H. Tilly

High-dose therapy with autologous stem-cell transplantation (ASCT) after first progression prolonged survival of follicular lymphoma patients included in the prospective GELF 86 protocol

BACKGROUNDnAmong the 566 patients with follicular lymphomas (FL) included in the GELF 86 prospective trials from October 1986 to September 1995, 372 with progressive/relapsing disease were analyzed retrospectively to identify prognostic factors at first relapse.nnnPATIENTS AND METHODSnFor progressive FL, patients received mono- (22%) or polychemotherapy (78%) followed by high-dose therapy (HDT) with ASCT for 83 patients (22%). The median time to progression from initial treatment was 23 months (range 3-102 months) and 24% of documented patients (52 of 217) had histological transformation (HT). Salvage therapy produced an overall response in 64% of patients and the five-year survival from progression was 42%.nnnRESULTSnFor patients who underwent HDT with ASCT compared to standard treatment, five-year freedom from second failure was at 42% vs. 16% (P = 0.0001) and five-year survival was 58% vs. 38% (P = 0.0005), respectively. The benefit of HDT and ASCT remained if we consider only patients less than 65 years (five-year survival at 60% vs. 40%; P = 0.001). Multivariate analysis of parameters significant according to univariate analysis found that no ASCT at first progression, age at relapse > 50 years, progression on-therapy were adversely significant on survival.nnnCONCLUSIONSnHDTwith ASCT compared to standard treatment prolonged remission and survival after first progression of FL patients.

The outcome of reduced intensity allogeneic stem cell transplantation and autologous stem cell transplantation when performed as a first transplant strategy in relapsed follicular lymphoma: an analysis from the Lymphoma Working Party of the EBMT

Both auto-SCT and reduced intensity allo-SCT (RIST) are employed in the treatment of relapsed follicular lymphoma (FL). We have analysed the outcome of these two transplant procedures when used as a first transplant in this setting. We conducted a retrospective comparison of 726 patients who underwent an auto-SCT and 149 who underwent a RIST as a first transplant procedure for relapsed FL as reported to the Lymphoma Working Party of the European Bone Marrow Transplant. The non-relapse mortality (NRM) was significantly worse for patients undergoing a RIST (relative risk (RR) 4.0, P<0.001). The 1-year NRM was 15% for those undergoing a RIST compared with 3% for those undergoing an auto-SCT. Disease relapse or progression were significantly worse for those receiving an auto-SCT (RR 3.1, P<0.001). Patients undergoing a RIST had a 5-year relapse rate of 20% compared with 47% for those undergoing an auto-SCT. The PFS at 5 years was 57% for patients receiving a RIST compared with 48% for those receiving an auto-SCT. There was no significant difference in OS between the two groups. RIST is associated with a higher NRM and lower relapse rate in patients with relapsed FL.

Peripheral blood stem cell transplantation for relapsed or refractory aggressive lymphoma in patients over 60 years of age

Intensive chemotherapy with autologous bone marrow transplantation is now considered the treatment of choice for young patients with sensitive relapse of non-Hodgkin’s lymphoma (NHL) but results of this procedure in older patients remain unknown. We evaluated the feasibility of two cycles of salvage therapy followed by an autologous peripheral blood stem cell (PBSC) transplantation in 13 patients aged more than 60 years (median age: 62; range 61–72) suffering from relapsed (nu2009=u200910) or refractory (nu2009=u20093) aggressive NHL. All patients had previously received first-line treatment containing doxorubicin. An association of ifosfamide, VP16, cytosine-arabinoside with or without high-dose methotrexate was used as salvage and priming therapy prior to collection of PBSC. All patients received G-CSF following salvage therapy. PBSC collection could be performed in 10 patients and yielded a median number of CFU-GM: 98.4u2009×u2009104/kg (range 68–369). Nine patients underwent a transplantation using BEAM conditioning regimen. The median time to granulocyte and platelet recovery was 13 days (range respectively: 9–25 and 9–16). One patient died from sepsis after transplantation. The main adverse experience occurring after transplantation was a prolonged decline of performance status. Seven patients achieved a complete remission and one failed to respond. Three patients are still alive in CR. We conclude that PBSC collection was possible in selected patients over 60 years of age with refractory or relapsed aggressive NHL and myeloablative therapy could be used with tolerable toxicity. Hematologic recovery and organ toxicity appears to be similar to those observed in younger patients. Deterioration of performance status after transplantation is the most important factor that could limit this procedure. Further investigations are necessary to determine which patients will be able to benefit by this procedure in terms of survival and quality of life.

Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B)

BACKGROUNDnThe superiority of a chemotherapy with doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) in comparison with cyclophosphamide, doxorubicin, vincristin and prednisone plus radiotherapy for young patients with localized diffuse large B-cell lymphoma (DLBCL) was previously demonstrated. We report the results of a trial which evaluates the role of rituximab combined with ACVBP (R-ACVBP) in these patients.nnnPATIENTS AND METHODSnUntreated patients younger than 66 years with stage I or II DLBCL and no adverse prognostic factors of the age-adjusted International Prognostic Index were randomly assigned to receive three cycles of ACVBP plus sequential consolidation with or without the addition of four infusions of rituximab.nnnRESULTSnA total of 223 patients were randomly allocated to the study, 110 in the R-ACVBP group and 113 in the ACVBP group. After a median follow-up of 43 months, our 3-year estimate of event-free survival was 93% in the R-ACVBP group and 82% in the ACVBP group (P = 0.0487). Three-year estimate of progression-free survival was increased in the R-ACVBP group (95% versus 83%, P = 0.0205). Overall survival did not differ between the two groups with a 3-year estimates of 98% and 97%, respectively (P = 0.686).nnnCONCLUSIONnIn young patients with low-risk localized DLBCL, rituximab combined with three cycles of ACVBP plus consolidation is significantly superior to ACVBP plus consolidation alone.

Prognostic value of baseline total metabolic tumor volume (TMTV0) measured on FDG-PET/CT in patients with peripheral T-cell lymphoma (PTCL)

BACKGROUNDnMost peripheral T-cell lymphoma (PTCL) patients have a poor outcome and the identification of prognostic factors at diagnosis is needed.nnnPATIENTS AND METHODSnThe prognostic impact of total metabolic tumor volume (TMTV0), measured on baseline [(18)F]2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography, was evaluated in a retrospective study including 108 PTCL patients (27 PTCL not otherwise specified, 43 angioimmunoblastic T-cell lymphomas and 38 anaplastic large-cell lymphomas). All received anthracycline-based chemotherapy. TMTV0 was computed with the 41% maximum standardized uptake value threshold method and an optimal cut-off point for binary outcomes was determined and compared with others prognostic factors.nnnRESULTSnWith a median follow-up of 23 months, 2-year progression-free survival (PFS) was 49% and 2-year overall survival (OS) was 67%. High TMTV0 was significantly associated with a worse prognosis. At 2 years, PFS was 26% in patients with a high TMTV0 (>230 cm(3), n = 53) versus 71% for those with a low TMTV0, [P < 0.0001, hazard ratio (HR) = 4], whereas OS was 50% versus 80%, respectively, (P = 0.0005, HR = 3.1). In multivariate analysis, TMTV0 was the only significant independent parameter for both PFS and OS. TMTV0, combined with PIT, discriminated even better than TMTV0 alone, patients with an adverse outcome (TMTV0 >230 cm(3) and PIT >1, n = 33,) from those with good prognosis (TMTV0 ≤230 cm(3) and PIT ≤1, n = 40): 19% versus 73% 2-year PFS (P < 0.0001) and 43% versus 81% 2-year OS, respectively (P = 0.0002). Thirty-one patients (other TMTV0-PIT combinations) had an intermediate outcome, 50% 2-year PFS and 68% 2-year OS.nnnCONCLUSIONnTMTV0 appears as an independent predictor of PTCL outcome. Combined with PIT, it could identify different risk categories at diagnosis and warrants further validation as a prognostic marker.

Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma

BACKGROUND Rituximab plus chemotherapy has been shown to be effective in patients with advanced‐stage, previously untreated follicular lymphoma; nevertheless, most patients will have a relapse. Combination immunotherapy with lenalidomide and rituximab is an immunomodulatory regimen that has shown promising activity in patients with indolent B‐cell non‐Hodgkins lymphoma. METHODS We conducted this multicenter, international, phase 3 superiority trial to evaluate rituximab plus lenalidomide, as compared with rituximab plus chemotherapy, in patients with previously untreated follicular lymphoma. Patients were randomly assigned to receive one of the two regimens, followed by maintenance monotherapy with rituximab. Treatment with rituximab plus lenalidomide consisted of 18 cycles of the two drugs, followed by rituximab maintenance therapy every 8 weeks for 12 cycles (six additional doses). Treatment with rituximab plus chemotherapy consisted of the investigators choice of one of three rituximab‐based regimens, followed by maintenance monotherapy with rituximab every 8 weeks for 12 cycles. The primary end points were complete response (confirmed or unconfirmed) at 120 weeks and progression‐free survival. RESULTS A total of 1030 patients were randomly assigned to receive rituximab plus lenalidomide (513 patients) or rituximab plus chemotherapy (517 patients). The rate of confirmed or unconfirmed complete response at 120 weeks was similar in the two groups: 48% (95% confidence interval [CI], 44 to 53) in the rituximab–lenalidomide group and 53% (95% CI, 49 to 57) in the rituximab–chemotherapy group (P=0.13). The interim 3‐year rate of progression‐free survival was 77% (95% CI, 72 to 80) and 78% (95% CI, 74 to 82), respectively. A higher percentage of patients in the rituximab–chemotherapy group had grade 3 or 4 neutropenia (32% vs. 50%) and febrile neutropenia of any grade (2% vs. 7%), and a higher percentage of patients in the rituximab–lenalidomide group had grade 3 or 4 cutaneous reactions (7% vs. 1%). CONCLUSIONS Among patients with previously untreated follicular lymphoma, efficacy results were similar with rituximab plus lenalidomide and rituximab plus chemotherapy (with both regimens followed by rituximab maintenance therapy). The safety profile differed in the two groups. (Funded by Celgene; RELEVANCE ClinicalTrials.gov numbers, NCT01476787 and NCT01650701, and EudraCT number, 2011‐002792‐42.)

INTEGRATIVE ANALYSIS OF FEATURES ASSOCIATED WITH TET2, IDH2, DNMT3A, AND RHOA MUTATIONS IN ANGIOIMMUNOBLASTIC T CELL LYMPHOMA: A LYSA STUDY

phoma) FFPE samples screened by RT‐PCR (Haematologica, June 2016; 101(6)). Here, we screened by RT‐PCR the above described CD28 fusions in 257 frozen diagnostic tumor samples (104 AITL, 25 T‐follicular helper‐derived [TFH] PTCL, 59 PTCL‐NOS, 26 CTCL, 14 ENKTCL, 11 EATL [enteropathy associated T‐cell lymphoma], 9 ALK‐ negative ALCL [anaplastic large cell lymphoma], 6 ATLL, and 3 HSTL [hepatosplenic T‐cell lymphoma]) from the Tenomic biobank. Methods: 500 ng of trizol‐extracted and quality‐controlled mRNA (bioanalyser) was reverse‐transcribed using SuperScript III enzyme and random hexamers. CD28 fusions and beta‐actin (internal control, 198 BP) PCR products were analyzed by agarose gel electrophoresis. Three fusions were cloned into expression vector and transduced into HEK293T cells to generate positive controls. All positive samples and a subset of negative samples were cross‐validated in 2 different laboratories. Results: CD28 fusions were detected in 13/257 (5%) cases (8 TFH‐ derived PTCL, 3 PTCL‐NOS, 1 ATLL, and 1 CTCL). Three of these cases harbored 2 different translocations. The most common rearrangement was ICOS(ex1)_CD28(ex2) (11/16 fusions), followed by CTLA4(ex3) _CD28(ex4) (3/16 fusions) while the other two CTLA4 translocations were identified in one patient each. Thus, the prevalence of CTLA4(ex3)_CD28(ex4) fusion (found in one case each of TFH‐derived PTCL, PTCL‐NOS and CTCL) was 1.2%. CD28 fusions were found in 8/129 (6.2%) AITL and other TFH‐derived PTCLs. All the positive cases harbored ICOS(ex1)_CD28(ex2) rearrangement and one case with a dual rearrangement had an additional CTLA4(ex3)_CD28(ex4) fusion. In a subset of 85 TFH‐derived PTCL also explored by targeted deep sequencing analysis, CD28 fusions in 4 patients were mutually exclusive to CD28 mutations. Overall, CD28 alterations in 12/85 (14%) of these patients did not impact OS or PFS. Conclusion: Known CD28 translocations with CTLA4 or ICOS are rare events in PTCL (5%) and are most commonly represented by ICOS(ex1)_CD28(ex2) fusion (69%).

LOW NK CELL COUNT AT DIAGNOSIS IS ASSOCIATED WITH SHORTER PFS IN ELDERLY PATIENTS WITH DLBCL TREATED WITH RCHOP AND RANDOMIZED FOR LENALIDOMIDE MAINTENANCE: a LYSA STUDY

LOW NK CELL COUNT AT DIAGNOSIS IS ASSOCIATED WITH SHORTER PFS IN ELDERLY PATIENTS WITH DLBCL TREATED WITH RCHOP AND RANDOMIZED FOR LENALIDOMIDE MAINTENANCE: A LYSA STUDY M.H. Delfau‐Larue* | A. Beldi‐Ferchiou | J. Jais | N. Godard | G.A. Salles | R. Casasnovas | H. Tilly | C. Fruchart | F. Morschhauser | C. Haioun | J. Lazarovici | A. Perrot | C. Sebban | R. Bouabdallah | H. Gonzalez | B. Corront | L. Oberic | J. Briere | P. Gaulard | B. Coiffier | C. Thieblemont Biological Hematology and Immunology department, APHP, Groupe Hospitalier Mondor, INSERM U 955, Creteil, France; Biostatistics Unit, APHP, Univ Paris Descartes, Paris, France; Hematology, Centre Hospitalier Lyon Sud, Pierre‐Benite, France; Hematology, CHU Dijon ‐ Hopital du Bocage, Dijon, France; 5 INSERM U918, Centre Henri Becquerel, Rouen, France; 6 Institut dHématologie de Basse Normandie, CHU Caen, Caen, France; Clinical Hematology, CHU Lille, Lille, France; Lymphoid Malignancies Unit, APHP, Groupe Hospitalier Mondor, Creteil, France; Clinical Hematology, Gustave Roussy Cancer Center, Villejuif, France; Hematology department, CHU Brabois, Vandoeuvre les Nancy, France; Onco Hematology, Centre Leon Berard, Lyon, France; Onco Hematology, Institut Paoli Calmettes, Marseille, France; Hematology, CH Rene Dubos, Pontoise, France; Hematology, CH Annecy Genevois, Epagny Metz‐Tessy, France; Hematology, IUC ‐ Oncopole CHU Toulouse, Toulouse, France; Pathology, APHP, Hopital Saint‐Louis, Paris, France; Pathology, APHP, Hopital Henri Mondor, Creteil, France; CNRS UMR5239, Centre Hospitalier Lyon Sud, Pierre Benite, France; Hemato‐Oncology, APHP, Hopital Saint‐Louis, Paris, France

Radioimmunotherapy-augmented BEAM chemotherapy vs BEAM alone as the high-dose regimen for autologous stem cell transplantation (ASCT) in relapsed follicular lymphoma (FL): a retrospective study of the EBMT Lymphoma Working Party

Relapse remains the most common cause of treatment failure in patients receiving autologous stem cell transplantation (ASCT) for follicular lymphoma (FL). The aim of this study was to evaluate the effect of adding radioimmunotherapy or rituximab (R) to BEAM (carmustine, etoposide, ara-c, melphalan) high-dose therapy for ASCT in patients with relapsed FL. Using the European Society for Blood and Marrow Transplantation registry, we conducted a cohort comparison of BEAM (n=1973), Zevalin-BEAM (Z-BEAM) (n=207) and R-BEAM (n=179) and also a matched-cohort analysis of BEAM vs Z-BEAM including 282 and 154 patients, respectively. BEAM, Z-BEAM and R-BEAM groups were well balanced for age, time from diagnosis to ASCT and disease status at ASCT. The cumulative incidences of relapse (IR) at 2 years were 34, 34 and 32% for Z-BEAM, R-BEAM and BEAM, respectively. By multivariate analysis, there were no significant differences with Z-BEAM or R-BEAM compared with BEAM for IR, non-relapse mortality, event-free survival or overall survival. With the caveat that the limitations of registry analyses have to be taken into account, this study does not support adding radioimmunotherapy or R to BEAM in ASCT for relapsed FL. However, we cannot rule out the existence a particular subset of patients who could benefit from Z-BEAM conditioning that cannot be identified in our series, and this should be tested in a randomized trial.

Glycosylation des régions variables du récepteur du lymphocyte B pour l’antigène : une étape clé dans l’oncogenèse des lymphomes folliculaires ?

Les lymphomes folliculaires sont caracterises par la translocation t(14;18)(q32;q21). Si cet evenement genetique est necessaire pour la transformation tumorale du lymphocyte, il est a lui seul insuffisant et doit s’associer a des alterations genetiques secondaires. Le processus de mutation somatique, active lors du passage du lymphocyte B dans le centre germinatif, pourrait etre l’un des mecanismes a l’origine d’evenements genetiques secondaires. Il conduit a l’introduction de mutations ponctuelles dans les regions variables (V) des genes d’immunoglobulines. Ces mutations sont a l’origine de l’acquisition de sites de N-glycosylation de maniere quasi universelle dans les lymphomes folliculaires et pourraient jouer un role determinant dans l’oncogenese de ces lymphomes. Ces sites de type asparagine-X-serine/threonine (N-X-S/T) sont egalement observes dans 40 % des lymphomes diffus et 80 % des lymphomes de Burkitt. Ils sont en revanche presents dans moins de 10 % de la population lymphocytaire B normale, dans 13 % des leucemies lymphoides chroniques et dans 9 % des lymphomes du MALT, indiquant une selection positive de ces motifs dans les cellules tumorales de certains sous-types de lymphomes. Les sites sont localises dans 90 % des cas au niveau des regions hypervariables en contact avec l’antigene (CDR) et sont le plus souvent la consequence de la mutation d’un seul nucleotide au niveau du codon 1. Le CDR2 est la localisation la plus frequente, mais des sites de N-glycosylation sont egalement observes dans la region aminoterminale du CDR3, suggerant qu’ils ont pu apparaitre precocement durant l’ontogenie des lymphocytes B, lors de la recombinaison V HDJ H et de la N-addition. Ces sites sont glycosyles in vivo mais la nature/structure exacte des N-glycanes est encore indeterminee. Il est probable que ces oligosaccharides exprimes a la surface du lymphocyte B interagissent avec des lectines, proteines ayant la capacite de traduire l’information biologique codifiee dans la structure tridimensionnelle des sucres, et favoriser la survie cellulaire. Le blocage des voies biochimiques impliquees dans la glycosylation par des agents pharmacologiques pourrait constituer une nouvelle approche therapeutique dans les lymphomes exprimant une immunoglobuline de surface glycosylee.