NAC Irradiation Recommendations: Update May 5, 2017 NAC Meeting, Alt Hotel – Toronto, ON Doug Morrison and Oksana Prokopchuk-Gauk

Background NAC Irradiation Working Group formed in late 2015 Doug Morrison (Chair), with adult and pediatric TM experts Collaborative contribution sought from CCNMT  participated in co- authorship of recommendations document Draft recommendations document released Sept 26, 2016 Thank you to the working group!! Distributed for stakeholder consultation Comments compiled into Excel document NAC Irradiation Working Group co-chair sought March 2017 Oksana Prokopchuk-Gauk approached and agreed to participate with the support of the Working Group Revisions to the existing draft throughout April 2017 Collaborative discussion between co-chairs via email or phone

Revision and Consolidation Processes undertaken in 2017: Review and incorporation of feedback provided by stakeholders and individuals Comparison of recommendations phrases to published guidelines to reaffirm wording – verbatim vs adapted ANZSBT 2011 BCSH 2010 Review of phrases in newly published CSTM standards Consultation of literature for information clarification

Objectives Present “What’s New” in terms of the document organization Highlight changes to the Recommendations Address discussion points arising from revision, to move towards document finalization

What’s New Title – acknowledgement of the CCNMT as collaborators to the recommendations document authorship NAC-CCNMT Irradiation Working Group Background – inclusion of 3 subheadings Document Authorship Rationale for use of Irradiated Blood Document Scope and Guide

What’s New Document Scope and Guide Special annotations following each recommendation will be included to inform the reader of the recommendation reference:  The name of the published guideline or source which serves as the basis of the recommendation. An asterisk (*), to indicate a verbatim statement from the referenced guideline. A level of evidence description for the recommendation may be included from the original guideline document, if available. Recommendation statements without a reference are considered best practice statements by NAC and the Working Group.  

Examples - References Recommendation: For at-risk patients, all red cell, platelet and granulocyte concentrates should be irradiated, except cryopreserved red cells after deglycerolization. It is not necessary to irradiate fresh frozen plasma, cryoprecipitate or fractionated plasma products. (BCSH 2010, Grade 1 recommendation; level B evidence)* Recommendation: Patients at risk of TA-GVHD should be made aware of their need for irradiated blood components. It is the responsibility of the most responsible health care practitioner to inform patients at risk of TA-GVHD of their need for irradiated blood components. (BCSH 2010)    

The Recommendations Rationale for newly added recommendations: Request following stakeholder feedback Clarification of existing recommendations Rationale for modified recommendations: Adjustment of wording to align with verbatim statement from an existing irradiation guideline Consideration – numbering of recommendations Not yet done Perhaps when finalized? Separation of the national neonatal transfusion practice survey and responses as a ‘Supplement’

Summary of Changes and Discussion Points

Age Age of blood at irradiation Inclusion of CSTM Standards (April 2017) and upcoming voluntary CBS adoption of the COE recommendation CSTM 2017 - 5.4.4.1.6 The TS shall have policy with respect to permitted storage periods for irradiated blood components. CSTM 2017 - 5.6.9.4 Red Cells may be irradiated up to 28 days post collection. Irradiated red cells shall be transfused as soon as possible, but no later than 14 days after irradiation, and in any case, no later than 28 days after the unit was collected. Note: refer to the most recent NAC recommendations for context of this clause.

Communication Recommendation: To ensure consistency of patient care across jurisdictions, particularly between hospital facilities that participate in the shared care of patients, a communications process between clinicians and the transfusion medicine laboratory facilitating sharing details of special transfusion requirements should be implemented and maintained. (BCSH 2010) Wording adjusted as per Canadian Neonatology Network Discussion: Does NAC want to make a recommendation based on communication/local procedure requirement for communication regarding TM service notification if patients receive immunosuppressant medications with an indication for irradiation (ex. by pharmacy?) What about BMT and communication to TM service of when to start and stop providing irradiated blood?

Inventory Management PROPOSED NEW ADDED RECOMMENDATIONS: Recommendation:  Irradiation of RCCs should occur as close as possible geographically and temporally to the site and time of transfusion.   Suggested by J Acker Recommendation:  Irradiated RCCs should not routinely be transfused to the general population who do not have an indication to receive irradiated blood, except in the situation of a blood shortage event. Position suggested by J Callum A similar stance was included in the text in the initial recommendations document CSTM 2017: 5.4.4.1.5 Irradiated blood components may be released to recipients not requiring irradiated blood components.11.7.4 Note: refer to the most recent NAC recommendations for inventory management of irradiated blood

Inventory Management NEW TO THIS SECTION: PROPOSED NEW RECOMMENDATION Recommendation:  Where there is concern about the immunosuppressive potency of new drugs and uncertainty about the risk of TA-GVHD, in the absence of on-site irradiation or pre-storage irradiated inventory, pre-storage leukoreduced red cells that have been stored for more than 14 days should be provided. PROPOSED NEW RECOMMENDATION Recommendation:  Pathogen inactivation or reduction technologies cannot yet be advocated as an alternative or equivalent to irradiation. (ANZSBT 2011)* Addition suggested by CCNMT  

Clinical Recommendations CSTM 2017 5.4.4.1.3 Irradiated cellular components should be selected for recipients at risk. Note: refer to the most recent NAC recommendations for the list of appropriate recipient conditions. 5.4.4.1.4 There shall be an established process to ensure that recipients of irradiated blood components continue to receive irradiated components as long as clinically indicated. 11.7.3

Clinical Recommendations Allogeneic Bone Marrow Transplantation Recommendation: Irradiated blood components should be continued while the patient continues to receive graft-versus-host disease (GVHD) prophylaxis, i.e. usually for 6  months post-transplant, or until the lymphocyte count is greater than 1x109/L. If chronic GVHD is present or if continued immunosuppressive treatment is required, irradiated blood components should be given indefinitely. (BCSH 2010, Grade 2 recommendation; level C evidence)* Discussion points: Controversy regarding including an option to stop providing irradiated components – transplanters say ‘for life’ post-BMT overall NZ guidelines say 12 mo. Do we want to include a range? Include another recommendation regarding discrection of BMT physician and considerations for stopping, with suggested d/c criteria?

Clinical Recommendations Aplastic Anemia Recommendation: In view of the recent switch from horse anti-thymocyte globulin (ATG) to the more immunosuppressive rabbit ATG, we now recommend use of irradiated blood components for aplastic anemia patients receiving immunosuppressive therapy with ATG (and/or alemtuzumab). (BCSH 2010, Grade 2 recommendation; level C evidence)* Recommendation: We cannot make a firm recommendation as to how long irradiated blood components should continue to be used after ATG administration. (BCSH 2010)*   Discussion: Universal ATG statement including both Horse vs Rabbit?? What about ATG used in the setting of allogeneic HSCT and indication for irradiated blood?

Clinical Recommendations Aplastic Anemia NEW PROPOSED RECOMMENDATION: (for clarification) Recommendation:  Patients not receiving immunosuppressive therapy do not definitively need to receive irradiated red cells and platelets. (ANZSBT 2011)*

Clinical Recommendations Directed or HLA Matched Donations Recommendation: All transfusions from first- or second-degree relatives should be irradiated, even if the patient is immunocompetent. (BCSH 2010, Grade 1 recommendation; level B evidence)* (ANZSBT 2011) Recommendation: All HLA-selected platelets should be irradiated, even if the patient is immunocompetent. (BCSH 2010, Grade 2 recommendation; level C evidence)* (ANZSBT 2011)    Discussion: Should vs must?? (BCSH vs ANZSBT wording)

Clinical Recommendations Immunodeficiency states, acquired Title change NEW SECTION ADDITION PROPOSED: Immunodeficiency states, congenital Recommendation: All severe T lymphocyte immunodeficiency syndromes should be considered as indications for irradiation of cellular blood components. Once a diagnosis of immunodeficiency has been suspected, irradiated components should be given while further diagnostic tests are being undertaken. A clinical immunologist should be consulted for advice in cases where there is uncertainty. (BCSH 2010, Grade 1 recommendation; level A evidence)* (ANZSBT 2011)

Clinical Recommendations Purine Analogues Recommendation: All patients with non-Hodgkins lymphoma on purine analogues and related drugs (see Appendix B) should receive irradiated cellular blood components indefinitely (BCSH 2010; ANZSBT 2011)   Discussion: This statement not verbatim, evidence removed NZ guideline discusses consideration of removing requirement for irradiation after 1 year Suggestion provided in feedback comments to add a consideration of ‘stop timeline’ after purine analog administration Thoughts? Evidence?

Clinical Recommendations Purine Analogues Recommendation: Patients treated with purine analogue drugs (fludarabine, cladribine and deoxycoformicin) should receive irradiated blood components indefinitely. (BCSH 2010, Grade 1 recommendation; level B evidence)*  The NZ guidelines say: All patients treated with nucleoside analogues must receive irradiated cellular blood components; there are however, currently no data to support a stated period of time to use irradiated red cells and platelets for patients following treatment with nucleoside analogues; however, continued use for at least 1 year is recommended, and indefinite use could be considered. Discussion: Does NAC want to provide a timeline recommendation??

Clinical Recommendations Neonatal Transfusions Combined IUT and Exchange Transfusion title NEW PROPOSED RECOMMENDATION: Recommendation:  Red cells for exchange transfusion should be as fresh as possible, ideally less than 5 days of age, and must be transfused within 24 hours of irradiation. (BCSH 2010; ANZSBT 2011)   Timeline addition recommended by Canadian Neonatology Group RECOMMENDATION MOVED UP IN SECTION: Recommendation: Where the patient is at particular risk from hyperkalemia, e.g. intrauterine or neonatal exchange transfusion, it is recommended that red cells be transfused within 24 hours of irradiation or that cells are additive-depleted (single-washed or saline replaced). (BCSH 2010; ANZSBT 2011) Wording clarification added on review of ‘washed’

Clinical Recommendations Neonatal small volume (top-up) transfusion Recommendation:  Irradiated cellular components are recommended for neonates who have received an IUT, in which case irradiated components should be administered until 6 months after the expected delivery date (40 weeks gestation), or the donation has come from a first- or second-degree relative. (BCSH 2010; ANZSBT 2011)   Recommendation: Irradiated cellular components are recommended for top-up transfusions given to neonates born with a very low birthweight (less than 1200  grams) and who require transfusion up to 4 months of age. (NAC Survey results; ANZSBT 2011)   Wording was revised from the original recommendation (clarification) Discussion – LBW definition  1200g – 1250g – 1300g AABB Technical manual and Mintz text 2011 state 1200g Cdn Network of Neonatologists suggests 1250g as a ‘more practical cut off’ The NZ guideline says 1300 g

Clinical Recommendations Neonatal small volume (top-up) transfusion Discussion: Washing (additive depletion/saline replacement) of RBC if >24 hours from irradiation -- is it necessary? Ie. Would these neonates be at risk of hyperkalemia? Would the weight of the baby matter? Ex. <10 kg? CCNMT description of the ‘alternative method’ of providing irradiated product if no there is no on-site irradiator suggests that split units for small volume transfusions to neonates are not washed, but no more than 7 days from irradiation of a fresh RBC unit. Thoughts?

Clinical Recommendations Congenital Cardiac Anomalies Recommendation:  There is no need to irradiate red cells or platelets for infants undergoing cardiac surgery unless clinical or laboratory features suggest a coexisting T lymphocyte immunodeficiency syndrome. (BCSH 2010, Grade 2 recommendation; level B evidence)* (ANZSBT 2011) Dysmorphic features, craniofacial abnormalities, hypocalcaemia and lymphopenia are suggestive of an immunodeficiency syndrome (ANZSBT 2011)* NEW proposed addition Discussion: Keep new addition of described non-cardiac features here? Or perhaps add to the congenital immunodeficiency section? (From the NZ guidelines)

Clinical Guidelines Discussion needed regarding Recommendation: From NAC Survey: (18/23 respondents agreed with THIS statement) Although 22q11.2 deletion syndrome (encompasses DiGeorge Syndrome) is most commonly associated with conotruncal lesions, the variety of heart defects described in patients with this syndrome is extensive. In order to avoid missing a neonate or young infant with immunodeficiency, it is recommended that neonates and young infants with congenital heart defects receive irradiated cellular components up to 6 months of age, at which time those suspected of having 22q11.2 deletion syndrome should have been tested for this disorder. Compare with the following recommendation as currently included: Recommendation: All neonates with complex cardiac abnormalities  should receive irradiated cellular components until 22q11.2 deletion associated with immunodeficiency states, which include DiGeorge Syndrome, have been excluded. If 22q11.2 deletion is confirmed, irradiated cellular components should be provided for life (NAC Survey results ).

Clinical features of del 22q11 Discussion: Do we want to include a list of potential (complex) congenital cardiac defects? J Med Genet. 1997;34:798-804

Clinical Recommendations NEW PROPOSED RECOMMENDATION – AUTOLOGOUS CELL SALVAGE Recommendation:  In patients with malignancy undergoing surgery, it is not necessary to irradiate blood collected by intraoperative cell salvage provided that a small-pore microfiber leukoreduction filter is used during blood the preparation process.  

Appendix Updates Appendix A: Quick reference of clinical indications for irradiated blood component transfusion Categories and columns updated to reflect proposed changes within recommendations Far-right “Yes/No” column removed Appendix B: Quick reference of potent immunosuppressive medications thought to increase TA-GVHD risk, and for which irradiated component transfusion should be considered Consideration for adding the following: Anti-thymocyte globulin (ATG), rabbit or horse - When used in the setting of severe aplastic anemia or allogeneic bone marrow transplant only   

Thank you for your attention!