Rituximab and Intravenous Immune Globulin for Desensitization during Renal Transplantation

Ashley A. Vo, Pharm.D., Marina Lukovsky, Pharm.D., Mieko Toyoda, Ph.D., Jennifer Wang, M.D., Nancy L. Reinsmoen, Ph.D., Chih-Hung Lai, Ph.D., Alice Peng, M.D., Rafael Villicana, M.D., and Stanley C. Jordan, M.D.

ABSTRACT

Background Few options for transplantation currently exist for patients highly sensitized to HLA. This exploratory, open-label, phase 1–2, single-center study examined whether intravenous immune globulin plus rituximab could reduce anti-HLA antibody levels and improve transplantation rates.

Methods Between September 2005 and May 2007, a total of 20 highly sensitized patients (with a mean [±SD] T-cell panel-reactive antibody level, determined by use of the complement-dependent cytotoxicity assay, of 77±19% or with donor-specific antibodies) were enrolled and received treatment with intravenous immune globulin and rituximab. We recorded rates of transplantation, panel-reactive antibody levels, cross-matching results at the time of transplantation, survival of patients and grafts, acute rejection episodes, serum creatinine values, adverse events and serious adverse events, and immunologic factors.

Results The mean panel-reactive antibody level was 44±30% after the second infusion of intravenous immune globulin (P<0.001 for the comparison with the pretreatment level). At study entry, the mean time on dialysis among recipients of a transplant from a deceased donor was 144±89 months (range, 60 to 324). However, the time to transplantation after desensitization was 5±6 months (range, 2 to 18). Sixteen of the 20 patients (80%) received a transplant. At 12 months, the mean serum creatinine level was 1.5±1.1 mg per deciliter (133±97 µmol per liter), and the mean survival rates of patients and grafts were 100% and 94%, respectively. There were no infusion-related adverse events or serious adverse events during the study. Long-term monitoring for infectious complications and neurologic problems revealed no unanticipated events.

Conclusions These findings suggest that the combination of intravenous immune globulin and rituximab may prove effective as a desensitization regimen for patients awaiting a transplant from either a living donor or a deceased donor. Larger and longer trials are needed to evaluate the clinical efficacy and safety of this approach. (ClinicalTrials.gov number, NCT00642655 [ClinicalTrials.gov] .)

Treatment of Patients with the Hypereosinophilic Syndrome with Mepolizumab

Marc E. Rothenberg, M.D., Ph.D., Amy D. Klion, M.D., Florence E. Roufosse, M.D., Ph.D., Jean Emmanuel Kahn, M.D., Peter F. Weller, M.D., Hans-Uwe Simon, M.D., Ph.D., Lawrence B. Schwartz, M.D., Ph.D., Lanny J. Rosenwasser, M.D., Johannes Ring, M.D., Ph.D., Elaine F. Griffin, D.Phil., Ann E. Haig, B.S.N., Paul I.H. Frewer, M.Sc., Jacqueline M. Parkin, M.B., B.S., Ph.D., Gerald J. Gleich, M.D., for the Mepolizumab HES Study Group

ABSTRACT

Background The hypereosinophilic syndrome is a group of diseases characterized by persistent blood eosinophilia, defined as more than 1500 cells per microliter with end-organ involvement and no recognized secondary cause. Although most patients have a response to corticosteroids, side effects are common and can lead to considerable morbidity.

Methods We conducted an international, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of an anti–interleukin-5 monoclonal antibody, mepolizumab, in patients with the hypereosinophilic syndrome. Patients were negative for the FIP1L1–PDGFRA fusion gene and required prednisone monotherapy, 20 to 60 mg per day, to maintain a stable clinical status and a blood eosinophil count of less than 1000 per microliter. Patients received either intravenous mepolizumab or placebo while the prednisone dose was tapered. The primary end point was the reduction of the prednisone dose to 10 mg or less per day for 8 or more consecutive weeks.

Results The primary end point was reached in 84% of patients in the mepolizumab group, as compared with 43% of patients in the placebo group (hazard ratio, 2.90; 95% confidence interval [CI], 1.59 to 5.26; P<0.001)> activity of the hypereosinophilic syndrome. A blood eosinophil count of less than 600 per microliter for 8 or more consecutive weeks was achieved in 95% of patients receiving mepolizumab, as compared with 45% of patients receiving placebo (hazard ratio, 3.53; 95% CI, 1.94 to 6.45; P<0.001).> occurred in seven patients receiving mepolizumab (14 events, including one death; mean [±SD] duration of exposure, 6.7±1.9 months) and in five patients receiving placebo (7 events; mean duration of exposure, 4.3±2.6 months).

Conclusions Our study shows that treatment with mepolizumab, an agent designed to target eosinophils, can result in corticosteroid-sparing for patients negative for FIP1L1–PDGFRA who have the hypereosinophilic syndrome. (ClinicalTrials.gov number, NCT00086658 [ClinicalTrials.gov] .)

An Immunodeficiency Disease with RAG Mutations and Granulomas

Catharina Schuetz, M.D., Kirsten Huck, M.D., Sonja Gudowius, M.D., Mosaad Megahed, M.D., Oliver Feyen, Ph.D., Bernd Hubner, Ph.D., Dominik T. Schneider, M.D., Burkhard Manfras, M.D., Ulrich Pannicke, Ph.D., Rein Willemze, M.D., Ruth Knüchel, M.D., Ulrich Göbel, M.D., Ansgar Schulz, M.D., Arndt Borkhardt, M.D., Wilhelm Friedrich, M.D., Klaus Schwarz, M.D., and Tim Niehues, M.D.

SUMMARY We describe three unrelated girls who had an immunodeficiency disease with granulomas in the skin, mucous membranes, and internal organs. All three girls had severe complications after viral infections, including B-cell lymphoma associated with Epstein–Barr virus (EBV). Other findings were hypogammaglobulinemia, a diminished number of T and B cells, and sparse thymic tissue on ultrasonography. Molecular analysis revealed that the patients were compound heterozygotes for mutations in recombination activating gene 1 or 2 (RAG1 or RAG2). In each case, both parents were heterozygous carriers of a RAG mutation. The mutations were associated with reduced function of RAG in vitro (3 to 30% of normal activity). The parents and one sibling in the three families were healthy.

Toll-like Receptor 4 Polymorphisms and Aspergillosis in Stem-Cell Transplantation

Pierre-Yves Bochud, M.D., Jason W. Chien, M.D., Kieren A. Marr, M.D., Wendy M. Leisenring, Sc.D., Arlo Upton, M.D., Marta Janer, Ph.D., Stephanie D. Rodrigues, Sarah Li, John A. Hansen, M.D., Lue Ping Zhao, Ph.D., Alan Aderem, Ph.D., and Michael Boeckh, M.D.

ABSTRACT

Background Toll-like receptors (TLRs) are essential components of the immune response to fungal pathogens. We examined the role of TLR polymorphisms in conferring a risk of invasive aspergillosis among recipients of allogeneic hematopoietic-cell transplants.

Methods We analyzed 20 single-nucleotide polymorphisms (SNPs) in the toll-like receptor 2 gene (TLR2), the toll-like receptor 3 gene (TLR3), the toll-like receptor 4 gene (TLR4), and the toll-like receptor 9 gene (TLR9) in a cohort of 336 recipients of hematopoietic-cell transplants and their unrelated donors. The risk of invasive aspergillosis was assessed with the use of multivariate Cox regression analysis. The analysis was replicated in a validation study involving 103 case patients and 263 matched controls who received hematopoietic-cell transplants from related and unrelated donors.

Results In the discovery study, two donor TLR4 haplotypes (S3 and S4) increased the risk of invasive aspergillosis (adjusted hazard ratio for S3, 2.20; 95% confidence interval [CI], 1.14 to 4.25; P=0.02; adjusted hazard ratio for S4, 6.16; 95% CI, 1.97 to 19.26; P=0.002). The haplotype S4 was present in carriers of two SNPs in strong linkage disequilibrium (1063 A/G [D299G] and 1363 C/T [T399I]) that influence TLR4 function. In the validation study, donor haplotype S4 also increased the risk of invasive aspergillosis (adjusted odds ratio, 2.49; 95% CI, 1.15 to 5.41; P=0.02); the association was present in unrelated recipients of hematopoietic-cell transplants (odds ratio, 5.00; 95% CI, 1.04 to 24.01; P=0.04) but not in related recipients (odds ratio, 2.29; 95% CI, 0.93 to 5.68; P=0.07). In the discovery study, seropositivity for cytomegalovirus (CMV) in donors or recipients, donor positivity for S4, or both, as compared with negative results for CMV and S4, were associated with an increase in the 3-year probability of invasive aspergillosis (12% vs. 1%, P=0.02) and death that was not related to relapse (35% vs. 22%, P=0.02).

Conclusions This study suggests an association between the donor TLR4 haplotype S4 and the risk of invasive aspergillosis among recipients of hematopoietic-cell transplants from unrelated donors.