Induction Therapy Agents Research Articles

Clinical Correlates and Outcomes of Dual Basiliximab and Antithymocyte Globulin Induction in Kidney Transplant Recipients: A National Study.

We used national transplant registry data to study clinical correlates and outcomes of single versus dual induction therapy in adult kidney-only transplant recipients in the United States (2005-2018). The risk of death and graft loss at 1 and 5 y, according to induction therapy type, was assessed using multivariate Cox regression analysis (adjusted hazard ratio with 95% upper and lower confidence limits [LCLaHRUCL]). Of the 157 351 recipients included in the study, 67% were treated with ATG alone, 29% were treated with IL2rAb alone, and 5% were treated with both. Compared with IL2rAb alone, the strongest correlates of dual induction included Black race, calculated panel reactive antibody ≥80%, prednisone-sparing maintenance immunosuppression, more recent transplant eras, longer cold ischemia time, and delayed graft function. Compared with ATG alone, dual induction was associated with an increased 5-y risk of death (aHR 1.071.151.23; P < 0.0001), death-censored graft failure (aHR 1.051.131.22; P < 0.05), and all-cause graft failure (aHR 1.061.121.18; P < 0.0001). Further research is needed to develop risk-prediction tools to further inform optimal, individualized induction protocols for kidney transplant recipients.

Serum Free Light Chain Assay Measurement at Disease Relapse for Prognostication in Patients with Multiple Myeloma in the Novel Agent Era

BackgroundMonoclonal serum free light chains (sFLC) are detected in patients with B-cell proliferative disorders including multiple myeloma (MM) at diagnosis and disease relapse. Several previous studies demonstrated prognostic impact of the involved and uninvolved sFLC ratio (rFLC) in patients with newly diagnosed MM, patients with monoclonal gammopathy with undetermined significance, and smoldering MM. However, the prognostic impact of rFLC and differences between involved and uninvolved FLCs (dFLC) at the time of disease relapse have not been fully elucidated.Patients and methodsWe identified consecutive patients with symptomatic MM, diagnosed and treated at Kameda Medical Center from January 2006 to April 2017. Patients who experienced initial relapse during June 2007 (the time where we began to routinely measure sFLC in MM patients) to April 2017 were identified. We reviewed background and outcome data from the electronic record. IMWG response criteria were used for assessing response and disease progression. rFLC was defined as involved FLC (iFLC) level divided by uninvolved FLC (uFLC) level. dFLC was calculated by subtracting uFLC from iFLC. Time to second progression (2nd TTP) and overall survival after first relapse (OS after 1st relapse) were defined as the time from the date of first progression to the date of second progression and death from any cause, respectively. Receiver operating characteristic (ROC) analysis determined optimal cutoff levels of rFLC and dFLC. We divided patients into high or low rFLC or dFLC, according to these cutoff levels. To clarify the relationship between rFLC increase at relapse and subsequent prognosis, patients were divided into 4 groups according to the rFLC levels: patients with rFLC >0 and ≤10, >10 and ≤100, >100 and ≤1000, and >1000.ResultsThere were 240 patients diagnosed with symptomatic MM. Among them, 124 patients experienced disease relapse at least once during the observation period. Of the 124 patients, 97 were classified as having intact immunoglobulin MM and 27 had light chain MM. Median observation period from first relapse and age at first relapse of the 124 patients was 19.8 (range: 0.7 - 111.4) months (m) and 73.7 (range: 46.7 - 90.1) years, respectively. All patients received novel induction therapy agents. Using ROC analysis, we determined the optimal cutoff of rFLC and dFLC for predicting highest risk of second relapse within 1 year of first relapse as 19.7 and 122.9 mg/L, respectively. Patients with higher rFLC (n=57) had significantly shorter 2nd TTP and OS after 1st relapse than those with lower rFLC (n=67) (median 2nd TTP, 4.1 vs 24.7 m; P<0.001, and median OS after 1st relapse, 19.3 vs 42.7 m; P<0.001, respectively). Patients with higher dFLC (n=57) had significantly shorter 2nd TTP and OS after 1st relapse than those with lower rFLC (n=67) (median 2nd TTP, 5.5 vs 20.5 m; P<0.001, median OS after 1st relapse, 19.1 vs 42.7 m; P<0.001, respectively). Both 2nd TTP and OS after 1st relapse were significantly shorter when associated with increased rFLC levels. The median survival of patients with rFLC >0 and ≤10 (n=57), >10 and ≤100 (n=30), >100 and ≤1000 (n=22), and >1000 (n=15) were 30.5, 9.9, 4.7 and 1.6 m, respectively for 2nd TTP and 72.6, 33.6, 24.9 and 14.7 m respectively for OS after 1st relapse (both, P<0.001), whereas no significant difference was detected among the four risk groups of patients for age at first relapse, international staging system (ISS), revised ISS, the level of albumin, beta-2 microglobulin, creatinin, hemoglobin, lactate dehydrogenase abnormality, high-risk cytogenetic abnormality, or chemotherapy after first relapse.ConclusionAt disease relapse, both rFLC and dFLC clearly identified different patient risk groups for subsequent prognosis. High rFLC and dFLC at relapse related to shorter 2nd TTP and OS after 1st relapse. Our data indicate that serial measurement of serum FLC assays may predict prognosis after relapse in patients with MM who receive novel agents and experience disease progression. [Display omitted] DisclosuresKitadate:Kyowa Kirin: Research Funding; Eisai: Research Funding; Asahi Kasei: Research Funding; Pfizer: Research Funding; Otsuka: Research Funding; Chugai: Research Funding; Novartis: Research Funding; Fujimoto: Research Funding; Toyama kagaku: Research Funding.

Induction therapy with mesenchymal stromal cells in kidney transplantation: a meta-analysis

ObjectiveThe aim of this meta-analysis was to evaluate the therapeutic effects of mesenchymal stromal cells (MSCs) versus traditional regimens for induction therapy in kidney transplantation (KT), especially the safety of MSC infusion, practicability of MSCs as induction therapy agents, and posttransplant complications.MethodsPubMed, Embase, EBSCO, Ovid, and the Cochrane Library were searched for prospective clinical trials that compared MSCs with traditional regimens for induction therapy in KT.ResultsFour trials were included, including a total of 197 patients. The pooled results revealed that MSC therapy had a lower 1-year infection rate than did the traditional therapies (RR = 0.65, 95% CI: 0.46–0.9, P = 0.01). There were no significant differences between the two protocols regarding the 1-year acute rejection (AR) rate (RR = 0.77, 95% CI: 0.41–1.45, P = 0.42), 1-year graft survival rate (RR = 0.99, 95% CI: 0.95–1.03, P = 0.74), delayed graft function (DGF) rate (RR = 0.54, 95% CI: 0.21–1.38, P = 0.2) and renal graft function at 1 month (MD = −1.56, 95% CI: − 14.2–11.08, p = 0.81), 3 months (MD = 0.15, 95% CI: − 5.63–5.93, p = 0.96), 6 months (MD = − 1.95, 95% CI: − 9.87–5.97, p = 0.63), and 12 months (MD = − 1.13, 95% CI: − 7.16–4.89, p = 0.71) postsurgery. Subgroup analysis demonstrated that the 1-year AR rate, 1-year graft survival rate, DGF rate, and renal graft function at 12 months postsurgery did not significantly differ between the low-dose calcineurin inhibitor (CNI) group and the standard-dose CNI group, indicating the potential benefits of successful CNI sparing in combination with MSC treatment. Moreover, when MSCs were applied as an alternative therapy rather than an additional therapy or allogeneic MSCs were utilized instead of autologous MSCs, all of the outcomes mentioned above were comparable.ConclusionInduction therapy with MSCs is safe and has similar immune response modulation effects to those of traditional regimens in the short term in KT recipients. However, regarding the long-term effects, as suggested by the 1-year infection rate and the potential of CNI sparing, MSC therapy has significant advantages. However, these advantages should be further verified in more well-designed, multicenter randomized controlled trials (RCTs) with large sample sizes and long follow-up periods.

Low Immunologic Risk Living Related Renal Transplant Using Very Low-Dose Antithymocyte Globulin as Induction Therapy: A Single Tertiary Hospital Experience

The aim of induction therapy in the management of kidney transplant is to reduce the incidence of acute rejection and delayed graft function after kidney transplant. The agent for induction therapy differs depending on the recipient risks. The regimen can be either polyclonal (rabbit antithymocyte globulin [rATG]) or monoclonal antibody (basiliximab). Basiliximab is commonly used in patients with low immunologic risk. However, to date we know that the use of rATG on T cell depletion is dose dependent and more potent antirejection therapy. Therefore, we would like to look at 1-year graft function of very low-dose rATG in low immunologic risk recipients.All low immunologic risk patients who received low-dose rATG (0.5 mg/kg of body weight daily) during transplant (day 0) and on days 1 and 2 were recruited. Their renal function, HLA donor-specific antibodies, lymphocyte counts, protocol biopsy results, and cytomegalovirus (CMV) polymerase chain reaction were monitored as per clinical practice.All 10 patients had immediate graft function. Low-dose rATG caused lymphocyte counts to deplete immediately on day 0, and the effect lasted about 1 month post-transplant. All the patients had stable graft function without any significance episode of rejection. Only one patient had de novo HLA-DQ antibody. It is good to know that without prophylaxis antiviral in CMV+ donor to CMV+ recipient, the incidence of CMV viremia is considerably low in our cohort.Very low-dose rATG is an effective induction immunosuppression in low immunologic risk patients with acceptable infection risk.

Patterns of Care and Outcomes in Mantle Cell Lymphoma in the Modern Immunochemotherapy Era

Patterns of Care and Outcomes in Mantle Cell Lymphoma in the Modern Immunochemotherapy Era

A Cost-effectiveness Analysis of Rabbit Antithymocyte Globulin Versus Antithymocyte Globulin-fresenius as Induction Therapy for Patients With Kidney Transplantation From Donation After Cardiac Death in China

PurposeInduction immunosuppression therapy is used to support optimal outcomes in kidney transplantation. This study was to assess the cost-effectiveness of rabbit antithymocyte globulin (r-ATG) versus ATG-Fresenius (ATG-F) in kidney transplantation in the Chinese setting from the perspective of the health care payer. MethodsA 2-part survival model was developed, consisting of a short-term part and a long-term part. The short-term part analyzed the first year, using the decision tree, and consisted of the functioning transplant, acute rejection (AR), delayed graft function (DGF), dialysis, and death health states. The long-term part analyzed 2 to 5 years, using Markov model, and consisted of the functioning transplant, chronic dysfunction, recurring primary disease, dialysis, and death health states, with capture of the association between DGF and graft loss. Costs, including drug acquisition and other direct medical costs, were derived from China IQVIA database (formerly known as IMS) hospital database, chart review, and physician interviews. Clinical outcomes and utility were retrieved from published literature. The model calculated quality-adjusted life-years (QALYs) and total costs per patient. Costs and QALYs were discounted at an annual rate of 3.5%. Univariate sensitivity analysis and probability sensitivity analysis (PSA) were conducted to assess the impact of uncertainty of the variables on the results. FindingsPatients who received r-ATG had more clinical effectiveness than patients who received ATG-F mainly because of less AR, DGF, and dialysis. The incremental QALY was 0.01 over a 1-year time horizon and 0.0496 over a 5-year time horizon. R-ATG and ATG-F drug costs were ¥10,783 and ¥8409, respectively. However, the total treatment costs of the r-ATG arm were lower than the ATG-F arm because of lower costs related to DGF, AR, dialysis, and adverse events. In total, r-ATG saved ¥5423 over the 1-year and ¥7042 over the 5-year time horizon. R-ATG was dominant with lower total direct medical costs and higher QALYs compared with ATG-F. Both univariate sensitivity analysis and PSA found the robustness of the model results. PSA results indicated that r-ATG was cost-effective compared with ATG-F in 86.81% of the simulations, considering <3 times the gross domestic product per capita as the threshold. ImplicationsFrom the perspective of the health care payer, r-ATG should be considered as the preferred treatment agent for induction therapy for Chinese patients undergoing kidney transplantation because of its lower overall medical costs and greater QALYs gained compared with ATG-F. The study was limited by lack of long-term efficacy data among the Chinese population and lack of comprehensive real-world higher quality costs data.

Acute Cellular Rejection and Infection Rates in Alemtuzumab vs Traditional Induction Therapy Agents for Lung and Heart Transplantation: A Systematic Review and Meta-analysis

Background and ObjectivesHeart and lung transplantation is a high-risk procedure requiring intensive immunosuppressive therapy for preventing organ rejection. Alemtuzumab, a CD52-specific monoclonal antibody, is increasingly used for induction therapy compared with conventional agents. However, there has been no systematic review comparing its efficacy with traditional therapeutic drugs. MethodsPubMed and EMBASE were searched to October 1, 2017, for articles on alemtuzumab in cardiothoracic transplant surgery. Of the 433 studies retrieved, 8 were included in the final meta-analysis. ResultsIn lung transplantation, alemtuzumab use was associated with lower odds of acute cellular rejection compared with antithymocyte globulin (odds ratio [OR], 0.21; 95% CI, 0.11–0.40; P < .001), lower acute rejection rates (OR, 0.12; 95% CI, 0.03–0.55; P < .01), and infection rates (OR, 0.69; 95% CI, 0.35–1.36; P = .33) when compared with basiliximab. Multivariate meta-regression analysis found that mean age, male sex, single lung transplant, double lung transplant, cytomegalovirus or Epstein-Barr virus status, idiopathic pulmonary fibrosis, cystic fibrosis, and mean ischemic time did not significantly influence acute rejection outcomes. For heart transplantation, alemtuzumab use was associated with lower acute rejection rates when compared with tacrolimus (OR, 0.44; 95% CI, 0.30–0.66; P < .001). ConclusionsAlemtuzumab use was associated with lower rejection rates when compared with conventional induction therapy agents (antithymocyte globulin, basiliximab, and tacrolimus) in heart and lung transplantation. However, this was based on observational studies. Randomized controlled trials are needed to verify its clinical use.

WITHDRAWN: Acute Cellular Rejection and Infection Rates in Alemtuzumab vs Traditional Induction Therapy Agents for Lung and Heart Transplantation: A Systematic Review and Meta-analysis

The Publisher regrets that this article is an accidental duplication of an article that has already been published in Transplant Proc. 2018; 50 (10):3739-3747, https://doi.org/10.1016/j.transproceed.2018.08.018. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Acute Rejection Rates and Graft Outcomes According to Induction Regimen among Recipients of Kidneys from Deceased Donors Treated with Tacrolimus and Mycophenolate.

IL-2 receptor antagonist (IL2-RA) is recommended as a first-line agent for induction therapy in renal transplantation. However, this remains controversial in deceased donor renal transplantation (DDRT) maintained on tacrolimus (TAC)/mycophenolic acid (MPA) with or without steroids. We studied the United Network for Organ Sharing Registry for patients receiving DDRT from 2000 to 2012 maintained on TAC/MPA at transplantation hospital discharge (n=74,627) to compare outcomes of IL2-RA and other induction agents. We initially divided the cohort into two groups on the basis of steroid use at the time of discharge: steroid (n=59,010) versus no steroid (n=15,617). Each group was stratified into induction categories: IL2-RA, rabbit antithymocyte globulin (r-ATG), alemtuzumab, and no induction. The main outcomes were incidence of acute rejection within the first year and overall graft failure (defined as graft failure and/or death) post-transplantation. Propensity score (PS), specifically inverse probability of treatment weight, analysis was used to minimize selection bias caused by nonrandom assignment of induction therapies. Median (25th, 75th percentiles) follow-up times were 3.9 (1.1, 5.9) and 3.2 (1.1, 4.9) years for steroid and no steroid groups, respectively. Acute rejection within the first year and overall graft failure within 5 years of transplantation were more common in the no induction category (13.3%; P<0.001 and 28%; P=0.01, respectively) in the steroid group and the IL2-RA category (11.1%; P=0.16 and 27.4%; P<0.001, respectively) in the no steroid group. Compared with IL2-RA, PS-weighted and covariate-adjusted multivariable logistic and Cox analyses showed that outcomes in the steroid group were similar among induction categories, except that acute rejection was significantly lower with r-ATG (odds ratio [OR], 0.68; 95% confidence interval [95% CI], 0.62 to 0.74). In the no steroid group, compared with IL2-RA, odds of acute rejection with r-ATG (OR, 0.80; 95% CI, 0.60 to 1.00) and alemtuzumab (OR, 0.68; 95% CI, 0.53 to 0.88) were lower, and r-ATG was associated with better graft survival (hazard ratio, 0.86; 95% CI, 0.75 to 0.99). In DDRT, compared with IL2-RA induction, no induction was associated with similar outcomes when TAC/MPA/steroids were used. r-ATG seems to offer better graft survival over IL2-RA in steroid avoidance protocols.

Novel Agents Versus Conventional Drugs for the Treatment of Relapsed Multiple Myeloma Patients: Experience of a Single Center over the Last 25 Years

Background: New active classes of drugs such as proteasome inhibitors (e.g., bortezomib) and immunomodulatory drugs-IMiDs (e.g., thalidomide and lenalidomide) are nowadays the standard treatment for multiple myeloma (MM) patients, alone or in association with old agents. The achievement of deeper responses, using novel agents instead of conventional treatment, is a significant prognostic factor for the outcome of these patients, resulting in an improved overall survival (OS) and progression-free survival (PFS). Here, we report the single center real life comparison between the outcome achieved with old agents with that obtained with novel agents in young MM patients treated at first relapse over a 25-year period.Patients and Methods: We analyzed a cohort of 258 young (median age 55 years; range 19-69) newly diagnosed MM patients treated at our Center between August 1989 and November 2014. All patients received old or novel agents followed by autologous hematopoietic stem cell transplantation (single or tandem) as first line treatment. Of the 258 patients, 144 experienced a progression of disease after a median of 34 months (range 7-195) and received old or novel agents as second line therapy. Old agents used as first and second line treatment were prevalently vincristine, doxorubicin and dexamethasone (VAD), melphalan and prednisone (MP) or cyclophosphamide and dexamethasone (CD); novel agents included velcade-based or IMiD-based regimens. Our cohort was divided into four different groups: 1) 51 patients treated with old agents as first and second line therapy (35.4%);2) 79 patients treated with old agents as first line therapy and novel agents as second line therapy (54.8%);3) 2 patients treated with novel agents in induction therapy and subsequently with old agents as second line therapy (1.4%);4) 12 patients treated with novel agents both in first and second line (8.3%). Our analysis focused on groups 1 and 2; group 3 was not considered for the small number of patients and because the choice of treatment was based exclusively on a worsening of the clinical condition; group 4 was not included for the small number of patients and because of the short follow-up. Our aim was to compare the results obtained in patients treated only with old agents both as first and second line treatment with the outcome of patients who received old agents as first treatment and novel agents as second line treatment, to assess the impact of novel agents in real life MM patients' management.Results: The OS at 5 years for patients of group 2 was significantly higher than that of group 1 patients (41.6% vs 14.1%); even at 10 years, the OS was significantly better for group 2 (20.4% vs 2.4%, p<0.0001); median OS was 4.1 years for group 2 and 1.4 years for group 1. The PFS was superior for patients treated with novel agents as second line treatment both at 5 years (12% vs 6.9%) and at 10 years (10% vs 2.3%) (p=0.02); median PFS was 1.4 years for group 2 and 0.7 for group 1. PFS2, considered as the interval from the start of first line treatment to the date of second relapse, showed also significantly better results for group 2 patients compared to group 1 patients both at 5 (61.8% vs 33.3%) and 10 years (25.7% vs 9.2%). Median PFS2 was 6.8 years for group 2 and 3.7 years for group 1(p=0.0002).Conclusions: We analyzed the effect of the introduction of novel agents in a cohort of young MM patients treated at our Center over a 25-year period, between 1989 and 2014. Patients treated in the earlier years received old agents both as first and second line treatment, while in more recent years all patients who experienced a relapse were treated with novel agents as second line treatment. Our analysis underlines that patients receiving novel agents witnessed a significantly better OS and PFS compared to patients treated only with old agents. When focusing on PFS2, we could determine that the duration of response obtained with proteasome inhibitors and IMiDs was significantly longer than that obtained with conventional chemotherapy. This currently ongoing study and a longer follow-up in a larger number of group 4 patients will allow to conclusively define the true real life impact of novel agents when used both as first and second line treatment for the management of young MM patients. DisclosuresPetrucci:Celgene, Janssen-Cilag, Amgen, Mundipharma, BMS: Honoraria.

Induction therapy in pancreas transplantation

Induction therapy, the initial high-dose bolus of immunosuppression given perioperatively to transplant patients, is almost ubiquitous in pancreas transplantation. Despite the frequent use, scientific data on the risks and benefits of induction therapy are scarce, especially as it concerns use specifically for pancreas transplantation. Indeed, none of the currently used induction agents are approved as induction therapy for pancreas transplantation, yet potential benefit is largely extrapolated from trials in kidney transplant recipients. This review summarizes which induction therapy agents are available both now and historically, their mechanisms of action, and provides an overview of the published literature describing the use of these agents in simultaneous pancreas-kidney transplant and solitary pancreas transplant recipients. In summary, there are two multicenter randomized trials, several single-center randomized trials, and many other single-center descriptive reports. Overall, the main benefit of induction therapy is the ability to wean steroids earlier, and the main downside is a higher risk of opportunistic infections. Despite a lack of solid evidence, over 90% of pancreas transplants performed annually in the United States receive some type of induction immunosuppression.

Pharmacokinetics and Pharmacodynamics of Fluconazole for Cryptococcal Meningoencephalitis: Implications for Antifungal Therapy andIn VitroSusceptibility Breakpoints

Fluconazole is frequently the only antifungal agent that is available for induction therapy for cryptococcal meningitis. There is relatively little understanding of the pharmacokinetics and pharmacodynamics (PK-PD) of fluconazole in this setting. PK-PD relationships were estimated with 4 clinical isolates of Cryptococcus neoformans. MICs were determined using Clinical and Laboratory Standards Institute (CLSI) methodology. A nonimmunosuppressed murine model of cryptococcal meningitis was used. Mice received two different doses of fluconazole (125 mg/kg of body weight/day and 250 mg/kg of body weight/day) orally for 9 days; a control group of mice was not given fluconazole. Fluconazole concentrations in plasma and in the cerebrum were determined using high-performance liquid chromatography (HPLC). The cryptococcal density in the brain was estimated using quantitative cultures. A mathematical model was fitted to the PK-PD data. The experimental results were extrapolated to humans (bridging study). The PK were linear. A dose-dependent decline in fungal burden was observed, with near-maximal activity evident with dosages of 250 mg/kg/day. The MIC was important for understanding the exposure-response relationships. The mean AUC/MIC ratio associated with stasis was 389. The results of the bridging study suggested that only 66.7% of patients receiving 1,200 mg/kg would achieve or exceed an AUC/MIC ratio of 389. The potential breakpoints for fluconazole against Cryptococcus neoformans follow: susceptible, ≤ 2 mg/liter; resistant, >2 mg/liter. Fluconazole may be an inferior agent for induction therapy because many patients cannot achieve the pharmacodynamic target. Clinical breakpoints are likely to be significantly lower than epidemiological cutoff values. The MIC may guide the appropriate use of fluconazole. If fluconazole is the only option for induction therapy, then the highest possible dose should be used.

Targeted treatments to improve stem cell outcome: old and new drugs

Thalidomide, lenalidomide and bortezomib have been approved for the treatment of relapsed or refractory multiple myeloma in the recent years. These agents are now being increasingly integrated into therapeutic regimens for newly diagnosed patients. First data are available on the promising activity of these novel agents in induction therapy, as well as maintenance treatment to improve outcome after stem cell transplantation. Whether these early results will lead to prolonged overall survival and thereby ultimately redefine the role of stem cell transplantation in first-line treatment of multiple myeloma will be one of the most important questions to be answered in the coming years. Bone Marrow Transplantation (2007) 40, 1129-1137; doi:10.1038/sj.bmt.1705829; published online 3 September 2007.

Immunophenotypic Analysis of Cellular Infiltrate of Renal Allograft Biopsies in Patients with Acute Rejection after Induction with Alemtuzumab (Campath-1H)

Alemtuzumab is a humanized anti-CD52 mAb that has emerged as a safe and effective lymphocyte-depleting agent for induction therapy in renal transplantation. Recent reports have suggested that acute cellular rejection (ACR) of renal allografts in patients who receive alemtuzumab induction may be mediated by an atypical population of monocytes and not through "classical" T cell-dependent pathways of allorecognition. However, more recently, T cells with memory phenotype have been described in renal biopsies that were taken from alemtuzumab-treated patients who were experiencing ACR. This study investigated the cellular basis of ACR after alemtuzumab induction as compared with ACR that was associated with nondepleting therapy. Twelve biopsies from patients who were treated with a single dose of alemtuzumab at the time of transplantation and subsequently developed ACR were stained for the following cell markers: CD3 (T cells), CD68 (monocytes), CD20 (B cells), and CD45RO and CD45RA (memory and naïve T cells). ACR biopsies from six patients who received no induction therapy were used as controls. In alemtuzumab-treated patients, ACR occurred despite profound lymphopenia. A consistent number of CD3+ T cells was found in all ACR biopsies, and the majority of infiltrating CD3+ T cells displayed a memory phenotype (CD45RO+, CD45RA-). The number of infiltrating CD3+ T cells and B cells (CD20+) was similar in the two groups of patients, whereas a higher number of monocytes (CD68+) were found in the alemtuzumab than in the control group. Despite profound peripheral T cell depletion by alemtuzumab, ACR occurs and is associated with T and B cell and monocyte infiltration of the kidney. Specifically, T cells express on their surface the memory phenotype, suggesting that memory T cells may have eluded the depleting agent.

CD52 antigen as a target for immunotherapy

T he antigenic epitope CD52 is expressed on the surface membranes of peripheral blood lymphocytes, monocytes, and macrophages, as well as the epithelial lining of the male reproductive system. The structural features of the CD52 antigen, specifically its small size, lateral mobility, and closeness to the cell membrane, as well as the sheer abundance of the antigen (CD52 is expressed on 5% of the lymphocyte surface), make it an ideal target for antibody-mediated killing1 (Fig 1). Alemtuzumab (CAMPATH 1H; ILEXTM Oncology, Inc [ILEX], San Antonio, TX), a humanized monoclonal antibody against the CD52 epitope, has a relatively low affinity and requires a concentration of approximately 50 g/mL to achieve maximum binding2 (Fig 2). Nevertheless, it is an extremely potent agent for depletion of lymphocytes in vivo, and a short course of treatment with as little as 40 mg (total) gives rapid and long-lasting depletion of lymphocytes, particularly CD4 cells, in transplant patients.3,4 The potent activity of alemtuzumab appears to be primarily initiated through cell-mediated killing (antibody-dependent cell-mediated cytotoxicity), which is maximal at concentrations as low as 10 ng/mL, whereas optimum activation of complement-mediated lysis requires concentrations of 10 g/mL5 (Fig 3). In patients with chronic lymphocytic leukemia, the indication for which alemtuzumab is approved, both the route of administration and the tumor burden influence the time necessary to achieve peak serum levels. The time to reach peak serum antibody levels is shorter with intravenous administration than with subcutaneous administration, and the blood levels reached after intravenous administration are higher in patients who have a good clinical response. In contrast, serum levels among bone marrow transplant recipients were more consistent among patients, presumably because they did not have a substantial burden of CD52 tumor cells.4 Pharmacokinetic analysis of serum from bone marrow transplant recipients shows that the half-life of alemtuzumab is in the range of 1 to 3 weeks. Therapeutic antibodies have long been used to mediate immunosuppression and prevent acute rejection in transplant recipients. An issue with antibody therapy, however, is the development of antiantibodies that can limit efficacy. Antithymocyte globulin is currently the most commonly used T-cell– depleting agent for induction therapy in kidney transplant recipients. Although antithymocyte globulin has been associated with high graft survival rates ( 98%) and low infection rates ( 10%), the potential for development of xenogeneic antibodies is high ( 78%). Muromonab anti-CD3 (OKT3) is less immunogenic; however, human antimouse antibody development is possible because of its murine origin. Because alemtuzumab is a humanized From the Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom. Address reprint requests to Geoff Hale, PhD, Therapeutic Antibody Centre, Old Road, Headington, Oxford OX3 7JT, United Kingdom. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/S0955-470X(03)00073-9 Figure 1. Structure of the CD52 antigen showing the closeness of the Campath epitope to the lipid anchor. (Modified and reprinted with permission from Hale G. The CD52 antigen and development of the CAMPATH antibodies. Cytotherapy 2001; 3:137. Published by Taylor & Francis.)

Disseminated Histoplasmosis Complicated by Small-Bowel Perforation in a Patient With Acquired Immune Deficiency Syndrome

Disseminated Histoplasmosis Complicated by Small-Bowel Perforation in a Patient With Acquired Immune Deficiency Syndrome