Guideline on the clinical use of apheresis procedures for the treatment of patients and collection of cellular therapy products

The guideline group was selected to be representative of relevant UK-based medical and nursing experts. Systematic literature searches were conducted between September to December 2012 using MEDLINE, OVID PLUS and EMBASE for publications in English, using keywords: plasma exchange; apheresis; exchange transfusion; extracorporeal photopheresis; lipoprotein apheresis; leucocytapheresis; peripheral blood stem cells (PBSC); peripheral blood progenitor cells (PBPC) and other relevant keywords related to the subsections of this guideline. Relevant recent publications e.g. guideline documents, which came to the attention of the group subsequent to December 2013, were also included in the following discussion with the full writing group. The draft guideline was reviewed by a sounding board of British haematologists, the BCSH and the British Society for Haematology Committee. The ‘GRADE’ system was used to quote levels and grades of evidence, details of them can be found at http://www.bcshguidelines.com. This guideline is an update to the archived BCSH guideline on the clinical use of cell separators (BCSH Joint Working Party, 1998). The scope has been extended into a comprehensive description of best practise in Clinical Apheresis. The objective of this guideline is to provide healthcare professionals with clear guidance on the use of clinical apheresis. In 2014, clinical apheresis is a distinct subspecialty overlapping Haematology, Transfusion Medicine and Renal Medicine (Weinstein, 2007), with more procedures being carried out (Stegmayr et al., 2005) and more procedures taking place outside the UK Transfusion Services, such as allogeneic and autologous haemopoietic progenitor cells–apheresis (HPC-A; also known as peripheral blood stem cells or PBSC) collections carried out by Haematology teams, plasma exchange undertaken by Nephrology teams on dialysis equipment, and the development of extracorporeal photopheresis (ECP) as a treatment for graft-versus-host disease and cutaneous T-cell lymphomas. There has also been a move towards ‘evidence-based apheresis medicine’, with publication of guidelines by the American Society for Apheresis (ASFA) (Schwartz et al., 2013), American Academy of Neurology (AAN) (Cortese et al., 2011) and the ‘Kidney Disease: Improving Global Outcomes’ group (KDIGO Work Group, 2012). Although these are helpful, the AAN and KDIGO guidelines cover only a few specific indications for plasma exchange. The ASFA guidelines take the form of an extensive alphabeticised list of indications with broad treatment recommendations; some aspects of clinical management of patients/donors undergoing apheresis, and of management of the service as a whole are not considered in detail. A new guideline is therefore required to address clinical apheresis as practised in the UK. The 1998 BCSH guideline focused on procedures carried out on ‘cell separators’ (i.e. excluding plasma exchange carried out on renal dialysis equipment) and included collection of donor plasma, platelets and red cells by apheresis, which are excluded from the current guideline, as best practise is described elsewhere by separate publications within the UK Transfusion Services. The remit of the current guideline, covering all plasma exchange regardless of equipment used, all therapeutic procedures undertaken on cell separators, and any autologous or allogeneic donor apheresis for procurement of cellular therapy products such as HPC-A, reflects a more contemporary definition of ‘Clinical Apheresis’. Scully et al. (2012) Exchange volume and frequency: Mathematical modelling of the removal of macromolecules such as antibodies by plasma exchange indicates that the optimum treatment volume for each procedure is 100–150% of the patient's plasma volume (Chopek & McCullough, 1980). To avoid excessive hypofibrinogenaemia while maximising removal of the target macromolecule, many centres initially perform a run of five exchanges at 100% plasma volume at daily or alternate-day intervals for the majority of indications, avoiding weekend days unless there is clinical urgency. Exceptions when more intensive exchange regimes are necessary include: TTP; anti-glomerular basement membrane (GBM) disease; prophylaxis and treatment of solid organ transplant rejection due to anti-ABO or anti-HLA antibodies and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. In these situations, more intensive regimes are recommended: details are summarised in Table 1. In Waldenström macroglobulinaemia, less intensive plasma exchange may be appropriate (Table 1). Maintenance plasma exchange is generally not recommended except in certain situations for hyperviscosity or cryoproteinaemias (Table 1), and for a few other rare indications as discussed in the ASFA guidelines (Schwartz et al., 2013). Occasionally, maintenance of plasma exchange may be indicated in antibody-mediated conditions that are refractory to drug therapy or where patients are intolerant of drug therapy; in such situations, the frequency of exchanges may vary from once every 2 weeks to once every 6 weeks, guided by symptoms and (where available) by measuring levels of the target molecule or other objective measurements of the patient's condition. Except for TTP and related thrombotic microangiopathies in which SD-FFP must be used as the sole replacement fluid for plasma exchange (Scully et al., 2012), 4.5% to 5% HAS is the most widely-used replacement fluid for plasma exchange in the UK (UK Transfusion Services, unpublished data) and also worldwide (Weinstein, 2010). In contrast to crystalloids such as 0.9% normal saline, HAS maintains the patient's whole blood viscosity and physiological albumin levels. Some centres also use crystalloid solutions as partial replacement fluid for plasma exchange, to reduce cost and minimise blood product exposure, but there is a lack of published data to demonstrate equivalent safety to HAS, and the incidence of vasovagal faints may be increased (Shemin et al., 2007). Use of a combination of 5% HAS with Gelofusine as replacement fluid may also be considered: if this approach is adopted, careful ongoing surveillance of safety and efficacy is recommended. Sickle cell disease (SCD) is the main indication for red cell apheresis. Transfusions in sickle cell disease can be used in emergency situations or electively, and may be either top-up or exchange transfusions. Exchange transfusions may be carried out by apheresis or manually. Apheresis red cell exchange has several advantages over manual exchange transfusion, primarily being more effective in preventing transfusional iron overload. Self-evidently, apheresis red cell exchange is also much less likely to lead to transfusional iron overload for patients requiring regular transfusions, compared to top-up transfusion. Other advantages include faster HbS reduction during acute events, and longer gaps between transfusions for patients on a chronic transfusion programme (Swerdlow, 2006). Emergency red cell exchange is primarily used in SCD, most commonly in acute chest syndrome (ACS) (Vichinsky et al., 2000), although it is used in other severe acute complications including sickle stroke. Initial top-up transfusion should be used for patients with severe anaemia or a significant drop in steady state haemoglobin concentration. The early institution of exchange transfusion for severe ACS is accepted as best practise, particularly in children (Velasquez et al., 2009), although short-term outcomes may not be superior to standard transfusion in adults (Turner et al., 2009). Standard top-up transfusion to reduce HbS percentage cannot be used if the patient's haemoglobin is within or above the normal range, as this will lead to hyperviscosity. Acute stroke in SCD can be treated with initial top up transfusion if the patient is severely anaemic, but urgent exchange transfusion lowers the risk of subsequent stroke compared to top-up transfusion. Patients with thrombotic stroke should receive regular blood transfusion, ideally exchange, to keep the HbS percentage below 30% indefinitely (Sickle Cell Society, 2008). For other life-threatening events in SCD, evidence from controlled trials is limited. Emergency exchange transfusion is indicated in severe sepsis, acute hepatic sequestration (Ahn et al., 2005), acute multi-organ failure (Hiran, 2005) and progressive intrahepatic cholestasis (Sickle Cell Society, 2008). Preparation for urgent surgery may also be an indication (NHS SCTSP, 2010; Howard et al., 2013). Emergency red cell exchange has also been used in severely ill malaria patients and in babesiosis (Schwartz et al., 2013) and occasionally together with anti-D immunoglobulin to reduce Rh(D) sensitisation risk following erroneous large-volume transfusion of Rh(D) positive blood to a Rh(D) negative female child or woman of childbearing years (Laspina et al., 2005). Elective red cell exchange in SCD may be considered for primary stroke prevention (Adams et al., 1998; Lee et al., 2006), secondary stroke prevention (Scothorn et al., 2002; Hulbert et al., 2006), elective surgery (Vichinsky et al., 1995; Howard et al., 2013), patients with severe disease who have not responded to or cannot take hydroxycarbamide, and painful crises in pregnancy (Sickle Cell Society, 2008). Red cell exchange in severely ill malaria patients with hyperparasitaemia (>10%) may be clinically useful according to case reports and case series publications. A meta-analysis did not find survival benefit from manual exchange transfusion compared to antimalarials and aggressive supportive care alone (Riddle et al., 2002). UK treatment guidelines for malaria suggest that exchange transfusion may be considered after discussion with an expert in the management of malaria in patients with hyperparasitaemia (>30% red blood cells parasitized) or >10% parasitaemia and other manifestations of severe disease (Lalloo et al., 2007). In polycythaemia vera the use of automated erythrocytapheresis (‘isovolaemic haemoreduction’) corrects hyperviscosity by lowering the haematocrit. Therapeutic erythrocytapheresis may be preferable to large volume venesection in some situations such as the haemodynamically unstable patient, for elective pre-operative reduction when cytoreductive therapy has been suboptimal, or for emergency pre-operative preparation. Erythrocytapheresis has also been used in haemochromatosis (Grabmer et al., 2014). Extracorporeal photopheresis (ECP) involves collecting a small proportion (5%) of a patient's mononuclear cells by apheresis, exposing them to ultraviolet (UV) A light in the presence of psoralen, and re-infusing them. The current methods for delivery of ECP use ‘closed’ or ‘open’ systems. Open ECP necessitates collection of a buffy coat on a cell separator, separation of the buffy coat from the system and subsequent UVA irradiation in a separate device, before reinfusion to the patient. By contrast the closed system incorporates an internal UVA source in the apheresis device with no separation of the buffy coat from the device, before return to the patient. While the open system has the potential advantages of increased cell dose and the ability to manipulate the cells further, there is an increased risk of microbial contamination with this technology. The closed system devices have integrated mononuclear cell collection and 8-methoxypsoralen/UVA irradiation, and regulatory approval for treating patients (Wong, 2012). Cutaneous T-cell lymphomas (CTCL): ECP has been shown, in a large number of clinical studies, to be an effective treatment with induction of remission in early and late stages of mycosis fungoides and Sézary syndrome. ECP is a recommended therapy for erythrodermic CTCL in several guidelines, including the European Organisation for the Treatment of Cancer (EORTC) mycosis fungoides/Sézary guidelines and the Joint British Association of Dermatology and UK Cutaneous Lymphoma Group guidelines. The latter is endorsed in the Improving Outcomes Guidance in Skin Cancer by NICE (2011). Several US bodies have also endorsed ECP for CTCL (Whittaker et al., 2003; Trautinger et al., 2006; National Comprehensive Cancer Network, 2011; Olsen et al., 2011; National Cancer Institute, 2012). Chronic Graft-versus-Host Disease (cGvHD): Chronic graft-versus-host disease affects approximately 60% of patients undergoing allogeneic transplantation. Second line therapy with ECP has been advocated for skin, mucosal or liver cGvHD with evidence of steroid intolerance, refractoriness or dependence, by the BCSH, the German Austrian and Swiss consensus and the UK consensus groups (Scarisbrick et al., 2008; Wolff et al., 2011; Dignan et al., 2012a). Other organ sites respond less well and there is currently insufficient published evidence to recommend ECP for cGvHD of the eyes, joints or lungs (Couriel et al., 2006). Acute Graft-versus-Host Disease (aGvHD): ECP has been used in the treatment and prevention of acute graft-versus-host disease, with encouraging results in steroid-refractory patients who would otherwise have very unfavourable outcomes (Dignan et al., 2012b; Das-Gupta et al., 2014). Other indications: There is published evidence to support ECP for prevention of graft rejection in heart and lung transplantation (Barr et al., 1998; Christie et al., 2010; Morrell et al., 2010), in the prevention of renal transplant rejection (Dall'Amico et al., 1998), and in the prevention of rejection in face transplantation (Petruzzo et al., 2012). Leucocytapheresis may be undertaken to treat hyperleucocytosis in patients with leukaemia or myeloproliferative neoplasms. Hyperleucocytosis is usually considered if the white blood cell count is more than 100 × 109 L−1 (Gancel et al., 2012; Schwartz et al., 2013). Leucocytapheresis may worsen the coagulopathy associated with acute promyelocytic leukaemia and so is not recommended for this type of leukaemia (Vahdat et al., 1994). Several retrospective analyses of patients with hyperleukocytosis treated with leucocytapheresis have been published (Tan et al., 2005; Bug et al., 2007; Chang et al., 2007; De Santis et al., 2011). Some, but not all, of these analyses showed decreased early mortality. None showed improvement of overall survival. Allogeneic HPC-A (PBSC) donors should have cells mobilised with a non-biosimilar granulocyte colony-stimulating factor (G-CSF) only (EBMT, 2011). For autologous HPC-A mobilisation, G-CSF may be used alone or in combination with chemotherapy. Plerixafor is effective along with G-CSF for patients failing to mobilise autologous HPC-A successfully by conventional means (Jantunen & Lemoli, 2012). So as not to subject a patient undergoing autologous HPC-A collection to apheresis when there is little or no prospect of achieving a transplantable cell dose, most centres perform a peripheral CD34+ cell count by flow cytometry (either after 4 days of G-CSF alone, or at the time of white blood cell count (WBC) recovery following chemomobilisation) before initiating apheresis. Apheresis should not be performed if the peripheral CD34+ count is less than 5 µL−1, and most UK centres use a peripheral CD34+ count ‘trigger’ of 10 µL−1 to initiate apheresis (UK Stem Cell Users' Group survey, December 2013). Although differential WBC and Sysmex ‘Progenitor Cell Count’ have both been used as alternatives to peripheral CD34+ count for initiation of apheresis for autologous HPC-A collection, peripheral CD34+ count is more reliable (Meehan et al., 2006). Most cell separators will default to process two blood volumes in a standard HPC-A collection. However, larger-volume apheresis (i.e. processing of three blood volumes or more) should be considered in patients undergoing autologous HPC-A collection with peripheral CD34+ count below 20 µL−1 at the time of apheresis (Moog & Moog, 2008; Majado et al., 2009) Lipoprotein (Lp) apheresis is a treatment option for severe familial hypercholesterolaemia (FH) (NICE, 2008). 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