Rescue alemtuzumab for refractory acute cellular rejection and bronchiolitis obliterans syndrome after lung transplantation

Abstract

Refractory acute cellular rejection (rACR) is associated with death and bronchiolitis obliterans syndrome (BOS) post-lung transplantation. We report the largest cohort of lung transplant recipients (LTRs) treated with rescue alemtuzumab for rACR or BOS. RACR outcomes included burden of ACR 30 days before and 180 days after rescue assessed by a novel composite rejection standardized score (CRSS, range 0-6) and freedom from ≥A2 ACR. BOS outcomes included freedom from BOS progression and FEV1 decline >10%. Univariate parametric and nonparametric statistical approaches were used to assess treatment response. Kaplan-Meier method with log rank conversion was used to assess freedom from events. Fifty-seven alemtuzumab doses (ACR 40 and BOS 17) given to 51 patients were included. Median time to rescue was 722 (IQR 42-1403) days. CRSS declined significantly (3 vs 0.67, P<0.001) after rescue. Freedom from ≥A2 was 62.5% in rACR. Freedom from BOS progression was 52.9% at 180 days in the BOS cohort. Freedom from FEV1 decline >10% was 70% in BOS grade 1 and 14.3% in advanced BOS grades 2-3. Infections developed in 72.5% and 76.5% of rACR and BOS groups. Rescue alemtuzumab appears useful for rACR. Patients with BOS 1 may have transient benefit, and patients with advanced BOS seem not to respond to alemtuzumab.

Rabbit antithymocyte globulin for the treatment of chronic lung allograft dysfunction

“…This study included 108 lung transplant recipients and represents the largest single cohort of patients treated with rATG for CLAD . While previous literature has assessed the impact of rATG therapy on CLAD, rigorous evaluation of confounders to treatment response and robust descriptions of adverse effects have not been previously reported in a single cohort . In this study, treatment with rATG was associated with a reversal in the decline in lung function in 40% of patients.…”

“…When used for induction therapy, variations in rATG dose have led to conflicting reports of changes in safety and efficacy . Additionally, current published literature evaluating the efficacy of cytolytic therapy for CLAD have used preparations other than rATG, were performed prior to the widespread use of tacrolimus‐based immunosuppression or report it being used as a salvage treatment of CLAD . The impact of rATG as a treatment for CLAD in the current era of immunosuppression has not been detailed.…”

Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies

“…216 Likewise, alemtuzumab was associated with stabilization in patients with stage 1 CLAD, but infections developed in 76.5% of subjects. 217 Importantly, "stabilization" may reflect the natural history of CLAD, 118 making it difficult to assess efficacy without inclusion of a control group. It is worth noting that none of these studies accounted for CLAD phenotypes.…”

Acute Cellular Rejection: Is It Still Relevant?

“…This is usually defined as at least two consecutive episodes of grade !A2 rejection not responding to at least two courses of first-line treatment with IV methylprednisolone. 155 The treatment of persistent or refractory ACR is not standardized and no randomized controlled trials have been conducted. Some specialists would repeat a course of IV corticosteroids, as for the initial episode, they would switch from cyclosporine to tacrolimus [156][157][158] and/or from azathioprine to MMF, 64 if not previously done, and they would consider proceeding to a second-line treatment.…”

“…Some specialists would repeat a course of IV corticosteroids, as for the initial episode, they would switch from cyclosporine to tacrolimus [156][157][158] and/or from azathioprine to MMF, 64 if not previously done, and they would consider proceeding to a second-line treatment. Second-line treatments that have been used include antilymphocyte antibodies, 155,[159][160][161] alemtuzumab, 155,160 aerosolized cyclosporine, 162 methotrexate, 163 total lymphoid irradiation, 164 and extracorporeal photopheresis. 165,166 Evidence is limited for these treatments in refractory ACR and comparative data are lacking.…”