Intensive Chemotherapy For Childhood Acute Lymphoblastic Leukemia: Results Of The

Randomized Intercontinental Trial ALL IC-BFM 2002

Stary, et al
Supplemental Table 1. Initial or recurrent CNS involvement

1. CSF with a chamber cell count of >5/µL WBC and a majority of blasts on a cytospin
preparation from a non-traumatic LP, i.e. with a RBC to WBC ratio of ≤100 on a
cytospin preparation
2. CSF with a chamber cell count of >5/µL WBC and a higher percentage of blasts in
CSF on a cytospin preparation than in PB in case of a traumatic LP, i.e. with a RBC
to WBC ratio of >100 on a cytospin preparation
3. Space-occupying lesion on CT or MRI scan of neurocranium/neuroaxis
4. Cranial nerve palsy unrelated to other cause
5. Retinal involvement

Legend

CNS denotes central nervous system; CT, computerized tomography; MRI, magnetic
resonance imaging; CSF, cerebrospinal fluid; WBC, white blood cell count; RBC, red
blood cell count; LP, lumbar puncture; and PB, peripheral blood.

Any of the above findings is diagnostic for CNS involvement, both at initial presentation
as well as at relapse. However, with the exception of the mutually exclusive criteria #1
and #2, these findings are not mutually exclusive.

At relapse, involvement confined to the CNS alone is considered an isolated CNS

relapse. However, co-involvement of the bone marrow and the CNS defines a combined
relapse.

CNS involvement at diagnosis is neither a stratifying criterion, nor does it per se entail
any modifications in the dose level of systemic chemotherapy. However, it dictates
reinforced locoregional (intrathecal) chemotherapy as well as therapeutic cranial
radiotherapy at age-adjusted dosage.
Supplemental Table 2. Cumulative doses of drugs in and length of delayed intensification

Drug Dosage SR-1 SR-2 IR-1 IR-2 HR-2A HR-2B HR-1

2
DNR/ADM mg/m 120 (180) 120 (180) 120 (240) 180 (300) 240 (390) 150 (300) 180
(330)
2
VCR mg/m 6 6 6 9 12 9 9

2
CTX mg/m 1,000 1,000 1,000 1,500 2,000 2,000 1,500

2
IFO mg/m 4,000

2
DEXA mg/m 210 280 210 420 420 510 420

2
L-ASP KIU/m 40 80 40 120 80 190 120

2
ARA-C mg/m 600 1,200 600 1,800 1,200 12,600 1,800

2
6-TG mg/m 840 1,680 840 2,520 1,680 840 2,520

IT-MTX doses 2 4 2 6 4 2 (+3 TIT) 6

2
HD-MTX g/m 10

2
VDS mg/m 6
 2
VP-16 mg/m 500

2
6-MP mg/m 3,500 2,800 1,400 2,800

2
PO-MTX mg/m 200 160 80 160

Duration months 2.25 5.50 2.25 6.50 5.50 4.75 6.50

Legend
SR-1, IR-1, HR-2A (AIEOP option), HR-2B (BFM option) denote the control arms, and SR-2, IR-2, HR-1 denote the
experimental arms in the standard-, intermediate-, and high-risk group, respectively. The choice of the HR control arm
was up to each national group based on its own experience, but must be stuck to for the entire duration of the study.
DNR stands for daunorubicin; ADM, for doxorubicin; VCR, for vincristine; VDS, for vindesine; CTX, for cyclophosphamide;
IFO, for ifosfamide; DEXA, for dexamethasone; L-ASP, for L-asparaginase; ARA-C, for cytosine arabinoside; 6-TG, for 6-
thioguanine; VP-16, for etoposide; HD-MTX, for high-dose methotrexate; 6-MP, for 6-mercaptopurine; and PO-MTX, for
oral methotrexate.
Vacant cells mean nil of the corresponding drug for the given arm.
The grand total dose of anthracyclines (daunorubicin and doxorubicin) delivered over the entire treatment is given in
parentheses.
Oral daily 6-mercaptopurine and weekly methotrexate were given as interim maintenance therapy during the delayed
intensification phase in all the experimental arms over 10 weeks x1 (SR-2) or 4 weeks x2 (IR-2 and HR-1) and in one of
the HR control arms over 4 weeks x1 (HR-2A).
IT-MTX denotes intrathecal methotrexate; and TIT denotes triple intrathecal therapy, i.e. 3-drug intrathecal administration
of methotrexate, cytosine arabinoside, and (methyl)predniso(lo)ne, both in terms of the number of doses given during
delayed intensification. The dosage of intrathecal medications was always adjusted to the actual age attained by the time
due at treatment delivery as follows:
Age (yr) MTX (mg) ARA-C (mg) P (mg)
≥3 12 30 10
≥2 to <3 10 26 8
≥1 to <2 8 20 6
<1 6 16 4
Supplemental Table 3.
NCI-CTCAE v2.0, as modified by The German Society of Pediatric Oncology and Hematology (GPOH).

UPN: RG: SR IR HR
1 2 2A 2B

Acute Toxicity During / After ALL IC- BFM 2002

Protocol I: Phase 1 Phase 2 Protocol I': Phase 1 Phase 2

Protocol mM: 1.MTX 2.MTX 3.MTX 4.MTX Protocol M: 1.MTX 2.MTX

3.MTX 4.MTX

1. 2. HR-1' Block 1. 2. HR-2' Block 1.

2. HR-3' Block

1. 2. Protocol II: Phase 1 Phase 2 1. 2. 3. Protocol III:

Phase 1 Phase 2

Start of therapy block/phase: __ __ . __ __ . __ __ d/m/y End of therapy block/phase: __ __ . __

__ . __ __ d/m/y

Please check off appropriate box for each parameter (maximal toxicity during & after block until
start of next phase)
Classification According To NCI CTC, Modified By GPOH

Grade 0 1 2 3 4
General condition normal mild age-related activities bedridden, intensive care,
activity impairment strongly limited in need for nursing very sick
Infection
Infection none mild pathogen not identified, pathogen identified septic shock
IV antibiotics IV antibiotics
Fever (°C)  38 38 – 39  39 – 40  40  24 h  40  24 h
Gastrointestinal toxicity
Nausea none adequate food markedly decreased food almost no food TPN necessary
intake intake intake
Vomiting (in 24 h) 0 1 2–5 6 - 10  10/TPN necessary
Stomatitis none painless ulceration, painful ulceration, can still painful ulceration, TPN required due to
erythema eat cannot eat stomatitis
Diarrhea none 2-3 4 – 6 or night stools or 7 – 9 or incontinence ≥ 10 or bloody diarrhea
(stool frequency/day) light cramps or strong cramps or TPN required
Liver toxicity
S- bilirubin normal for age  N – 1.5 x N  1.5 – 3.0 x N  3.0 – 10.0 x N  10.0 x N
S- ALT/ S- AST normal for age  N – 2.5 x N  2.5 – 5.0 x N  5.0 – 20.0 x N  20.0 x N
Renal toxicity:
Creatinine normal for age  N – 1.5 x N  1.5 – 3.0 x N  3.0 – 6.0 x N  6.0 x N
Proteinuria (g/L) none  3.0 3.0 – 10.0  10.0 nephrotic syndrome
Hematuria none microscopic macroscopic w/o clots macroscopic with clots transfusion required
Creatinine clearance  90 60 - 89 40 – 59 20 - 39  19
(ml/min/1,73m2)
Cardiac toxicity
Arrhythmia none asymptomatic, recurrent / persistent, therapy required hypotension, ventr.
no therapy no therapy arrhyth., defibrillation
Cardiac function normal for age EF   20% from EF   20% from mild cardiac insuff., severe / refractory
baseline value baseline value therapeutically cardiac insufficiency
compensated
Echo-CG: LVSF  30%  24% -  30%  20% -  24%  15% -  20%  15%
Neurologic toxicity
Central neurotoxicity none transient lethargy somnolence  50% of the somnolence  50% of coma, seizures
day, the day,
moderate disorientation disorientation,
hallucinations
Peripheral neurotoxicity, none paresthesias and/or severe paresthesias unbearable paralysis
Myopathy decreased tendon and/or mild weakness paresthesias,
reflexes marked motor deficits
Skeletal toxicity:
acute & delayed
Osteonecrosis none asymptomatic and symptomatic with symptomatic and symptomatic, crippling
detectable only by decreased function, but restrictions in everyday
imagining techniques no limitations in everyday living
living
Notes/other complications: (severe & life-threatening complications as well as extraordinary accidents & toxic deaths
must be notified within 24 – 72 h to National Study Coordinator, and reported without delay to him/her and National Data
Manager on the SAE Form)
Supplemental Table 4. Very-high-risk group – the outcome† of patients transplanted
in CR1 vs. patients treated by chemotherapy only

Indication N 5-y EFS, % SE, % Mantel-Byar p

Induction failure
CT only 66 50 7 0.33
HSCT 38 65 8
t(9;22)
CT only 79 52 6 0.83
HSCT 43 57 8
PPR + BCP-ALL t(9;22) neg,
CT only 91 53 6 0.79
HSCT 21 62 11
PPR + T-ALL
CT only 134 69 4 0.53
HSCT 39 69 7
Legend
CR1 denotes first complete remission; N, number of patients; 5-y EFS, probability of
event-free survival at 5 years; SE, standard error; CT, chemotherapy; HSCT,
hematopoietic stem-cell transplantation; PPR, prednisone poor response; BCP-ALL,
B-cell precursor acute lymphoblastic leukemia; and T-ALL, T-cell acute lymphoblastic
leukemia.
†
EFS of patients surviving at least 6 months from diagnosis.
Patients may happen to be in more than one group, e.g. t(9;22) and induction failure.