The Main Protocols in Pediatric Oncohematology

and Fabiana Gatti de Menezes2



(1)
Curitiba, Paraná, Brazil

(2)
São Paulo, São Paulo, Brazil

 



The protocols cited here are for quick reference, not dispensing the full study of each protocol before prescribing. Protocols may vary according to each institution.





List of tables



















































































































































































































































































































































































































Table 3.1
Protocol ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)
  

Table 3.2
Protocol COPP (cyclophosphamide, vincristine, procarbazine, and prednisone)
  

Table 3.3
Protocol COPDAC (cyclophosphamide, vincristine, dacarbazine, and prednisone)
  

Table 3.4
Protocol OPPA (doxorubicin, vincristine, procarbazine, and prednisone)
  

Table 3.5
Protocol OEPA (doxorubicin, vincristine, etoposide, and prednisone)
  

Table 3.6
Protocol COPP/ABV (cyclophosphamide, vincristine, procarbazine and prednisone/doxorubicin, bleomycin and vinblastine)
  

Table 3.7
Protocol VAMP (vinblastine, doxorubicin, methotrexate [MTX], and prednisone)
  

Table 3.8
Protocol DBVE (doxorubicin, bleomycin, vincristine, and etoposide)
  

Table 3.9
Protocol ABVE-PC (doxorubicin, bleomycin, vincristine and etoposide – prednisone and cyclophosphamide)
  

Table 3.10
Protocol BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and procarbazine)
  

Table 3.11
Protocol CVP (cyclophosphamide, vinblastine, and prednisolone)
  

Table 3.12
CML hematological control with hydroxyurea – variation I (of INCA – Brazilian National Institute of Cancer)
  

Table 3.13
CML Hematological Control with Hydroxyurea – Variation II
  

Table 3.14
Imatinib for CML chronic phase, newly diagnosed, Ph+
  

Table 3.15
Imatinib for CML chronic phase, Ph+
  

Table 3.16
Imatinib for CML accelerated phase or blast crisis, Ph+
  

Table 3.17
Cytoreductive phase for acute myeloid leukemia in the 2004 protocol of the German Leukemia Treatment Group (BFM2004): for patients with initial leukocyte count greater than 50,000/mm3 or large visceromegalies
  

Table 3.18
Induction phase of acute myeloid leukemia protocol of 2004 of the German Leukemia Treatment Group (BFM2004)
  

Table 3.19
Dose of intrathecal cytarabine in induction phase of acute myeloid leukemia protocol of 2004 of the German Leukemia Treatment Group (BFM 2004)
  

Table 3.20
Examination of bone marrow induction phase of acute myeloid leukemia protocol of 2004 of the German Leukemia Treatment Group (BFM2004): To do the bone marrow examination on D15 of the induction phase
  

Table 3.21
Second induction for acute myeloid leukemia of the 2004 protocol of the German Leukemia Treatment Group (BFM2004)
  

Table 3.22
Dose of intrathecal cytarabine – second induction phase for acute myeloid leukemia of the 2004 protocol of the German Leukemia Treatment Group (BFM2004)
  

Table 3.23
Adjustment of cytarabine EV dose of the 2004 protocol of the German Leukemia Treatment Group (BFM2004): according to age
  

Table 3.24
Consolidation phase for acute myeloid leukemia in the 2004 protocol of the German Leukemia Treatment Group (BFM2004) – part I (AI)
  

Table 3.25
Dose of intrathecal cytarabine – consolidation phase for acute myeloid leukemia in the 2004 protocol of the German Leukemia Treatment Group (BFM2004) – part I (AI)
  

Table 3.26
Consolidation phase for acute myeloid leukemia of the 2004 protocol of the German Leukemia Treatment Group (BFM2004) – part two (haM)
  

Table 3.27
Dose of intrathecal cytarabine – consolidation phase for acute myeloid leukemia of the German Leukemia Treatment Group (BFM2004) – part two (haM)
  

Table 3.28
Intensification phase (HAE) for acute myeloid leukemia of the 2004 protocol of the German Leukemia Treatment Group (BFM2004)
  

Table 3.29
Dose of intrathecal cytarabine – enhancement phase for acute myeloid leukemia of the German Leukemia Treatment Group (BFM2004)
  

Table 3.30
Maintenance phase for acute myeloid leukemia of the German Leukemia Treatment Group (BFM2004)
  

Table 3.31
Dose of intrathecal cytarabine – maintenance phase for acute myeloid leukemia of the German Leukemia Treatment Group (BFM2004)
  

Table 3.32
Adjusting the dose of thioguanine according to the German Leukemia Treatment Group (BFM2004): according to leukocyte count
  

Table 3.33
Tretinoin (ATRA) in children with acute myeloid leukemia M3, the 2004 protocol of the German Leukemia Treatment Group (BFM2004)
  

Table 3.34
Start of chemotherapy in children with acute myeloid leukemia M3, the 2004 protocol of the German Leukemia Treatment Group (BFM2004)
  

Table 3.35
Protocol IDA-FLAG (idarubicin, fludarabine, cytarabine, and filgrastim)
  

Table 3.36
Induction – phase I protocol I, of the 1995 protocol of the German Leukemia Treatment Group (BFM95) for acute lymphoid leukemia
  

Table 3.37
Phase II of the 1995 protocol of the German Leukemia Treatment Group (BFM95) for acute lymphoid leukemia
  

Table 3.38
Maintenance phase (M) of the 1995 protocol of the German Leukemia Treatment Group (BFM95) for acute lymphoid leukemia – It is an extracompartment therapy (only low and medium-risk patients)
  

Table 3.39
Reinduction phase: protocol II/phase I of the 1995 protocol of the German Leukemia Treatment Group (BFM95) for acute lymphoid leukemia
  

Table 3.40
Reinduction phase: protocol II/phase II of the 1995 protocol of the German Leukemia Treatment Group (BFM95) for acute lymphoid leukemia
  

Table 3.41
Therapy I for high-risk patients (HR-I) of the 1995 protocol of the German Leukemia Treatment Group for acute lymphoid leukemia (BFM95)
  

Table 3.42
Therapy II for high-risk patients (HR-II) of the 1995 protocol of the German Leukemia Treatment Group (BFM95) for acute lymphoid leukemia
  

Table 3.43
Therapy III for high-risk patients(HR-III) of the 1995 protocol of the German Leukemia Treatment Group (BFM95) for acute lymphoid leukemia
  

Table 3.44
Maintenance therapy of the 1995 protocol of the German Leukemia Treatment Group (BFM95) for acute lymphoid leukemia
  

Table 3.45
Maintenance therapy, for medium-risk randomized into MR-B patients, of the 1995 protocol of the German Leukemia Treatment Group (BFM95) for acute lymphoid leukemia
  

Table 3.46
First induction phase of the Brazilian Childhood Cooperative Group protocol of 1999, GBTLI ALL-99, for low-risk patients with acute lymphoid leukemia
  

Table 3.47
Second induction phase of the Brazilian Childhood Cooperative Group protocol of 1999, GBTLI ALL-99, for low-risk patients with acute lymphoid leukemia
  

Table 3.48
Intensification phase of the Brazilian Childhood Cooperative Group protocol of 1999, GBTLI ALL-99, for low-risk patients with acute lymphoid leukemia
  

Table 3.49
Late consolidation first phase of the Brazilian Childhood Cooperative Group protocol of 1999, GBTLI ALL-99, for low-risk patients with acute lymphoid leukemia
  

Table 3.50
Late consolidation second phase of the Brazilian Childhood Cooperative Group protocol of 1999, GBTLI ALL-99, for low-risk patients with acute lymphoid leukemia
  

Table 3.51
Maintenance therapy with intermittent 6-mercaptopurine and methotrexate, of the Brazilian Childhood Cooperative Group protocol of 1999, GBTLI ALL-99, for low-risk patients with acute lymphoid leukemia
  

Table 3.52
Phase I of protocol I’ (standard-risk B-cell precursor ALL only) and protocol I (standard-risk T-cell ALL, all intermediate-risk and-high-risk patients) of induction therapy of ALL IC-BFM 2002 protocol, elaborated by the Berlin-Frankfurt-Münster Group, for acute lymphoid leukemia patients
  

Table 3.53
Phase II of protocol I’ (standard-risk B-cell precursor ALL only) and protocol I (standard-risk T-cell ALL, all intermediate-risk and high-risk patients) of induction therapy of ALL IC-BFM 2002 protocol, elaborated by the Berlin-Frankfurt-Münster Group, for acute lymphoid leukemia patients
  

Table 3.54
Protocol mM (B-cell precursor ALL, standard and intermediate risks only) of consolidation therapy of ALL IC-BFM 2002 protocol, elaborated by the Berlin-Frankfurt-Münster Group, for acute lymphoid leukemia patients
  

Table 3.55
Protocol M (T-cell ALL, standard and intermediate risks only) of consolidation therapy of ALL IC-BFM 2002 protocol, elaborated by the Berlin-Frankfurt-Münster Group, for acute lymphoid leukemia patients
  

Table 3.56
Block HR-1’ (all high-risk patients) of consolidation therapy of ALL IC-BFM 2002 protocol, elaborated by the Berlin-Frankfurt-Münster Group, for acute lymphoid leukemia patients
  

Table 3.57
Block HR-2’ (all high-risk patients) of consolidation therapy of ALL IC-BFM 2002 protocol, elaborated by the Berlin-Frankfurt-Münster Group, for acute lymphoid leukemia patients
  

Table 3.58
Block HR-3’ (all high-risk patients) of consolidation therapy of ALL IC-BFM 2002 protocol, elaborated by the Berlin-Frankfurt-Münster Group, for acute lymphoid leukemia patients
  

Table 3.59
Delayed intensification phase I of protocol II (for standard-risk 1, intermediate-risk 1, high-risk 2A, and high-risk 2B) of ALL IC-BFM 2002 protocol, elaborated by the Berlin-Frankfurt-Münster Group, for acute lymphoid leukemia patients
  

Table 3.60
Delayed intensification phase II of protocol II (for standard-risk 1, intermediate-risk 1, high-risk 2A, and high-risk 2B) of ALL IC-BFM 2002 protocol, elaborated by the Berlin-Frankfurt-Münster Group, for acute lymphoid leukemia patients
  

Table 3.61
Delayed intensification phase I of protocol III (for standard-risk 2, intermediate-risk 2, and high-risk 1) of ALL IC-BFM 2002 protocol, elaborated by the Berlin-Frankfurt-Münster Group, for acute lymphoid leukemia patients
  

Table 3.62
Delayed intensification phase II of protocol III (for standard-risk 2, intermediate-risk 2, and high-risk 1) of ALL IC-BFM 2002 protocol, elaborated by the Berlin-Frankfurt-Münster Group, for acute lymphoid leukemia patients
  

Table 3.63
Interim maintenance therapy of ALL IC-BFM 2002 protocol, elaborated by the Berlin-Frankfurt-Münster Group, for acute lymphoid leukemia patients
  

Table 3.64
Maintenance therapy of ALL IC-BFM 2002 protocol, elaborated by the Berlin-Frankfurt-Münster Group, for acute lymphoid leukemia patients
  

Table 3.65
Protocol of high-dose – cyclophosphamide, doxorubicin, and vincristine (HD-CAV)
  

Table 3.66
Cycle A of Protocol with cyclophosphamide, vincristine, cisplatin, and etoposide (COPE/Baby Brain I)
  

Table 3.67
Cycle B of Protocol with cyclophosphamide, vincristine, cisplatin, and etoposide (COPE/Baby Brain I)
  

Table 3.68
Protocol 8 in 1 – variation 1
  

Table 3.69
Protocol 8 in 1 – variation 2
  

Table 3.70
Cycles 1, 2, 4, and 6 of protocol with cyclophosphamide, doxorubicin, vincristine, cisplatin, and etoposide (CAV-P/VP)
  

Table 3.71
Cycles 3, 5, and 7 of protocol with cyclophosphamide, doxorubicin, vincristine, cisplatin, and etoposide (CAV-P/VP)
  

Table 3.72
Protocol with doxorubicin, vincristine, and dactinomycin (AVD)
  

Table 3.73
Protocol with dactinomycin and vincristine (AV)
  

Table 3.74
Protocol with cyclophosphamide, cisplatin, doxorubicin, and etoposide (CCDE)
  

Table 3.75
Non-Hodgkin lymphoma: cyclophosphamide, vincristine, doxorubicin, and methotrexate (CODOX-M)
  

Table 3.76
COP phase of protocol for high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia treatment, of the French Society of Pediatric Oncology LMB86
  

Table 3.77
COPADM 1 Phase of Protocol for high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia treatment, of the French Society of Pediatric Oncology LMB86
  

Table 3.78
COPADM 2 protocol for high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia treatment, of the French Society of Pediatric Oncology LMB86
  

Table 3.79
Phases CYVE 1 and 2 for CNS-, of protocol for high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia treatment, of the French Society of Pediatric Oncology LMB86
  

Table 3.80
Phases CYVE 1 and 2 for CNS+, of protocol for high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia treatment, of the French Society of Pediatric Oncology LMB86
  

Table 3.81
Phases Mini CYVE 1 and 2 for CNS-, of protocol for high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia treatment, of the French Society of Pediatric Oncology LMB86
  

Table 3.82
Phases Mini CYVE 1 and 2 for CNS+, of protocol for high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia treatment, of the French Society of Pediatric Oncology LMB86
  

Table 3.83
M1 phase of protocol for high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia treatment, of the French Society of Pediatric Oncology LMB86
  

Table 3.84
M2 phase of protocol for high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia treatment, of the French Society of Pediatric Oncology LMB86
  

Table 3.85
M3 phase of protocol for high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia treatment, of the French Society of Pediatric Oncology LMB86
  

Table 3.86
M4 phase of protocol for high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia treatment, of the French Society of Pediatric Oncology LMB86
  

Table 3.87
Classification of risk groups for the protocol for Burkitt’s lymphoma treatment, of the French Society of Pediatric Oncology (LMB89)
  

Table 3.88
Pre-phase (COP) of protocol for Burkitt’s lymphoma treatment, of the French Society of Pediatric Oncology (LMB89) (Only groups B and C)
  

Table 3.89
Induction phase (COPADM n°1) of protocol for Burkitt’s lymphoma, of the French Society of Pediatric Oncology (LMB89) (Only groups B and C)
  

Table 3.90
Induction phase 2 (COPADM n°2) of protocol for Burkitt’s lymphoma, of the French Society of Pediatric Oncology (LMB89) (Only groups B and C)
  

Table 3.91
Induction COPAD phase for risk group A of protocol for Burkitt’s lymphoma, of the French Society of Pediatric Oncology (LMB89)
  

Table 3.92
Consolidation phase for group B (CYM n ° 1 and 2) of the protocol for Burkitt’s lymphoma, of the French Society of Pediatric Oncology (LMB89)
  

Table 3.93
Consolidation phase for group C (CYM n ° 1 and 2) of the protocol for Burkitt’s lymphoma, of the French Society of Pediatric Oncology (LMB89)
  

Table 3.94
Maintenance phase 1 (m1) of the Protocol for Burkitt’s lymphoma, of the French Society of Pediatric Oncology (LMB89)
  

Table 3.95
Maintenance phases 2 and 4 (m2 and m4) of the protocol for Burkitt’s lymphoma, of the French Society of Pediatric Oncology (LMB89)
  

Table 3.96
Maintenance phase 3 (m3) of the protocol for Burkitt’s lymphoma, of the French Society of Pediatric Oncology (LMB89)
  

Table 3.97
Protocol with high-dose methotrexate (HD MTX)
  

Table 3.98
Protocol with ifosfamide, carboplatin, and etoposide (ICE)
  

Table 3.99
Ifosfamide, cisplatin, and doxorubicin (IPA)
  


3.1 Hodgkin Lymphoma


For the treatment of Hodgkin lymphoma in children, one of the most commonly used protocols in pediatrics is the ABVD protocol (doxorubicin, bleomycin, vinblastine, and dacarbazine, on days 1 and 15, repeating the cycle every 28 days); opinion on this protocol for children is not unanimous as it is in adults, due to the cardiotoxicity of anthracyclines and the risk of pulmonary fibrosis due to bleomycin [11, 17, 103].

Advances made in the treatment of Hodgkin lymphoma mean that most patients with this diagnosis are cured or that the disease can be controlled for years. Therefore, reduction of the long-term toxicity of the chemotherapy and the maintenance of a good quality of life are the major issues in the present pharmacological treatment of this disease [97].


Table 3.1
Protocol ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)


































Drug
Administration
Dose
Days (D)

Doxorubicin
IV
25 mg/m2/day
D1 and 15

Bleomycin
IV
10 IU/m2/day
D1 and 15

Vinblastine
IV
6 mg/m2/day
D1 and 15

Dacarbazine
IV
375 mg/m2/day
D1 and 15


Source: Based on information from Chu and the National Cancer Institute [11, 85]

IU International units



Table 3.2
Protocol COPP (cyclophosphamide, vincristine, procarbazine, and prednisone)


































Drug
Administration
Dose
Days

Cyclophosphamide
IV
600 mg/m2/day
D1 and 8

Vincristine
IV
1.4 mg/m2/day (maximum dose per day is 2 mg)
D1 and 8

Procarbazine
Oral
100 mg/m2/day
D1 to D15

Prednisone
Oral
40 mg/m2/day
D1 to D15


Source: Based on information from the National Cancer Institute [85]



Table 3.3
Protocol COPDAC (cyclophosphamide, vincristine, dacarbazine, and prednisone)


































Drug
Administration
Dose
Days

Cyclophosphamide
IV
600 mg/m2/day
D1 and 8

Vincristine
IV
1.4 mg/m2/day (maximum dose per day is 2 mg)
D1 and 8

Dacarbazine
IV
250 mg/m2/day
D1 to D3

Prednisone
Oral
40 mg/m2/day
D1 to D15


Source: Based on information from the National Cancer Institute [85]



Table 3.4
Protocol OPPA (doxorubicin, vincristine, procarbazine, and prednisone)


































Drug
Administration
Dose
Days

Doxorubicin
IV
40 mg/m2/day
D1 and 15

Vincristine
IV
1.5 mg/m2/day (maximum dose per day is 2 mg)
D1, 8 and 15

Procarbazine
Oral
100 mg/m2/day
D1 to D15

Prednisone
Oral
60 mg/m2/day
D1 to D15


Source: Based on information from the National Cancer Institute [85]



Table 3.5
Protocol OEPA (doxorubicin, vincristine, etoposide, and prednisone)


































Drug
Administration
Dose
Days

Doxorubicin
IV
40 mg/m2/day
D1 and 15

Vincristine
IV
1.5 mg/m2/day (maximum dose per day is 2 mg)
D1, 8 and 15

Etoposide
IV
125 mg/m2/day
D3 to 6

Prednisone
Oral
60 mg/m2/day
D1 to D15


Source: Based on information from the National Cancer Institute [85]



Table 3.6
Protocol COPP/ABV (cyclophosphamide, vincristine, procarbazine and prednisone/doxorubicin, bleomycin and vinblastine)

















































Drug
Administration
Dose
Days

Cyclophosphamide
IV
600 mg/m2/day
D0

Vincristine
IV
1.4 mg/m2/day (maximum dose per day is 2 mg)
D0

Procarbazine
Oral
100 mg/m2/day
D0 to D6

Prednisone
Oral
40 mg/m2/day
D0 to D13

Doxorubicin
IV
35 mg/m2/day
D7

Bleomycin
IV
10 IU/m2/day
D7

Vinblastine
IV
6 mg/m2/day
D7


Source: Based on information from the National Cancer Institute [85]



Table 3.7
Protocol VAMP (vinblastine, doxorubicin, methotrexate [MTX], and prednisone)


































Drug
Administration
Dose
Days

Vinblastine
IV
6 mg/m2/day
D1 and 15

Doxorubicin
IV
25 mg/m2/day
D1 and 15

Methotrexate
IV
20 mg/m2/day
D1 and 15

Prednisone
Oral
40 mg/m2/day
D1 to D14


Source: Based on information from the National Cancer Institute [85]



Table 3.8
Protocol DBVE (doxorubicin, bleomycin, vincristine, and etoposide)


































Drug
Administration
Dose
Days

Doxorubicin
IV
25 mg/m2/day
D1 and 15

Bleomycin
IV
10 IU/m2/day
D1 and 15

Vincristine
IV
1.5 mg/m2/day (maximum dose per day is 2 mg)
D1 and 15

Etoposide
IV
100 mg/m2/day
D1 to D5


Source: Based on information from the National Cancer Institute [85]



Table 3.9
Protocol ABVE-PC (doxorubicin, bleomycin, vincristine and etoposide – prednisone and cyclophosphamide)












































Drug
Administration
Dose
Days

Doxorubicin
IV
30 mg/m2/day
D0 and D1

Bleomycin
IV
10 IU/m2/day
D0 and D7

Vincristine
IV
1.4 mg/m2/day (maximum dose per day is 2 mg)
D0 and D7

Etoposide
IV
75 mg/m2/day
D0 to D4

Prednisone
Oral
40 mg/m2/day
D0 to D9

Cyclophosphamide
IV
800 mg/m2/day
D0


Source: Based on information from the National Cancer Institute [85]



Table 3.10
Protocol BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and procarbazine)

















































Drug
Administration
Dose
Days

Bleomycin
IV
10 IU/m2/day
D7

Etoposide
IV
200 mg/m2/day
D0 to D2

Doxorubicin
IV
35 mg/m2/day
D0

Cyclophosphamide
IV
1200 mg/m2/day
D1 and D8

Vincristine
IV
2 mg/m2/day (maximum dose per day is 2 mg)
D7

Prednisone
Oral
40 mg/m2/day
D0 to D13

Procarbazine
Oral
100 mg/m2/day
D0 to D6


Source: Based on information from the National Cancer Institute [85]



Table 3.11
Protocol CVP (cyclophosphamide, vinblastine, and prednisolone)





























Drug
Administration
Dose
Days

Cyclophosphamide
IV
500 mg/m2/day
D1

Vinblastine
IV
6 mg/m2/day
D1 and 8

Prednisolone
Oral
40 mg/m2/day
D1 to D8


Source: Based on information from the National Cancer Institute [85]


3.2 Chronic Myeloid Leukemia (CML)


The first-line treatment is done with imatinib; can consider referring the patient for an allogeneic transplantation if he/she have a compatible bone marrow donor. The treatment of CML in the chronic phase, after the failure of imatinib, consists of autologous transplantation. Treatment of CML in the accelerated phase is done with allogeneic transplantation; imatinib can be used before. In CML in blast crisis, treatment is done with imatinib following an allogeneic transplantation, but only if the patient shows response to the treatment, including return to the chronic phase. The experience with imatinib in children, although limited, has shown cytogenetic responses similar to those in adult patients [17].


3.2.1 Hematological Control with Hydroxyurea





Table 3.12
CML hematological control with hydroxyurea – variation I (of INCA – Brazilian National Institute of Cancer)




















Drug
Administration
Dose

Hydroxyurea
Oral
50 mg/kg/day in children with weight <30 kg

2 g/m2/day in children with weight >30 kg

Hydroxyurea – Maintenance
Oral
10 to 30 mg/kg/day


Source: Based on information from the Brazilian Ministry Of Health [42]

Maintenance is interrupted if the number of leukocytes falls below 2500/mm3 and platelets fall to below 100,000/mm3, returning to maintenance when the values normalize.

A hematological response corresponds to a 50 % reduction of the initial leukocyte count, maintained for at least 2 weeks. Complete hematological response is considered as a leukocyte count below 10,000/mm3, the absence of pro-myelocytes or myeloblasts, less than 5 % myelocytes or metamyelocytes, and about 450,000 platelets/mm3, maintaining the above conditions for at least 4 weeks.

Cytogenetic response may be absent if the number of Philadelphia (Ph) chromosome-positive cells is greater than 90 %; response is considered to belower if 35–90 % of the cells are Ph chromosome-positive; partial, if there are 5–34 % of Ph chromosome-positive cells; complete if 0% of Ph chromosome-positive cells; or greater, which corresponds to the sum of full and partial responses (less than 35 % of Ph chromosome-positive cells) [42].


Table 3.13
CML hematological control with hydroxyurea – variation II
















Drug
Administration
Dose

Hydroxyurea
Oral
30–40 mg/kg/day or 0.5–1 g/m2/day. To be adjusted according to reduction of white blood cell count.


Source: Based on information from Lee [86]

Hydroxyurea should be discontinued when the white blood cell levels are around 20,000–10,000/mm3. Hydroxyurea can lead to complete hematological response in some cases, but there is an unusual cytogenetic response (in 0–5 % of the cases), in which it has no impact on the prevention of disease progression, or on the substantial prolongation of survival [66, 86].


3.2.2 Imatinib





Table 3.14
Imatinib for CML chronic phase, newly diagnosed, Ph+
















Drug
Administration
Dose

Imatinib
Oral
340 mg/m2/day once a day or divided into two doses. Maximum dose is 600 mg per day.


Source: Based on information from Taketomo et al. [59]



Table 3.15
Imatinib for CML chronic phase, Ph+
















Drug
Administration
Dose

Imatinib
Oral
400 mg once a day, may be increased to 600 mg per day.


Source: Based on information from Taketomo et al. [59]

Imatinib dose ranges of up to 800 mg/day, divided into two doses of 400 mg, are included in the U.S.A. National Comprehensive Cancer Network (NCCN) CML guidelines, if tolerated, for disease progression, lack of hematological response after 3 months, lack of cytogenetic response after 6–12 months, or loss of previous hematological or cytogenetic response [59].


Table 3.16
Imatinib for CML accelerated phase or blast crisis, Ph+
















Drug
Administration
Dose

Imatinib
Oral
600 mg once a day


Source: Based on information from Taketomo et al. [59]

If tolerated, the imatinib dose may be increased to 800 mg per day, divided into two doses of 400 mg, for disease progression, lack of hematological response after 3 months, lack of cytogenetic response after 6–12 months, or loss of previous hematological or cytogenetic response [59].


3.3 Acute Myeloid Leukemia (AML)


Despite the lack of targeted therapy for most subtypes, and few new agents to treat AML, survival rates have reached as high as 60 % for children treated in developed countries, but cure rates for some subtypes of childhood AML remain very low, and novel therapies are needed [101].

The pharmacological treatment in general is divided into two phases: A remission induction and a post-induction treatment [36].


3.3.1 Protocol of the German Group for Acute Myeloid Leukemia Treatment Berlin-Frankfurt-Münster (BFM2004): Adapted from HEMORIO


The child protocol is used until age 16 years; later, the adult protocol 7 + 3 is used, as per the standardization of HEMORIO [29].

Patients should be divided into two risk groups:



  • Standard Risk [29]

    M3, AML in patients with Down syndrome, M1 or M2 with Auer rods, eosinophilic M4, AML with translocation of chromosomes (8; 21)/inversion (16).


  • High Risk [29]

    M0, M1/M2 without Auer rods, M4, M5, M6, and M7. If bone marrow on D15 > 5% of blasts, patient will be high-risk.

Patients with indication for stem cell transplantation are: all high-risk patients in first remission with related bone marrow donors; unrelated donors can be considered for high-risk patients with prolonged aplasia (more than 4 weeks after HAM protocol) without signs of spinal cord regeneration.


Table 3.17
Cytoreductive phase for acute myeloid leukemia in the 2004 Protocol of the German Leukemia Treatment Group (BFM2004): For patients with initial leukocyte count greater than 50,000/mm3 or large visceromegalies




















Drug
Administration
Dose

Thioguanine
Oral
40 mg/m2/day

Cytarabine
IV or SUB-Q
40 mg/m2/day


Source: Based on information from Hemorio [29]

Sub-Q Subcutaneous

The cytoreductive phase should not exceed 7 days, if no significant reduction in leukocyte counts on D3, start the induction.


Table 3.18
Induction phase of acute myeloid leukemia protocol of 2004 of the German Leukemia Treatment Group (BFM2004)







































Drug
Administration
Dose
Days

Cytarabine
IV in 48 h
100 mg/m2/day
D1 and 2

Cytarabine
IV
100 mg/m2/dose

12/12 h
D3 to 8

Idarubicin
IV in 4 h

(Before Ara-C)
12 mg/m2

D3, 5, and 7

Etoposide
IV in 1 h

(6 h before

Ara-C)
150 mg/m2

D6, 7, and 8

Cytarabine
IT
Dose according to age
D1 and 8


Source: Based on information from Hemorio [29]

Ara-C Cytarabine



Table 3.19
Dose of intrathecal cytarabine in induction phase of acute myeloid leukemia protocol of 2004 of the German Leukemia Treatment Group (BFM 2004)






















Age
Dose of intrathecal cytarabine

<1 year old
20 mg

1–2 years old
26 mg

2–3 years old
34 mg

3 years old or older
40 mg


Source: Based on information from Hemorio [29]



Table 3.20
Examination of bone marrow induction phase of acute myeloid leukemia protocol of 2004 of the German Leukemia Treatment Group (BFM2004): To do the bone marrow examination on D15 of the induction phase
















Blasts on D15
Continue the Protocol

<5 % or equal
D 28 if afebrile and in good general condition

>5 %
D16 if there is no fever or severe infection


Source: Based on information from Hemorio [29]




  • Second induction (HAM – High-dose cytarabine and mitoxantrone of second induction – Do not confuse with haM of second consolidation)

Only the high-risk group. Patients should have good general condition and leukocytes >1000/m3 on D15 to start the next block. If patient presents blasts on D15, he should receive the next block, even with fewer leukocytes, if the patient’s condition permits. Bone marrow puncture on D1.


Table 3.21
Second induction for acute myeloid leukemia of the 2004 protocol of the German Leukemia Treatment Group (BFM2004)





























Drug
Administration
Dose
Days

Cytarabine (high dose)
IV in 3 h
3 g/m2 every 12 h
D1 to 3 (six doses)

Mitoxantrone
IV in 30 min
10 mg/m2

D3 and 4

Cytarabine
IT
Dose according to age
D1 (with an interval of at least 2 h between the first Ara-C IV and IT dose)


Source: Based on information from Hemorio [29]

IT intrathecal



Table 3.22
Dose of intrathecal cytarabine – second induction phase for acute myeloid leukemia 2004 protocol of the German Leukemia Treatment Group (BFM2004)






















Age
Dose of intrathecal cytarabine

<1 year old
20 mg

1–2 years
26 mg

2–3 years
34 mg

3 years old or older
40 mg


Source: Based on information from Hemorio [29]



Table 3.23
Adjustment of cytarabine EV dose of the 2004 protocol of the German Leukemia Treatment Group (BFM2004): according to age





































Age (in months)
% of dose to be given

≥24
100

20 to 24
90

17 to 19
80

14 to 16
70

11 to 13
60

8 to 10
50

6 to 7
40

4 to 5
30

≤3
20


Source: Based on information from Hemorio [29]

Supportive care: lubricant eye drops every 4–6 h, starting 6 h prior to first dose of cytarabine and ending 12 h after the last dose.



  • Consolidation Phase – Part I (AI)

This phase begins 4 months after the induction in each group. The patient needs to have good general condition, absence of infection, polymorphonuclear neutrophil (PMN) count >1000/mm3, platelets >80,000/mm3.

Marrow puncture on D1.


Table 3.24
Consolidation phase for acute myeloid leukemia in the 2004 protocol of the German Leukemia Treatment Group (BFM2004) – part I (AI)





























Drug
Administration
Dose
Days

Cytarabine
IV in continuous infusion
500 mg/m2

D1 to 4

Idarubicina
IV in 60 min
7 mg/m2

D3 and 5

Cytarabine
IT
Dose according to age
D1 and 6


Source: Based on information from Hemorio [29]



Table 3.25
Dose of intrathecal cytarabine – consolidation phase for acute myeloid leukemia in the 2004 protocol of the German Leukemia Treatment Group (BFM2004) – part I (AI)






















Age
Dose of intrathecal cytarabine

<1 year old
20 mg

1–2 years old
26 mg

2–3 years old
34 mg

3 years old or older
40 mg


Source: Based on information from Hemorio [29]




  • Consolidation Phase (haM: high-dose cytarabine and mitoxantrone of second consolidation – Do not confuse with HAM of second induction) – Part Two

Starting 4 weeks after the part I, it is necessary that the patient is in good general condition, with no infections, PMN >1000/mm3 and platelets >80,000/mm3.


Table 3.26
Consolidation phase for acute myeloid leukemia of the 2004 protocol of the German Leukemia Treatment Group (BFM2004) – part two (haM)





























Drug
Administration
Dose
Days

Cytarabine (high dose)
IV in 3 h
1 g/m2 12 in 12 h
D1 to 3 (six doses)

Mitoxantrone
IV in 30 minutes
10 mg/m2

D3 and 4

Cytarabine
IT
Dose according to age
D1 and 6


Source: Based on information from Hemorio [29]



Table 3.27
Dose of intrathecal cytarabine – consolidation phase for acute myeloid leukemia of the German Leukemia Treatment Group (BFM2004) – part two (haM)






















Age
Dose of intrathecal cytarabine

<1 year old
20 mg

1–2 years old
26 mg

2–3 years old
34 mg

3 years old or older
40 mg


Source: Based on information from Hemorio [29]

Observe the precautions for use of cytarabine (dose adjustment, lubricant eye drops).



  • Intensification phase (HAE – High-dose cytarabine and etoposide of intensification phase)

For all patients without predicted transplantation.

Start 2–4 weeks after haM, the patient must have good general condition, absence of infections, PMN >1000/mm3, and platelets >80,000/mm3. Bone marrow puncture on D1.


Table 3.28
Intensification phase (HAE) for acute myeloid leukemia of the 2004 protocol of the German Leukemia Treatment Group (BFM2004)





























Drug
Administration
Dose
Days

Cytarabine (high dose)
IV in 3 h
3 g/m2 12 in 12 hours
D1 to 3 (six doses)

Etoposideo
IV in 60 minutes
125 mg/m2

D2 to 5 (6 h before Ara-C)

Cytarabine
IT
Dose according to age
D1


Source: Based on information from Hemorio [29]



Table 3.29
Dose of intrathecal cytarabine – enhancement phase for acute myeloid leukemia – of the German Leukemia Treatment Group (BFM2004)






















Age
Dose of intrathecal cytarabine

<1 year old
20 mg

1–2 years old
26 mg

2–3 years old
34 mg

3 years old or older
40 mg


Source: Based on information from Hemorio [29]

Observe the precautions in relation to Ara-C (dose adjustment, eye drops).



  • Maintenance Phase (duration 1 year)

Beginning 4 weeks after the end of the final of the intensification, parallel radiotherapy, provided that the general condition and hematological findings permit.


Table 3.30
Maintenance phase for acute myeloid leukemia of the German Leukemia Treatment Group (BFM2004)





























Drug
Administration
Dose
Days

Cytarabine
Sub-Q
40 mg/m2

D1 to 4 (every 4 weeks)

Thioguanine
Oral
40 mg/m2

Daily

Cytarabine
IT
Dose according to age
D1, 8, 15, and 22


Source: Based on information from Hemorio [29]



Table 3.31
Dose of intrathecal cytarabine – maintenance phase for acute myeloid leukemia – of the German Leukemia Treatment Group (BFM2004)






















Age
Dose of intrathecal cytarabine

<1 year old
20 mg

1–2 years old
26 mg

2–3 years old
34 mg

3 years old or older
40 mg


Source: Based on information from Hemorio [29]



Table 3.32
Adjusting the dose of thioguanine according to the German Leukemia Treatment Group (BFM2004): according to leukocyte count






















White blood cell count (in mm3)
Percentage of thioguanine to be administered

>3000
150 %

>2000
100 %

1000–2000
50 %

<1000
0 %


Source: Based on information from Hemorio [29]

Cytarabine should be given if the leukocyte count result is >2000/mm3 and platelets >80,000/mm3; if the results are lower, postpone for a week.



  • Children with AML and Down syndrome: Keep the protocol, with the following changes:

Reduce Ara-C dose according to reduction indicated for patients less than 2 years old, during induction (AIE – Ara-C, idarrubicina and etoposide) reduce the dose of idarubicin to 8 mg/m2; these patients should not receive the HAM (second induction) block of the protocol; idarubicin in the AI block to be reduced to 5 mg/m2 and mitoxantrone in the haM block (second consolidation) should be reduced to 7 mg/m2; treatment of the CNS must be restricted to seven doses of Ara-C IT.



  • Children with AML M3:

These children should be treated as a standard-risk group, regardless of the number of blasts on D15 of induction, followed by chemotherapy as the clinical condition allows.

Patients with a positive molecular marker after the HAE block should receive ATRA (trans retinoic acid or tretinoin; not to be confused with isotretinoin) to the negative of molecular marker, then go to the HAM block (of second induction).


Table 3.33
Tretinoin in children with acute myeloid leukemia M3; 2004 protocol of the German Leukemia Treatment Group (BFM2004)



















Drug
Administration
Dose
Period

ATRA
Oral, with meal
25 mg/m2/day (to divide this dose in two doses a day)
Start immediately after confirmation of the diagnosis, do 3 days before starting the chemotherapy protocol.


Source: Based on information from Hemorio [29]

ATRA trans retinoic acid, same as tretinoin. Not to be confused with isotretinoin

Administer intermittently for 14 days, with 7 days of rest. In general, complete remission is achieved after the third cycle of ATRA. After that, ATRA will be administred again at the beginning of the HAE cycle for 14 days. Then, it will be administred 3 months after the sart of maintenance, for 14 days, every 3 months.


Table 3.34
Start of chemotherapy in children with acute myeloid leukemia M3, the 2004 protocol of the German Leukemia Treatment Group (BFM2004)















If initial white blood cell count <5000/mm3

Start chemotherapy after the 3rd day of ATRA

If initial white blood cell count >5000/mm3

Start chemotherapy after the 1st day of ATRA

If initial white blood cell count >10,000/mm3

Start chemotherapy simultaneously with ATRA


Source: Based on information from Hemorio [29]

ATRA syndrome: This syndrome may occur usually 2–10 days after treatment; it is reversible with the temporary suspension of ATRA and treatment with dexamethasone 0.5–2 mg/kg. The ATRA syndrome is characterized by fever, pulmonary infiltrates, pleural or pericardial effusion, and renal failure.

Relapse: Perform FLAG protocol as induction, follow with second induction using the same protocol, followed by consolidation with the same protocol, or allogeneic stem cell transplantation [29].

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