Guidelines on the use of irradiated blood components

Summary of cases reported to SHOT

Apart from the case of intrauterine transfusion (IUT), none of the cases occurred in patients considered at high risk of TA-GvHD at the time of transfusion, and so these individuals would not normally have received irradiated components, although two may have been immunodeficient.

In the 21 years following the introduction of LD, only two cases of TA-GvHD were reported to SHOT: the first was a patient with B-cell acute lymphoblastic leukaemia (B-ALL) in 2000 and the second was in a baby following an emergency IUT of non-irradiated maternal blood in 2012.²⁵ This is despite reported omission of irradiation in 1478 patients identified as being at risk.³⁸ It is important to recognise that many of these patients are exposed to non-irradiated blood components on more than one occasion.

A detailed retrospective analysis was undertaken to review SHOT cases where the specific requirement for irradiation was not met between 2010 and 2016,³⁹ updated by P.H.B. Bolton-Maggs to include 2017 data. This included 637 reports. The three largest cohorts of patients were those having received purine analogue chemotherapy (n = 290, 46%), those with a history of Hodgkin lymphoma (HL; n = 132, 21%) and those treated with alemtuzumab (n = 53, 8%). For 43 patients the indication for irradiation was haematopoietic stem cell transplantation (HSCT). The number of components received by an individual was variable (not reported in 66, 10%) and ranged from 1 to 486. Overall, 477 (84%) patients received between 1 and 4 components. Where the patient received 486 non-irradiated blood components this was due to a failure to identify a historical diagnosis of HL.

Overall, from the SHOT data, given the dramatic reduction of reported cases in the UK since the introduction of universal LD, compared with 12 cases reported in immunocompetent recipients in the prior 3 years (1996–1999), it appears that standardised pre-storage LD is sufficient to ^prevent or markedly reduce TA-GvHD at least in the immune-competent non-HLA-matched recipients Table II.

In the recent ‘Recommendations For the Use of Irradiated Blood Components in Canada’ by the National Advisory Committee on Blood and Blood Products (https://nacblood.ca/resources/guidelines/downloads/Recommendations_Irradiated_Blood_Components.pdf), storage time of cellular blood components was recognised as a significant factor, with no cases of TA-GvHD reported in the literature involving components stored for >14 days^8-10

Prevention of TA-GvHD

Prevention of TA-GvHD requires a strategy to address risk factors for the development of the condition. It involves selection of an effective method for inactivation of lymphocytes in the transfused components, management of transfusions where HLA haplotypes are likely to be shared between donor and recipient, and identification of susceptible individuals where the intervention is necessary. It is likely that different interventions work in synergy to provide the best protection. Identification of susceptible individuals might vary in different countries, as it can be influenced by the overall characteristics of the population in terms of HLA typing. Specifications of cellular blood components and more specifically implementation and effectiveness of universal leucodepletion should be taken into consideration.

TA-GvHD is a rare condition with significant mortality and no randomised control trials available. It should be noted that the literature is scant and levels of evidence are low. In addition, local practices and processes for the development of blood components vary among countries. For these reasons there is considerable variation in recommendations between different national guidelines.

The writing group aims to offer guidance on selection of the effective method for inactivation of lymphocytes on the transfused component, identification of components requiring irradiation (either universally or selectively for susceptible individuals) and identification of susceptible individual. The guideline is based on information from the literature, data from the UK (where universal LD is standard practice since 1999) and cases reported to SHOT.

The authors aim to offer guidance for reduction rather than elimination of the risk of TA-GvHD acknowledging that exceptionally rarely the condition might be a complication of blood transfusion that cannot be predicted when there are no identifiable risk factors.

Inactivation or elimination of lymphocytes in the transfused components

Irradiation remains the main method of inactivating lymphocytes in the transfused component. Washing red cells using standard methods employed in the UK does not appreciably reduce the leucocyte content⁴¹ and therefore these need to be irradiated for susceptible patients. The authors, as part of the literature review, assessed LD and pathogen inactivation as alternative strategies to prevent TA-GvHD.

Irradiation

The major technology for preventing TA-GvHD is irradiation of blood components to inactivate residual lymphocytes. Gamma rays and X-rays are similar in their ability to inactivate T lymphocytes in blood components at a given absorbed dose. There is international interest in moving away from using radioactive sources for gamma irradiation due to concerns with respect to biosecurity. Dedicated X-ray blood irradiators are now available, have been widely used in North America and are also used within the UK Transfusion Services. Published data indicate that the small differences in red cell permeability found between X- and gamma-irradiated components are not clinically significant.⁴² Further work, commissioned by the Joint United Kingdom Blood Transfusion Services Professional Advisory Committee (JPAC) on blood components irradiated using the Radsource irradiator, concluded that gamma- and X-irradiation can be regarded as equivalent and both are suitable and safe for clinical use (JPAC Guidelines for the Blood Transfusion Services in the UK https://www.transfusionguidelines.org/document-library/position-statements).

Pathogen inactivation

Systems to pathogen inactivate platelets are now licensed in Europe. Due to their mechanism of action, as well as inactivating bacteria and viruses, they also inactivate lymphocytes.^{48, 49} The manufacturers therefore claim that these systems can be used as an alternative to irradiation for the prevention of TA-GvHD, and many centres that have implemented this technology have stopped irradiating platelets.⁵⁰ Although these systems are considered by some authors as potential future solutions for prevention of TA-GvHD,^{51, 52} they are not yet used in the UK, and similar systems in development for red cells are not yet licensed with limited data available.^{53, 54}

Red cells

Irradiation of red cells results in significant changes in some markers of red cell quality, most notably increased haemolysis and potassium leakage. Irradiation has no clinically significant effect on red cell pH, glucose consumption, ATP or 2,3-diphosphoglycerate (DPG) levels,⁵⁷ but can increase levels of microparticles⁵⁸ with no adverse effects reported. The magnitude of this effect of irradiation on red cells is dependent upon the age of red cells prior to irradiation, dose of irradiation and length of storage once irradiated. Irradiation of red cells in the last few weeks of their normal shelf life, currently permitted by AABB standards (Standards for Blood Banks and Transfusion Services, 32nd Edition),⁴⁴ and Council of Europe guide (Guide to the Preparation, Use and Quality Assurance of Blood Components, 20th Edition, 2020)³², results in increased haemolysis of red cells^{60, 61} and reduced post-transfusion red cell recovery, although recovery is still above the minimum defined as acceptable by the United States Food and Drug Administration (75%).^{62, 63} As red cells can be irradiated up to 14 days after collection and stored for a maximum of a further 14 days without significant loss of viability⁶⁴ or haemolysis,⁶¹ and there is little operational gain in enabling irradiation later in shelf life in the UK, it is recommended that red cells are irradiated within 14 days from collection, and stored for a maximum of 14 days after irradiation.

Both gamma- and X-irradiation of red cells result in significantly accelerated leakage of potassium and an increase in the level of extracellular potassium.^{42, 65, 66} Small volume ‘top-up’ transfusions given at standard flow rates do not constitute a risk of hyperkalaemia, even when given to premature neonates.⁶⁷ Potassium load may be clinically important in rapid large-volume transfusions, such as neonatal exchange blood transfusion (EBT) or IUT,^{68, 69} and therefore the shelf life of the latter components is restricted to 24 h following irradiation and by the end of Day 5 from collection to reduce the risk of hyperkalaemia.⁴⁰ These restrictions are also recommended for infants receiving other large volume transfusions such as for cardiac bypass or extracorporeal membrane oxygenation (ECMO): small infants are particularly susceptible to risks of hyperkalaemia due to their small size compared to extracorporeal circuits and the potential for high transfusion rates relative to weight. Routine removal of supernatant plasma and washing of irradiated red cells is not considered necessary. Rapid infusion of irradiated red cells for patients with massive haemorrhage could potentially contribute to the development of hyperkalaemia. With only limited data available,⁷⁰ it is probably safer to avoid transfusion of irradiated blood for patients with massive haemorrhage, unless irradiated blood is otherwise indicated.

For patients requiring washed and irradiated red cells, red cells can be irradiated at any time up to 14 days after collection. Due to the effect of the combination of washing and irradiation on red cell quality, the shelf life of these red cells is shorter than standard red cells (JPAC Guidelines for the Blood Transfusion Services in the UK https://www.transfusionguidelines.org/).

In a recently published retrospective study,⁷¹ prolonged storage of irradiated red cells was associated with a significant increase in non-allergic transfusion reactions. Overall, the irradiated red cells appeared to cause more non-allergic reactions compared with non-irradiated red cells with the leading type of reaction being febrile non-haemolytic transfusion reaction. Red cells units included in this study could be irradiated at any time before the expiry date and subsequently could be stored for up to 28 days or up to expiry date (whichever comes first). This finding has not been recorded in the UK haemovigilance system, where manufacturing practice is different with <15% of the reported febrile non-haemolytic transfusion reactions involving irradiated components (Bolton-Maggs, P, personal communication from SHOT data).

Platelets

Although recent laboratory studies suggest that irradiation may result in proteomic/metabolomic changes in platelets, irradiation <50 Gy has not been shown to produce significant clinical changes in platelet function.^{58, 72-74}

Granulocytes

The evidence for irradiation damage to granulocyte function is conflicting, but in any case, granulocytes should be transfused as soon as possible after production and irradiation, as granulocyte function declines rapidly with time.^{75, 76}

Labelling and documentation requirements

Irradiated components must be identified by the applied labelling and include any reduction in shelf life.

Labels that are sensitive to irradiation and undergo a visual change to indicate their irradiated status are available and are considered a useful indicator of exposure to irradiation. The dose at which the label changes to indicate irradiated status must be marked on the label. It must be remembered that such labels simply reflect that the unit has been exposed to radiation and their use does not replace the need for regular and precise dosimetry nor for carefully controlled working procedures.

Blood components that should be irradiated

TA-GvHD has been reported after transfusion of whole blood, red cells, platelets and granulocytes.⁷⁷ Scotland, Wales and Northern Ireland use universal irradiation of platelets, whereas England irradiates blood components on request. Internationally there is also variation. In the USA, a survey of irradiation practices at College of American Pathologists member institutions (>2000) showed considerable variation in practice for different conditions. Some institutions irradiated by specialty or service, and 75 institutions used universal irradiation.⁷⁸

Japan uses universal irradiation of all labile blood components,⁴⁵ as a higher rate of TA-GvHD has been reported due to common HLA tissue types.⁷⁹

Blood components that do not require irradiation

TA-GvHD has not been described following transfusion of frozen deglycerolised red cells, which are thoroughly washed free of leucocytes after thawing.⁸⁰

TA-GvHD has not been described following transfusion of cryoprecipitate, fresh frozen plasma or fractionated plasma products, such as clotting factor concentrates, albumin and intravenous immunoglobulin. Liquid (never frozen) plasma is not currently produced in the UK. In contrast to frozen plasma components, any contaminating lymphocytes can remain viable in the component during storage and the component has been implicated in cases of TA-GvHD.⁸¹ Therefore, this component, where produced, should be irradiated.

Pathogen inactivation systems for platelets may obviate the need for irradiation based on the capability of these systems to inactivate lymphocytes. Data and claims from the manufacturers of these systems should be reviewed to determine the effectiveness of lymphocyte inactivation and prevention of TA-GvHD.

Donations from family members and HLA-selected donors

Because of the sharing of HLA haplotypes, donations from family members pose a risk of TA-GvHD. Red cells, granulocytes, platelets and fresh plasma (not previously frozen) have all been implicated in TA-GvHD after transfusion from family members,⁴ and there is an increased risk with donations from both first- and second-degree relatives.

Several cases of TA-GvHD have been reported from Japan, where limited diversity of HLA haplotypes in the population increases the chance of a transfusion recipient receiving blood from a HLA-haploidentical or HLA-identical donor.⁸²

These observations are of relevance for patients receiving HLA-selected platelet concentrates from non-family members because of alloimmune refractoriness to random donor platelets. This would be expected to increase the risk of TA-GvHD, especially if the platelet donor is homozygous for one of the recipient HLA haplotypes (analogous to donations within families or within racial groups of limited genetic diversity).

Transfusion of donor lymphocytes whose HLA antigens are all shared by the recipient was recognised as the strongest risk factor for the development of TA-GvHD in the recent review⁸ of the world literature.

There are no reports of TA-GvHD following transfusion of HLA-matched red cells. However, it is likely for the risk to be similar to the transfusion of HLA-matched platelets.

Paediatric practice

The risk of TA-GvHD in the fetus and neonate, especially if preterm, is thought to be higher than in older recipients. Contributing factors are the immunological immaturity,⁸³ the use of fresher blood⁸ and transfusion of relatively large volumes in situations such as neonatal EBT. Donor lymphocytes have been found in the neonatal circulation up to 6–8 weeks after EBT,⁸⁴ and cases of TA-GvHD have been described in neonates and young infants.^{82, 85, 86} These cases were almost exclusively in the presence of additional risk factors: EBT with or without preceding IUT, congenital immunodeficiency syndromes, and transfusion from blood relatives. Moreover, many publications on TA-GvHD in neonates were prior to the introduction of pre-storage LD, known to have had a major impact on TA-GvHD reduction.^{8, 11}

International practice for irradiation of components for neonates and children varies,⁸⁷ although in the UK the same irradiation recommendations for the perinatal period have been in place since 1996.⁸⁸ In some countries and institutions, irradiation is undertaken for blood for older children because of concerns over unrecognised immunodeficiency.⁸⁹ However, potential benefits of universal irradiation need to be balanced against the ability to use multiple ‘paedipacks’ for neonatal top-up transfusions to reduce donor exposure (not practical in the UK if universally irradiated by blood centres) and the potential risk of hyperkalaemia following rapid transfusion of older irradiated blood to a neonate.⁴⁰ The combination of irradiation for high-risk patients together with pre-storage LD for all others is considered to be sufficient to prevent virtually all TA-GvHD in the UK.¹¹ Nonetheless, it is important for neonatologists and paediatricians to retain a high index of suspicion of undiagnosed immunodeficiency in infants and older children (see section on congenital immunodeficiencies in infants and children). It should also be noted that signs of TA-GvHD may present later in neonates than in adults.⁸²

Intrauterine and neonatal exchange red cell transfusions

A fatal case of TA-GvHD occurred following IUT of non-irradiated maternal blood in an emergency.²⁵ BSH guidelines recommended that maternal blood should not be used for IUT to avoid this risk.⁴⁰

Intrauterine transfusion (IUT)

Red cells for IUT are used by the end of Day 5 of storage. Despite current practice of LD and the few reported cases of TA-GvHD following IUT from unrelated donors (Naiman et al., 1969), irradiation is recommended given the setting of large-volume transfusion of fresh blood to a very immature recipient. Specific, irradiated, red cells for IUT should be used where possible, and local written protocols should be in place regarding alternatives for use in emergency.⁴⁰

Previous BSH irradiation guidelines^{88, 90} have recommended that irradiated components continue to be provided for routine ‘top-up’ neonatal transfusions following IUT, consistent with recommendations for EBT following IUT. This recommendation was based on the presumption of transfusion-induced tolerance or immune suppression following IUT and the knowledge of cases of TA-GvHD in the situation of IUT followed by EBT, rather than on specific evidence, and was originally made prior to universal pre-storage LD in the UK. Missed irradiation following IUT appears to be relatively common, in part due to miscommunication between fetal medicine and obstetric delivery centres. Although there have been 18 reports to SHOT from 2007 to 2017 where red cell irradiation was missed for transfusion following IUT (e.g. Bolton-Maggs et al.²⁵, SHOT 2012), none resulted in TA-GvHD. However, there is still previous evidence to suggest a degree of adaptive immune paresis following red cell IUT, although the clinical significance is uncertain (e.g. Radder et al.⁹¹). Therefore, although the risk of TA-GvHD is likely to be very low, the recommendation to irradiate transfusions of cellular blood components to infants following IUT remains.

Neonatal exchange blood transfusion (EBT)

Given that there were cases of TA-GvHD in the past reported following EBT, both with and without prior IUT,^{85, 86} it seems reasonable to continue with previous guidance to irradiate blood for this large-volume indication despite the introduction of LD. Blood issued routinely for EBT by the UK Blood Services is currently universally irradiated.

Intrauterine platelet transfusions

As platelet concentrates may contain small numbers of residual lymphocytes, the relevant recommendations for red cell transfusion should also apply to platelets.

Cardiac surgery in neonates and infants (and older patients)

There have been occasional published reports of TA-GvHD in apparently immunocompetent neonates and older patients undergoing cardio-pulmonary bypass surgery.^{9, 11, 94} There should be a high index of suspicion concerning co-existing cardiac defects and immunodeficiency. If in doubt, blood should be irradiated until a definitive diagnosis is made. Irradiated components are essential if an immunodeficiency syndrome increasing the risk of TA-GvHD is diagnosed, such as the severe T-lymphocyte immunodeficiency syndrome that may be associated with DiGeorge syndrome or CHARGE syndrome (rare complex genetic disorders).

Only around 0·5–1% of infants with suspected DiGeorge or CHARGE syndrome will have a severe co-existing immunodeficiency,^{95, 96} and most of the severe immunodeficiencies will be diagnosed within the first year of life. Genetic testing (FISH) detects the majority of patients with DiGeorge syndrome, but the presence or absence of a 22q11 chromosomal deletion by FISH does not predict an associated immunodeficiency. Ideally, immunological assessment comprising T-lymphophenotype enumeration, including naïve (CD45⁺ (+/− CD27⁺ or CD31⁺) CD4⁺) T lymphocytes, and T-lymphocyte proliferation measurement will be performed prior to cardiac surgery for all infants with the suspected syndromes.

For those infants where this is not possible prior to urgent cardiac surgery, irradiated cellular blood components should be given. For infants with a T-lymphocyte count of >400 cells/μl of which ≥30% are naïve T lymphocytes, and no other evidence of immune deficiency, administration of non-irradiated blood is considered safe.⁹⁷ For children aged 1 to <2 years without a significant history of infection the risk of TA-GvHD will be extremely low, but for this age group it is reasonable to follow the recommendations for neonates and infants regarding immunological testing and use of irradiated cellular blood components. From 2 years of age without a significant history of infection, it is reasonable to follow the recommendations for adults below, even in the absence of immunological testing. Sometimes it is discovered during infant cardiac surgery that the patient has no thymus, indicating probable immunodeficiency. In this situation where there is no specific evidence to guide practice it is reasonable to wait for irradiated blood to arrive if this is practical, but not to delay surgery if this would cause a significant detrimental clinical impact given that all blood in the UK is LD.

Acquired immunodeficiency states in childhood

Transient defects of T-lymphocyte function can occur following common childhood viral infections and in the setting of tuberculosis, leprosy, autoimmune disorders, malnutrition and burns. TA-GvHD has not been reported in these situations and irradiation of blood components is not recommended. Despite the profound T-lymphocyte defect in human immunodeficiency virus (HIV) infection, no cases of TA-GvHD have been described in children or adults.

Recommendation

All recipients (adult and paediatric) of allogeneic HSCT should receive irradiated blood components from the time of initiation of conditioning chemo/radiotherapy. The recommendation applies for all conditions where HSCT is indicated regardless of the underlying diagnosis (1/B).

If chronic GvHD is present or continued immunosuppressive treatment is required, irradiated blood components should be given indefinitely (2/C).

Treatment with irradiated blood components should continue indefinitely if this is required based on transplant conditioning, underlying disease or previous treatment, e.g. previous diagnosis of HL or previous purine analogue treatment (1/C).

Allogeneic cellular blood components transfused to bone marrow and peripheral blood stem cell donors of all ages within 7 days prior to or during the harvest should also be irradiated (2/C).

Recommendations

Patients (adult and paediatric) undergoing bone marrow or peripheral blood stem cell collections for future autologous re-infusion should receive irradiated cellular blood components for 7 days prior to and during the bone marrow/stem cell harvest to prevent the collection of viable allogeneic T lymphocytes, which can potentially withstand cryopreservation (1/C).

All patients undergoing ASCT irrespective of underlying diagnosis or indication for this treatment should receive irradiated cellular blood components from initiation of conditioning chemo/radiotherapy until 3 months post-transplant (6 months if total body irradiation was used in conditioning) unless conditioning, disease or previous treatment determine indefinite duration, for example previous diagnosis of HL or previous purine analogue treatment (1/C).

Recommendation

All adults and children with HL at any stage of the disease should have irradiated red cells and platelets indefinitely (2/C).

Patients treated with purine analogues (regardless of the underlying condition)

The purine analogues fludarabine, cladribine and pentostatin induce profound lymphopenia with low CD4 counts that may persist for several years after treatment.¹¹⁴ There are case reports of TA-GvHD following treatment of low-grade B-cell malignancies with fludarabine^{115, 116} and cladribine.¹¹⁷

Although no cases of TA-GvHD secondary to purine analogues have been reported in the UK since the introduction of universal LD, there is no adequate evidence in the literature to support modification of current recommendations. It remains a recommendation that cellular blood components should be irradiated for patients receiving purine analogues.

Haematology patients and patients with rare types of immune dysfunction treated with alemtuzumab (campath 1H-anti-CD 52) or anti-thymocyte globulin (ATG)

Use of alemtuzumab (campath 1H; anti-CD 52) has been considered as an indication for irradiation of blood components. This recommendation was based on a reported non-infection-related fatality in a Cancer and Leukaemia Group B (CALGB010101) study, a Phase II study of fludarabine and rituximab induction followed by alemtuzumab in chronic lymphocytic leukaemia (CLL)^{44, 119} Treatment schedule varies in different series, with the most common treatment dose to be up to 30 mg three-times a week for 12 weeks.¹²⁰

The risk for development of TA-GvHD for aplastic anaemia patients treated with alemtuzumab remains unclear.

Currently, there is no evidence to discontinue irradiation for patients receiving alemtuzumab for treatment of haematological malignancies or bone marrow failure. It is not possible, based on existing evidence, to make a firm recommendation on how long irradiated blood components should be used for this group of patients.

The risk of development of TA-GvHD for patients with aplastic anaemia following treatment with anti-thymocytic globulin (ATG) is considered to be low. However, it remains unclear if the absence of reported cases is due to the low risk or whether the current guidance for using irradiated blood components is highly effective. In view of the seriousness of TA-GvHD, and unless new evidence emerges, current guidance remains unchanged and irradiated blood components are recommended for bone marrow failure patients receiving ATG (see also solid organ transplant section). This is in line with the BSH guidelines¹²¹ and European Group for Blood and Marrow Transplantation (EBMT) recommendations.^{122, 123} It is not known how long the use of irradiated blood components following ATG treatment should be continued, but it is considered reasonable to continue while patients are still taking ciclosporin following ATG therapy.

Rarely, potent immunosuppressive (T-cell depleting) agents are used for treatment of immunology patients. An example is the use of ATG for treatment of familial haemophagocytic lymphohistiocytosis.¹²⁴ Most centres treating these rare patients utilise irradiated components. Although there is no evidence from the literature, the authors consider this as a prudent practice. For patients receiving potent T-cell depleting serotherapy (e.g. ATG) for inherited immune dysfunction, irradiation will continue until there is evidence of immune reconstitution (will require immunological review).

Chimeric antigen receptor T-cell (CAR-T) therapy

CAR-T therapy is a complex and innovative treatment and it is currently approved in the UK for the treatment of some cases of lymphoma and acute leukaemia. A patient's own T cells are collected and genetically altered to recognise target antigens expressed on the cell surface of specific neoplastic cells.¹²⁵ CAR-T therapy can lead to significant immunosuppression.

In addition to the immunosuppression associated with CAR-T administration, the process of development of CAR-T therapy involves autologous lymphocyte collection by apheresis; the apheresis product could theoretically contain viable lymphocytes, which could contaminate the final product and lead to TA-GvHD. Therefore, it is recommended that the guidance for autologous stem cells also be followed for CAR-T cells. It has to be noted that no cases of TA-GvHD secondary to CAR-T cells administration have been reported to SHOT, nor were any cases found in the literature review; it is expected that patients receiving CAR-T therapy will already have other indications for blood component irradiation.

Aplastic anaemia

Adult and paediatric patients following the diagnosis of aplastic anaemia are not known to have increased susceptibility for TA-GvHD and no cases have been identified by the literature search or reported to SHOT.

Acute leukaemia and non-Hodgkin lymphoma (NHL)

Use of irradiated blood components is not routinely recommended for adults or children receiving treatment for acute leukaemia or NHL, except for HLA-selected platelets, granulocytes, donations from first- or second-degree relatives or if patients receive treatment with purine analogues, alemtuzumab or HSCT (1/B).⁹⁰ This is consistent with adult and paediatric practice in the UK, with no cases of TA-GvHD reported since 2012. For intermediate forms of lymphoma that show some features of HL, such as grey zone lymphoma, there is no current evidence to suggest that irradiation is required.

Use of irradiated cellular blood components for patients receiving immunosuppressive agents (ATG or alemtuzumab) for non-haematological indication: multiple sclerosis (MS), vasculitis and solid organ transplantation

Potent immunosuppressive agents are used with increasing frequency for patients with autoimmune conditions or in the context of solid organ transplantation. The writing group reviewed the evidence for irradiation when alemtuzumab is used for treatment of patients with MS, vasculitides and solid organ transplantation with the following conclusions and recommendations.

Multiple sclerosis (MS)

Alemtuzumab was licensed as a treatment for active MS in 2013 (EU) and 2014 (USA). Evidence in relation to the level of immunosuppression is based on the results of Phase III clinical trials^126-128 and subsequent publications¹²⁹ and¹³⁰ assessing the incidence of opportunistic and other infections in relation to treatment. Vaccinations are effective at ≥1 month after each treatment cycle.¹³¹ Overall patients are immunocompetent following alemtuzumab treatment when given according to the published regimes and current protocols for MS (alemtuzumab [12 mg/day], infused intravenously on 5 days at baseline and 3 days at 12 months) and therefore they should not be considered at risk of TA-GvHD.

There are currently no reported cases of TA-GvHD following treatment with alemtuzumab for MS. The summary of product characteristics (SPC) for alemtuzumab (now marketed as Lemtrada® for MS) does not include a recommendation for irradiation of cellular blood components.

Vasculitis

Alemtuzumab has been used ‘off label’ for refractory vasculitides and Behçet's syndrome since 1989 in approximately 250 patients. It is mentioned as a treatment option in the NHS England Behçet's syndrome treatment pathway. No data are available from randomised controlled trials. Mortality, side-effects, development of opportunistic and other infections as well as autoimmune complications have been published.^132-135 A range of opportunistic infections has been observed after alemtuzumab, but these have not differed in type or frequency from those seen with other immunosuppressive treatments. There has been no obvious increased risk of late infection or increased risk of malignancy and no cases of TA-GvHD have been reported.

Solid organ transplantation

GvHD is a rare complication of solid organ transplantation. Most reported cases have been in liver and intestinal transplant recipients, likely reflecting the large lymphoid load within the transplanted organ.

Since 2001 the majority of solid organ transplant recipients have received induction immunosuppression, with either interleukin 2 (IL2) receptor-blocking antibody (basiliximab) or T-cell depleting antibody (ATG or alemtuzumab). The induction dose of ATG is typically 6mg/kg, and a single dose of 30mg of alemtuzumab.

Although the existing recommendation is that alemtuzumab-treated patients should receive irradiated cellular blood components, practice in UK solid organ transplant units is variable. A retrospective review of >600 transfused patients treated with alemtuzumab conditioning for renal transplantation in one centre did not identify any risk of TA-GvHD,¹³⁶ despite receiving non-irradiated cellular blood components according to the local practice. Similarly, most USA blood banks do not routinely irradiate blood following treatment with alemtuzumab for solid organ transplantation.⁷⁸

Use of irradiated cellular blood components for solid organ transplanted recipients treated with ATG (either as a pre-transplant conditioning or for treatment of graft rejection) has not been recommended in previous guidelines⁹⁰ and it is not included at the licence indications for Atgam®¹³⁷(commonly used preparation of ATG).

There have been no confirmed cases of TA-GvHD in the UK since routine LD of blood components became standard practice in 1999, while >50 000 patients have received an organ transplant since then. Accordingly, there is no indication for irradiation of cellular blood components administered to alemtuzumab or ATG-treated solid organ transplant recipients.

Rituximab (anti-CD20)

Use of irradiated components following treatment with rituximab is not recommended⁹⁰ and no case of TA-GvHD has been reported in the literature or to SHOT following this treatment (regardless of the patient's underlying diagnosis).

Recommendation:

Treatment of patients with rituximab is not an indication for use of irradiated cellular blood components unless this is indicated for a different reason (underlying diagnosis, type of component or previous treatment) (1/B).

New immunosuppressive agents

Despite the development and wide usage of new potent immunosuppressive agents, no cases of TA-GvHD have been reported in the literature. The authors are unable to make any recommendation for those agents and advise that manufacturers’ recommendations should be followed.

Recommendations

Where patients require irradiated cellular blood components, components must be requested and clearly prescribed as irradiated (1/C).

Specific requirements, including need for irradiated blood components, must be part of the bedside check prior to administration of all blood components with documentation of checks (1/C).

Clinical areas and transfusion laboratories should agree and implement communication processes to ensure specific requirements and provision of irradiated cellular blood components are met for patients under shared care (1/C).

Patients requiring irradiated cellular blood components should receive appropriate information. Where possible patients should carry cards to facilitate provision of appropriate components (1/C).