Blood Transfusion for Pediatric Oncology Patient

1 Blood Transfusion for Pediatric Oncology Patient Abstract Pediatric oncology patient management involves transfusion therapy as the main way of dealing with hematological abnormalities due to malignancies. Most drugs used in the management of cancer in pediatric oncology patient ends up affecting the production of the blood cells in the bone marrow. Some of the blood cells produced while one is suffering from hematological disorders are not able to function normally. Different countries have not adopted the standard protocol of blood and blood products transfusion hence this study tries to highlight the guidelines followed by different states in USA and UK. The study involved secondary collection of data from relevant journals, web sites and texts.

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2

The information collected includes common blood products involved in the management of cancer in children. Various types of cancers affecting children were recorded. Data on the distribution of cancer among races, age, sex and ethnicity in the USA and UK was collected. The survival time from the year of diagnosis of cancer among male and female pediatric oncology patients was also noted. Transfusion reactions associated with pediatric oncology patient were analyzed. The information collected was presented in form of tables was used to come up with appropriate conclusions about the study.

3 Blood Transfusion for Pediatric Oncology Patient Introduction The prevalence and incidence of anemia amongst patients receiving cancer chemotherapy is high [1]. Approximately 15% of the cancer patients who are anemic are transfused with approximately two packs of the red blood cells [2]. According to the WHO studies, approximately 1-3% of the population must donate blood to provide the high quality blood products needed in every country [3]. Within Europe, the range of blood donors is approximately 2.4-54.1 per 1,000 inhabitants while the average number of RBC transfusion ranges from 3.057.4 per 1,000 inhabitants, creating a very wide gap [4]. The availability of high quality blood products for anemia treatment is a major problem in Europe [5]. Scientific organizations have formulated guidelines to be used in treating anemia with transfusion. Hemoglobin level of less than 9g/dl for asymptomatic patients has been used by most of them as a cut off value [6]. Other factors that are put into consideration in those guidelines are patient complaints and the cardiac problems [7].

Blood products transfusions are associated with various complications [8]. Complications of transfusion are classified as procedural, iron overload, direct immune injury, viral or and bacterial infections, and immune modulation. Voluntary blood donation is the most common method adopted by most of the countries [10]. In Europe, blood donation with no financial benefits to the donor has lea to limited availability of blood products. Blood donated can only be stored for 42 days [11]. Quality of the blood products decreases with the increase in the period of storage due to changes in metabolism, rhealogy and shape due to loss of carbohydrates, proteins and lipids leading to the alteration in oxygen delivery, secretion and adhesion [12]. Non immune hemolysis is also a problem associated with blood storage and administration [13]. The most

4 common problem associated with transfusion of the blood products is the transfusion of the incorrect blood component [14]. In USA, 1 in 600,000-800,000 transfusion errors leading to death and 1 in 12,000-19,000 cases leading to nonlethal events have been reported [15]. In UK, approximately 335 per 5.5 million of the RBCs transfused have been associated with compatibility errors. Approximately 1% of the blood transfusions have been associated with circulatory overload [16].

Transfusion associated circulatory overload (TACO) is mostly associated with the patients who are suffering from renal failure or cardiovascular problems [17]. To ensure that blood and blood products are safe for transfusion, there is a great need of screening for diseases that can be transmitted through transfusion. Some of the viral diseases that are screened before transfusion are human immunodeficiency virus (HIV)-1 and (HIV)-2, hepatitis B virus (HBV), human T-cell lymphocytic virus (HTLV) I and HTLV II, and hepatitis C virus (HCV) [18, 19, 20]. The screenings for these diseases have been limited by lack of blood products’ systematic testing. In Europe the incidences of bacterial infections through RBCs is 1 in 38,500, 1 in 5,500,000 for HIV infections in RBC units, 1 in 4,400,000 HCV infections in RBCs unit and 1 in 1,100,000 for HBV infections in RBC units. Pre-existing antibodies result to hemolytic transfusion reactions. Approximately 1 in 100,000 hemolytic transfusion reactions have been reported [21]. The antibodies involved with hemolytic reaction are the naturally occurring anti-A and anti-B, immunoglobulin (Ig) M and the IgG alloantibodies which are able to fix the complement. RBCs transfusion are also associated with delayed hemolytic transfusion reactions (DHTRs) which occurs in between the third and tenth day of transfusion, even though the blood was compatible after the cross-matching test. The case of DHTRs occurs in 1 to 1,500 cases of the red blood cells transfused [22]. The antigens associated with DHTRs are the Rh and Kidd

5 system antigens, through pregnancy or transfusion [23]. To avoid DHTRs there is a great need of taking transfusion history of the patient to decrease the risks of DHTRs. Approximately 1 in 20,000-50,000 cases of anaphylactic reaction have been reported. Anaphylactic reactions are associated with IgA deficiency, anticomplement antibodies, and the anti-human leukocyte antigen (HLA) antibodies [24].

One (1) in 2,500,000 RBC transfusions are associated with mortality due to transfusion reactions associated with the lungs [25]. Transfusion reactions associated with lungs are caused by the antineutrophil antigen antibodies (Anti-HNA) or the anti-HLA antibodies of the class I and class II though other factors play a great role [26]. Children with no pre existing acute lung injury (ALI) may suffer from acute respiratory distress syndrome (ARDS) which is a transfusion related acute lung injury (TRALI) within 6 hours of transfusion therapy [transfusion related acute lung injury in a child with leukemia [27].TRALI is a common transfusion risk associated with pediatric patients who receive blood transfusion for the management of chronic anemia [28] TRALI is mostly associated with acute leukemia in pediatric oncology patients because they require frequent blood transfusion in their health problem management [29,30,31].

Post –transfusion purpura is the other risk effect associated to blood transfusion, though these cases are rare but very severe [32]. Post-transfusion purpura is associated with platelet destruction which results to thrombocytopenia and purpura. 1 in 50,000-100,000 RBC transfusions result to post-transfusion purpura. Post-transfusion purpura occurs 5-10 days upon blood transfusion [33]. Post-transfusion purpura results from antibodies which are specific to platelet antigens [34]. The incidences of transfusion related graft versus host disease are rare in blood transfusion. The incidence of the transfusion related graft versus host diseases are 0.11.0% in patients who are immunocompromised [35]. Transfusion related graft versus host

6 disease leads to 80-90% mortality due to infections and bleeding. Lymphocytes immune responses against the lymphoid tissues of the recipients lead to transfusion related graft versus host disease [36].

One of the concerns with blood transfusion in pediatric oncology patients is iron overload. Ruccione in 2012 carried a cohort study to investigate transfusion iron burden amongst the children cancer survivors and concluded that iron overload is attributed to the treatment intensity of packed red blood cells. The study involved collecting data in the registry for the cancer patients to determine their iron overload with transfusion [37]. The study projected that iron overload in the treatment of cancer is significantly associated with the projected iron burden at younger age patients [37]. Iron overload results to deposition in the vital organs like the liver leading to impaired growth, liver diseases, cardiomyopathy with arrhythmias, diabetes mellitus, infertility hypothyroidism and other endocrine abnormalities [38].

Acute promyelocytic leukemia is associated with bleeding, leading to death. According to Chang et al, [39] in their study, clinical bleeding events were associated with coagulation profile.

Chang and colleagues involved 116 APL patients and related various hematological and coagulation parameters in this study. The researchers also identified 132 APL patients in the registry database in Taiwan [40]. For the patients who were involved the bleeding was graded.

According to the WHO scale 3 or 4, 26 (22.4%) of the patients suffered a significant bleeding.

Thirteen (13) patients (11.2%) of the case suffered a severe hemorrhage (Bleeding scale 4). All the 13 patients with severe hemorrhage died of bleeding. Chang et al concluded that hemorrhage is one of the factors that cause death in APL patients and can be managed using blood products to counter check bleeding. Chang and colleagues concluded that the most common sites for bleeding among APL patients who have not received transfusion therapy are the lungs and the

7 brain. In the Chang’s case study, death due to hemorrhage was more than 50%. The authors also concluded that prolonged PT, increased WBC count and prolonged APTT are found in APL patients [39].

In his study, Hartley [41] examined policy guidelines for oncology transfusion observed by the states involved. These guidelines were: Irradiated blood and blood products transfused to pediatric oncology patients. Pediatric oncology patients to get CMV free blood products.

Oncology pediatric patients with allergic reactions after treatment with hydrocortisone (2mg/kg) or diphenhydramine (1.25mg/kg) to receive products of blood after washing. Packed red blood cells only transfused to pediatric oncology patients when anemia is symptomatic (hemoglobin levels less than 8g/dl) with tachycardia. Packed red blood cells were transfused to patients with hemoglobin level greater than 8g/dl if only they were to be discharged from hospital within a period of less than 2 week and if the chemotherapy dose was high. Platelets transfusion carried out to patients with less than normal levels of platelets (thrombocytopenia) with less than 10,000 platelets per microliter of blood or to patients with bleeding disorder or those suffering from platelet dysfunction. Cryoprecipitate to be administered to patients suffering from severe liver disease, those with widespread intravascular cougulopathy (DIC), those with afibrinogenemia or those with significant indications associated with hypofibrinogemia. Patients suffering from Factor XIII deficiency and those who were taking second line therapy for Von Willebrands disorder. Fresh frozen plasma is used in pediatric oncology patients who have received warfarin and are in a bleeding state which is life-threatening, such as patients with liver disease. He also investigated on some of the diseases that are screen for before blood is transfused [41].

Materials and Methods

8 Secondary collection of data involved materials like published journal, web sites and relevant texts to provide information concerning the guidelines, protocols and administration of blood and blood products to pediatric oncology patients in USA and UK and other countries, which have a well-organized registry of transfusion therapy in pediatric oncology patients. Some of the libraries that were searched include MEDLINE and ERIC. Other libraries available via the EBSCOhost portal were important in finding resourceful peer reviewed sources. The key search terms included blood transfusion, pediatric oncology patients, and cancer therapy among others.

The collected data involved children with age less than seventeen years, but also information about oncology patients with greater than seventeen years was collected in order to relate the prevalence of cancer with different ages.

The data collected involved age, sex, race, ethnicity and regions in the countries involved. The pediatric oncology patient survival upon management of chemotherapy and blood and blood products transfusion data was collected. The laboratory procedure involved in pretransfusion testing of the blood and blood products before transfusion was investigated.

Information on post transfusion reactions detected amongst the pediatric oncology patients was collected. Post- transfusion reactions in patients not suffering from any form of cancer were collected to check whether some the post-transfusion reactions are found in pediatric oncology patients only or not. The collection of data was organized well in form of tables with clear indication of all the information in a simple manner before it was analyzed to come up with a conclusion. Data concerning prevalence, lifetime risk, survival, incidence and mortality rate was also collected. The data was analyzed using appropriate statistical procedures like the student t score. The information from the analyzed data was used to come up with the conclusion for the study.

9 Results According Schrijvers [20], hemoglobin levels and the prevailing symptoms of the patient are very important in determining when to carry out transfusion therapy. Different scientific organizations have different cutoff hemoglobin level for transfusion therapy.

Table 1 RBC transfusion guidelines according to various organizations Organization

Year

RBC transfusion indication

United Kingdom blood

2007

Hb≤9.0g/dl

2007

Hb<9.00g/dl if clinically

services EORTC

indicated ASH/ASCO

2010

Hb<12.0 g/dl if clinically indicated

NCCN

2010

Asymptomatic: Hb7-9g/dl Symptomatic: Hb8-10g/dl Symptomatic coronary: Hb≥10g/dl

Source: Schrijvers [20]: Management of anemia in cancer patients: Transfusions Abbreviations: ASH/ASCO, American society of hematology/ American society of clinical oncology: EORTC, European organization for research and treatment of cancer: NCCN, national comprehensive cancer network

10 Table 2 Anemia and Cancer Treatment Outcome Study

Tumor

treatment

outcome

Hb level

Result (%)

(g/dl) Brizel (1999)

Head and

Radiotherapy

3 yr OS

neck Zenda et

Esophagus

Chemoradiation CR

al(2008)

Grogan et

Cervix

Radiotherapy

5yr OS

al(1999) Dunst et

Cervix

raditherapy

3 yr LRFS

al(2003)

<13

35

≥13

83

<13

24

≥13

60

<12

45

≥12

74

<13

72

≥13

94

Abbreviations: CR< complete response, LRFS, local relapse free survival, OS overall survival Source: Schrijvers [20]: Management of anemia in cancer patients: Transfusions Table 3: Blood products for neonates and children requirements (From Hartley [41]) Blood product

Irradiated

CMV

Blood group

Seronegative

matched

Yes

yes

Rhesus matched

IUT Plasma reduced blood cells

Yes

RH-ve

11 Platelets

Yes

Yes

yes

Rh-ve

Yes

Yes

yes

Yes

PRBCs

Yes

Yes

yes

Yes

Platelets

Yes

Yes

yes

Yes

FFP

No

Yes

yes

No

cryoprecipitate

No

Yes

yes

No

PRBCs

Yes

yes

yes

Yes

FFP

No

yes

yes

No

cryoprecipitate

No

yes

yes

No

PRBCs

Yes

no

yes

Yes

Platelets

Yes

no

yes

Yes

FFP

No

yes

yes

No

Neonate( previou s IUT) Plasma reduced RBCS

Neonates suspected from cellular immunodeficiency HLA matched

Neonate none of the above

12

cryoprecipitate

No

yes

yes

Yes

PRBCs

No

no

yes

Yes

Platelets

No

no

yes

yes

FFP

No

no

yes

no

cryoprecipitate

No

no

yes

No

Child more than 1 year

According to the study, various blood products are used in transfusion management of pediatric oncology patients. The indication for various blood products depends with the form of the cancer and the presenting symptoms of the patients.

Table 2: Blood Products commonly used in Management of Cancer in Pediatric Patients Blood products

Indication

Packed red blood cells (PRBCs)

Symptomatic anemia

Platelets

Thrombocytopenia, platelet defects, Hemorrhage.

Irradiated products

Patients with risks of GvHD development, patients under high chemotherapy and radiation dose. Patients with bone marrow transplant and Hodgkin’s disease patients.

Washed products

Allergic patients.

Cryoprecipitate

Severe liver disease patients.

Fresh frozen plasma (FFP)

Life threatening bleeding patients, patients

13 suffering from severe liver disease White blood cells

Patients with less response to antibiotics or those who suffer frequently from bacterial or fungal infections.

Incidences of various immune reactions

Reactions

incidence

Hemolytic transfusion reaction

1/10,000-1/50,000

Febrile nonhemolytic transfusion reaction

33/1,000

Anaphylactic transfusion reaction

1/20,000-1/47,000

Transfusion-related acute lung injury

1/2,500,000

Post transfusion purpura

1/50,000-1/100,000

Transfusion associated graft versus host

1/1,000-1/100

disease Transfusion related immunodulation Alloimmunization after chronic transfusions

2/100-8/100

Source: Schrijvers [20]: Management of anemia in cancer patients: Transfusions Transfusion number of PRBC with iron intensity Treatment intensity level Cohort total N=15

1(n=15)

2(n=93)

3(n=66)

4(n=40)

p-value

14 No. PRBC

<0.0001

transfusions Median

8

0

4

13

22

range

0-89

0-4

0-20

0-89

4-86

No. patients

181(84.6)

5(33.3)

80(82.5)

64(91.4)

40(100)

<0.0001

(%) receiving ≥1 transfusion Cumulative

<0.0001(d)

PBRC volume(ml/Kg) Median

2,038

0

987

3,965

6,282

range

0-26,902

0-0-818

0-5495

0-26,902

116523,314

Adjusted

<0.0001(d)

cumulative PBRC volume ml/kg Median

66

0

44

101

177

range

0-1,406

0-78

0-194

0-455

37-1,406

adjusted Projected total iron load burden (mg)

<0.0001(d)

15 Median

1,426

0

691

2,636

4,401

range

0-18,150

0-573

0-3,849

0-18,158

817-15,853

Adjusted

<0.0001(d)

projected total iron burden mg/kg Median

45

0

31

71

121

range

0-953

0-55

0-126

0-313

22-953

4.2

0

2.9

6.7

11.4

<0.0001(d)

163(76.2)

4(26.7)

62(66.7)

56(84.9)

40(100.0)

<0.0001 (c)

75(35.0)

0

9(9.7)

32(48.5)

33(82.5)

<0.0001 ( c

Projected hepatic iro content(mg/g) Median No(%) ≥1.6mg/g No.(%)≥7.0 mg/g

)

Characteristics of patients with or without severe bleeding according to Chang et al [39] Severe bleeding

No severe bleeding

p

16 n=13

N=103

PT

5.66±0.96

2.80±0.28

0.0079

APTT

3.88±1.38

1.34±0.90

0.017

Platelets

45.17±14.46

34.93±3.57

0.75

Fibrinogen

141.25±20.76

204.58±12.18

0.134

WBC

20.9±5.07

15.03±3.02

0.0276

Leukemic burden %

82.64±3.90

81.30±1.50

0.87

Discussion According to Chang et al, the bleeding disorders are associated with APL whereby the studies indicate that 13 cases presented severe bleeding and died of hemorrhage. Bleeding in APL patient emanate from thrombocytopenia, resulting to prolonged PT, APTT, and increased white blood cells in the circulation [39]. According to Chang et al, 22.4% of those whole are suffering from APL will end up suffering and dying of severe bleeding. Most of the APL patients will die due to hemorrhage in the lungs and the brain which are vital organs in the human body.

Hemorrhage due to APL can be investigated using various hematological parameters like the APTT and the PT whereby they are prolonged due to APL [39].

According to Ruccione’s study on the intensity of the iron burden in the management of malignancies, it comes out very clear that with subsequent brood transfusion therapy amongst those who survive with malignancies, the iron burden increases [37]. Iron burden amongst those who are receiving blood for malignancy management will lead to damage of the vital organs of the body, hence causing death. Red blood cells are indicated for the pediatric oncology patient during acute and chronic types of anemia, which are symptomatic [33]. Deglycerolized and

17 frozen red blood cells are used in the management of symptomatic anemia conditions in pediatric oncology patients who their bodies have alloantibodies targeting their red blood cells. Red blood cells transfusion guidelines are not clear-cut; hence, the physician needs to decide when red blood cells transfusion is appropriate depending on the condition of the pediatric oncology patient and after evaluating the benefits and risks that are associated with the red blood cell transfusion [24]. Before any red blood cell transfusion, a cross-matching procedure should be carried out to test for the compatibility testing [34]. While carrying out red blood cells transfusion, it is good to keep on checking the recipient’s hemoglobin level so as to avoid excessive amount of iron in the body which may end up in iron overload. Iron overload is common in pediatric patients who receive an average of 2-4 red cell units per months.

Accumulation of iron in the body poses a great danger to the health of the patient since accumulated iron affects the functioning of the liver, the pancreas and the heart because it is deposited in those organs leading to their damage [35].

According to the study made by Schrijvers [20], it comes out clearly that transfusions involve a lot of risks. Incidence of these risks differs with the reaction, the incidence of the hemolytic transfusion reaction is1/10,000-1/50,000. The incidence of the Febrile nonhemolytic transfusion is 33/1,000 reactions, the incidence of the anaphylactic transfusion reaction is 1/20,000-1/47,000, the incidence of the transfusion-related acute lung injury is 1/2,500,000, the incidence of the post transfusion purpura is 1/50,000-1/100,000, the incidence of the transfusion associated graft versus host disease is 1/1,000-1/100, and the incidence of the Alloimmunization after chronic transfusions is 2/100-8/100 [36] Pediatric oncology patients with thrombocytopenia require platelet transfusion [37].

Platelet transfusion prevents bleeding. Low platelet levels in the body lead to nose bleeding, skin

18 bruising and skin pinpoint bleeding [38]. Oncologists and hematologists determine the best time for platelet transfusion by determining the platelet levels in the blood. In most of the cancer centers, this is done when the platelet level is below 5,000 microliters [39]. Platelets are obtained from a single donor. They are also pooled from different donors through apheresis [40]. White blood cells are removed from platelet units through filtration; they should also be irradiated.

Pediatric patients with few or no white blood cells in their circulation should be transfused with granulocytes.

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