Alemtuzumab Induction Therapy Research Articles

Differential expression of circulating miRNAs after alemtuzumab induction therapy in lung transplantation

Alemtuzumab is a monoclonal antibody targeting CD52, used as induction therapy after lung transplantation (LTx). Its engagement produces a long-lasting immunodepletion; however, the mechanisms driving cell reconstitution are poorly defined. We hypothesized that miRNAs are involved in this process. The expression of a set of miRNAs, cytokines and co-signaling molecules was measured with RT-qPCR and flow cytometry in prospectively collected serum samples of LTx recipients, after alemtuzumab or no induction therapy. Twenty-six LTx recipients who received alemtuzumab and twenty-seven matched LTx recipients without induction therapy were included in the analysis. One year after transplantation four miRNAs were differentially regulated: miR-23b (p = 0.05) miR-146 (p = 0.04), miR-155 (p < 0.001) and miR-486 (p < 0.001). Expression of 3 miRNAs changed within the alemtuzumab group: miR-146 (p < 0.001), miR-155 (p < 0.001) and miR-31 (p < 0.001). Levels of IL-13, IL-4, IFN-γ, BAFF, IL-5, IL-9, IL-17F, IL-17A and IL-22 were different one year after transplantation compared to baseline. In no-induction group, concentration of sCD27, sB7.2 and sPD-L1 increased overtime. Expression of miR-23b, miR-146, miR-486, miR-155 and miR-31 was different in LTx recipients who received alemtuzumab compared to recipients without induction therapy. The observed cytokine pattern suggested proliferation of specific B cell subsets in alemtuzumab group and co-stimulation of T-cells in no-induction group.

Short-Time Effect of Alemtuzumab Induction Therapy on B- and T-cell Subsets After Lung Transplantation

<h3>Purpose</h3> Alemtuzumab is a monoclonal antibody targeting CD52, one of the most predominant antigens on the surface of lymphocytes. It induces cell lysis and leads to a profound immune cell depletion. However, little is known how T- and B-cell repopulate and if there is predominance towards certain subtypes. <h3>Methods</h3> B- and T cell subsets were analyzed from whole blood samples of 25 patients, prospectively collected at time of listing (=baseline) and 6 months post-transplant. Cell subsets were measured by FACS. Patients received alemtuzumab induction followed by low-dose tacrolimus and steroids. <h3>Results</h3> Median age of the cohort was 59 years (51-64) and 36% of patients were female. Underlying diagnoses were COPD (36%), fibrosis (20%), CF (12%), PPH (4%), EAA (12%) and others (16%). B- and T cell counts significantly decreased compared to baseline (p=0.009, p<0.001). Within B cell population, relative frequency of IgM⁺CD27⁻CD38^high, IgM⁺CD27⁺CD38^high and regulatory B cells increased 6 months after Tx (p=0.017, p=0.016, p=0.028, respectively). Within T cell population, CD4⁺ T cells decreased 6 months after Tx (p<0.001), while relative frequency of CD8⁺ T cells was significantly higher (p<0.001). A detailed analysis revealed a shift towards CD4⁺CD57⁺(p=0,002), PD1⁺CD4⁺(p<0.001), CD45RA+CD197-CD4⁺ (p=0.0013), CD45RA⁻CD197⁻CD4⁺ (p<0.001), CD27⁻CD28⁺ (p<0.001), CD27⁺CD28⁺ (p<0.001), PD1⁺CD8⁺ (p<0.001), CD45RA⁺CD197⁻CD8⁺ (p=0.039) and regulatory FoxP3⁺-T cells (p=0.005) at 6 months after Tx. <h3>Conclusion</h3> After alemtuzumab induction therapy, the composition of B and T cell subsets is altered compared to baseline. Expansion of subsets such as PD1 T cells and regulatory B- and T cells suggests an immunomodulatory effect of alemtuzumab on cell repopulation.

Outcomes with alemtuzumab induction therapy in lung transplantation: a comprehensive large-scale single-center analysis.

Alemtuzumab is a monoclonal antibody targeting CD52, increasingly used as induction therapy after transplantation. The aim of this study was to analyze the outcomes of alemtuzumab induction therapy followed by a low-dose maintenance immunosuppression in a large single-center cohort of lung transplant recipients. All patients, who received alemtuzumab induction followed by a low-dose maintenance immunosuppression were included in the analysis. Short- and long-term outcomes were analyzed. 721 lung transplant recipients, transplanted between January 2008 and June 2019, were included in this retrospective study. Freedom from higher-grade ACR at 1, 5, and 10years was 98%, 96%, and 96%, respectively. Thirty-nine patients (5%) developed clinical AMR. Twenty-one percent of patients developed high-grade CKD. A total of 1488 infections were recorded. Sixteen percent were diagnosed within the first 3months. Sixty-two patients (9%) developed a malignancy during follow-up. Freedom from CLAD at 1, 5, and 10years was 94%, 72%, and 53%, respectively. Overall survival rates at 1, 5, and 10years were 85%, 71%, and 61%, respectively. Alemtuzumab induction combined with a low-dose tacrolimus protocol is safe and associated with low rates of acute and chronic rejection, as well as an excellent long-term survival.

PD45-01 A SINGLE INSTITUTION EXPERIENCE OF THE DIAGNOSIS, TREATMENT, AND OUTCOMES OF COVID-19 POSITIVE RENAL TRANSPLANT PATIENTS AFTER ALEMTUZUMAB INDUCTION

You have accessJournal of UrologyRenal Transplantation & Vascular Surgery II (PD45)1 Sep 2021PD45-01 A SINGLE INSTITUTION EXPERIENCE OF THE DIAGNOSIS, TREATMENT, AND OUTCOMES OF COVID-19 POSITIVE RENAL TRANSPLANT PATIENTS AFTER ALEMTUZUMAB INDUCTION Chris Du, Zhenyue Huang, Kevin Liang, Heng Ruan, and Frank Darras Chris DuChris Du More articles by this author , Zhenyue HuangZhenyue Huang More articles by this author , Kevin LiangKevin Liang More articles by this author , Heng RuanHeng Ruan More articles by this author , and Frank DarrasFrank Darras More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002059.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Immunocompromised kidney transplant (KTX) recipients with the coronavirus of severe acute respiratory syndrome coronavirus 2 (COVID-19) may be at increased risk of morbidity and mortality. We sought to evaluate a series of COVID-19 positive KTX recipients hospitalized at our institution during both the first and second wave of the COVID-19 pandemic. METHODS: We retrospectively examined our KTX recipients hospitalized from March 2020 to June 2020 for the first wave, and November 2020 to February 2021 for the second wave of COVID-19. Data for demographics, clinical course, laboratory tests, outcomes, and management were collected. Descriptive statistics were performed for all data. RESULTS: We identified 25 KTX from the first and 17 from the second COVID-19 wave. All study subjects had their KTX performed at our institution, tested positive, and were hospitalized. Since August 2003, all KTX recipients received a single dose of alemtuzumab induction therapy. During the first wave, the average length of stay (LOS) was 9.4 days. Four patients (16%) required ICU level of care, 3 patients were intubated, and there were no mortalities. 6 (24%) and 7 (28%) patients had their mycophenolate (MMF) and tacrolimus (TAC) immunosuppression held. 19 (76%) received hydroxychloroquine, 3 (12%) received steroids, 1 (4%) received Remdesivir. During the second wave, average LOS was 7.6 days. One patient (6%) required ICU level of care with intubation, and 2 (12%) patients suffered mortality. No patients received hydroxychloroquine, 9 (53%) received steroids, and 3 (18%) received Remdesivir. MMF was not held and TAC was held in 1 (5.9%) patient. Table 1 illustrates the demographic and clinical data of COVID19 positive KTX patients hospitalized during the pandemic. There were no events of acute rejection in KTX patients during either wave. CONCLUSIONS: At our institution, the clinical manifestations and outcomes of COVID-19 in KTX recipients are variable and similar to non-immunocompromised patients. Our approach to diagnosis and management is similar to that for the general population, with adjustments made based on the individual disease severity. Nonetheless, we have a low threshold for evaluating, hospitalizing, and treating COVID KTX recipients. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e742-e742 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Chris Du More articles by this author Zhenyue Huang More articles by this author Kevin Liang More articles by this author Heng Ruan More articles by this author Frank Darras More articles by this author Expand All Advertisement PDF downloadLoading ...

Combined low-dose everolimus and low-dose tacrolimus after Alemtuzumab induction therapy: a randomized prospective trial in lung transplantation

BackgroundLong-term outcomes of lung transplantation are severely affected by comorbidities and development of chronic rejection. Among the comorbidities, kidney insufficiency is one of the most frequent and it is mainly caused by the cumulative effect of calcineurin inhibitors (CNIs). Currently, the most used immunosuppression protocols worldwide include induction therapy and a triple-drug maintenance immunosuppression, with one calcineurin inhibitor, one anti-proliferative drug, and steroids. Our center has pioneered the use of alemtuzumab as induction therapy, showing promising results in terms of short- and long-term outcomes. The use of alemtuzumab followed by a low-dose double drug maintenance immunosuppression, in fact, led to better kidney function along with excellent results in terms of acute rejection, chronic lung allograft dysfunction, and survival (Benazzo et al., PLoS One 14(1):e0210443, 2019). The hypothesis driving the proposed clinical trial is that de novo introduction of low-dose everolimus early after transplantation could further improve kidney function via a further reduction of tacrolimus. Based on evidences from kidney transplantation, moreover, alemtuzumab induction therapy followed by a low-dose everolimus and low-dose tacrolimus may have a permissive action on regulatory immune cells thus stimulating allograft acceptance.MethodsA randomized prospective clinical trial has been set up to answer the research hypothesis. One hundred ten patients will be randomized in two groups. Treatment group will receive the new maintenance immunosuppression protocol based on low-dose tacrolimus and low-dose everolimus and the control group will receive our standard immunosuppression protocol. Both groups will receive alemtuzumab induction therapy. The primary endpoint of the study is to analyze the effect of the new low-dose immunosuppression protocol on kidney function in terms of eGFR change. The study will have a duration of 24 months from the time of randomization. Immunomodulatory status of the patients will be assessed with flow cytometry and gene expression analysis.DiscussionFor the first time in the field of lung transplantation, this trial proposes the combined use of significantly reduced tacrolimus and everolimus after alemtuzumab induction. The new protocol may have a twofold advantage: (1) further reduction of nephrotoxic tacrolimus and (2) permissive influence on regulatory cells development with further reduction of rejection episodes.Trial registrationEUDRACT Nr 2018-001680-24. Registered on 15 May 2018

Idiopathic pulmonary fibrosis lung transplant recipients are at increased risk for EBV-associated posttransplant lymphoproliferative disorder and worse survival.

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (EBV-PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single-center retrospective study to evaluate the risks for PTLD in LTRs over a 7-year period. Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan-Meier analysis showed a decreased freedom from PTLD in idiopathic pulmonary fibrosis (IPF)-LTRs (P<.02). Using a multivariable Cox proportional hazards model, we found IPF (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.33-8.21, P=.01) and alemtuzumab induction therapy (HR 2.73, 95% CI 1.10-6.74, P=.03) as risk factors for PTLD, compared to EBV mismatch (HR: 34.43, 95% CI 15.57-76.09, P<.0001). Early PTLD (first year) was associated with alemtuzumab use (P=.04), whereas IPF was a predictor for late PTLD (after first year) (P=.002), after controlling for age and sex. Kaplan-Meier analysis revealed a shorter time to death from PTLD in IPF LTRs compared to other patients (P=.04). The use of alemtuzumab in EBV mismatch was found to particularly increase PTLD risk. Together, our findings identify IPF LTRs as a susceptible population for PTLD. Further studies are required to understand the mechanisms driving PTLD in IPF LTRs and develop strategies to mitigate risk.

BK Virus in Renal Transplant Patients Using Alemtuzumab for Induction Immunosuppression.

Alemtuzumab, a monoclonal antibody utilized as induction immunosuppression in renal transplant, targets CD52-positive lymphocytes, causing profound B- and T-cell depletion. The administration of such novel, potent immunosuppressive agents, with the goal of reducing rejection, poses an increased threat of BK virus infection in renal transplant recipients. This internal review boardapproved retrospective analysis included 676 renal transplant patients during a 9-year period. All patients were induced with alemtuzumab, and most received a steroid-minimizing regimen. BK viremia was defined as a clinically significant BK virus infection confirmed by polymerase chain reaction. Of total study recipients, 58 (8.6%) were positive for BK viremia. African American race/ethnicity, age > 65 years, and rejection showed significant associations with BK viremia. Kaplan-Meier analyses demonstrated significant differences in 3-year (P = .032), 5-year (P = .025), and overall rejection (P = .031) between patients with and without BK viremia. Differences were found in overall (P = .002) and 5-year (P = .001) death-censored graft survival for patients positive for BK viremia plus another non-BK infection versus patients without BK viremia or other infection. BK viremia-positive patients with other infections had significantly lower overall (P = .010) and 5-year (P = .010) death-censored graft survival than patients with BK viremia but without other infections. When we excluded other infections, we observed no differences between BK viremia-positive and BK viremia-negative patients. BK viremia incidence following alemtuzumab induction therapy appears to be comparable to that shown in other reports and slightly lower than the incidence in patients receiving non-alemtuzumab immunosuppression. BK virus may increase risk of rejection, and BK virus plus another infection may lead to decreased graft survival. African American patients, patients > 65 years old, and patients with rejection history may be at increased risk of BK virus. Closer screening should be considered in these populations.

Donor-Specific Antibodies and Antibody-Mediated Rejection after Alemtuzumab Induction Therapy: A Retrospective Analysis of a High-Volume Lung Transplant Center

Purpose Within the last years increasing attention has been given to antibody-mediated rejection (AMR) due to its poor long-term outcomes. The impact of alemtuzumab on donor-specific antibodies (DSAs) and AMR in lung transplantation is currently unclear and most evidence comes from kidney transplantation. This study aimed to analyze the impact of alemtuzumab induction on the incidence of DSAs and AMR. Methods All patients transplanted between 2007 and 2017, who received alemtuzumab as induction therapy, were included in this retrospective single-center analysis. The following parameters were evaluated: donor-specific antibodies, C4d deposition, lung histology and occurrence of antibody-mediated rejection. Results Within the study period 525 patients received alemtuzumab as induction therapy. Pre-transplant DSAs were present in 64 (12.2%) recipients (53 anti-HLA class I and 40 anti-HLA class II). De novo (dn) DSAs developed in 93 (17.7%) recipients after transplantation (78 anti-HLA class I and 113 anti-HLA class II). Median time to development of dnDSA was 104 days (42-165) and incidence rates at 1 and 5-years after transplantation were 12.1% and 21.4%, respectively. In 20 (3.8%) recipients clinical AMR was diagnosed. Among them, 7 (35%) patients had a definite diagnosis, 9 (45%) a probable one and 4 (20%) a possible one as defined by the latest ISHLT AMR grading system. Deposition of C4d was only positive in 4 (20%) clinical AMR patients. Capillaritis was observed in 4 (20%) cases and neutrophilic septal margination in 3 cases (15%). Anti-HLA class I and class II were positive in 11 (55%) and 13 (65%) recipients, respectively. Long-term survival of recipients, who developed AMR, was significantly worse than other recipients, with a 5-years rate of 45% vs 75% (p Conclusion Alemtuzumab induction therapy is associated with a low incidence of dnDSAs and AMR. Long-term outcome of these patients remains poor.

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 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.

Diagnostic Value of Peripheral and Bronchoalveolar Leukocyte Profile in Lung Transplant Recipients After Alemtuzumab Induction Therapy. A Single Center Experience

Early diagnosis of lower respiratory tract infection (LRTI) and acute cellular rejection (ACR) is crucial for adequate treatment in lung transplant recipients. A recently described algorithm (Speck 2016) for LRTI and ACR prediction which includes differences in peripheral blood (PBIC) and bronchoalveolar lavage immune cells (BALIC) was tested in LuTX patients treated with alemtuzumab induction therapy.

Campath, calcineurin inhibitor reduction, and chronic allograft nephropathy (the 3C Study) - results of a randomized controlled clinical trial.

Calcineurin inhibitors (CNIs, eg, tacrolimus) reduce short‐term kidney transplant failure, but chronic nephrotoxicity may contribute to late transplant loss. Elective conversion to inhibitors of the mammalian target of rapamycin (mTOR, eg, sirolimus) pathway might avoid long‐term CNI renal damage and improve outcomes. The 3C Study was a pragmatic randomized controlled trial of sequential randomizations between alemtuzumab and basiliximab induction therapy (at the time of surgery) and between tacrolimus and sirolimus maintenance therapy at 6 months posttransplantation. The primary outcome of this analysis was estimated glomerular filtration rate (eGFR) at 18 months after maintenance therapy randomization; 197 patients were assigned sirolimus‐based and 197 to tacrolimus‐based therapy. Allocation to sirolimus had no significant effect on eGFR at 18 months: baseline‐adjusted mean (SEM) eGFR was 53.7 (0.9) mL/min/1.73 m2 in the sirolimus group versus 54.6 (0.9) mL/min/1.73 m2 in the tacrolimus group (P = .50). Biopsy‐proven acute rejection (29 [14.7%]) vs 6 [3.0%]; P < .001) and serious infections (defined as opportunistic infections or those requiring hospitalization; 95 [48.2%] vs 70 [35.5%]; P = .008) were more common among participants allocated sirolimus. Compared with tacrolimus‐based therapy, sirolimus‐based maintenance therapy did not improve transplant function at 18 months after conversion and was associated with significant hazards of rejection and infection. ClinicalTrials.gov identifier NCT01120028 and ISRCTN88894088.

Alemtuzumab as Antirejection Therapy: T Cell Repopulation and Cytokine Responsiveness.

Alemtuzumab induction therapy in kidney transplant patients results in T cell depletion followed by slow immune reconstitution of memory T cells with reduced immune functions. The kinetics and functional characteristics of T cell reconstitution when alemtuzumab is given during immune activation, ie, as antirejection therapy, are unknown. Patients (n = 12) with glucocorticoid-resistant or severe vascular kidney transplant rejection were treated with alemtuzumab. Flow cytometric analysis was performed on whole blood to measure cell division by the marker Ki-67, and cytokine responsiveness by IL-2-mediated and IL-7-mediated phosphorylation of signal transducer and activator of transcription 5 of T cells before and during the first year after rejection therapy. At 1 year after alemtuzumab antirejection therapy, the total T cell population recovered to baseline level. Repopulation of CD4+ and CD8+ T cells was associated with increased percentages of Ki-67+ proliferating T cells (P < 0.05). In addition, both populations showed a phenotypic shift toward relatively more memory T cells (P < 0.01). At the functional level, IL-7 reactivity of CD4+ memory T cells was diminished, reflected by a decreased capacity to phosphorylate signal transducer and activator of transcription 5 during the first 6 months after alemtuzumab treatment (P < 0.05), whereas reactivity to IL-2 was preserved. CD8+ T cells were affected in terms of both IL-2 and IL-7 responses (both P < 0.05). After reconstitution, relatively more regulatory T cells were present, and a relatively high proportion of Ki-67+ T cells was observed. Preliminary data from this small series suggest that alemtuzumab antirejection therapy induces homeostatic proliferation of memory and regulatory T cells with diminished responsiveness to the homeostatic cytokine IL-7. IL-2 responsiveness was affected in repopulated CD8+ T cells.

The Impact of Alemtuzumab and Basiliximab Induction on Patient Survival and Time to Bronchiolitis Obliterans Syndrome in Double Lung Transplantation Recipients.

We examined the effect of alemtuzumab and basiliximab induction therapy on patient survival and freedom from bronchiolitis obliterans syndrome (BOS) in double lung transplantation. The United Network for Organ Sharing database was reviewed for adult double lung transplant recipients from 2006 to 2013. The primary outcome was risk-adjusted all-cause mortality. Secondary outcomes included time to BOS. There were 6117 patients were identified, of whom 738 received alemtuzumab, 2804 received basiliximab, and 2575 received no induction. Alemtuzumab recipients had higher lung allocation scores compared with basiliximab and no-induction recipients (41.4 versus 37.9 versus 40.7, p < 0.001) and were more likely to require mechanical ventilation before to transplantation (21.7% versus 6.5% versus 6.2%, p < 0.001). Median survival was longer for alemtuzumab and basiliximab recipients compared with patients who received no induction (2321 versus 2352 versus 1967 days, p = 0.001). Alemtuzumab (hazard ratio 0.80, 95% confidence interval 0.67-0.95, p = 0.009) and basiliximab induction (0.88, 0.80-0.98, p = 0.015) were independently associated with survival on multivariate analysis. At 5 years, alemtuzumab recipients had a lower incidence of BOS (22.7% versus 55.4 versus 55.9%), and its use was independently associated with lower risk of developing BOS on multivariate analysis. While both induction therapies were associated with improved survival, patients who received alemtuzumab had greater median freedom from BOS.

Opportunistic infections complicating solid organ transplantation with alemtuzumab induction.

Opportunistic infections remain a common complication of solid organ transplantation. Despite significant changes in immunosuppression and infectious diseases prophylaxis, data are limited on the contemporary epidemiology and outcomes of opportunistic infections. Alemtuzumab, a potent lymphocyte-depleting antibody, has been used with increased frequency in solid organ transplant recipients in the last decade. A literature review was performed to summarize the current understanding of the epidemiology, risk factors, and outcomes of opportunistic infections complicating solid organ transplantation with and without alemtuzumab induction therapy. Areas where data are limited regarding opportunistic infections in solid organ transplantation with alemtuzumab induction are indicated.

Lymphocytes as an Indicator for Initial Kidney Function: A Single Center Analysis of Outcome after Alemtuzumab or Basiliximab Induction.

Alemtuzumab, an anti-CD52 T-cell and B-cell depleting monoclonal antibody, is established for induction therapy in renal transplantation (KTx). We herein provide a comparative analysis between alemtuzumab and basiliximab induction therapy and correlate lymphocyte depletion and recovery with the clinical course after KTx. This is a single center retrospective analysis of 225 patients/consecutive kidney transplantations treated with alemtuzumab for lymphocyte depletion and 205 recipients treated with basiliximab. Mean lymphocyte counts were 22.8 ± 9.41% before Tx and 2.61 ± 3.11% between week 1 and week 3 in the alemtuzumab group and 23.77 ± 10.42% before Tx and 13.92 ± 8.20% in the basiliximab group. Delayed graft function (DGF), cytomegalovirus (CMV) status, and recipient age showed a significant correlation with lymphocyte counts in the alemtuzumab group only. The outcome was read in reference to the velocity of lymphocyte recovery and in comparison to the control group. Lymphocyte counts early after transplantation, following alemtuzumab treatment, could be identified as a predictive factor for kidney function early after transplantation. A detailed analysis of phenotype and function of lymphocytes after alemtuzumab induction together with a correlation with the clinical course is warranted.

Loss of donor chimerism in remission after allogeneic stem cell transplantation of T-prolymphocytic leukemia patients following alemtuzumab induction therapy.

T-cell prolymphocytic leukemia is a rare aggressive malignancy with low susceptibility to conventional chemotherapy. The anti-CD52 antibody alemtuzumab induces remission, which requires consolidation by stem cell transplantation in eligible patients. In this case series, three chemotherapy-naïve T-PLL patients received alemtuzumab for remission induction and allogeneic SCT after reduced-intensity conditioning. While primary hematopoietic engraftment occurred in a timely fashion, donor chimerism declined in all patients between day 28 and day 290 post-transplantation. Loss of chimerism was not associated with disease recurrence, and full chimerisms were regained on donor leukocyte infusion. In six B-CLL patients, treated with identical regimens of alemtuzumab and SCT, a similar pattern of failing chimerism was not observed. We surmise that an accumulation of uncleared alemtuzumab in the plasma may impede the incoming graft after allogeneic SCT, which would indicate the need for close monitoring and management of engraftment to secure complete donor chimerism and putative cure in T-PLL patients.

Alemtuzumab in Lung Transplantation: An Open-Label, Randomized, Prospective Single Center Study

Induction therapy with alemtuzumab followed by lower maintenance immunosuppression (IS) has been associated with reduced morbidity and mortality in abdominal and heart transplantation (TX). In the current study, alemtuzumab, in combination with reduced levels of maintenance IS, was compared to thymoglobulin in combination with standard IS. Sixty consecutive patients who underwent lung transplantation (LUTX) at a single center were prospectively randomized in two groups: group A received alemtuzumab in conjunction with reduced doses of tacrolimus, steroids and mycophenolate mofetil. Group B received thymoglobulin in association with standard dose IS. Patient and graft survival, freedom from acute cellular rejection (ACR), lymphocytic bronchiolitis, bronchiolitis obliterans syndrome, kidney function, infectious complications and posttransplant lymphoproliferative disorder were analyzed. Alemtuzumab induction therapy resulted in complete the absence of ACR episodes ≥ A2 within the first year post-TX. The difference to thymoglobulin was significant (alemtuzumab 0 vs. ATG 0.33; p = 0.019). All other factors studied did not show any differences between the two groups. Alemtuzumab induction therapy after LUTX in combination with reduced maintenance IS significantly reduces higher-grade rejection rates. This novel therapeutic agent had no impact on survival, infections rates, kidney function and incidence of malignancies.

Alemtuzumab induction therapy in kidney transplantation

Alemtuzumab induction therapy in kidney transplantation

Pancreas transplantation: The Wake Forest experience in the new millennium.

To investigate the Wake Forest experience with pancreas transplantation in the new millennium with attention to surgical techniques and immunosuppression. A monocentric, retrospective review of outcomes in simultaneous kidney-pancreas transplant (SKPT) and solitary pancreas transplant (SPT) recipients was performed. All patients underwent pancreas transplantation as intent-to-treat with portal venous and enteric exocrine drainage and received depleting antibody induction; maintenance therapy included tapered steroids or early steroid elimination with mycophenolate and tacrolimus. Recipient selection was based on clinical judgment whether or not the patient exhibited measureable levels of C-peptide. Over an 11.25 year period, 202 pancreas transplants were performed in 192 patients including 162 SKPTs and 40 SPTs. A total of 186 (92%) were primary and 16 (8%) pancreas retransplants; portal-enteric drainage was performed in 179 cases. A total of 39 pancreas transplants were performed in African American (AA) patients; of the 162 SKPTs, 30 were performed in patients with pretransplant C-peptide levels > 2.0 ng/mL. In addition, from 2005-2008, 46 SKPT patients were enrolled in a prospective study of single dose alemtuzumab vs 3-5 doses of rabbit anti-thymocyte globulin induction therapy. With a mean follow-up of 5.7 in SKPT vs 7.7 years in SPT recipients, overall patient (86% SKPT vs 87% SPT) and kidney (74% SKPT vs 80% SPT) graft survival rates as well as insulin-free rates (both 65%) were similar (P = NS). Although mortality rates were nearly identical in SKPT compared to SPT recipients, patterns and timing of death were different as no early mortality occurred in SPT recipients whereas the rates of mortality following SKPT were 4%, 9% and 12%, at 1-, 3- and 5-years follow-up, respectively (P < 0.05). The primary cause of graft loss in SKPT recipients was death with a functioning graft whereas the major cause of graft loss following SPT was acute and chronic rejection. The overall incidence of acute rejection was 29% in SKPT and 27.5% in SPT recipients (P = NS). Lower rates of acute rejection and major infection were evidenced in SKPT patients receiving alemtuzumab induction therapy. Comparable kidney and pancreas graft survival rates were observed in AA and non-AA recipients despite a higher prevalence of a "type 2 diabetes" phenotype in AA. Results comparable to those achieved in insulinopenic diabetics were found in the transplantation of type 2 diabetics with detectable C-peptide levels. In the new millennium, acceptable medium-term outcomes can be achieved in SKPT and SPTs as nearly 2/3rds of patients are insulin independent following pancreas transplantation.