The most common childhood cancer is acute lymphoblastic leukemia (ALL). Chemotherapy-associated hematological toxicity is well-known; however, there are few studies on hematologic toxicity incidence in children with ALL. We investigated the severity and incidence of hematologic toxicity during intense chemotherapy processes in children treated with ALL IC-BFM 2009 protocol. The study included 41 leukemic children in standard (SR) and intermediate risk (IR) groups treated between 2011 and 2015. During the induction period, the incidence of grade 4 toxicity in neutrophil count was 60%; the incidence of grade ≥ 3 toxi city in hemoglobin level was 34%; and the incidence of grade ≥ 3 toxicity in the platelet count was 51%. Deep neutropenia duration was 36.6 ± 12.7 (18-68) days during the induction. 53% of the febrile neutropenic (FEN) episodes developed during the induction period. There were no statistical differences between SR and IR risk groups with respect to hemogram values deep neutropenia duration and the number of FEN episodes (p > 0.05, all). There was a positive correlation between the number of FEN episodes and duration of neutropenia. During the induction, the mean neutrophil count remained between 0.5-1 × 10 9 /L. FEN episodes most commonly developed during the induction phase.
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and represents 30% of all childhood cancers [
Anemia and thrombocytopenia frequently occur as a side effect of cytotoxic chemotherapy and blood product transfusions are needed during treatment. Blood transfusions involve several risks including infection transmission, allergic reactions, immunosensitivity, iron overload, graft versus host disease. Being aware of the extent of transfusion administered to patients may be interesting with respect to reminding the extent of the risks confronted by the patients. While chemotherapy-associated hematologic toxicity is a well-known topic, there are a few studies evaluating chemotherapy-associated hematologic toxicity [
In this trial, we investigated the level of severe neutropenia, anemia, thrombocytopenia incidence, deep neutropenia duration, incidence of febrile neutropenic episodes, and the extent of transfusion during intense chemotherapy in leukemic children, treated with ALL IC-BFM 2009 protocol.
Forty-one children (2 - 17 years old) with a diagnosis of intermediate or standard risk ALL who were treated with chemotherapy between April 2011 and June 2015 whose files were complete, were included in this study. Three relapsed patients were excluded, due to they were treated with a different protocol (ALL- REZ BFM 2002) and 3 children with high risk ALL were excluded because their consolidation treatment is different from children in the SR and IR risk groups. The patient data were obtained retrospectively from the hospital’s information system. Demographic features, risk groups, hemogram data obtained during treatment, number of febrile neutropenic episodes, the quantities of erythrocyte, and apheresis suspension were recorded. Approval of the local ethics committee and written informed consent are from the children’s families.
The diagnosis of ALL was made if blast count in bone marrow was 25% or more. Peripheral blood and bone marrow smears were stained with May- Grünwald-Giemsa and evaluated according to French-American-British criteria. Immunophenotyping was performed by flow cytometry with monoclonal antibodies reactive with B-(CD10, CD19, CD22, cytoplasmic IgM, cytoplasmic IgG), T-(CD2, CD3, CD4, CD5, CD7, CD8), and precursor-cell (TdT, HLADR, and CD34) associated antigens. Chromosomal analyses were performed in bone marrow for three important translocations, including t(12;21), t(9;22), and t(4;11). Patients were classified in three groups as standard, intermediate and high risk groups according to the ALL IC BFM 2009 protocol [
Chemotherapy protocol consists of induction (Protocol I phase A and Phase B), consolidation (protocol M) and re-induction (protocol II phase 1 and phase 2) periods. Consolidation treatment starts 14 days after the end of induction treatment, and 14 days after that, re-induction treatment is initiated. Maintenance treatment is started 14 days after the end of re-induction.
In the IR risk group, patients are given daunorubicin in addition to 22 and 29 days, different from the SR risk group in Protocol I phase A. During the consolidation period, HDMTX is given to SRs at a dose of 2 g/m2 and to IRs at a dose of 5 g/m2. In addition, there is no difference in the drug doses taken by the two groups. Maintenance treatment consists of only oral methotrexate and purinethol treatment. Therefore, the study assessed the induction, consolidation and re-induction phases where intense chemotherapy was administered. The drug doses, duration and the mode of administration used during the protocol are presented in
The level of toxicity in blood values was classified based on the Common Terminology Criteria for Adverse Events 2010 guideline [
Standard risk group (SR) | High Risk group (HR) |
---|---|
(All the criteria below should exist) | (One of the criterion below is adequate) |
Age at diagnose ≥ 1 year or < 6 year | Intermediate risk group and blast count in bone marrow at day 15% ≥ 25% |
Leukocyte count at the beginning < 20.000/mm3 | Blast count in peripheral blood at day 8 > 1000/mm3 |
Blast count in peripheral blood at day 8 < 1000/mm3 | Blast count in bone marrow at day 15% ≥ 5% |
Blast count in bone marrow at day 15% < 25% | t (9; 22) [BCR/ABL] or t (4; 11) [MLL/AF4] positivity |
Blast count in bone marrow at day 15% < 5% | Hipodiploidy ≤ 45 |
Intermediate risk group (IR): Patients not fully complying with the criteria of standard or high risk groups |
Drug | Dose | Days of administration | |
---|---|---|---|
Induction (Protocol I) Phase A (SR/IR) | |||
Prednisone (PO) Vincristine (IV) Daunorubicin (PI, 1 hour) L-Asparaginase (PI, 1 hour) Methotrexate (IT) | 60 mg/m2/per day 1, 5 mg/m2/per dose 30 mg/m2/per dose 5000 IU/m2/per dose 12 mg per dose | 1 - 28a 8, 15, 22, 29 8, 15, 22b, 29b 12, 15, 18, 21, 24, 27, 30, 33 1, 12 | |
Induction (Protocol I) Phase B (SR/IR) | |||
Cyclophosphamide (PI, 1 hour) Cytarabine (ARA-C)* (PI, 1 hour) 6-Mercaptopurine (PO) Methotrexate (IT) | 1000 mg/m2/per dose 75 mg/m2/per dose 60 mg/m2/per dose 12 mg per dose | 36, 64 (38 - 41), (45 - 48), (52 - 55), (59 - 62) 33 - 63 45, 49 | |
Consolidation (Protocol M) (pre B ALL, SR) | |||
6-Mercaptopurine (PO) Methotrexate (PI, 24 hours) Methotrexate (IT) | 25 mg/m2/per day 2 g/m2/per dose 12 mg per dose | 1 - 56 8, 22, 36, 50 8, 22, 36, 50 | |
Consolidation (Protocol M) (pre B ALL IR and T ALL, SR/IR) | |||
6-Mercaptopurine (PO) Methotrexate (IV, 24 hours) Methotrexate (IT) | 25 mg/m2/per day 5 g/m2/per dose 12 mg per dose | 1 - 56 8, 22, 36, 50 8, 22, 36, 50 | |
Reinduction (Protocol II) Phase 1 (SR/IR) | |||
Dexamethasone (PO) | 10 mg/m2/per day | 1 - 21a | |
Vincristine (IV) | 1.5 mg/m2 | 8, 15, 22, 29 | |
Adriamycin (IV, 1 hour) | 30 mg/m2/per dose | 8, 15, 22, 29 | |
L-asparaginase (IV, 1 hour) | 5000 IU/m2 per dose | 8, 15, 22, 29 | |
Reinduction (Protocol II) Phase 2 (SR/IR) | |||
Cyclophosphamide (PI, 1 hour) Cytarabine (PI, 1 hour) 6-Thioguanine (PO) Methotrexate (IT) | 1000 mg/m2/per dose 75 mg/m2/per dose 60 mg/m2/per day 12 mg per dose | 36 38 - 41, 45 - 48 36 - 49 38, 45 |
PO, orally; IV, intravenous push; PI, intravenous infusion; IT, intrathecally; SR, standard risk group; IR, intermediate risk group; a: Steroid is given up in 9 days by being decreased; b: Two doses of daunorubicin has been added in IR patients; *: Applied as four days’ blocks.
threshold value transfusion was set at hemoglobin <8 g/L and platelet <20 × 109/L. The incidence of grade 4 neutropenia, grade ≥ 3 anemia and thrombocytopenia, the erythrocyte suspension used, the amount of apheresis suspension, and the number of febrile neutropenic episodes was calculated for each treat-
Grade 1 | Grade2 | Grade3 | Grade 4 | |
---|---|---|---|---|
Hb (g/L) | LLN - 10 | 8 - 10 | <8 | life-threatening anemia |
ANC (×109/L) | LLN - 1.5x1 | 1.5 - 1 | 1 - 0.5 | <0.5 |
PLT (×109/L) | LLN - 75 | 75 - 50 | 50 - 25 | <25 |
AST and ALT (IU/L) | >ULN - 3XULN | 3 - 5XULN | 5 - 20xULN | >20xULN |
Hb, hemoglobin; ANC, absolute neutrophil count; PLT, platelet count, AST, aspartat aminotransferase; ALT, alanine aminotransferase; LLN: lower limit of normal; ULN, upper limit of normal.
ment phase. Patients were divided into two groups as the SR and IR risk groups. Hemoglobin, leukocyte, neutrophil, platelet counts, deep neutropenia duration, and the number of febrile neutropenic episodes were compared for the treatment phases of the two groups. The correlations between the absolute neutrophil count (ANC), the duration and the number of febrile neutropenic episodes were investigated.
During the protocol, the change in the ANC was converted to a graph. For this purpose, the lowest, highest and the mean ANC were used on days 1 - 8, 8 - 15, and 15 - 33 during the induction phase, the cytarabine (ARA-C) block, and the remaining parts of the protocol.
All analyses were performed with SPSS 21.0 statistical packaged software (SPSS for Windows 21.0; SPSS, Chicago, IL, USA). The normality of distributions was evaluated using the Kolmogorov-Smirnov test. Descriptive statistics used the mean and standard deviation (mean ± SD) for normally distributed variables, and the median and interquartile distribution range was used for other variables. The comparisons between the SR and IR risk groups were made with the Mann Whitney U test and independent t test. In order to evaluate the correlation between the variables, Pearson correlation test was applied. P < 0.05 was considered to indicate statistical significance.
A total 41 children with ALL were enrolled in this study. Thirty-eight (92%) patients had B ALL, 3 (8%) had T-ALL. There were 22 (51.2%) females and 19 (46.3%) males; 21(51.2%) were in the SR and 20 (48.8%) were in the IR group; the mean age was 6.41 ± 4.42 (2-17) years. During the whole protocol, the deep neutropenia duration was 61.7 ± 21.5 (31 - 109) days, and during the induction, this duration was 36.6 ± 12.7 (18 - 68) days. The number of febrile neutropenic episodes per patient was 4.9 ± 1.17 (3 - 9), the amount of transfused erythrocyte suspension was 10.6 ± 3.70 (3 - 20) units, and the amount of apheresis suspension was 7.8 ± 5.13 (0 - 22) units. The demographics of patients and the number of febrile neutropenic episodes per patient, the amount of erythrocyte and apheresis suspension used, deep neutropenia duration during the whole protocol and the induction period are presented in
The incidence of grade 4 toxicity in ANC (<0.5 × 109/L) was calculated as 68%, 68% and 60% respectively in protocol II phase 1, Phase 2 and protocol I phase B. Grade ≥ 3 toxicity in hemoglobin level (<8 g/L) was calculated as 34% in protocol I phase B, grade ≥ 3 toxicity in the platelet count (<50 × 109/L) was 51% in protocol I phase B and A (
During the whole chemotherapy process, 463 units of erythrocyte and 320 units of apheresis suspension were used; blood products were most commonly used during the protocol I phase B. Thirty-nine percent of the erythrocyte suspension and 45% of the apheresis suspension was used during this period. The quantities and percentages of erythrocyte and apheresis suspension are given in
There was no statistically significant difference in hemoglobin, leukocyte, neutrophil, platelet counts, and deep neutropenia duration between the SR and IR groups (p > 0.05, for all) (
Age | 6.41 ± 4.42 (2 - 17) |
---|---|
Gender (F/M) | 22 (53.7%)/19 (46.3%) |
SR/IR | 21 (51.2%)/20 (48.8%) |
B ALL/T ALL | 38 (92%)/3 (8%) |
Number of febrile neutropenic episodes | 4.9 ± 1.17 (3 - 9) |
Number of erythrocyte suspension (units) | 10.6 ± 3.70 (3 - 20) |
Number of apheresis suspension (units) | 7.8 ± 5.13 (0 - 22) |
Deep neutropenia duration (days) | 61.7 ± 21.5 (31 - 109)a 36.6 ± 12.7 (18 - 68)b |
SR, standard risk group; IR, intermediate risk group; a: During the whole protocol; b: During the induction period.
Protocol I phase A | Protocol I phase B | Protocol M | Protocol II phase 1 | Protocol II phase 2 | P | |
---|---|---|---|---|---|---|
Hb (g/L) SR IR | 8.8 (8.2 - 9.1) 9.1 (8.8 - 9.6) | 8.4 (8.1 - 8.9) 8.7 (8.2 - 9.3) | 10.29 ± 0.91 10.6 ± 0.91 | 12.7 ± 1.04 13.0 ± 1.17 | 9.4 (8.3 - 10.2) 9.0 (8.3 - 9.6) | >0.05 |
Leukocyte (×109/L) SR IR | 2.67 (1.8 - 3.14) 2.38 (1.5 - 4.5) | 2.10 (1.5 - 2.75) 1.87 (1.3 - 3.0) | 3.05 ± 0.87 3.42 ± 1.09 | 4.61 (3.6 - 6.2) 3.92 (3.2 - 4.9) | 1.78 (1.1 - 2.3) 1.88 (1.1 - 2.3) | >0.05 |
ANC (×109/L) SR IR | 0.82 (0.4 - 1.0) 0.84 (0.4 - 1.1) | 0.72 (0.5 - 1.1) 0.89 (0.5 - 1.3) | 1.4 (1.0 - 1.64) 1.68 (1.1 - 2.0) | 2.98 (2.1 - 4.3) 2.5 (1.98 - 3.3) | 0.55 (0.3 - 0.9) 0.69 (0.4 - 1.1) | >0.05 |
PLT (×109/L) SR IR | 124.8 (88.2 - 190.8) 117.7 (86.2 - 159.7) | 104.4 (60.2 - 159.2) 123.8 (81.3 - 169.0) | 201.2 ± 80.7 194.8 ± 59.0 | 194.5 (139.4 - 233.7) 163.7 (128.9 183.5) | 157.8 ± 71.4 131.5 ± 84.7 | >0.05 |
DND (days) SR IR | 17.9 ± 10.5 18.2 ± 12.8 | 21.5 ± 7.3 20.7 ± 12.0 | 4 (0 - 14) 1 (0 - 5) | 2 (0 - 10) 7 (1 - 11) | 12.2 ± 7.1 11.4 ± 6.0 | >0.05 |
FEN (n/%) SR IR | 24 (22%) 20 (22%) | 34 (31%) 30 (32%) | 10 (9%) 4 (4%) | 22 (20%) 20 (22%) | 20 (18%) 18 (19%) | >0.05 |
Hb, hemoglobin; ANC, absolute neutrophil count; PLT, platelet count; DND, deep neutropenia duration; FEN: Febril neutropenic episode; SR, standard risk group; IR, intermediate risk group.
groups, the induction phase was the period during which the deep neutropenia duration was the longest and febrile neutropenic episodes developed mostcommonly (
The most severe hematologic toxicity of cytotoxic chemotherapy is neutropenia. Chemotherapy predisposes the patients to infection by both suppressing the
neutrophil production and through its cytotoxic effects on the digestive tract cells [
In a study assessing 366 pediatric patients who received chemotherapy due to leukemia, lymphoma and solid tumors, the mean neutropenia duration was 11 days; the results showed that this time was longer during the initial chemotherapy period in ALL patients (18 days on average) [
Nearly all chemotherapy drugs cause myelosuppression, mucositis and nausea/vomiting. The most important toxic effect of daunorubicin is cardiotoxicity [
In our study, there was no difference between the SR and IR groups with respect to febrile neutropenic episodes incidence. In the previous two studies, no difference was shown between the risk groups with respect to infection incidence [
Anemia is an important issue commonly observed in patients with malignity. Decreased erythrocyte production due to nutritional deficiencies, inadequate response to erythropoietin, tumor infiltration of the bone marrow and inadequate erythrocyte production due to chemotherapy drugs may lead to anemia [
Thrombocytopenia is a side effect of chemotherapeutic drugs. In the USA, based on the data from electronic medical records of 47.159 adult patients with solid tumors, the incidence of grade 3 and higher-grade thrombocytopenia was reported as 10.6% [
In our study, the incidence of grade 3 and higher grade thrombocytopenia was between 12% and 51%.
Induction period is the period where the bone marrow is most severely suppressed in leukemic children treated with the ALL IC BFM 2009 protocol. In this period, both the number of febrile neutropenic episodes and the requirement for transfusion is higher than other periods. The most important factor to determine the incidence of febrile neutropenic episodes is the neutropenia duration and the absolute neutrophil count. One should be careful during this period against infections and protective measures need to be increased. Considering the amount of transfusion administered during chemotherapy, studies on the use of erythropoietic and thrombopoietic agents to increase the life quality of patients, and protect against transfusion-related complications would be important.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
None declared.
Özdemir, Z.C., Kar, Y.D., Turhan, A.B. and Bör, Ö. (2017) Assessment of Hematological Toxicity in Children with Acute Lymphoblastic Leukemia, Receiving Treatment with ALL IC-BFM 2009 Protocol. Open Access Library Journal, 4: e3807. https://doi.org/10.4236/oalib.1103807