 53.3%, respectively. In a multivariate analysis, chemoresistance disease (SD, refractory or progressing disease at the time of allo-SCT and aGVHD grade III/IV were the only adverse prognostic factors for OS (p= 0.027 and p=0.033, respectively). Disease status at transplantation influenced EFS (p= 0.0032) and a HLA-mismatched donor increased TRM (p= 0.0386). A plateau was reached after one and a half year after allo-SCT. Only 5 out of 59 patients in CR after allo-SCT experienced a relapse. The 5-year OS rate for chemo-resistant patients was also encouraging. These patients were not curable with conventional approaches and near of one third have taken advantage of allo-SCT. Furthermore, two patients received DLI at relapse and they both reached a second durable CR. Taken together, this suggests that there is a graft versus T-/NK-lymphoma effect which may play a role in the curative potential of allo-SCT. we conclude that randomized clinical trials comparing allo-SCT versus conventional chemotherapy upfront for PTCL, aggressive AITL or histopathological subtypes (HSL, HTLV-1 lymphomas) have to be encouraged.
Background : 18Fluorodeoxyglucose-PET has been advocated as a powerful mean to evaluate response in aggressive non-Hodgkin's lymphoma. Its relative merits compared to the widely accepted ...International Workshop Criteria (IWC) (Cheson, 1999. J Clin Oncol 17: 1244) have been investigated (Juweid, 2005 J Clin Oncol 23:4652), but need to be further confirmed.
Materials and methods : We studied 103 patients with diffuse large B-cell lymphoma after 4 cycles of inductive CHOP or CHOP-like chemotherapy, with (n=51) or without Rituximab (n=52) using the IWC criteria and PET. The patients where also evaluated with an early PET after 2 courses, the results of which did not influence treatment decisions. PET response criteria have already been published (Haioun, Blood 2005; 106). The interpretation of PET took into account the results of the early PET, in particular to define progressive disease.
Results : The baseline characteristics of the patients where as follows : Median age 53y (19–78); age >60 : 25 (24%); LDH > normal : 71 (69%); > 1 extranodal site : 53 (51%); poor performance status (>=2) : 37 (36%); stage III–IV: 84 (81%). The international prognostic index (IPI) score was 0–2 in 40 pts (39%) and 3–5 in 63 (61%). The comparative response evaluation using IWC criteria or the combination of IWC criteria and PET is shown in the following table.
Three years after completion of therapy, patients being in CR by PET at 4 cycles had an estimated event-free survival (EFS) of 83% if in CR/CRu by IWC criteria, and of 80% if in PR or SD by IWC. Patients not in CR by PET had an EFS of 51% when in CR/CRu by IWC criteria and of 8% when in PR, SD or PD by IWC criteria (p<0.0001 as compared to CR patients). The same differences were seen whether the patients had received Rituximab or not. In a multivariate Cox regression analysis, event free survival was adversely affected by a non-CR response after 4 cycles evaluated by PET (p<0.0001, relative risk (RR) = 8.3), but not by a poor IPI (3–5) (p = 0.6, RR = 0.81) or Rituximab-based treatment (p = 0.74, RR = 1.13).
Conclusion : We confirm the higher predictive power of PET as compared to IWC criteria. The CRu category disappears from evaluation criteria when integrating informations delivered by PET, and PR patients can be separated into CR versus PR patients. The predictive value of PET is seen in patients treated with, as well as without Rituximab.
IWC + PETResponseCRCRuPRSDPDTotalIWCCR23010024CRu43080253PR9030214SD100012PD001056*Total76013010101*** 4 pts showed progression between 2 and 4 cycles on the basis of PET** 2 pts had no PET at 4 cycles because of early progression
AITL, as most T cell lymphomas, follows an aggressive clinical course with a 5-year overall survival of about 30%. Features consistent with B cell hyperstimulation including hypergammaglobulinemia ...with M component, autoimmune manifestations and B blast expansion in the tumoral tissue (sometimes culminating in overt B-cell lymphoma) are frequently seen. Clonal immunoglobulin gene rearrangements are detected in 20 to 40% of AITL. We postulated that AITL might benefit from a treatment with anti-CD20 monoclonal antibody (rituximab) combined to the standard CHOP regimen (R-CHOP). Between january 2001 et august 2004, 9 consecutive patients older than 60 years with newly diagnosed AITL were treated in our institution with a combination of rituximab (375mg/m2 given at day 1 of each cycle) and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone at day 1) chemotherapy delivered every 3 weeks. Patients were planned to receive 8 cycles, if a good response (at least partial response) was observed after the first 4 cycles. All patients presented characteristic features of AITL with generalized lymphadenopathy and poor performance status. Elevated LDH were seen in 6 patients. Four out of 9 patients had a serum M-component. Autoimmune hemolytic anemia was concomitantly diagnosed in 3 patients. Histopathological analysis revealed features of AITL in all cases associated with a significant expansion of large CD20+ B cells in 5 patients, CD10 positivity of tumor cells in 7 cases and EBV association in 5 cases (LMP-1 expression and/or EBER in situ hybridization positivity). DNA extracted from the biopsies was amplified using PCR and analyzed on a ABI 310 sequencing analyser. B and T-cell clonality analyses were performed according to the Biomed 2 procedure (Dongen et al. Leukemia 2003). Analysis of tumoral lymph node were available in 8 patients: a dominant T-cell clone was present in 5 cases, 2 of them showing also a dominant B-cell clone and 3 an oligoclonal B-cell repertoire. The 3 remaining cases had oligoclonal T-cell populations with a polyclonal B-cell repertoire. Eight patients achieved a complete remission at the end of treatment and one patient progressed after 3 cycles. Two patients relapsed at 13 and 14 months. Among these 3 refractory/relapsed patients, two were salvaged with additional treatment (alkylating agent alone or MabCampath). In July 2005, with a median follow-up of 12 months (7 to 53 months), all the patients are alive, 8 of them without evolutive disease. No additionnal toxicity was observed in this population of T-cell lymphoma patients as compared to that observed in elderly patients with diffuse large B-cell lymphoma treated with R-CHOP (Coiffier, N Engl J Med 2002). These results led us to consider that rituximab adjunction to CHOP could improve the prognosis of AITL in elderly patients. This approach is currently evaluated in an ongoing multicentric phase II study led by the GELA.
Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous in clinical presentation, histopathological and biological findings, and outcome. Today, risk-adapted treatment decisions are mainly based on ...the International Prognostic Index (IPI). Recently, molecular profiling has been shown to correlate with survival in DLBCL patients treated with conventional chemotherapy. Immunohistochemistry (IHC) has been proposed as a surrogate of molecular profiling (« phenotypic profiling»). Besides, we and others have shown that early response evaluation (after 2 cycles) with 18FDG-PET scanning is predictive of patient outcome in DLBCL, independently of IPI (Haioun & al, Blood 2005; 106: 1376). We retrospectively investigated the phenotypic profile of 81 patients (pts) from our recently published series with a confirmed diagnosis of DLBCL and available material for extensive IHC analyses. Diagnosis was based on a nodal (n=45), extranodal (n=25) or mediastinal (n=11) specimen. IHC was performed with the markers bcl2, CD10, bcl6 and MUM1, and scored by two observers. Pts were classified as having a germinal center (GC) or non germinal center (nGC) profile using the following algorithm: GC pts were to be CD10+ or bcl6+ and MUM1−, and all others were nGC (Hans & al, Blood 2004; 103: 275). Bcl2 was positive in 53%, CD10 in 36%, bcl6 in 58% and MUM1 in 45% of interpretable cases. Seventy-four pts (91%) had an interpretable profile, 39 (52%) were in the GC group, 35 (48%) in the nGC group. All pts received a doxorubicin-containing regimen as induction treatment, with rituximab for 46% of them. Pretreatment characteristics and early response by 18FDG-PET according to phenotypic profile are shown in the table below. With a median follow-up of 33 months, estimated 2-y OS and EFS were 75% and 67%. Survival analysis confirmed the poor prognostic value of a positive early 18FDG-PET scan: 2-y EFS was 46% in the PET-positive group and 80% in the PET-negative group (p = 0.0003). Two-year EFS was 61% and 73% in the bcl2-positive and negative groups, respectively (p = 0.08). We could not observe any prognostic influence of the GC vs nGC profile: Two-year EFS was 72% in the GC and 64% in the nGC group (p=0.62). In this limited series, we confirm the high predictive value of early response evaluation with 18FDG-PET scanning, but did not observe any significative influence of phenotypic profile, contrarily to several published reports. The reasons for this discrepancy, be they related to treatment type (including rituximab), disease presentation (many pts with extranodal disease) or IHC evaluation (fixation, scoring), remain to be understood. Meanwhile, 18FDG-PET should be an early guide for first-line strategies in DLBCL.
Characteristics according to phenotypic profileGC (n=39)nGC (n=35)pAge <= 6074 %78 %0.68IPI Int-Hi/Hi65 %54 %0.71Bone marrow involvement17 %39 %0.03Biopsy territory Nodal/Extranodal/Mediastinal50/36/14 %54/31/15 %0.5618FDG-PET positive after 2 cycles34 %39 %0.77bcl2 positive50 %520.92
Background : High-dose therapy with autologous stem cell support (HDT) is an established treatment for chemosensitive relapse in aggressive lymphoma. However, not all patients are candidates for HDT ...because of age, comorbidities or previous HDT. Effective and well tolerated salvage therapies with minimal toxicities are thus needed.
Methods : We designed the R-GEMOX regimen, with rituximab 375mg/m2 d1, gemcitabine 1000 mg/m2 d2 and oxaliplatin 100 mg/m2 d2 (recycling on d15). Between January 2002 and April 2004, 31 patients with refractory/relapsing B-cell lymphoma not eligible for HDT were enrolled in an open unicenter pilot study whose primary objective was to determine the overall response rate (ORR) after 4 cycles (induction phase) of R-GEMOX. Patients were planned to receive 8 cycles if a good response (at least PR) was observed after 4 cycles. Median age was 63 years (range: 43–77) and histological subtypes were : diffuse large B-cell lymphoma (n=22), follicular (n=6) and mantle cell (n=3). Prior treatment included anthracyclin in 30 patients (98%), rituximab in 16 (52%) and HDT in 8 (26%). International prognostic index at enrollment was ≥ 2 in 13 patients (42%). The median number of prior treatments was 2 (range : 1 to 5) and 9 patients had received at least 3 prior regimens.
Results : 226 cycles were given. The dose administered was 100% of the intended dose for the three drugs in all patients but 6, for whom the dose of oxaliplatin was reduced due to neurotoxicity (n=5) or preexisting renal insufficiency (n=1). The median number of cycles per patient was 8 (range: 2–8).Three patients progressed during the induction phase. After 4 cycles, observed responses were : 6 CR, 8 CRu, 12 PR and 2 failures resulting in an ORR of 84 %. At the end of treatment, among the 26 responder-patients at 4 cycles, 23 patients achieved CR/CRu and one patient progressed. As of August 2004, 22 patients are alive, 17 in continuous complete remission and 5 with evolutive disease. NCIC grade 3–4 neutropenia and thrombocytopenia were reported in 49% and 23% of the cycles. Six patients developed a grade 4 infection during one cycle. There was no renal toxicity.
Conclusion : The R-GEMOX regimen shows promising activity with an acceptable toxicity. It is currently evaluated in an ongoing multicentric phase II study on diffuse large B-cell lymphoma patients at first relapse. (=69.03% taille max abstract)
Follicular lymphomas have an indolent evolution with a median survival ranging between 8–10 years. At relapse, high-dose therapy followed by autologous stem-cell transplantation (ASCT) can be ...considered as an alternative to conventional chemotherapy. However, efficacy of this strategy remains controversial.
The purpose of our retrospective study is to evaluate ASCT in the pre and post rituximab era as consolidation after 2nd or 3rd remission (at least PR).
Between March 1989 and Apr 2004, 54 pts were treated at relapse with ASCT in our institution. At initial diagnosis, median age was 47 yrs (range 24–61) and FLIPI score was ≥ 3 in 18%. ASCT was performed in 2nd remission in 43 cases and in 3rd remission in 11 median delay diagnosis-ASCT=44 months (range 7–139) and 53 months (range 21–227), respectively. The conditioning regimens used were: VP16/cyclophosphamide/TBI in 33 cases, cyclophosphamide/TBI in 9, BEAM in 10 and cyclophosphamide/busulfan in 2. After ASCT, 49 pts achieved CR, 4 achieved PR and one pt progressed. In Dec 2004, with a median follow-up of 4.7 yrs, 27 pts (50%) had relapsed after ASCT with a median time to relapse of 12 months (range 2–95) and 18 pts have died. Causes of death were: lymphoma recurrence in 8 cases, secondary malignancy in 6 cases (3 MDS/AML, 2 radiation-associated solid tumors, 1 EBV associated lymphoma after a new salvage treatment including allogenic transplantation), and late infection in 4 cases, 2 of them occurring in remission (varicella and septicaemia) and 2 others after a new salvage therapy (cellulitis during chemotherapy-induced neutropenia and HHV6 encephalitis after allogenic transplantation). Ten-year overall survival (OS) from initial diagnosis was 68%. Five-year OS and event-free survival after ASCT were 74 and 52%, respectively.
Patients treated at relapse before 1998 did not receive rituximab (rituximab-naive pts: n=29) and those treated after 1998 received a rituximab-based salvage regimen before ASCT (rituximab-treated pts: n=25). The main characteristics of the two populations were as indicated in the table below:
rituximab-naive grouprituximab-treated groupN2925FLIPI at initial diagnosis (Low/Intermediate/High) %41/48/1127/46/27Median age at ASCT (yrs)50 (range35–60)52 (range 30–62)ASCT performed in 2nd remission2320ASCT performed in 3rd remission65Median duration of response following last treatment line prior to ASCT (months)21 (range 1–91)11 (range1–49)
After adjusting for the follow-up (median follow-up of the rituximab-treated group: 3.8 yrs), comparison between the two groups of pts treated with ASCT at relapse shows a significantly better OS of the rituximab-treated group as compared to that of the rituximab-naïve group (100 vs 61% at 4 years, p=0.01). These data suggest that the well-established efficacy of rituximab in FL is not abrogated by consolidative ASCT delivered at relapse in pts not previously treated with rituximab and further emphasize the superiority of immunochemotherapy over chemotherapy alone.
Nul mieux que ce livre n'affirme que l'espace est aussi domaine des historiens, car la vie sociale, la vie administrative des groupements humains, leurs usages culturels aussi, s'inscrivent dans des ...territoires qui se juxtaposent, s'articulent, se singularisent, se chevauchent parfois. Les notions de frontières et de limites prennent alors tout leur sens. Quinze études et de riches discussions apportent ici des regards croisés et complémentaires sur l'Afrique du Nord antique. C'est également l'occasion de rendre hommage à Pierre Salama, non seulement épigraphiste et numismate, mais aussi spécialiste hors-pair de géographie historique. La Carte du réseau routier, diffusée en 1947, puis intégrée en 1951 au livre sur Les voies romaines de l'Afrique du Nord, a connu une brillante destinée, car elle a constamment servi de point d'appui au travail des historiens des nouvelles générations. Cette carte est une œuvre de synthèse, et d'abord une synthèse de l'espace, exprimée en réduction; mais elle synthétise aussi le temps, car les cités dont le nom apparaît ont duré de longs siècles, structurant fortement la vie politique et sociale des provinces romaines, et reflétant par leur apparition et leur permanence les changements dans les modes de vie.
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