We studied the value of leukocyte depletion of platelet transfusions for the prevention of secondary human leukocyte antigen (HLA)- alloimmunization in patients with a high-risk of prior immunization induced by pregnancies. Seventy-five female patients with hematologic malignancies (mostly acute leukemia) and a history of pregnancy were randomized to receive either standard random single-donor platelet transfusions (mean leukocytes, 430 x 10(6) per transfusion) or leukocyte-depleted random single-donor platelet transfusions. Leukocyte depletion to less than 5 x 10(6) leukocytes per platelet transfusion (mean leukocytes, 2 x 10(6) per transfusion) was achieved by filtration. Of the 62 evaluable patients, refractoriness to random donor platelets occurred in 41% (14 of 34) of the patients in the standard group and in 29% (8 of 28) of the patients in the filtered group (P = .52); anti-HLA antibodies developed in 43% (9 of 21) of individuals in the standard group and 44% (11 of 25) of cases in the filtered group. The time toward refractoriness and development of anti- HLA antibodies was similar for both groups. We conclude that leukocyte depletion of random single-donor platelet products to less than 5 x 10(6) per transfusion does not reduce the incidence of refractoriness to random donor platelet transfusion because of boostering of anti-HLA antibodies.

An urgent need for new treatment modalities is emerging in elderly patients with acute myeloid leukemia (AML). We hypothesized that targeting VEGF might furnish an effective treatment modality in this population. Elderly patients with AML were randomly assigned in this phase 2 study (n ‫؍‬ 171) to receive standard chemotherapy (3 ؉ 7) with or without bevacizumab at a dose of 10 mg/kg intravenously at days 1 and 15. In the second cycle, patients received cytarabine 1000 mg/m 2 twice daily on days 1-6 with or without bevacizumab. The complete remission rates in the 2 arms were not different (65%). Event-free survival at 12 months was 33% for the standard arm versus 30% for the bevacizumab arm; at 24 months, it was 22% and 16%, respectively (P ‫؍‬ .42). The frequencies of severe adverse events (SAEs) were higher in the bevacizumab arm (n ‫؍‬ 63) compared with the control arm (n ‫؍‬ 28; P ‫؍‬ .

Background Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been established as a powerful treatment modality for patients with hematological malignancies. The graft-versus-leukemia effect, however, is strongly associated with the occurrence of graft-versus-host disease (GVHD) and subsequent transplant-related mortality (TRM). Several strategies are applied in order to prevent GVHD following T-cell replete alloHSCT including conventional immunosuppression (CIS) with post-transplant administration of cyclosporine A (CyA) and mycophenolic acid (MA), or post-transplant cyclophosphamide (PT-Cy) either or not combined with CIS. Studies in haplo- and HLA matched donor transplantation have shown that PT-Cy is well tolerated and associated with low rates of severe GVHD and TRM. However, evidence from randomized clinical trials on the efficacy of PT-Cy as compared to CIS in the setting of HLA matched alloHSCT is scarce. Aims In the present prospective randomized, multicenter, phase III trial we set out to compare a PT-Cy based immunosuppressive regimen with CIS and address the question whether PT-Cy would be associated with improved GVHD-free/relapse-free survival (GRFS). Endpoints included time to acute and chronic GVHD, progression free survival (PFS), GRFS, overall survival (OS), and adverse events. Methods Hematological patients (pts) with a matched related donor or at least an 8 out of 8 matched unrelated donor were included. Pts randomized for the CIS regimen received CyA twice daily until day +120 followed by tapering until day +180 and MA 16 mg/kg twice daily with a maximum dose of 2160 mg a day until day 84 post-transplant. Pts randomized for PT-Cy received 50 mg/kg of cyclophosphamide on day +3 and +4 combined with CyA from day +5 until day +70. Results A total of 160 pts was randomized 1:2 between CIS and PT-Cy, of whom 94% proceeded to transplant (52 versus 99 pts). Median age was 58 years (range: 20-70), 66% were male. Two pts received myeloablative conditioning. The donor type was matched related in 31% and matched unrelated in 69% of pts. Transplants were derived from peripheral blood in 97% of pts and consisted of median 6.14x106/kg CD34+ cells/kg (range: 1.36-19.4) and median 230x106/kg CD3+ T cells (range: 0-519). Baseline patient and transplantation characteristics were equally distributed between the two treatment arms. The cumulative incidence (CI) at six months of grade II-IV acute GVHD was 48% in recipients of CIS versus 32% following PT-Cy (SHR 0.52, 95%CI 0.31-0.87, p=0.014), and grade III-IV 12% versus 6%. In recipients of PT-Cy, acute GVHD was generally limited to stage 1 skin involvement, whereas more severe skin involvement and bowel involvement were observed following CIS. The two-year CI of chronic extensive GVHD was 50% in recipients of CIS versus 19% following PT-Cy (SHR 0.38, 95%CI 0.21-0.67, p=0.001). The three-year estimate of PFS was 60% (44%-73%) and 58% (46%-67%). The three-year CI of progression/relapse was 26% in the CIS arm versus 32% in the PT-Cy arm. The three-year estimate of OS was 69% (53%-80%) and 63% (52%-73%). The one-year estimate (95% confidence interval) of GRFS was 22% (12%-34%) and 45% (35%-55%), respectively. Conclusion Use of high-dose PT-Cy results in a significant reduction in severe acute and chronic GVHD without affecting relapse, thereby resulting in improved GRFS. Hence, a more intensified immunosuppression regimen with PT-Cy might be preferred as GVHD prophylaxis in the setting of RIC alloHSCT. Figure Disclosures Nur: Novartis Pharmaceuticals: Consultancy. Maertens:Cidara: Other: Personal fees and non-financial support; Gilead Sciences: Other: Grants, personal fees and non-financial support; Amplyx: Other: Personal fees and non-financial support; Merck: Other: Personal fees and non-financial support; Pfizer: Other: Grant and personal fees; Astellas Pharma: Other: Personal fees and non-financial support; F2G: Other: Personal fees and non-financial support. Deeren:Alexion, Amgen, Janssen, Roche, Sunesis, Takeda, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Preventing late toxicity has become the cornerstone in the management of HL as global results greatly improved regarding event-free (EFS) and overall survival (OS) rates. With this aim, the EORTC and GELA groups conducted a trial (H9-F) comparing three radiation doses in patients in complete remission (CR/CRu) after chemotherapy. Adult patients with supradiaphragmatic CS I-II HL and favorable features (age < 50, and CS I-II2–3, and A + ESR < 50 or B + ESR < 30, and MT ratio < 0.35) were eligible. After 6 cycles of EBVP (epirubicin, bleomycin, vinblastine, prednisone), CR/CRu patients were randomized between 36 Gy involved-field radiotherapy (IF-RT), 20 Gy IF-RT and no RT. From September 1998 to May 2004, 783 patients were enrolled in 111 institutions from 10 European countries. Inclusion of patients in the no-RT arm was stopped in May 2002 because stopping rules were met (i.e. > 20% of events). After 6 EBVP response rates were 50% CR, 26% CRu, 18% PR, 3% no change or progression, and 3% unspecified. Of the 591 CR/CRu patients, 13 (2%) were not randomized (6 refusals, 3 protocol violations, 4 causes unspecified). After a median follow-up of 51 months (range 14–81), 130 events (36 progressions, 91 relapses, 1 toxic death, 2 deaths of second cancer) were observed. At July 2005, the 4-year EFS and OS rates are as follows: Treatment No. Pts. Prog. /Rel. /Death 4-yr EFS 4-yr OS 6 EBVP + IF-RT 36 Gy 239 2 /18 /0 88% 98% 6 EBVP + IF-RT 20 Gy 209 5 /16 /0 85% 100% 6 EBVP + no RT 130 1 /35 /1 69% 98% P value < 0.001 0.241 6 EBVP, no random. 205 28 /22 /2 68% 93% Non-randomized patients experienced a significantly worse OS than did complete responders (P=0.0012). Relapses in nodal sites were more frequent in the no RT arm (35 in unirradiated sites) than in RT arms (6 + 10 in irradiated sites). 15 patients have died, 10 of progressive disease, 2 of treatment-related complication, 1 of intercurrent disease and 2 of second cancer (1 AML, 1 NHL). In favorable early stage HL patients who achieve CR(u) after 6 cycles of EBVP, omission of IF-RT leads to an unacceptable failure rate; In contrast, with the current follow-up, IF-RT 20 Gy provides results equivalent to those of IF-RT 36 Gy.

In this multicenter study, the efficacy of and tolerability for meropenem were compared with those for the combination of cefuroxime-gentamicin (±metronidazole) for the treatment of serious bacterial infections in patients ≥65 years of age. A total of 79 patients were randomized; thirty-nine received meropenem (1 g/8 h), and 40 received cefuroxime (1.5 g/8 h) plus gentamicin (4 mg/kg of body weight daily) for 5 to 10 days. Metronidazole (500 mg/6 h) could be added to the cefuroxime-gentamicin regimen for the treatment of intra-abdominal infections (n = 10). Seventy patients were evaluable for clinical efficacy; the primary diagnoses were as follows: pneumonia in 41 patients (20 treated with meropenem, 21 treated with cefuroxime-gentamicin), intra-abdominal infection in 10 patients (7 meropenem, 3 cefuroxime-gentamicin-metronidazole), urinary tract infection (UTI) in 11 patients (6 meropenem, 5 cefuroxime-gentamicin), sepsis syndrome in 7 patients (4 meropenem, 3 cefuroxime-gentamicin), and “other” in 1 patient (cefuroxime-gentamicin). The pathogens isolated from 18 patients with bacteremia were as follows:Staphylococcus spp. (n = 2),Streptococcus spp. (n = 2), members of the family Enterobacteriaceae (n = 11), and Bacteroides spp. (n = 3). A satisfactory clinical response at the end of therapy was achieved in 26 of 37 (70%) and 24 of 33 (73%) evaluable patients treated with meropenem and combination therapy, respectively. Clinical success was achieved in 23 of 31 (74%) and 21 of 28 (75%) evaluable patients with infections other than UTIs, respectively. A satisfactory microbiological response occurred in 15 of 22 (68%) patients in the meropenem group compared with 12 of 19 (63%) treated with combination therapy. Renal failure occurred during therapy in 2 of 39 (5%) meropenem recipients compared with 5 of 40 (13%) of those treated with combination therapy. The findings in this small study indicate that meropenem is as efficacious for and as well tolerated by elderly patients as the combination of cefuroxime-gentamicin (±metronidazole).

Susceptibility to chemically induced lung tumorigenesis has previously been mapped to a genomic interval of 27 kb in the MHC class III region of the mouse using two H2 (a/b) intra- H2 recombinants, B10.A(1R) and B10.A(2R). Three genes are located within this interval, G7e (encoding a viral envelope protein), G7a/ Vars2 (encoding valyl-tRNA synthetase), and G7c (a gene with unknown function). A 70 kb contig, spanning the 27 kb region and extending 20 kb either side, was constructed from lambda phage libraries with genomic inserts derived from mouse strains B10.A(1R) and B10.A(2R). The region was analyzed for single-nucleotide polymorphisms, which would facilitate further fine mapping of the interval. Analysis of the expression levels of the candidate genes did not reveal any difference between B10.A(1R) and B10.A(2R). In addition, no differences were found at the sequence level in the 27 kb interval except for an A to T transition in intron 7 of G7c. A database comparison of the sequence surrounding this polymorphism did not identify any DNA-binding or enhancer consensus sequence. In conclusion, the previously observed phenotype could not be associated with or assigned to any of the candidate genes G7e, G7a/ Vars2, or G7c, nor could any of the other susceptibility loci, which have been reported to map to this region ( Cps1, Acp, Orch1, and Igis1).

No abstract

Treatment results in elderly patients (> 65 yrs) with aggressive Non-Hodgkin lymphoma (NHL) are associated with a lower complete response (CR) rate and a worse survival (OS). Efforts have been made to improve the outcome by adding Rituximab to standard CHOP chemotherapy or by intensifying CHOP from 21 days to 14 days intervals (2-weekly CHOP, CHOP14). The Dutch HOVON and the Scandinavian Nordic groups have performed a prospective, multi-center, randomized phase III trial to compare 8 cycles of CHOP14 chemotherapy with or without 6 administrations of Rituximab (R-CHOP14), supported by G-CSF in previously untreated, older patients with intermediate or high-risk B-cell NHL. Inclusion criteria were mantle cell lymphoma, follicular lymphoma grade III or diffuse large B-cell lymphoma; intermediate or high age adjusted IPI score; CD20-positive NHL; age greater than 65 yrs. The target number was 400 patients to be accrued in 5 years based on an expected increase in failure free survival with hazard ratio HR=0.70. Based on a planned interim analysis the Data and Safety Monitoring Board stopped the trial because of a significant difference for primary endpoints. At final analysis 243 of 261 patients were eligible and evaluable. The median follow up was 20 months (range 3–46). The median age was 72 years (range 65–85 years), 80 % had DLBCL, 60 % had intermediate-high/high age-adjusted IPI score, 65 % had increased serum LDH. 64% of patients completed the planned treatment, while 22% went off treatment because of toxicity, of which 2 % was cardiovascular. 14% of patients experienced CTC grade 3–4 infections. The number of patients who went off treatment because of toxicity was 15 % in those aged < 70 and increased with age up to 38 % in those over 75 yrs. After 3–4 cycles 16 % of the patients in the R-CHOP arm achieved a CR(u) as compared to 12 % with CHOP14; after 8 cycles the difference was 66 % vs 46 %. Overall response (PR+CRu) was 92 % and 83 %, respectively. Overall survival (OS) by Cox regression analysis adjusted for aaIPI and diagnosis was better with R-CHOP14 than with CHOP14 (relative hazard ratio HR=0.69, 95 % CI 0.46-1.05, p=0.09). The primary endpoint Failure free survival (FFS) was better in the R-CHOP14 arm (38 failures: 9 non-responders, 29 relapses, FFS2yr =55%)) than in the CHOP14 arm (65 failures: 20 non-responders, 45 relapses, FFS2yr =33%) with hazard ratio HR=0.60 (P=0.007). In the subgroup of DLBCL, FFS2yr was 62 %, while log-rank OS (p=0.05) and FFS (p=0.004) were both superior with R-CHOP14. These data indicate that in an elderly population (median age 72 yrs) with highly aggressive NHL, the CHOP14 regimen is tolerable and achievable in > 60 % of patients, and that the addition of Rituximab improves CR rate, OS and FFS.