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Precision Medicine

Carfilzomib therapy may enhance longevity in lung transplant recipients

Pulmonary transplantation is surgically performed in selected end-stage lung-disease patients to extend lifespan. However, this process is associated with complications with a median survival time post-transplantation of six years. The preponderance of complications is due to a form of lung allograft rejection called antibody-mediated rejection (AMR), which is a risk factor for chronic lung allograft dysfunction (CLAD). AMR occurs with a high incidence within one year of lung transplantation and diminishes chances of long-term survival. As optimal AMR treatment options are not yet well defined, gaining further insight into AMR biology is crucial for reducing complications and improving patient outcomes and life expectancy after lung transplantations. The International Society of Heart and Lung Transplantation (ISHLT) has improved the clinicopathological diagnosis of AMR by providing defining hallmarks that include circulating donor-specific, anti-human leukocyte antibodies (DSAs), clinically apparent allograft dysfunction, lung injury pathology, capillary C4d deposition and exclusion of other potential causes of allograft dysfunction. Typically, AMR treatment entails a combinatorial regimen comprising plasmapheresis (PLEX), intravenous immunoglobulin (IVIG), and rituximab (RTX). PLEX and IVIG function by reducing circulating immunoglobulins without affecting antibody production. On the other hand, RTX directly targets CD20, a surface antigen on naïve and memory B cells. However, the deficiency of RTX treatment is the lack of effect on DSA levels. The most potent treatment options to date appear to be proteasome inhibitors, which deplete pre-existing DSA levels while also targeting DSA producing plasma cells. The most commonly used proteasome inhibitor in AMR treatment has been bortezomib in kidney transplantation patients. But there is also precedence of positive responses after bortezomib treatment for AMR in lung transplantation. Carfilzomib (CFZ) is a second-generation irreversible proteasome inhibitor that has been previously used for AMR treatment in lung transplantation. To gain further insight on how well CFZ mitigates AMR, Christine Pham, PharmD, and Howard J. Huang, MD, at the Houston Methodist Department of Medicine performed a single-center observational retrospective study of adult lung transplant recipients treated with CFZ for AMR between 2014 and 2019. AMR treatment with PLEX and IVIG was previously protocolized at Houston Methodist in 2018. In this study, 28 patients were administered CFZ (in combination with PLEX and IVIG) at a dosage of 20mg/m2 on days 1, 2, 8, 9, 15 and 16. The full course of six doses was received by 75 percent of patients. Active infections, clinical decompensation, and withdrawal of care prevented the remaining 25 percent from receiving all six doses. Exclusion criteria included patients who received CFZ before the treatment regimen. The primary endpoint of this study was a positive response to CFZ treatment characterized by either loss of DSA C1q fixing ability, clearance of de novo DSA (dnDSA) or a decrease in the relative dnDSA mean fluorescence intensity (MFI) of the immunodominant DSA. Eighty-two percent of patients and 74 percent of AMR episodes demonstrated a positive response suggesting CFZ as a potentially effective treatment modality for AMR. However, since treatment regimens included CFZ in addition to PLEX and IVIG, positive responses may not be solely caused by CFZ. CFZ-based AMR treatment resulted in DSA depletion or conversion to non-complement activating antibodies. DSAs, which can be against class I or class II antigens, are the main risk factors for allograft survival. Based on the timing of the initial appearance, AMR is classified as early or late (beyond one-year post-transplantation); the latter is associated with greater CLAD risk. CFZ can be used to treat both early and late AMR. However, the optimal time of CFZ administration needs to be explored to maximize patient outcomes and minimize expendable treatments. Furthermore, there are two categories of patients: responders (those that respond to AMR treatment) and non-responders. The response is characterized by the capacity to stay alive and CLAD-free for one-year post-AMR treatment. These two groups also differ in the degree of the forced expiratory volume (FEV1) decline at the time of AMR diagnosis, 30 days and 90 days post AMR diagnosis. Interestingly, factors such as AMR identification, time to treatment decision, and level of comfort with CFZ changed during the five-year course of the study period. At the outset, CFZ was used more as a last-line option, whereas toward the end, results encouraged CFZ usage in earlier stages. Since longevity is a key concern in lung transplantation cases, CFZ effectiveness toward survival must be assessed. The study has a few notable limitations. First, it has a small sample size of 28. However, it is difficult to find many patients for lung transplantation studies, and this study is the largest to date. In addition, the statistical tests used such as Fischer’s exact test to draw conclusions were quite appropriate for a small sample size. Second, as with typical retrospective studies, there were missing data points, protocol deviations and selection bias. Moreover, 57 percent of the study population that received CFZ therapy died. The median time from transplant to death was 2.9 years whereas that from CFZ therapy to death was 0.8 years. Lastly, it should be noted that an estimated 33 percent of patients spontaneously cleared DSAs without treatment, indicating that the number of positive responses may be inflated. Larger prospective interventional studies investigating the ideal time from dnDSA development to initiating AMR treatment, and defining the most appropriate time to utilize CFZ are needed.
Christine Pham, PharmD, Clinical Specialist
Howard J. Huang, MD
Our cohort is the largest describing use of CFZ for the treatment of AMR in lung transplant recipients to date. The positive response that a majority of our patients experienced was determined by a decrease in both class I and II DSA MFI, elimination of dnDSAs, and reversal of C1q positivity. Although more than half of our cohort died within 2 years of CFZ administration, responders still experienced a far better -one-year survival benefit compared to non-responders.
Howard J. Huang, MD
Houston Methodist Department of Medicine
Christine Pham, PharmD
Clinical Specialist, Solid Organ Transplant
Treatment of pulmonary AMR is devised based on treatment regimens used for other solid organ transplants. AMR is the predominant cause of long-term graft loss and morbidity in lung transplantation cases. Strategies to alleviate AMR symptoms and prolong long-term graft survival are necessary and, to this end, larger interventional studies are crucial.
Christine Pham, PharmD, Brett J. Pierce, PharmD, Duc T. Nguyen, MD, PhD, Edward A. Graviss, PhD, and Howard J. Huang, MD. Assessment of Carfilzomib Treatment Response in Lung Transplant Recipients with Antibody-mediated Rejection. Transplant Direct. 2021 Apr; 7(4): e680. Published online 2021 Mar 16. doi: 10.1097/TXD.0000000000001131
Abanti Chattopadhyay, PhD, July 2021
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