Table 2. Rationale for the stepwise... | American Society of Hematology

Table 2.

Rationale for the stepwise strategy for eligibility for a pediatric SCD curative trial

Pediatric SCD staging system for curative therapies
Stage	Symptoms	Rationale
4	Neurologic event with imminent risk for progression Overt stroke	Near-term significant risk of a second stroke even with regular blood transfusion therapy is 1.9 (95% CI, 1.0-2.9) recurrence strokes per year.¹
3	Nonstroke neurologic event requiring chronic blood transfusion therapy and imminent risk for progression SCI aTCD velocity with MRA-defined vasculopathy	Ongoing risk of infarct recurrence stroke or recurrent cerebral infarcts despite chronic transfusion therapy is 2.0 events per 100 person-y.¹¹ Children with aTCD velocities and regular transfusions still have a higher risk of stroke than children without SCD.¹³
2	Nonneurologic event with rationale indicating imminent risk of progressive vital organ disease or impaired QoL Life-threatening ACS requiring respiratory support in an intensive care unit Right heart catheter confirmed pHTN Essential HTN despite medical therapy Recurrent vaso-occlusive pain while adherent to maximum medical therapy and without unmanaged asthma, adjudication review Recurrent major priapism (lasting at least 4 h), at least twice in 12 mo or 3 times in 24 mo, adjudication review Chronic psychosocial stress	Although risk factors for recurrent life-threatening ACS have not been established, a single event of severe ACS has been deemed life-threatening.^20-22 Right heart catheter–confirmed pHTN in adults with SCD is associated with a markedly increased risk for mortality.^23-26 Blood pressure in SCD is associated with pHTN, SCI, and renal disease. Higher baseline SBP in children is associated with neurologic injury.^27-29 Frequent acute vaso-occlusive pain events despite maximized therapy are associated with decreased QoL improved by HCT.^30-34 A single episode of major priapism lasting >4 h is a major risk factor for permanent sexual dysfunction and permanent erectile dysfunction with no established effective secondary prevention. The impact of repeated priapism episodes are at least equivalent to that of severe pain episodes.^35-37 An adjudication process standardizes when pain clinical management is complex and hydroxyurea therapy is variable.
1	Symptoms with low imminent risk of progressive organ disease or impaired QoL	Asymptomatic or mildly symptomatic without the above symptoms do not have identifiable imminent risk of morbidity or mortality.

Pediatric SCD staging system for curative therapies
Stage	Symptoms	Rationale
4	Neurologic event with imminent risk for progression Overt stroke	Near-term significant risk of a second stroke even with regular blood transfusion therapy is 1.9 (95% CI, 1.0-2.9) recurrence strokes per year.¹
3	Nonstroke neurologic event requiring chronic blood transfusion therapy and imminent risk for progression SCI aTCD velocity with MRA-defined vasculopathy	Ongoing risk of infarct recurrence stroke or recurrent cerebral infarcts despite chronic transfusion therapy is 2.0 events per 100 person-y.¹¹ Children with aTCD velocities and regular transfusions still have a higher risk of stroke than children without SCD.¹³
2	Nonneurologic event with rationale indicating imminent risk of progressive vital organ disease or impaired QoL Life-threatening ACS requiring respiratory support in an intensive care unit Right heart catheter confirmed pHTN Essential HTN despite medical therapy Recurrent vaso-occlusive pain while adherent to maximum medical therapy and without unmanaged asthma, adjudication review Recurrent major priapism (lasting at least 4 h), at least twice in 12 mo or 3 times in 24 mo, adjudication review Chronic psychosocial stress	Although risk factors for recurrent life-threatening ACS have not been established, a single event of severe ACS has been deemed life-threatening.^20-22 Right heart catheter–confirmed pHTN in adults with SCD is associated with a markedly increased risk for mortality.^23-26 Blood pressure in SCD is associated with pHTN, SCI, and renal disease. Higher baseline SBP in children is associated with neurologic injury.^27-29 Frequent acute vaso-occlusive pain events despite maximized therapy are associated with decreased QoL improved by HCT.^30-34 A single episode of major priapism lasting >4 h is a major risk factor for permanent sexual dysfunction and permanent erectile dysfunction with no established effective secondary prevention. The impact of repeated priapism episodes are at least equivalent to that of severe pain episodes.^35-37 An adjudication process standardizes when pain clinical management is complex and hydroxyurea therapy is variable.
1	Symptoms with low imminent risk of progressive organ disease or impaired QoL	Asymptomatic or mildly symptomatic without the above symptoms do not have identifiable imminent risk of morbidity or mortality.

The incremental expansion strategy was developed using rationale based on the time-sensitive nature of brain, heart, lung, and genitourinary disease while receiving optimal medical care.

CI, confidence interval, MRA, magnetic resonance angiography; pHTN, pulmonary hypertension; QoL, quality of life; SBP, systolic blood pressure.

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