ASH Draft Recommendations for SCD Related Transfusion Support

ASH Draft Recommendations for SCD Related Transfusion Support INTRODUCTION American Society of Hematology (ASH) guidelines are based on a systematic review of available evidence. Through a structured process, a guideline panel makes judgements about the evidence and forms recommendations. The public comment period occurs after recommendations are formed but before a manuscript report of the guidelines has been finalized and before ASH organizational approval of the guidelines. Comments collected during the open comment period are provided to the guideline panel for review prior to finalizing the guidelines. These draft recommendations are not final and therefore are not intended for use or citation. To submit comments on the draft recommendations, please visit https://scdtransfusion.questionpro.com. Only comments submitted via the online survey will be reviewed by the guideline panel. The public comment period for these draft recommendations ends October 1, 2018. RECOMMENDATIONS Question 1: Should extended red cell antigen profile at first presentation by genotype* or serology vs. ABO/RhD type only be used for patients with sickle cell disease? The ASH guideline panel suggests an extended red cell antigen profile by genotype or serology over ABO/RhD typing alone in all patients with sickle cell disease (all genotypes) (conditional recommendation; very low certainty evidence). Remarks: Extended antigen profile includes: C, c, E, e, K, Jka, Jkb, Fya, Fyb, M, N, S, s Red cell antigen profiles should be made available across hospital systems Genotyping is preferred over serologic phenotyping (more extensive antigen profile) when feasible A serologic phenotype may be inaccurate if the patient has been transfused in the past 3 months Reduction in alloimmunization requires the use of red cell antigen profiles in conjunction with antigen matching protocols

Question 2: Should prophylactic Rh (C, E or C/c, E/e), and K matched RBCs by serologic or genotype predicted red cell antigen profile/prophylactic Rh (C, E or C/c, E/e), K and extended matched (Jk, Fy, S) RBCs by serologic or genotype predicted red cell antigen profile vs. ABO/RhD matched RBCs be used for patients with SCD receiving transfusions? The ASH guideline panel suggests prophylactic Rh (C, E or C/c, E/e), and K matched red cells by serologic or genotype predicted red cell antigen profile over ABO/RhD matched red cells for patients with sickle cell disease (all genotypes) receiving transfusions (conditional recommendation, very low certainty evidence). Remarks: Extended matching (Jka/Jkb, Fya/Fyb, S/s) may provide further protection from alloimmunization Patients identified by genotype with the hybrid RHD*DIIIa-CE (4-7)-D allele that encodes a partial C antigen and no conventional RHCE*Ce or *CE allele should be transfused with serologic C negative red cells to prevent anti-c formation Question 3: Should immunosuppressive therapy (IVIg, steroids, rituximab) vs. no immunosuppressive therapy be used for patients with sickle cell disease (all genotypes) with acute need for transfusion at high risk of hemolytic transfusion reaction? The ASH guideline panel suggests immunosuppressive therapy (IVIg, steroids, and/or rituximab) over no immunosuppressive therapy in patients with sickle cell disease (all genotypes) with an acute need for transfusion at high risk of acute hemolytic transfusion reaction (i.e. patient with alloantibodies for whom antigen-negative blood is unavailable) or with a history of multiple or life-threatening delayed hemolytic transfusion reaction(s) (conditional recommendation, very low certainty evidence). Remarks: Be judicious with red cell transfusion Have ongoing consultation with a transfusion medicine specialist When choosing the specific agent (IVIg, steroids, and/or rituximab), consider the respective mechanisms of action (e.g., the role of rituximab is to prevent new antibody formation in an at risk individual), adverse effects, and the specific clinical circumstances Engage the patient in the decision-making process

Question 4: Should immunosuppressive therapy (IVIg, steroids, rituximab, eculizumab) vs. no immunosuppressive therapy be used for patients with sickle cell disease (all genotypes) with ongoing hyperhemolysis (defined as rapid hemoglobin decline to below the pre-transfusion level or rapid decline of post-transfusion hemoglobin A)? The ASH guideline panel suggests immunosuppressive therapy (IVIg, steroids, eculizumab, and/or rituximab) over no immunosuppressive therapy in patients with sickle cell disease (all genotypes) with a delayed hemolytic transfusion reaction and ongoing hyperhemolysis (conditional recommendation; very low certainty evidence). Remarks: Hyperhemolysis is defined as a rapid hemoglobin decline to below the pre-transfusion level and rapid decline of post-transfusion hemoglobin A level Immunosuppressive therapy should be initiated promptly in patients with life threatening hyperhemolysis First line immunosuppresive agents include IVIg and high dose steroids; second line agent includes eculizumab Rituximab is primarily indicated for potential prevention of additional alloantibody formation in patients who may require further transfusion Be judicious with red cell transfusion If transfusion cannot be avoided, consider extended matched red cells Supportive care should be initiated in all patients, potentially including epogen, and IV iron Seek consultation with a transfusion medicine specialist Question 5: Should automated red cell exchange (RCE) vs. simple transfusion be used for patients with SCD receiving chronic transfusions? The ASH guideline panel suggests using automated red cell exchange (RCE) over manual RCE or simple transfusion in patients with sickle cell disease (all genotypes) receiving chronic transfusions (conditional recommendation; very low certainty of evidence). Remarks: Peripheral access is preferred, if possible The decision-making process should involve clinical indication; patient preferences, particularly with regard to the need for central venous access; iron overload status and iron chelation compliance; and availability of compatible red cell

Question 6: Should erythrocytapheresis (automated or manual) vs. simple transfusions be used for patients with SCD and moderate to severe acute chest syndrome? 6a. The ASH guideline panel suggests red cell exchange transfusion (automated or manual) over simple transfusions in patients with sickle cell disease and severe acute chest syndrome (conditional recommendation, very low certainty evidence). 6b. The ASH panel suggests either red cell exchange transfusion (automated or manual) or simple transfusions in patients with sickle cell disease and moderate acute chest syndrome (conditional recommendation, very low certainty evidence). Remarks: Provide red cell exchange transfusion to patients with: (1) rapidly progressive ACS; (2) those who do not respond to initial treatment (including simple transfusion); or (3) those with a high hemoglobin level (> 9-10 gm/dl) that precludes administration of simple transfusion When delays with initiation of red cell exchange transfusion are anticipated, administer simple transfusion first while arranging for red cell exchange Question 7: Should red cell exchange (RCE) with isovolemic hemodilution vs. standard red cell exchange (RCE) be used for patients with SCD receiving chronic transfusions? The ASH guideline panel suggests either red cell exchange with isovolemic hemodilution (RCE-IHD) or standard red cell exchange (RCE) in patients with sickle cell disease (all genotypes) receiving chronic transfusions (conditional recommendation; low certainty of evidence). Remarks: Isovolemic hemodilution is contraindicated when acute induction of further anemia may be detrimental (i.e. recent stroke/transient ischemic attack) Question 8: Should prophylactic transfusion at regular intervals vs. standard care (transfusion when clinically indicated for a complication or hemoglobin lower than baseline) be used for pregnant patients with SCD? The ASH guideline panel suggests either prophylactic transfusion at regular intervals or standard care (transfusion when clinically indicated for a complication or hemoglobin lower than baseline) in pregnant patients with sickle cell disease (all genotypes) (conditional recommendation, very low certainty evidence). Remarks: Consider initiating prophylactic transfusion at regular intervals at the onset of pregnancy in women: with a history of SCD-related complications prior to current pregnancy (including during previous pregnancies) with additional features of high risk pregnancy seeking to improve maternal outcomes Women who develop SCD-related complications during the current pregnancy would benefit from initiating regular transfusion.

Question 9: Should pre-operative transfusion vs. no pre-operative transfusion be used for patients with SCD (all genotypes) undergoing surgeries requiring general anesthesia and lasting > 1 hour? The ASH guideline panel suggests pre-operative transfusion over no pre-operative transfusion in patients with sickle cell disease (all genotypes) undergoing surgeries requiring general anesthesia and lasting > 1hour (conditional recommendation based on very low certainty evidence). Decision making should be individualized based on the following factors: Genotype (recommendation based on evidence relating to SS genotype, and SS genotype more likely to require transfusion) Risk level of surgery (higher risk surgery, i.e. neurosurgery or cardiac surgery, more likely to need transfusion) Baseline hemoglobin (lower hemoglobin, i.e. < 9 gm/dl, more likely to need transfusion) Complications with past transfusion Disease phenotype (history of ACS) Remarks: Provide red cell exchange transfusion for patients who require pre-operative transfusion but have a high hemoglobin level (> 9-10 gm/dl) that precludes administration of simple transfusion Question 10a: Should iron overload screening by MRI for liver iron content vs. serial monitoring of ferritin levels alone be used for patients with SCD receiving chronic transfusion therapy with ferritin > 1000 ng/ml? The ASH guideline panel suggests iron overload screening by MRI for liver iron content every 1 to 2 years compared to serial monitoring of ferritin levels alone in patients with sickle cell disease (all genotypes) receiving chronic transfusion therapy (conditional recommendation, very low certainty evidence). Remarks: Use validated methods; if not available, refer to specialized center Use the same method over time If patients are receiving chronic transfusion and on iron chelation, MRI for liver iron content is helpful for titrating iron chelation, regardless of the ferritin level If patients are receiving chronic transfusion by red cell exchange and have no evidence of iron loading (ferritin < 1000 ng/ml), then MRI for liver iron content is likely not needed Question 10b: Should iron overload screening by MRI for cardiac iron content vs. serial monitoring of ferritin levels alone be used for patients with SCD receiving chronic transfusion therapy with ferritin > 1000 ng/ml? The ASH panel suggests against adding routine iron overload screening by MRI for cardiac iron content compared to serial monitoring of ferritin levels alone in patients with sickle cell disease (all genotypes) receiving chronic transfusion therapy (conditional recommendation, very low certainty evidence).

Remarks: The panel suggests screening the subgroup of SCD patients with prolonged (years) high iron burden (LIC > 15 mg/g dw), history of exceptionally elevated liver iron, evidence of end organ damage due to transfusional iron overload, or evidence of cardiac dysfunction Use validated methods; if not available, refer to specialized center Use same method over time

QUESTION 1 Should Extended red cell antigen profile at first presentation by genotype* or serology vs. ABO/RhD type only be used for patients with Sickle Cell Disease? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: Patients with Sickle Cell Disease Extended red cell antigen profile at first presentation by genotype or serology ABO/RhD type only Time to transfusion (delay to treatment); Time to antibody identification; Alloimmunization in CEK matched and extended matched compared to ABO/D matched; Alloimmunization in CEK matched compared to ABO/D matched; Hemolytic transfusion reaction (HTR), in patients with extended matched RBC; Hemolytic transfusion reaction (HTR), in patients with CEK matched RBC; Mortality; Morbidity; SETTING: PERSPECTIVE: BACKGROUND: CONFLICT OF INTEREST: ASSESSMENT Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large Varies Don't know The panel noted potential benefits are: Long term reduction of alloimmunization Facilitation of antibody identification and prevention of subsequent delays in transfusion Identification of rare phenotype The panel expressed concern about the availability of information across hospital systems. The panel noted that reduction in alloimmunization requires use in conjunction with red cell matching protocols.

Outcomes Impact of participants () Certainty of the evidence (GRADE) Time to transfusion (delay to treatment) The transfusion timeline before genotyping was about 1 week, and with extended genotyped-matched blood this changed to 30 days. (1 study) a Alloimmunization 3 compared alloimmunization in patients receiving extended matched Red Blood Cells (RBC), versus non-extended matched RBC, it showed no significant difference, OR: 0.17 (95% CI 0.02 to 1.60, I2=50.2%). (3 ) a Hemolytic transfusion reaction (HTR) The study reported that there were no HTR in the ABO, D, C, E, c, e and Kell matched or in the ABO, D, matched groups. (1 study) a a. High ROB, Imprecision Undesirable Effects How substantial are the undesirable anticipated effects?

Large Moderate Small Trivial Varies Don't know Outcomes Impact of participants () Certainty of the evidence (GRADE) Time to transfusion (delay to treatment) The transfusion timeline before genotyping was about 1 week, and with extended genotyped-matched blood this changed to 30 days. (1 study) a Alloimmunization 3 compared alloimmunization in patients receiving extended matched Red Blood Cells (RBC), versus non-extended matched RBC, it showed no significant difference, OR: 0.17 (95% CI 0.02 to 1.60, I2=50.2%). (3 ) a Hemolytic transfusion reaction (HTR) The study reported that there were no HTR in the ABO, D, C, E, c, e and Kell matched or in the ABO, D, matched groups. (1 study) a a. High ROB, Imprecision Certainty of evidence What is the overall certainty of the evidence of effects?

Very low Low Moderate High No included Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison? Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies Don't know

Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know Within a hypothetical cohort of initially transfusion-naïve patients, implementing prophylactic limited matching for chronically transfused patients instead of history-based limited matching is expected to cost an additional $766 million over 10 years, but result in 2,072 fewer alloimmunization events. Within the same cohort, implementing prospective extensive matching is expected to cost $1.86 billion more than history-based extensive matching, but result in 2,424 fewer alloimmunization events. The panel judged that cost of antigen profiles by serology or genotype is small over the transfusion lifetime of the patient. The panel noted that cost would be reduced if hospital systems exchange information to avoid duplicate testing. Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison? Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies No included Within a hypothetical cohort of initially transfusion-naïve patients, implementing prophylactic limited matching for chronically transfused patients instead of history-based limited matching is expected to cost an additional $766 million over 10 years, but result in 2,072 fewer alloimmunization events. Within the same cohort, implementing prospective extensive matching is expected to cost $1.86 billion more than history-based extensive matching, but result in 2,424 fewer alloimmunization events. Averting a single alloimmunization event using prospective matching would cost $369,482 769,284. Among a dynamic population over 10 years, prospective limited matching is expected to cost $358 million more than history-based limited matching. The panel judged that the identified evidence is not relevant. The panel noted that antigen profiles by serology or genotype could be cost effective if it reduced transfusion delays. Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased

Increased Varies Don't know Acceptability Is the intervention acceptable to key stakeholders? No Probably no Probably yes Yes Varies Don't know Feasibility Is the intervention feasible to implement? No Probably no Probably yes Yes Varies Don't know The panel noted that some laboratories will need to accommodate additional work. SUMMARY OF JUDGEMENTS JUDGEMENT DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included

JUDGEMENT VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies No included EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know TYPE OF RECOMMENDATION Strong recommendation against the intervention Conditional recommendation against the intervention Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention CONCLUSIONS Recommendation The ASH guideline panel suggests an extended red cell antigen profile by genotype or serology over ABO/RhD typing alone in all patients with sickle cell disease (all genotypes) (conditional recommendation; very low certainty evidence). Remarks: Extended antigen profile includes: C, c, E, e, K, Jka, Jkb, Fya, Fyb, M, N, S, s Red cell antigen profiles should be made available across hospital systems Genotyping is preferred over serologic phenotyping (more extensive antigen profile) when feasible

A serologic phenotype may be inaccurate if the patient has been transfused in the past 3 months Reduction in alloimmunization requires the use of red cell antigen profiles in conjunction with antigen matching protocols Justification Subgroup considerations The extended antigen profile at initial presentation to an institution (clinic, inpatient) expedites transfusion for patients presenting with a positive antibody screen, as typing red blood cells for the corresponding antigen must be performed as part of antibody identification but is not accurate for patients recently transfused (unless performed by genotyping which has at least a 48 hour turn around). Implementation considerations Establishment of a shared registry of red blood cell antigen typing by genotype or phenotype for patients with sickle cell disease, in conjunction with a red blood cell alloantibody registry, would be informative, decrease duplication of testing, and would improve transfusion safety. National and/or international registries should be considered. Monitoring and evaluation Research priorities

Development and comparison of new sequencing methods to traditional genotyping platforms that may improve accuracy, increase availability, and decrease cost. Development of low-cost genotyping methods to identify patients with RH variants. GRADE Evidence Profile Question 1: Extended red cell antigen profile at first presentation by genotype or serology compared to ABO/RhD type only in Patients with Sickle Cell Disease Certainty assessment of Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Impact Certainty Importance Time to transfusion (delay to treatment) Time to transfusion was not reported in any study - Time to antibody identification Time to antibody identification was not reported in any study - Alloimmunization in CEK matched and extended matched compared to ABO/D matched 1 not serious not serious serious serious a none IRR of 0.30 (95% CI: 0.14 to 0.58). CRITICAL Alloimmunization in CEK matched compared to ABO/D matched 1 not serious not serious serious serious none IRR: 0.17 (95% CI: 0.05 to 0.51) Hemolytic transfusion reaction (HTR), in patients with extended matched RBC 2 serious a not serious serious not serious none 2 reported HTR events in patients with extended matched RBC, the pooled rate was 0% (95% CI 0% to 3%, I2= 0). CRITICAL Hemolytic transfusion reaction (HTR), in patients with CEK matched RBC

of Certainty assessment Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Impact Certainty Importance 1 serious not serious serious serious none One study reported HTR events in patients with CEK matched, with a rate of 3% (95% CI: 1% to 11%) Mortality Mortality was not reported in any study - Morbidity Morbidly was not reported in any study - CI: Confidence interval; OR: Odds ratio Explanations a. High ROB, Imprecision

QUESTION 2 Should Prophylactic Rh (C, E or C/c, E/e), and K matched RBCs by serologic or genotype predicted red cell antigen profile// Prophylactic Rh (C, E or C/c, E/e), K and extended matched (Jk, Fy, S) RBCs by serologic or genotype predicted red cell antigen profile vs. ABO/RhD matched RBCs be used for Patients with SCD receiving transfusions? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: Patients with sickle cell disease receiving transfusions Prophylactic Rh (C, E or C/c, E/e), and K matched RBCs by serologic or genotype predicted red cell antigen profile Prophylactic Rh (C, E or C/c, E/e), K and extended matched (Jk, Fy, S) RBCs by serologic or genotype predicted red cell antigen profile ABO/RhD matched RBCs Alloimmunization rate, CEK matched and extended matched vs. ABO/D matched; Alloimmunization rate, CEK matched vs. ABO/D matched; Alloimmunization rate; Hemolytic transfusion reactions (HTR) in extended matched RBC; Hemolytic transfusion reactions (HTR) in CEK matched RBC; Alloimmunization prevalence; Mortality; Morbidity; Acute chest syndrome, CEK matched vs. no transfusion; Fever, CEK matched vs. ABO/D matched; Allergic reaction, CEK matched vs. ABO/D matched; SETTING: PERSPECTIVE: BACKGROUND: CONFLICT OF INTEREST: ASSESSMENT Desirable Effects How substantial are the desirable anticipated effects?

Trivial Small Moderate Large Varies Don't know Outcomes of participants () Follow up Certainty of the evidence (GRADE) Relative effect (95% CI) Anticipated absolute effects * (95% CI) Risk with ABO/RhD matched RBCs Risk difference with Prophylactic Rh (C, E or C/c, E/e), and K matched RBCs by serologic or genotype predicted red cell antigen profile// Prophylactic Rh (C, E or C/c, E/e), K and extended matched (Jk, Fy, S) RBCs by serologic or genotype predicted red cell antigen profile Alloimmunization rate CEK matched and extended matched vs. ABO/D matched 0 (1 study) Rate ratio 0.30 (0.14 to 0.58) 0 per 0 fewer per (0 fewer

to 0 fewer) Alloimmunization rate CEK matched vs. ABO/D matched 0 (1 study) Rate ratio 0.17 (0.05 to 0.51) 0 per 0 fewer per (0 fewer to 0 fewer) Alloimmunization rate 0 (21 ) VERY a - 21 reported alloimmunization incidence rate in patients with extended matched RBC transfusion. 5 reported alloimmunization rate in extended matched patients with a pooled rate of 8% (95% CI: 2% to 18%, I2=77.5%). 15 reported alloimmunization rate in CEK matched patients, the pooled rate was 18% (95% CI: 10% to 27%, I2=92.8%). One study reported alloimmunization rate in patients with both CEK matched and extended matched RBC, with a rate of 18% (95% CI: 8% to 34%), 5 2-6 reported alloimmunization rate in ABO/D matched patients with a pooled rate of 35%

(95% CI: 19% to 53%, I2=91.62%). Hemolytic transfusion reactions (HTR) in extended matched RBC 112 (2 ) VERY b not estimable 0 per 0 fewer per (0 fewer to 0 fewer) Hemolytic transfusion reactions (HTR) in CEK matched RBC 63 (1 study) Rate 3 (1 to 11) 0 per 0 fewer per (0 fewer to 0 fewer) Alloimmunization prevalence 0 (25 ) VERY b - C: 5.5%, D: 1.7%, Duffy: 1.4%, E: 9.2%, Fy: 1.6%, Fya: 2.8%, Go: 1.1%, Js: 3.3%, Jsa: 0.6%, K: 5.8%, Kell: 2.3%, Kidd: 3.3%, Kpa: 1.1%, Lea: 1.0%, Lutheran: 1.7%, M: 1.3%, MNSs: 5.9%, S: 2.1%, V: 2%, Wra: 0.7%. Mortality 0 ( ) - - Mortality was not reported in any study.

Morbidity 0 (5 ) - 1) 4 cases of HTN, 3 cases of vasoocclusive crisis, and 1 case of TIA in 63 patients in the CEK matched transfusion group. 2) 5% ACS, 32% vaso-occusive pain, 1% priapism, and 1% symptomatic avascular necrosis of the hip in the CEK matched. Acute chest syndrome CEK matched vs. no transfusion 129 (1 study) OR 0.29 (0.10 to 0.86) 227 per 149 fewer per (199 fewer to 25 fewer) Fever CEK matched vs. ABO/D matched 500 (1 study) OR 0.16 (0.01 to 2.72) 26 per 22 fewer per (26 fewer to 41 more) Allergic reaction CEK matched vs. ABO/D matched 500 (1 study) OR 0.070 (0.004 to 1.130) 59 per 55 fewer per (59 fewer

to 7 more) a. Inconsistency b. High risk of bias Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial Varies Don't know The panel judged that delays in transfusion would be a potential harm.

Outcomes of participants () Follow up Certainty of the evidence (GRADE) Relative effect (95% CI) Anticipated absolute effects * (95% CI) Risk with ABO/RhD matched RBCs Risk difference with Prophylactic Rh (C, E or C/c, E/e), and K matched RBCs by serologic or genotype predicted red cell antigen profile// Prophylactic Rh (C, E or C/c, E/e), K and extended matched (Jk, Fy, S) RBCs by serologic or genotype predicted red cell antigen profile Alloimmunization rate CEK matched and extended matched vs. ABO/D matched 0 (1 study) Rate ratio 0.30 (0.14 to 0.58) 0 per 0 fewer per (0 fewer

to 7 more) a. Inconsistency b. High risk of bias Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability

Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison? Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies Don't know Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison?

Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies No included Within a hypothetical cohort of initially transfusion-naïve patients, implementing prophylactic limited matching for chronically transfused patients instead of history-based limited matching is expected to cost an additional $766 million over 10 years, but result in 2,072 fewer alloimmunization events. Within the same cohort, implementing prospective extensive matching is expected to cost $1.86 billion more than history-based extensive matching, but result in 2,424 fewer alloimmunization events. Averting a single alloimmunization event using prospective matching would cost $369,482 769,284. Among a dynamic population over 10 years, prospective limited matching is expected to cost $358 million more than history-based limited matching. The panel judged that the identified data was not informative, since the cost model used was hypothetical. Cost was based on manual serology versus automated genotyping which would cost less. Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know Acceptability Is the intervention acceptable to key stakeholders? No Probably no Probably yes Yes Varies Don't know Feasibility Is the intervention feasible to implement?

No Probably no Probably yes Yes Varies Don't know SUMMARY OF JUDGEMENTS JUDGEMENT DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies No included EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know

Consider extended matching in patients who already have developed multiple antibodies associated with hemolytic transfusion reaction Establishment of a shared registry of red blood cell alloantibodies for patients with sickle cell disease, in conjunction with information about a patient s red blood cell antigen profile (by genotype or phenotype), would be informative, decrease duplication of testing, and improve transfusion safety. National and/or international registries should be considered. Monitoring and evaluation Research priorities Studies investigating the logistical feasibility of providing extended matched red blood cells. Studies evaluating the feasibility of RH matching by genotype. Studies comparing outcomes of Rh and K matched red blood cells versus a higher level of matching, including extended antigen matching or RH genotype matching, in clinical scenarios with a higher risk of red blood cell alloimmunization (e.g. acute chest syndrome). Development of tools/models to predict the risk of alloimmunization in patients with sickle cell disease.

GRADE Evidence Profile Question 2: Prophylactic Rh (C, E or C/c, E/e), and K matched RBCs by serologic or genotype predicted red cell antigen profile// Prophylactic Rh (C, E or C/c, E/e), K and extended matched (Jk, Fy, S) RBCs by serologic or genotype predicted red cell antigen profile compared to ABO/RhD matched RBCs in Patients with sickle cell disease receiving transfusions Certainty assessment of patients Effect of Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Prophylactic Rh (C, E or C/c, E/e), and K matched RBCs by serologic or genotype predicted red cell antigen profile// Prophylactic Rh (C, E or C/c, E/e), K and extended matched (Jk, Fy, S) RBCs by serologic or genotype predicted red cell antigen profile ABO/RhD matched RBCs Relative (95% CI) Absolute (95% CI) Certainty Importance Alloimmunization rate CEK matched and extended matched vs. ABO/D matched 1 not serious not serious not serious not serious none Rate ratio 0.30 (0.14 to 0.58) -- per 1000 patient(s) per years (from -- to --) Alloimmunization rate CEK matched vs. ABO/D matched 1 not serious not serious not serious not serious none Rate ratio 0.17 (0.05 to 0.51) -- per 1000 patient(s) per years (from -- to --) Alloimmunization rate 21 not serious serious a not serious not serious none 21 reported alloimmunization incidence rate in patients with extended matched RBC transfusion. 5 reported alloimmunization rate in extended matched patients with a pooled rate of 8% (95% CI: 2% to 18%, I2=77.5%). 15 reported alloimmunization rate in CEK matched patients, the pooled rate was 18% (95% CI: 10% to 27%, I2=92.8%). One study reported alloimmunization rate in patients with both CEK matched and extended matched RBC, with a rate of 18% (95% CI: 8% to 34%), 5 2-6 reported alloimmunization rate in ABO/D matched patients with a pooled rate of 35% (95% CI: 19% to 53%, I2=91.62%). CRITICAL

Certainty assessment of patients Effect of Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Prophylactic Rh (C, E or C/c, E/e), and K matched RBCs by serologic or genotype predicted red cell antigen profile// Prophylactic Rh (C, E or C/c, E/e), K and extended matched (Jk, Fy, S) RBCs by serologic or genotype predicted red cell antigen profile ABO/RhD matched RBCs Relative (95% CI) Absolute (95% CI) Certainty Importance Hemolytic transfusion reactions (HTR) in extended matched RBC 2 serious b not serious not serious not serious none 1/112 (0.9%) - - - CRITICAL Hemolytic transfusion reactions (HTR) in CEK matched RBC 1 serious not serious not serious not serious none 2/63 (3.2%) - - - Alloimmunization prevalence 25 very serious b not serious not serious not serious none C: 5.5%, D: 1.7%, Duffy: 1.4%, E: 9.2%, Fy: 1.6%, Fya: 2.8%, Go: 1.1%, Js: 3.3%, Jsa: 0.6%, K: 5.8%, Kell: 2.3%, Kidd: 3.3%, Kpa: 1.1%, Lea: 1.0%, Lutheran: 1.7%, M: 1.3%, MNSs: 5.9%, S: 2.1%, V: 2%, Wra: 0.7%. CRITICAL Mortality Mortality was not reported in any study. - Morbidity 5 not serious not serious not serious not serious none 1) 4 cases of HTN, 3 cases of vasoocclusive crisis, and 1 case of TIA in 63 patients in the CEK matched transfusion group. 2) 5% ACS, 32% vaso-occusive pain, 1% priapism, and 1% symptomatic avascular necrosis of the hip in the CEK matched. CRITICAL

Certainty assessment of patients Effect of Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Prophylactic Rh (C, E or C/c, E/e), and K matched RBCs by serologic or genotype predicted red cell antigen profile// Prophylactic Rh (C, E or C/c, E/e), K and extended matched (Jk, Fy, S) RBCs by serologic or genotype predicted red cell antigen profile ABO/RhD matched RBCs Relative (95% CI) Absolute (95% CI) Certainty Importance Acute chest syndrome CEK matched vs. no transfusion 1 serious not serious not serious not serious none 5/63 (7.9%) 15/66 (22.7%) OR 0.29 (0.10 to 0.86) 149 fewer per (from 25 fewer to 199 fewer) Fever CEK matched vs. ABO/D matched 1 not serious not serious not serious serious none 0/113 (0.0%) 10/387 (2.6%) OR 0.16 (0.01 to 2.72) 22 fewer per (from 26 fewer to 41 more) Allergic reaction CEK matched vs. ABO/D matched 1 not serious not serious not serious serious none 0/113 (0.0%) 23/387 (5.9%) OR 0.070 (0.004 to 1.130) 55 fewer per (from 7 more to 59 fewer) CI: Confidence interval; OR: Odds ratio Explanations a. Inconsistency b. High risk of bias

QUESTION 3 Should Immunosuppressive therapy (IVIg, steroids, rituximab) vs. No immunosuppressive therapy be used for patients with sickle cell disease (all genotypes) with acute need for transfusion at high risk of hemolytic transfusion reaction.? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: Patients with SCD (all genotypes) with acute need for transfusion at high risk of hemolytic transfusion reaction. Immunosuppressive therapy (IVIg, steroids, rituximab) No immunosuppressive therapy Alloimmunization; Hemolytic transfusion reaction (HTR); ICU admission; Mortality; Infection; Pain; Adverse effects (aseptic meningitis, avascular necrosis (AVN)); SETTING: PERSPECTIVE: BACKGROUND: CONFLICT OF INTEREST: ASSESSMENT Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large Varies Don't know The panel judged that any benefit would likely vary dependent on the clinical scenario. Illustrative scenarios 1- Patients with urgent need for transfusion with alloantibodies and but for whom there is inability to find antigen-negative blood, with a historical antibody not currently present 2- Patients with urgent need for transfusion with alloantibodies but for whom there is inability to find antigen-negative blood and the corresponding antibody is currently present 3- Patients with history of at least one hemolytic transfusion reaction (either acute or delayed) with no antibody identified

Outcomes Impact of participants () Certainty of the evidence (GRADE) 4- Patients with history of multiple delayed hemolytic transfusion reactions despite optimal red cell matching 5- Patients with history of severe life threatening DHTR with or without hyperhemolysis despite optimal red cell matching Alloimmunization 1 case series with 8 patients reported no new alloantibodies after treatment, while a case report reported new reactivity in two of seven screening cells that were negative for the antigens against which he had previously identified antibodies. (1 study) a Hemolytic transfusion reaction (HTR) The case series with 8 patients reported 4 hemolytic transfusion reactions and one case report reported a hemolytic transfusion reaction. (1 study) a ICU admission The case series with 8 patients reported 1 ICU admission and one case report reported 1 ICU admission. (1 study) a Mortality The case report reported one case of mortality. (1 study) b Infection The case report reported that the patients did not develop an infection. (1 study) b

Pain The case report reported that the patient developed severe whole body pain 3 days after the transfusion. (1 study) b Adverse effects (aseptic meningitis, avascular necrosis (AVN)) The case series of 8 patients reported 3 patients with post-transfusion vasoocclusive crisis and hemoglobinuria. This study also reported no severe adverse events. A case report reported that the patient developed respiratory failure and fever. (1 study) a a. High risk of selection bias b. High selection bias Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial Varies Don't know Outcomes Impact of participants () Certainty of the evidence (GRADE) Alloimmunization 1 case series with 8 patients reported no new alloantibodies after treatment, while a case report reported (1 study) a

new reactivity in two of seven screening cells that were negative for the antigens against which he had previously identified antibodies. Hemolytic transfusion reaction (HTR) The case series with 8 patients reported 4 hemolytic transfusion reactions and one case report reported a hemolytic transfusion reaction. (1 study) a ICU admission The case series with 8 patients reported 1 ICU admission and one case report reported 1 ICU admission. (1 study) a Mortality The case report reported one case of mortality. (1 study) b Infection The case report reported that the patients did not develop an infection. (1 study) b Pain The case report reported that the patient developed severe whole body pain 3 days after the transfusion. (1 study) b Adverse effects (aseptic meningitis, avascular necrosis (AVN)) The case series of 8 patients reported 3 patients with post-transfusion vasoocclusive crisis and hemoglobinuria. This study also reported no severe adverse events. A case (1 study) a

report reported that the patient developed respiratory failure and fever. a. High risk of selection bias b. High selection bias Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability

Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison? Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies Don't know Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know The panel noted that cost will vary by the specific medication. Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison?

Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies No included Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know Acceptability Is the intervention acceptable to key stakeholders? No Probably no Probably yes Yes Varies Don't know Feasibility Is the intervention feasible to implement?

TYPE OF RECOMMENDATION Strong recommendation against the intervention Conditional recommendation against the intervention Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention CONCLUSIONS Recommendation The ASH guideline panel suggests immunosuppressive therapy (IVIg, steroids, and/or rituximab) over no immunosuppressive therapy in patients with sickle cell disease (all genotypes) with an acute need for transfusion at high risk of acute hemolytic transfusion reaction (i.e. patient with alloantibodies for whom antigen-negative blood is unavailable) or with a history of multiple or life-threatening delayed hemolytic transfusion reaction(s) (conditional recommendation, very low certainty evidence). Remarks: Be judicious with red cell transfusion Have ongoing consultation with a transfusion medicine specialist When choosing the specific agent (IVIg, steroids, and/or rituximab), consider the respective mechanisms of action (e.g., the role of rituximab is to prevent new antibody formation in an at risk individual), adverse effects, and the specific clinical circumstances Engage the patient in the decision-making process Justification In patients who develop life-threatening anemia or a SCD-related complication that requires RBC transfusion but are at high risk of an acute hemolytic transfusion reaction (i.e. patient with alloantibodies for whom antigen-negative blood is unavailable) or have a history of multiple or life-threatening delayed hemolytic transfusion reaction(s), the potential benefit of immunosuppression likely outweighs the potential harms (i.e. medication side effects). Subgroup considerations Determination of an individual s risk for an acute or delayed hemolytic transfusion reaction is multifactorial. The patient s alloantibody specificities and their general clinical significance, ability to identify the antibody, ability to obtain sufficient antigen negative donor units, severity and number of prior hemolytic transfusion reactions, and the patient s current concomitant comorbidities should all be considered in the decision whether to treat with immunosuppression and the choice of therapy. Implementation considerations

Delayed hemolytic transfusion reaction (DHTR) is defined as a significant drop in hemoglobin within 21 days post transfusion associated with one or more of the following: new red cell alloantibody (or alloantibodies), hemoglobinuria, accelerated Hb S% increase with a concomitant fall in Hb A post-transfusion, relative reticulocytopenia or reticulocytosis from baseline, or significant lactate dehydrogenase (LDH) rise from baseline, and exclusion of an alternative cause. In patients with an acute need for transfusion at high risk of an acute hemolytic transfusion reaction (i.e. patient with alloantibodies for whom antigen-negative blood is unavailable) or with a history of multiple or lifethreatening delayed hemolytic transfusion reaction(s), immunosuppression may reduce the risk. However, transfusion should be used judiciously as the efficacy of immunosuppression in preventing a HTR is highly variable. Choice of therapy is dependent on the clinical situation and may warrant different approaches. Steroids and IVIg may be more effective at preventing antibody mediated destruction of transfused red blood cells and Rituximab is primarily indicated for potential prevention of additional alloantibody formation. Monitoring and evaluation In patients with an acute need for transfusion at high risk of acute or delayed hemolytic transfusion reaction, a pre- and post-transfusion hemoglobin quantification is recommended. If a HTR is suspected, measuring the proportion of hemoglobin A, S, and C is recommended, in addition to serial monitoring of the hemoglobin, hematocrit, and reticulocyte count. Research priorities Tools or models to predict the clinical relevance of alloantibodies in a given patient. Studies of the mechanism(s) responsible for red blood cell clearance following incompatible transfusion against different RBC antigens. Studies of methods to prevent alloantibody-mediated red blood cell clearance. High quality to evaluate the efficacy of current immunomodulatory agents in preventing hemolytic transfusion reactions in at risk patients. GRADE Evidence Profile Question 3: Immunosuppressive therapy (IVIG, steroids, rituximab) compared to No immunosuppressive therapy in Patients with SCD (all genotypes) with acute need for transfusion at high risk of hemolytic transfusion reaction. Certainty assessment of Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Impact Certainty Importance Alloimmunization 1 very serious a not serious not serious not serious none 1 case series with 8 patients reported no new allo-antibodies after treatment, while a case report reported new reactivity in two of seven screening cells that were negative for the antigens against which he had previously identified antibodies. CRITICAL