Association of Killer Cell Immunoglobulin-Like Receptor Genes with Hodgkin's Lymphoma in a Familial Study

BACKGROUND: Epstein-Barr virus (EBV) is the major environmental factor associated with Hodgkin's lymphoma (HL), a common lymphoma in young adults. Natural killer (NK) cells are key actors of the innate immune response against viruses. The regulation of NK cell function involves activating and inhibitory Killer cell Immunoglobulin-like receptors (KIRs), which are expressed in variable numbers on NK cells. Various viral and virus-related malignant disorders have been associated with the presence/absence of certain KIR genes in case/control studies. We investigated the role of the KIR cluster in HL in a family-based association study. METHODOLOGY: We included 90 families with 90 HL index cases (age 16–35 years) and 255 first-degree relatives (parents and siblings). We developed a procedure for reconstructing full genotypic information (number of gene copies) at each KIR locus from the standard KIR gene content. Out of the 90 collected families, 84 were informative and suitable for further analysis. An association study was then carried out with specific family-based analysis methods on these 84 families. PRINCIPAL FINDINGS: Five KIR genes in strong linkage disequilibrium were found significantly associated with HL. Refined haplotype analysis showed that the association was supported by a dominant protective effect of KIR3DS1 and/or KIR2DS1, both of which are activating receptors. The odds ratios for developing HL in subjects with at least one copy of KIR3DS1 or KIR2DS1 with respect to subjects with neither of these genes were 0.44[95% confidence interval 0.23–0.85] and 0.42[0.21–0.85], respectively. No significant association was found in a tentative replication case/control study of 68 HL cases (age 18–71 years). In the familial study, the protective effect of KIR3DS1/KIR2DS1 tended to be stronger in HL patients with detectable EBV in blood or tumour cells. CONCLUSIONS: This work defines a template for family-based association studies based on full genotypic information for the KIR cluster, and provides the first evidence that activating KIRs can have a protective role in HL

CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: A study by the Groupe d'Etude des Lymphomes de I'Adulte

Purpose Chemoradiotherapy has been considered standard treatment for patients with limited-stage aggressive lymphoma on the basis of trials conducted before the introduction of the International Prognostic Index. To evaluate this approach in elderly patients with low-risk localized lymphoma, we conducted a trial comparing chemoradiotherapy with chemotherapy alone. Patients and Methods Previously untreated patients older than 60 years with localized stage I or II histologically aggressive lymphoma and no adverse prognostic factors of the International Prognostic Index were randomly assigned to receive either four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus involved-field radiotherapy (299 patients) or chemotherapy alone with four cycles of CHOP (277 patients). Results With a median follow-up time of 7 years, event-free and overall survival did not differ between the two treatment groups (P =.6 and P =.5, respectively). The 5-year estimates of event-free survival were 61% for patients receiving chemotherapy alone and 64% for patients receiving CHOP plus radiotherapy; the 5-year estimates of overall survival were 72% and 68%, respectively. In a multivariate analysis, overall survival was affected by stage II disease (P <.001) and male sex (P =.03). Conclusion In this large prospective study, CHOP plus radiotherapy did not provide any advantage over CHOP alone for the treatment of low-risk localized aggressive lymphoma in elderly patients

Single or Tandem Autologous Stem-Cell Transplantation Given According to Prognostic Factors at Relapse for Hodgkin Lymphoma.

Abstract Patients with relapsed hodgkin lymphoma (HL)have a different prognostic after high-dose therapy (HDT)according to time to relapse and extend of relapse. From 1995 to 1997, 48 patients with early relapse or refractory HL were included in a pilot study of tandem transplantation to evaluate the feasibility before the protocol. From 1998 to 2002, 200 patients with refractory disease or first relapse of HL were prospectively treated with induction chemotherapy followed by HDT and autologous stem-cell transplantation (ASCT). Patients were stratified in 2 groups according to prognostic factors at relapse: groupe 1 (unfavorable relapse: primary refractory disease or early/disseminated relapse) and group 2 (favorable relapse: patients with either early or disseminated relapse). Induction chemotherapy consisted of ifosfamide/etoposide with doxorubicin (IVA) in 70% of patients or with vinorelbine and mitoguazone (MINE)for the remainings. Group 1, patients received 2 cycles of chemotherapy, PBSC collection and tandem ASCT, with a CBV mitoxantrone (30 mg/m2) and 2 months later cytarabine (6g/m2), melphalan (140mg/m2)with total body irradiation (40%) or busulfan (12 mg/kg) followed by the second ASCT. Group 2, patients received 3 cycles of chemotherapy, PBSC collection and a BEAM regimen followed by ASCT. Final results, updated, January 2005 are presented with 245 evaluable patients. Results: after induction chemotherapy overall response rate was at 61% in group 1 and 96% in group 2. In group 1, 70% received the two ASCT, the major reason not to receive the procedure was disease progression after induction chemotherapy (10%) or after the first ASCT (15%), than low stem-cell collection (4%) or toxicity (2%). In group 2, 97% of patients received ASCT and 1 patient received a tandem ASCT for refractory relapse. 5 patients died from toxicity in group1 and none in group2, but 2 secondary leukemia were observed in this group. In intent to treat analysis, at a 3 years median follow-up from the relapse, the EFS was at 45% in group 1 versus 75% in group 2 and the survival at 55% in group 1 versus 80% in group 2. Despite a different consolidation between group 1 and 2, results remained better in group 2. In conclusion, these results confirmed the importance of prognostic factors at relapse of HL.No differences were found in the unfavorable group 1 between refractory patients and early/disseminated relapse. HL patients with adverse prognostic factors (group 1) but responding to second line chemotherapy and eligible for tandem ASCT may benefit from this procedure with an EFS at 70%. The major cause of failure was chemoresistance either at induction or after high-dose therapy.</jats:p

Prognostic Value of Angiogenic Factors (Vacular Endothelial Growth Factor [VEGF] and Basic Fibroblast Growth Factor [bFGF]) and Endostatin in Patients with Non-Hodgkin Lymphoma.

Abstract Introduction: Tumor angiogenesis is gaining importance in hematological malignancies; it is balanced by many known and unknown positive and negative angiogenic factors. However, studies related to the prognostic significance of angiogenic factors and lymphoproliferative diseases are limited compared to solid tumors. This is a single institution study evaluating the prognostic impact of serum Endostatin, VEGF, and bFGF in non-Hodgkin’s lymphoma (NHL). Patients and methods: Pretreatment serum level of Endostatin (S-Endostatin), VEGF (S-VEGF), and bFGF (S-bFGF) were measured by Enzyme-Linked Immunoabsorbant Assay (ELISA) on 136 NHL patients: 82 patients (60%) had aggressive NHL (diffuse large B cell lymphoma [DLBCL] or other aggressive non-DLBCL) and 54 patients (40%) had indolent lymphomas (follicular lymphoma [FL] or other indolent non-FL). For each angiogenic factor, univariate progression-free survival (PFS) and overall survival (OS) analyses were performed according to the quartiles of the distribution of serum level values. Each of the analyses was aimed to detect a trend between prognosis and the serum level of the angiogenic factor. Eight prognostic groups were defined according to the type of NHL and the prognostic indexes (International Prognostic Index [IPI] for DLBCL and aggressive non-DLBCL, and Follicular International Prognostic Index [FLIPI] for FL). Survival analyses stratified on the prognostic group were used to test the independent prognostic value of each angiogenic factor. Survival curves were compared with logrank tests. Distributions of serum level values were compared with Kruskal-Wallis tests. The median follow-up was 78 months. Results: Pretreatment angiogenic serum levels were not significantly different between all categories of NHL, except for VEGF level, which was slightly higher in the aggressive group compared to the indolent group (666 pg/ml vs. 465 pg/ml; p=0.03). Low S-Endostatin and high S-VEGF at diagnosis were associated with poor PFS (p=0.002 and p=10−4 respectively) and poor OS (p=0.04 and p=10−6 respectively). Patients with S-Endostatin within the lowest quartile had only 29% PFS and 49% OS in contrast to a 67% PFS and 82% OS among patients with Endostatin within the highest quartile. Similarly, patients with S-VEGF within the highest quartile had only 20% PFS and 26% OS in contrast to a 70% PFS and 85% OS among patients with VEGF within the lowest quartile. The VEGF/Endostatin ratio was used to combine the results from S-VEGF and S-Endostatin. The 4 groups corresponding to the quartiles of the distribution of VEGF/Endostatin ratio had different OS and PFS (p&amp;lt;10−6 for both); PFS and OS were respectively 15% and 16% for patients from the highest quartile VEGF/Endostatin ratio and 79% and 84% for those from the lowest quartile Figure 1. The independent prognostic impact of S-Endostatin, S-VEGF and VEGF/Endostatin ratio remained significant on PFS (p=0.0003, p=0.001 and p&amp;lt;10−6 respectively) and OS (p=0.01, p=10−4 and p&amp;lt;10−6 respectively) after stratification on the prognostic group. We did not find any relation between pretreatment S-bFGF and prognosis in our patients. Conclusion: Our results showed that pretreatment serum levels of VEGF and Endostatin are significantly related to outcome in NHL patients; the higher the VEGF/Endostatin ratio is, the poorer the prognosis. A better understanding of angiogenesis in lymphoproliferative diseases is mandatory in order to develop new anti-angiogenic targeted therapeutic agents that can change the outcome of these patients. Figure Figure</jats:p

High-Dose Methotrexate and Cytarabine Chemotherapy May Be Effective and Safe in Solid Organ Transplant Recipients with Primary CNS Lymphomas (PCNSL)

Abstract Background: Post transplant lymphoproliferative disorder (PTLD), especially primary CNS lymphoma (PCNSL), is a serious complication of solid organ transplantation. Treatment has proved difficult and includes dose reduction of immune suppression (RIS), combination chemotherapy and radiotherapy. Recently the monoclonal antibody Rituximab, has been added to the therapeutic choice. Chemotherapy used in PCNSL is based on high-dose methotrexate (HDMTX), but need to be carefully monitored in adult patients (pts), especially with renal transplant. HDMTX could be associated with deleterious effects on renal graft function. We report here the results of HDMTX in pts with PCNSL after solid organ transplantation treated at the Institut de Cancérologie Gustave Roussy. Methods: From February 2000, 18 pts with PTLD were referred to our Institute. 9 of them had PCNSL following renal (6), hepatic (1) or both renal and pancreatic (2) transplants. In all cases, RIS was not associated with PCNSL regression. Except in one case, all pts were treated with chemotherapy with HDMTX in 3-hour infusion. Folinic acid rescue was given IV every 6 hours (50 mg/m2) combined with alkaline hyper-hydration until MTX serum level was below 1 X 10–7 M. Immune suppressive therapy (IST) was reduced to solupred (10 mg/day) during chemotherapy and was reduced for 8 months after chemotherapy. 4 cycles of chemotherapy was planned and efficacy assessed every two cycles. If CR was reached with chemotherapy alone, no radiotherapy was delivered. Results: From March 2007, 9 pts (4 males) developed PCNSL with a median of 6 years after transplant (1–26 years). Median age was 55 (range 33–70). PS was &gt; 2 in 8/9 and 3 in one case. 8/9 pts had glomerular filtration rate &gt; 60 ml/mn and received HDMTX without renal toxicity. One pt with GFR &lt; 60 ml/mn was treated with 3 cycles of HD cytarabine + rituximab and adryamicin and is alive in complete remission (CR) 31 months after therapy. With a median follow up of 15 months, 4/9 pts are alive and in CR 45, 31, 29 and 7 months after therapy. 3 of them received radiotherapy. 5 pts died, 2 of lymphoma progression, 2 of chemotherapy toxicity (sepsis) and one of a gastric cancer. No graft rejection was observed. Conclusions: our results suggest HDMTX can be given in pts with PCNSL and long term CR can be reached without graft failure. As chemotherapy regimens used for in those pts are in themselves immunosuppressive, IST may be reduced during chemotherapy without major risk.</jats:p

Prognostic Factors in Localized Hodgkin’s Lymphoma: How To Define Intermediate/Unfavourable Disease?.

Abstract Actually, the prognosis of localized Hodgkin’s lymphoma (HL) patients may be assessed by different scoring systems. Although many similar characteristics have been identified, these scoring systems are not easy to relate to advanced stage HL. The aim of the present study was to refine the assessment of risk using the published scoring systems and to construct a statistical model for predicting risk of death. We report here the results of the EORTC, GHSG and Canadian-ECOG scoring systems obtained in 1156 patients for whom hematological data were available among the 1390 patients with localized HL prospectively treated within GELA centres in H8 (518 pts) and H9 (638 pts) trials. The International prognostic score (IPS) was available only for the H9 subset. All patients have been treated with radio-chemotherapy of different intensity or duration according to their prognostic factors. Median age was 30 yr [14–69] and age≥45yr.: 18%, female 50%; stage 1: 25%; stage 2: 75%; B symptoms with elevated ESR: 40%; number of nodal sites 1–2: 52%; ≥3: 48%; extra nodal involvement: 8%, bulky mediastinum&amp;gt; 0.35, 28%; elevated ESR&amp;gt; 50:33%; Hb&amp;lt; 10.5 g/dl: 7%; Lymphocytes &amp;lt; 600/μl: 6%; WBC &amp;gt; 15000/μl:11 %; albumin&amp;lt; 40g/l: 37%. With the EORTC scoring system 36% of patients had favourable HL, with GHSG 35% and with Canadian-ECOG 38%. The IPS was 0 in 19% and 1 in 45%. With a median follow up of 42 months, 54 patients died. Survival curves according to the different scoring systems significantly discriminated favourable and unfavourable patients outcomes (5 yrs OS 95% vs 92%, p=0.01). By multivariate Cox analysis, age &amp;gt; 45yr (RR=2.0), sex male (RR=2.5), haemoglobin &amp;lt;10.5g/dl (RR=2.3), lymphocytes &amp;lt; 600/μL (RR=3.6), B symptoms with elevated ESR (RR=3.6), extra nodal sites (RR=1.2) retained a significant prognostic value. The 5 yrs OS was 99%, 98%, 92%, 82%, 73% for patients with 0,1, 2, 3, 4–5 factors respectively (p&amp;lt; 0.0001, see figure). 10% of the patients had 3–5 factors. The covariates selection was validated by the bootstrap method. The introduction of albumin&amp;lt; 40g/l in the H9 subset population did not bring more significant information. In conclusion, these factors are similar with those described in the IPS when stages 3–4 are replaced by extra nodal (E) localization. They should be validated in other prospective trials because such a scoring system could unify the assessment of the prognosis for HL patients and facilitate the treatment choice. Figure Figure</jats:p

Plitidepsin Is Active in Peripheral T-Cell Lymphoma (PTCL): A Subset Analysis from An Ongoing Multicenter Phase II Trial.

Abstract Background: Peripheral T-cell lymphomas (PTCL) represent a small (&amp;lt;10%) yet a particularly aggressive subset of NHL. Up to 75% of those patients (pts) eventually become relapsed/refractory, with no effective options available. Thus, a prospective open-label, multicenter phase II study to evaluate the activity of plitidepsin (Aplidin®) in adult pts with relapsed/refractory aggressive lymphomas was planned and is currently ongoing. We report the preliminary results from a cohort of non-cutaneous PTCL. Patients and methods: As of July 2008, 14 pts were treated with plitidepsin 3.2 mg/m2 i.v. infusion over a 1-h on days 1, 8 and 15 q4wk. Eleven pts are evaluable, one is too early and two were non-evaluable as per protocol criteria: one had a hypersensitivity reaction and one had bone marrow (BM) infiltration only, but achieved a biopsy-documented BM clearance. Pts had a median of 3 (1–6) previous regimens, including 4 pts (33%) with prior autologous transplantation. Lymphoma histology: 8 PTCL-nos, 2 anaplastic large-cell, 2 angioimmunoblastic and 2 NK/T nasal type. Ten pts were male, median age was 56 y (35–74), with performance status 0 in 6 pts, 1 in 5 pts and 2 in 3 pts. Results: One confirmed CR and 3 PR were observed for a 36% objective response rate (95% CI: 11%–70%). Median duration of response was 4 months (range: 1+ – 12+). Median overall survival was 11 months (range 1+ – 24+). Plitidepsin was tolerable in this heavily pre-treated population, particularly with low hematologic toxicity. Of 2 cases of grade (G) 4 neutropenia, 1 was already present at baseline and only 1 pt developed G3 thrombocytopenia during treatment. Transient and reversible G3 ALT/AST elevations occurred in 7 patients and 2 G3 bilirrubin increases. Clinical toxicities mainly consisted of mild to moderate muscular weakness, myalgia and cramps, plus G1-2 fatigue and nausea in 1/3 of the patients. One pt discontinued due to hypersensitivity reaction before being evaluated for response and one pt was diagnosed with Guillain-Barré syndrome while progressing after 2 cycles. Conclusion: Plitidepsin (Aplidin®) shows promising activity and an acceptable safety profile in this difficult-to-treat subset of patients. Remarkably, no significant hematologic toxicity was seen in this heavily pretreated cohort. To confirm these preliminary data an expansion of the cohort is currently ongoing. Updated results will be presented.</jats:p