H e m a t o lo g y E d u c a t io n - European Hematology Association

16 th Congress of the European Hematology Association
Table 5. Results of published protocols omitting CNS irradiation.
n number of CNS3 pts (%) EFS of all cohort EFS of CNS3 pts CI a of isolated CNS relapse CI of any CNS relapse
EORTC 58881 21 2025 49 (2.4) 69.6 % (SE:1%) 68.3 % (SE:6.2%) 3.57% (SE:0.42%) 7.6% (SE:0.6%)
(1989-1996) at 8 years at 8 years at 8 years at 8 years
COG ALL-9 33 859 21 (2.4) 81% (SE:1%) 67% (SE:10%) ? ?
(1997-2004) at 5 years at 5 years
St-Jude Total Therapy XV 20 498 9 (1.8) 85.6% (SE:5.7%) 43.2% (SE:23%) 2.7% (SE:0.8%) 3.9% (SE:1%)
(2000-2007) at 5 years at 5 year at 5 years at 5 years
a CI : Cumulative incidence.
for IT methotrexate (p=0.01). It thus appears that
triple IT therapy improves pre-symptomatic CNS
treatment but does not improve overall outcome in
standard-risk ALL.
A liposomal sustained release formulation of cytarabine
has been recently proposed. 36-42 The cytarabine in
this formulation has a prolonged half-life (100-263 h)
versus 3-4 hours for the free drug. 36 It seems effective
but toxicity can be associated with its use, including
arachnoiditis and central CNS neurotoxicity, particularly
if high-dose cytarabine or high-dose methotrexate
are used concomitantly. 42 Trials are ongoing in
adult and pediatric protocols to define its real efficacy
and safety profile.
– Systemic chemotherapy is of paramount importance
to prevent CNS relapse.
• Intensity of the treatment: CCG-105 was the first
randomized study to document the importance of
systemic treatment in the prevention of CNS
relapse. 43 Indeed, for intermediate-risk patients less
than 10 years of age, IT methotrexate with an intensified
systemic regimen provided a CNS prophylaxis
comparable to that provided by cranial radiotherapy,
whereas older patients had fewer systemic
relapses if they received CNS irradiation. 43
• High-dose methotrexate (HD-MTX): despite its
extensive use, the benefits of HD-MTX seem more
pronounced on the prevention of hematological
relapse than on CNS relapse in a meta-analysis. 44
One French randomized study suggested an advantage
of HD-MTX (4 cycles of 8 g/m 2 ) in intermediate-risk
B lineage ALL, the benefit being seen in
good early responders to chemotherapy in terms of
reduction of bone marrow and extra-medullary
relapse. 45 The current 5 g/m 2 dose used in many
groups is suggested to result in consistently cytotoxic
concentrations in the CSF(> 1 micromolar). An
adequate exposure to methotrexate (≥ 36h) before
beginning the rescue by folinic acid is mandatory, as
well as keeping this rescue to the minimum.
• High-dose cytarabine: less-used in ALL than in AML
or Burkitt’s lymphoma, no definite proof of its usefulness
exists. No benefit of intermediate or moderate
high-dose has been shown in medium-risk ALL
in the BFM-95, nor in EORTC 58881 studies. 46,47
• Dexamethasone versus prednisone: the possible
superiority of dexamethasone is still controversial.
Some trials have documented this superiority, particularly
in terms of CNS relapse, comparing 6
mg/m 2 /d of dexamethasone to 40 mg/m 2 /d of prednisone
or 10 mg/m 2 /d to 60 mg/m 2 /day during
induction therapy. 48-50 Others comparing 8 mg/m 2 /day
of dexamethasone to 60 mg/m 2 /day of prednisone
did not find a difference. 51
• Thiopurines: Three randomized trials have compared
6-Thioguanine (40 mg/m 2 /day) and 6-
Mercaptopurine (60 mg/m 2 /day). 52-54 Despite an
advantage in terms of CNS relapse reduction, an
unacceptable increase of veno-occlusive disease
was documented. 53,54
• Optimal administration of L-Asparaginase: two trials
have demonstrated the role of L-Asparaginase in
CNS relapse prevention. Indeed the EORTC group
and the DFCI group have randomized the administration
of Erwinia asparaginase versus native E.Coli
asparaginase at the same dose and at the same
rhythm. 55,56 In both trials an excess of CNS relapses
was documented in the Erwinia asparaginase arm.
This excess was documented only in the non-irradiated
patients in the DFCI protocol (no irradiation in
the EORTC protocol). 55,56 Despite the lack of formal
proof, this was most probably due to the shorter
half-life of Erwinia, resulting in a lesser asparagine
depletion both in plasma and CNS.
• Dasatinib for ALL with Philadelphia chromosome:
it has been recently documented that 11 clinically
evaluable patients with CNS disease responded to
dasatinib, a more potent tyrosine kinase inhibitor
than imatinib. 57 Complete responses, defined as
either disappearance of leukemic blasts from CSF or
radiologic findings in magnetic resonance imaging,
were observed in 7 patients. Four of these were
achieved with dasatinib monotherapy. The CNS
penetration of dasatinib, a more potent tyrosine
kinase inhibitor, seems considerably higher than
that achieved by imatinib. 57
• Thiotepa: A US trial has studied the possible role of
thiotepa for CNS relapse management, using an
upfront therapeutic window. 58 At the 65 mg/m 2
dose (one IV infusion), a complete clearance of
blasts at D8 was seen in 4 out of 9 patients with Bprecursor
ALL. 58
Finally, all these items point to the importance of systemic
treatment in the prevention of CNS relapse in ALL.
An analysis of ten trials performed in the 1990s,
involving 15,222 patients, was recently conducted by
Pui and Howard. 14 It showed that the variable association
of all these methods of CNS relapse prevention cur-
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