Jill Adamski

National Institutes of Health State of the Science Symposium in Therapeutic Apheresis: Scientific Opportunities in Extracorporeal Photopheresis

The clinical use of extracorporeal photopheresis (ECP) for accepted indications such as graft-versus-host disease, transplant rejection, and cutaneous T-cell lymphoma continues to increase. Expanded applications for ECP, such as the treatment of select autoimmune diseases, are being explored. Extracorporeal photopheresiss capacity to both immunotolerize in the autoreactive setting, while immunizing against a lymphoma is unusual and suggestive of a unique mechanism. It is likely that ECPs induction of dendritic cells is key to its efficacy in both of these settings, but exactly how ECP impacts other immune components and their interactions is not fully understood. Further basic science research is necessary to elucidate how these dissimilar cellular activities are functionally integrated. On the clinical side, collaborative multicenter trials designed to recognize the principal variables controlling therapeutic responses and improve prognostic indicators may enable tailoring devices, treatment schedules, and doses to the needs of the individual patients or diseases. This review describes our current understanding of how ECP influences the immune system, reviews the existing clinical applications of ECP, and explores areas for future basic science and clinical research as presented at the National Institutes of Health State of the Science Symposium in Therapeutic Apheresis in November 2012.

Multiorgan failure and bone marrow necrosis in three adults with sickle cell-β+-thalassemia†‡

Between April and November 2010, three patients with sickle-cell-b-thalassemia (HgbSb) were transferred to our tertiary care hospital for management of multiorgan failure following their first ever episodes of pain crisis, which resulted in bone marrow necrosis (BMN). The data collection methods and publication of their histories were reviewed and approved by the University of Alabama Institutional Review Board with a waiver of need for informed consent. Patient 1 was a previously healthy, 25-year-old black male with a 2-week history of fever, back, and abdominal pain. He was brought to his local hospital after being found unresponsive and in respiratory distress. The patient was intubated and noted to have several nonblanching petechiae on his shoulders and chest. Laboratory evaluation identified microcytic anemia and thrombocytopenia. He was transferred to our institution with a presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP). On admission, his platelet count was 44 3 10/ll, and the peripheral blood smear was remarkable for numerous immature leukocytes and nucleated red blood cells with very few schistocytes (Table I). These findings were not consistent with TTP, which was later confirmed by a normal ADAMTS13 activity. Patient 2 was a 53-year-old healthy black male who presented to a local emergency room (ER) with severe lower back pain. He was diagnosed with ‘‘muscle strain’’ and discharged with a prescription for a muscle relaxant and a narcotic. Several days later, he was brought back to the ER after being found on the ground, conscious but confused. His mental status rapidly declined, he developed respiratory insufficiency, and was intubated. Laboratory work-up showed anemia and thrombocytopenia. Like patient 1, he was transferred to our institution for the treatment of TTP and underwent one emergent plasma exchange procedure. Upon further review of his laboratory data and a peripheral blood smear (Table I), it was determined that he did not have TTP, and plasma exchange was discontinued. Both patients presented with elevated lactate dehydrogenase (LDH), ferritin, total, and indirect bilirubin (Table I). White blood cell counts were normal on admission, and all tests for bacterial and viral infections were nonrevealing. During their prolonged ICU stays (19 and 30 days, respectively) they had persistent altered mental status (AMS) and respiratory failure and developed renal and liver insufficiency. Magnetic resonance imaging (MRI) of both patients showed numerous microhemorrhages and infarcts. The electroencephalography (EEG) tracings from the patients were consistent with encephalopathy. The patients were also noted to have persistent anemia and thrombocytopenia for which bone marrow biopsies were performed. Histologic sections from both patients demonstrated complete necrosis of hematopoeitic elements (Fig. 1). Further clinical work-up failed to identify malignant, infectious, or drug-induced causes for BMN. However, hemoglobin electrophoresis revealed that both patients had hereto unknown HgbSb disease (Table II). Although patient 1 received two units of packed RBCs four days before hemoglobin electrophoresis, the findings of increased Hgb A2 (4.4%) and decreased mean corpuscular volume (74 fl) were consistent with b-thalassemia (Table I). Abdominal imaging (ultrasound and computed tomography in patients 1 and 2, respectively) demonstrated moderate splenomegaly, both measuring 15 cm, with evidence of acute splenic infarcts. Of note, neither patient had had any clinical manifestation of hemoglobinopathy before the events described in this report. Patient 1 underwent red cell exchange 5 days after admission, but showed no clinical improvement. After 19 days, he remained ventilator-dependent. He was transferred to a long-term care facility with permanent devastating neurologic deficits. Patient 2 did not receive red cell exchange and was subsequently transferred to an inpatient rehabilitation facility with persistent cognitive impairment and paralysis after 30 days in the ICU. One month after patient 2 presented, a 42-year-old black male with a 2-week history of severe back pain, fatigue, and weakness was found unresponsive at home and brought to an ER (patient 3). He had been in good health before this event, but had a history of HgbSb diagnosed during a routine military physical exam. Upon arrival to the ER, the patient was noted to be hypoxic and was emergently intubated due to respiratory failure. Laboratory tests showed anemia and

Single-center experience with extracorporeal photopheresis in pediatric heart transplantation

BACKGROUND The pediatric heart transplant literature contains little information regarding extracorporeal photopheresis (ECP), despite International Society for Heart and Lung Transplantation guidelines recommending it for recurrent/recalcitrant rejection. We report our experience with ECP in pediatric heart transplantation. METHODS Data were obtained on heart transplant patients who were aged ≤ 18 years at the time of transplantation and received ECP between 1990 and 2012 at our institution. RESULTS Twenty heart transplant patients underwent 22 courses of ECP. Median ages were 12.7 years (range, 0.3-18.5 years) at transplant and 15.3 years (range, 7.3-31 years) at initial ECP. Median time from transplant to ECP was 1.4 years (range, 0.1-12.6 years). The median ECP duration was 5.8 months (range, 1.9-16.1 months). Indications for ECP included rejection with hemodynamic compromise (HC) in 4 patients, rejection without HC in 12, and prophylaxis in 2. Eleven patients died at a median time of 3.1 years after the start of ECP. Survival after ECP was 84% at 1 year and 53% at 3 years. Eleven patients were considered non-compliant and had a trend toward lower survival of 75% at 1 year and 18% at 3 years (p = 0.06 compared with compliant patients). One patient developed Pneumocystis carinii pneumonia during ECP and post-transplant lymphoproliferative disease 21 months after finishing ECP. No other adverse effects or infectious complications associated with ECP were noted. CONCLUSIONS This case series represents the largest reported experience with ECP in pediatric heart transplantation. ECP can be safely applied in this patient group. Despite EPC, non-compliant patients showed a trend toward lower survival than compliant patients.

Relapses of Thrombotic Thrombocytopenic Purpura after Treatment with Rituximab

Rituximab has been added to therapeutic plasma exchange (TPE) in the last 10 years for refractory thrombotic thrombocytopenic purpura (TTP). We performed a retrospective single institution study to determine if patients with TTP treated with TPE and rituximab experienced relapses. We reviewed the electronic and apheresis records of patients treated between 2003 and 2008 and collected the following parameters: demographics, laboratory results, treatment characteristics, and follow‐up. We identified 12 patients with ADAMTS13 <5% due to an inhibitor who received TPE and rituximab during the study period. The mean number of TPEs required to achieve remission was 24 ± 3, time to remission was 28 ± 3 days, and hospital length of stay was 36 ± 4 days. During a mean follow‐up of 73.4 ± 6 months, four patients (33%) relapsed. On average, relapse occurred at 62 ± 8.5 months postachievement of remission. The one‐year, three‐year, and five‐year relapse free‐survival (RFS) rates were 92%, 75%, and 75%, respectively. On multivariate analysis, we failed to identify independent predictors of relapse. This retrospective analysis does not support the notion that rituximab prevents or decreases the rate of relapse in TTP. Prospective randomized studies are needed to confirm this observation. J. Clin. Apheresis, 28:390–394, 2013.

Extracorporeal photopheresis practice patterns: An international survey by the ASFA ECP subcommittee

Although many apheresis centers offer extracorporeal photopheresis (ECP), little is known about current treatment practices.

Carfilzomib: A cause of drug associated thrombotic microangiopathy

Carfilzomib is a selective proteosome inhibitor approved for treatment of relapsed and refractory multiple myeloma. Recent reports have linked exposure to carfilzomib with development of thrombotic microangiopathy (TMA). We describe two cases of biopsy proven thrombotic microangiopathy that occurred after the initiation of carfilzomib (dosed at 32 mg/m(2) and 23 mg/m(2), respectively) for relapsed multiple myeloma. Both patients were managed with discontinuation of the drug, therapeutic plasma exchange (TPE) and supportive care. Hemoglobin, platelets and renal function did not improve with TPE. TMA resolved with creatinine returning to baseline several weeks after discontinuation of the drug. The outcomes suggest that TPE is not beneficial for treating carfilzomib-induced TMA.

Establishing an institutional therapeutic apheresis registry

Apheresis was first performed as a therapeutic procedure in the 1950s. The first national therapeutic apheresis (TA) registry was established in Canada in 1981 and other national registries followed, including two attempts at establishing an international TA registry. There is no national registry in the United States. Our large, academic, tertiary hospital has a very active TA service. We created a TA database to track all procedures performed by the apheresis service by transferring data from paper appointment logs and the electronic medical records into a Microsoft Access database. Retrospective data from each TA procedure performed at UAB from January 1, 2003 through December 31, 2012 were entered, including the type of procedure, indication, date, and patient demographics. Microsoft Excel was used for data analysis. During the 10‐year period, our TA service treated 1,060 patients and performed 11,718 procedures. Of these patients, 70% received therapeutic plasma exchange (TPE), 21% received extracorporeal photopheresis (ECP), 4.5% received red cell exchange (RCE), 4.2% received leukocytapheresis, and 0.6% underwent platelet depletion. Among the procedures, 54% were TPEs, 44% were ECPs, 1.3% were RCEs, 0.5% were leukocytaphereses, and 0.1% were platelet depletions. According to the current literature, national and international TA use is underreported. We believe that the UAB TA registry provides useful information about TA practices in our region and can serve as a model for other institutions. Furthermore, data from multiple institutional registries can be used for clinical research to increase the available evidence for the role of TA in various conditions. J. Clin. Apheresis 31:516–522, 2016.

Peering into the future: Hepcidin testing

Hepcidin, a small 25 amino acid peptide, has been well established as the iron regulatory hormone. Its expression is upregulated in response to iron and inflammatory cytokines, and downregulated in anemic or hypoxic states. Hepcidin decreases iron export into the plasma by binding to and inducing the degradation of ferroportin, an iron channel located on macrophages and the basolateral surface of enterocytes. This leads to decreased absorption of parental iron by the enterocytes, reduced recycling of erythrocyte iron by macrophages, and increased iron stores in the hepatocytes. Although hepcidin assays are not currently approved for clinical use in the United States, there is much interest in the potential use of this biomarker for management of iron related medical conditions. This review briefly summarizes the current hepcidin test platforms under investigation and the challenges associated with development of a clinical assay for this biomarker. In addition, selected potential future applications hepcidin testing in the clinical setting are addressed. Am. J. Heamtol. 88:976–978, 2013.

Extracorporeal photopheresis: technique, established and novel indications.

Extracorporeal photopheresis (ECP) has had a major impact in the treatment of various conditions in the past 25 years. Although it was initially developed for the treatment of patients with resistant cutaneous T cell lymphoma (CTCL), this therapy was later used to treat recipients of solid organs and stem cell transplants with rejection or graft‐versus‐host disease (GVHD), respectively. A significant number of patients with CTCL can achieve long term remission with ECP therapy. Those patients with heart or lung transplants may experience fewer or shorter rejection episodes following ECP. Furthermore, patients that respond to ECP can generally reduce the dose of immunosuppression medication, thus minimizing the morbidity caused by drugs such as corticosteroids and calcineurin inhibitors. While the exact mechanism of action of ECP is not well‐understood, evidence suggests that reinfusion of the patients apoptotic white blood cells, the ultimate product of ECP, promotes immunomodulatory events that are beneficial in patients with CTCL, transplant rejection, GVHD, and possibly other inflammatory conditions. J. Clin. Apheresis 29:228–234, 2014.

Therapeutic plasma exchange rapidly improves cardiac allograft function in patients with presumed antibody-mediated rejection.

Background: Allograft dysfunction due to presumed antibody‐mediated rejection (pAMR) is one of the most serious complications of heart transplantation. Combination therapies of high‐dose steroids, intravenous immune globulin, and/or therapeutic plasma exchange (TPE) are often used in this setting. Methods: We performed a 9‐year retrospective review of all episodes of pAMR treated with TPE at our institution. pAMR diagnosis was based on clinical and pathologic findings. Left ventricular ejection fraction (LVEF) was measured at baseline, prior to initiation of TPE, and during the course of treatment. Results: There were 42 patients with 47 episodes of pAMR treated with TPE. The majority of episodes were treated with three TPE; however, eight required only two TPE and five episodes required >3 TPE. All episodes of pAMR had LVEF measured before and after the series of TPEs. The mean pre‐TPE LVEF was 38% compared with a post‐therapy mean LVEF of 50% (P < 0.0001). In 16 episodes of pAMR, for which LVEF was measured following each apheresis, there was significant improvement of allograft function after the first TPE (pre‐TPE mean LVEF of 31% and post‐first TPE mean LVEF of 37%; P = 0.02). Incremental and significant improvement in allograft function continued following each TPE. Changes in human leukocyte antigen‐donor specific antibodies and fibrinogen did not correlate with ejection fraction response. Conclusions: The rapid improvement in allograft function in our patients is most likely due to TPE as other pharmacologic interventions have longer onset. TPE should be considered a first‐line intervention in the setting of pAMR. J. Clin. Apheresis 29:316–321 2014.