In total, 8132 unique citations were identified in initial literature search (September 2019) and two update searches (latest: February 2023), see flowchart 1.

Flowchart 1

Flowchart of the inclusion and exclusion process (including the interim updates)

 

Four primary studies (3 RCTs, 1 pre-post trial) were included with a total number of 203 participants (see Fig. 1 in Supplemental Materials S6). All primary study characteristics and conclusions of evidence are shown in Supplemental Materials S6, including the inclusion and exclusion process. Moreover, seven (non-childhood cancer) guidelines were included with a total of 43 different single studies. An overview of the included studies, the conclusions of evidence, the evidence tables, and the GRADE assessments can be found in the Supplemental Materials S7. An overview of RBC transfusion recommendations for children and neonates with cancer is presented in Supplemental Materials S8. Within the overview of all recommendations, a color-coding system was used to improve understandability and to emphasize the strength of the recommendations. Below, all recommendations and their evidence-to-decision processes are discussed per subject. Given the number of recommendations and the extent of the supporting materials, only conclusions and important considerations of the guideline panel are shown. Full details, including the evidence to decision frameworks, are shown in the Supplemental Materials S9. The results section is divided into the different circumstances in which we recommend a prophylactic RBC transfusion. An overview of the recommendations for scientific research is included in Supplemental Materials S10.

The recommendations on RBC transfusions for children and neonates with cancer are visualized below (Figs. 1 and 2). These flowcharts are also offered separately with measurements of Hb in g/dL.

Fig. 1

Flowchart of RBC transfusion recommendations for children with cancer

Fig. 2

Flowchart of RBC transfusion recommendations for neonates with cancer

Prophylactic red blood cell transfusion in generalProphylactic red blood cell transfusion in children with cancer Recommendation 1.1.1.

We suggest a hemoglobin (Hb) threshold of 4.3 mmol/L for RBC transfusion in children with cancer. (weak recommendation, very low quality evidence).

Recommendation 1.1.2.

We suggest against an Hb threshold of 3.7 mmol/L for RBC transfusion in children with cancer. (weak recommendation, very low quality evidence).

Recommendation 1.1.3.

We recommend against an Hb threshold of 3.1 mmol/L or lower for RBC transfusion in children with cancer. (strong recommendation, very low quality evidence).

Recommendation 1.1.4.

We suggest against an Hb threshold greater than 4.3 mmol/L for RBC transfusion in children with cancer. (weak recommendation, very low quality evidence).

Evidence to decision

The comparison of an Hb threshold of 4.3 mmol/L to an Hb threshold greater than 4.3 mmol/L involved two pediatric oncology studies, one pediatric non-cancer study, and five adult non-cancer studies. Apart from significantly lower costs, there was no significant increased risk for mortality, morbidity, and transfusion-related complications with a threshold Hb of 4.3 mmol/L in comparison to an Hb threshold greater than 4.3 mmol/L in children with cancer (VERY LOW quality of evidence) [1, 10]. From the guidelines that included single studies with children in general and adults, one adult study reported significantly higher mortality in the group with an Hb < 4.3 mmol/L in comparison to an Hb > 4.3 mmol/L in group [11]. Another adult study reported significantly lower mortality in the group with an Hb < 4.3 mmol/L in comparison to an Hb > 4.3 mmol/L in group [12], while six other pediatric studies with cancer and adult studies reported no significant difference in mortality [1, 10, 12,13,14,15]. Based on the available evidence, the panel concluded that there is likely no increased mortality risk. Additionally, two studies demonstrated fewer infections with an Hb threshold of 4.3 mmol/L compared to an Hb threshold greater than 4.3 mmol/L [12, 16]. Furthermore, there was no significant increase in quality of life with a higher Hb threshold than 4.3 mmol/L [12]. Considering these findings, the guideline panel determined that the benefits of maintaining an Hb threshold of 4.3 mmol/L compared to an Hb threshold greater than 4.3 mmol/L are likely substantial. Therefore, we suggest an Hb threshold of 4.3 mmol/L in children with cancer. Moreover, no other study reported significant increase in benefits or harms from a higher Hb threshold, such as 5.0 mmol/L [1, 12, 14, 16,17,18,19]. Also, the guideline panel considered the potential risks of iron overload and increased costs associated with a higher Hb threshold, and therefore, we suggest against adopting an Hb threshold greater than 4.3 mmol/L.

Regarding the comparison of an Hb threshold of 3.7 mmol/L to an Hb threshold greater than 3.7 mmol/L, no pediatric oncology studies were found. However, there were two adult non-cancer studies identified from the included guidelines. Pooled results indicated a significantly increased mortality risk in adult patients with an Hb threshold of 3.7 mmol/L in comparison to an Hb threshold greater than 3.7 mmol/L [11, 13]. Similar to the previous comparison, no studies reported any potential benefit from an Hb threshold of 3.7 mmol/L. Therefore, we suggest against an Hb threshold of 3.7 mmol/L.

Regarding the comparison of an Hb threshold of 3.1 mmol/L to an Hb threshold greater than 3.1 mmol/L, no pediatric oncology studies were found. However, there were three adult non-cancer studies and one pediatric non-cancer study identified from the included guidelines. These studies consistently reported significantly higher mortality rates in hospitalized adults and children with an Hb of 3.1 mmol/L [11, 13, 20, 21]. Despite the low level of evidence, which is mainly derived from adult studies, the guideline panel strongly advised against offering this option due to the higher mortality rates.

Prophylactic red blood cell transfusion in neonates with cancer Recommendation 1.2.1.

We suggest an Hb threshold of 6.5 mmol/L for RBC transfusion in neonates with cancer when they are less than 1 week old.

(weak recommendation, very low quality evidence).

Recommendation 1.2.2.

We suggest an Hb threshold of 5.5 mmol/L for RBC transfusion in neonates with cancer when they are between 1 and 3 weeks old.

(weak recommendation, very low quality evidence).

Recommendation 1.2.3.

We suggest an Hb threshold of 4.5 mmol/L for RBC transfusion in neonates with cancer when they are between 3 and 4 weeks old.

(weak recommendation, very low quality evidence).

Evidence to decision

The incidence of cancer in neonates is exceedingly low. Despite this, it is crucial to provide recommendations for this specific patient group. Unfortunately, no pediatric oncology studies were identified to inform the guideline panel’s decision. However, the Dutch Association of Medical Specialists (FMS) [22] developed a high-quality guideline addressing this matter, receiving an AGREE II-score of 6 out of 7. They provided recommendations primarily based on studies conducted in very low birth-weight infants (birth weight of 1500 g or less). Although evidence specific to full-term and late-premature neonates (gestational age ≥ 32 weeks) is lacking, the FMS has adopted these thresholds for neonates in general. Considering the lack of evidence, the guideline panel decided to adopt the recommendations regarding neonates with cancer from the guideline of the FMS (2019).

Prophylactic red blood cell transfusion—sepsisProphylactic red blood cell transfusion in children with cancer during sepsis Recommendation 2.1.1.

We suggest an Hb threshold of 4.3 mmol/L for RBC transfusion in children with cancer during sepsis who are hemodynamically stable.

(weak recommendation, very low quality evidence).

Recommendation 2.1.2.

We believe that for hemodynamically unstable children with cancer during sepsis and evidence of oxygen deficiency (e.g., use of inotropes, elevated lactate), an Hb threshold that ranges between 4.3 and 6.2 mmol/L should be considered.

(expert opinion).

Evidence to decision

Regarding children with cancer during sepsis who are hemodynamically stable, one pediatric non-cancer study and one adult non-cancer study were identified. Based on this limited evidence, there is no suggestions that there is an increased risk for mortality or morbidity with an Hb threshold of 4.3 mmol/L in comparison to an Hb threshold greater than 4.3 mmol/L in children and adults with sepsis who are clinically stable [17, 23]. Furthermore, no studies reported any significant potential benefit from an Hb threshold greater than 4.3 mmol/L [17]. Therefore, we suggest an Hb threshold of 4.3 mmol/L in children with cancer during sepsis who are hemodynamically stable. However, in hemodynamically unstable children with cancer during sepsis and evidence of oxygen deficiency (e.g., use of inotropes, elevated lactate), it is suggested to consider an Hb threshold ranging between 4.3 mmol/L and 6.2 mmol/L as part of a comprehensive approach to improve oxygen delivery for children with unstable non hemorrhagic shock and evidence of oxygen debt (WEAK recommendation) [24].

Prophylactic red blood cell transfusion in neonates with cancer during sepsis Recommendation 2.2.1.

We suggest an Hb threshold of 6.5 mmol/L for RBC transfusion in neonates with cancer during sepsis when they are less than 1 week old.

(weak recommendation, very low quality evidence).

Recommendation 2.2.2.

We suggest an Hb threshold of 5.5 mmol/L for RBC transfusion in neonates with cancer during sepsis when they are between 1 and 3 weeks old.

(weak recommendation, very low quality evidence).

Recommendation 2.2.3.

We suggest an Hb threshold of 4.5 mmol/L for RBC transfusion in neonates with cancer during sepsis when they are between 3 and 4 weeks old.

(weak recommendation, very low quality evidence).

Evidence to decision

There were no studies found on neonates with cancer during sepsis. There was no suggestion for an increased risk for mortality and morbidity in hemodynamically stable children and adults with sepsis with an Hb threshold of 4.3 mmol/L in comparison to an Hb threshold greater than 4.3 mmol/L (“Prophylactic red blood cell transfusion in children with cancer during sepsis” section) [17, 23, 24]. Therefore, we concluded that children with sepsis do not derive additional benefits from a higher Hb threshold compared to children without sepsis. Based on these findings, and the absence of direct evidence in neonates with sepsis, the guideline panel determined that the recommendations for neonates with cancer can be applied to neonates with cancer during sepsis as well (“Prophylactic red blood cell transfusion in neonates with cancer” section).

Prophylactic red blood cell transfusion—radiotherapyProphylactic red blood cell transfusion in children who undergo radiotherapy Recommendation 3.1.1.

We believe an Hb threshold of 4.3 mmol/L for RBC transfusion should be maintained in children with cancer who undergo radiotherapy.

(expert opinion).

Evidence to decision

No studies specifically addressing children with cancer undergoing radiotherapy were identified. Several other studies including adults with cancer concluded that there was no improvement in outcomes with an Hb threshold greater than 4.3 mmol/L [25,26,27,28]. Therefore, we suggest an Hb threshold of 4.3 mmol/L for RBC transfusion in children with cancer who undergo radiotherapy.

Prophylactic red blood cell transfusion in neonates who undergo radiotherapy Recommendation 3.2.1.

We believe an Hb threshold of 6.5 mmol/L for RBC transfusion should be maintained in neonates with cancer who undergo radiotherapy when they are less than 1 week old.

(expert opinion).

Recommendation 3.2.2.

We believe an Hb threshold for RBC transfusion of 5.5 mmol/L should be maintained in neonates with cancer who undergo radiotherapy when they are between 1 and 3 weeks old.

(expert opinion).

Recommendation 3.2.3.

We believe an Hb threshold for RBC transfusion of 4.5 mmol/L should be maintained in neonates with cancer who undergo radiotherapy when they are between 3 and 4 weeks old.

(expert opinion).

Evidence to decision

No specific studies in neonates with cancer were identified. For the considerations of the recommendations we refer to “Prophylactic red blood cell transfusion in children who undergo radiotherapy” section.

Prophylactic red blood cell transfusion—cardiac and pulmonary comorbiditiesProphylactic red blood cell transfusion in children with cancer with cardiac and/or pulmonary comorbidities Recommendation 4.1.1.

We suggest an Hb threshold of 4.3 mmol/L for RBC transfusion in children with cancer and cardiac and/or pulmonary comorbidities.

(weak recommendation, very low quality evidence).

Recommendation 4.1.2.

We believe that in case of a hemodynamically unstable child with cancer and pulmonary and/or cardiac comorbidities (e.g., use of inotropes, elevated lactate), a higher Hb threshold can be considered.

(weak recommendation, very low quality evidence).

Recommendation 4.1.3.

For children on ECMO:

In critically ill children on ECMO, there is insufficient evidence to recommend a specific RBC transfusion decision-making strategy using physiologic-based metrics and biomarkers.

In critically ill children on ECMO, we believe in using physiologic metrics and biomarkers of oxygen delivery in addition to Hb concentration to guide RBC transfusion. Administration of a RBC transfusion should be based on evidence of inadequate cardiorespiratory support or decreased systemic and/or regional oxygen delivery.

(expert opinion).

Evidence to decision

No pediatric oncology studies were identified. Two pediatric non-cancer studies and one adult non-cancer study were identified. The evidence gathered from these studies indicated that there is no increased risk for mortality, morbidity, and hospital admission with an Hb threshold of 4.3 mmol/L compared to an Hb threshold greater than 4.3 mmol/L in children and adults with cardiac and pulmonary comorbidities [11, 17, 29]. Studies comparing higher restrictive Hb thresholds (such as 5.0 mmol/L or 5.6 mmol/L) also did not report significant better outcomes regarding mortality, morbidity, quality of life, and admission to hospital [19, 30, 31].  Therefore, the guideline panel decided to suggest an Hb threshold of 4.3 mmol/L in children with cancer and cardiac and pulmonary comorbidities. For hemodynamically unstable children with cancer and pulmonary and/or cardiac comorbidities, such as those requiring inotropes or exhibiting elevated lactate levels, an Hb threshold ranging between 4.3 and 6.2 mmol/L is considered. Regarding children on extracorporeal membrane oxygenation (ECMO), the guideline panel decided to adopt the recommendations stated above from the Valentine (2018) guideline [32], AGREE-II score 5 out of 7.

Prophylactic red blood cell transfusion in neonates with cancer with cardiac and/or pulmonary comorbidities Recommendation 4.2.1.

We suggest an Hb threshold of 7.5 mmol/L for RBC transfusion in neonates with cancer and cardiac and pulmonary comorbidities when they are less than 1 week old.

(expert opinion).

Recommendation 4.2.2.

We suggest an Hb threshold of 6.5 mmol/L for RBC transfusion in neonates with cancer and cardiac and pulmonary comorbidities when they are between 2 and 3 weeks old.

(expert opinion).

Recommendation 4.2.3.

We suggest an Hb threshold of 5.5 mmol/L for RBC transfusion in neonates with cancer and cardiac and pulmonary comorbidities when they are between 3 and 4 weeks old.

(expert opinion).

Evidence to decision

No pediatric oncology studies addressing this clinical question were found. However, the Dutch Association of Medical Specialists (FMS) [22] developed recommendations primarily based on studies conducted in very low birth-weight infants (birth weight of 1500 g or less) who required respiratory support. Although evidence specific to full-term and late-premature neonates (gestational age ≥ 32 weeks) is lacking, the FMS has adopted these thresholds for neonates requiring respiratory support. Taking this into account, the guideline panel decided to adopt the recommendations regarding neonates with cancer and pulmonary and/or cardiac comorbidities from the guideline of the FMS (2019).

Prophylactic red blood cell transfusion—hyperleukocytosisProphylactic red blood cell transfusion in children with cancer during hyperleukocytosis Recommendation 5.1.1.

In children with cancer and hyperleukocytosis, we believe that a RBC transfusion should be given with restraint until the number of leukocytes has fallen below 100 × 109 /L or in the presence of clinical symptoms of hyperleukocytosis.

Recommendation 5.1.2.

In children with cancer and hyperleukocytosis, we believe that a RBC transfusion should be given with restraint, unless there are severe clinical signs of anemia or in case of an Hb below 3.1 mmol/L.

Recommendation 5.1.3.

If needed, transfuse with a maximum of 5 ml/kg/4–6 h.

(expert opinion).

Evidence to decision

No specific studies addressing this topic were identified. However, a study focusing on the management of hyperleukocytosis in children and adults with cancer provided relevant information. According to this study, the use of RBC transfusions in such cases should generally be avoided due to the potential increase in blood viscosity and the associated risk of leukostasis development or exacerbation, unless the patient exhibits symptoms of anemia [33]. The guideline panel decided to take this into consideration in order to make a recommendation based on expert opinion. However, in cases where clinically significant hyperleukocytosis requires leukocytapheresis, a RBC transfusion may be utilized as replacement fluid to correct anemia in an isovolemic and controlled manner [34].

Prophylactic red blood cell transfusion in children and neonates with cancer during hyperleukocytosis Recommendation 5.2.1.

In neonates with cancer and hyperleukocytosis, we believe that a RBC transfusion should be given with restraint until the number of leukocytes has fallen below 100 × 109 /L or in the presence of clinical symptoms of hyperleukocytosis.

Recommendation 5.2.2.

In neonates with cancer and hyperleukocytosis, we believe that a RBC transfusion should be given with restraint unless there are severe clinical signs of anemia or in case of an Hb below 5.5 mmol/L in neonates with cancer when they are less than 1 week old.

Recommendation 5.2.3.

In neonates with cancer and hyperleukocytosis, we believe that a RBC transfusion should be given with restraint unless there are severe clinical signs of anemia or in case of an Hb below 4.5 mmol/L for RBC transfusion in neonates with cancer when they are between 1 and 3 weeks old.

Recommendation 5.2.4.

In neonates with cancer and hyperleukocytosis, we believe that a RBC transfusion should be given with restraint unless there are severe clinical signs of anemia or in case of an Hb below 3.5 mmol/L for RBC transfusion in neonates with cancer when they are between 3 and 4 weeks old.

Recommendation 5.2.5.

If needed, transfuse with a maximum of 5 ml/kg/4–6 h.

(expert opinion).

Evidence to decision

No specific studies addressing this topic were identified. For the considerations of the recommendations we refer to “Prophylactic red blood cell transfusion in children with cancer during hyperleukocytosis” section. The RBC thresholds were based on expert opinions.

Irradiated red blood cell transfusionsIrradiated red blood cell transfusions in children and neonates with cancer Recommendation 6.1.1.

We believe that irradiated blood products should be used in case of an HLA-related product and donor:

a)

Transfusion between 1st and 3rd degree relatives of cell-containing blood products

(expert opinion).

Recommendation 6.1.2.

We believe that irradiated blood products should be used in case of granulocyte transfusions.

(expert opinion).

Recommendation 6.1.3.

We believe that irradiated blood products should be used depending on the patient’s immune status:

a)

During intrauterine transfusions until 6 months after the due date;

b)

Children with congenital combined immune deficiencies (e.g., SCID); and

c)

Acquired immune deficiencies such as:

Allogeneic stem cell transplantations up to 1 year after transplantation;

Autologous stem cell transplantations up to 6 months after transplantation; and

After application of donor lymphocyte infusion (DLI) or infusion of cytotoxic T lymphocytes (CTL) up to 1 year after transfusion.

(expert opinion).

Recommendation 6.1.4.

We believe that irradiated blood products should be used in case of patients with prolonged T cell depletion after medication:

a)

Fludarabine or other T cell depleting therapy as indicated by the pharmacist (up to 6 months after discontinuation of the therapy)

Recommendation 6.1.5.

We believe that irradiated blood products should be used in case of patients that receive CAR-T cell therapy from 4 weeks before the leukapheresis until 1 year after the infusion. Unless otherwise described in the study protocol.

(expert opinion).

Evidence to decision

There were no pediatric oncology studies identified. However, the Dutch Association of Medical Specialists (FMS) (21) developed a high-quality guideline addressing this matter. The guideline drew its recommendations from a study of Kopolovic (2015) [