Acute Leukemias - Republican Scientific Medical Library

268 Chapter 21 · Central Nervous System Involvement in Adult Acute Lymphocytic Leukemia
SAM: good risk 9.6%, and poor risk 12.7%. In poor-risk
patients, approximately one third of the isolated CNS relapses
occurred before preventive CNS therapy was begun
at week 9. Hence, regimen S has provided better
CNS preventive therapy for both good- and poor-risk
patients (p < 0.001 overall) [62].
Several issues remain debatable: which drugs are the
best IT combinations, the preferred schedule of administration,
and the use of a risk-oriented strategy. Some
of the lessons learned from childhood ALL have been
analyzed in an attempt to answer these questions. A
risk-oriented approach is clearly indicated.
In low-risk childhood ALL patients, IT alone can effectively
prevent CNS disease, and this is the preferred
method for CNS prophylaxis for this group of patients
because of toxicities of cranial irradiation in a growing
child [61, 64]. Although the definition of low-risk disease
varies, CNS relapse rates in this group are £5%
in most studies. For intermediate-risk patients two
studies have combined IT with HDCT [65, 66] whereas
others combined low-dose (1200 rads) cranial irradiation
with IT [61]. Both approaches have similar response
rates with long-term CNS disease-free survival (DFS)
rates about 90% with or without cranial irradiation.
There are few studies regarding CNS prophylaxis in
adult ALL and they vary considerably with respect to inclusion
criteria, dose of radiation, dose of chemotherapy,
and timing of prophylaxis. A summary of selected
trials is presented in Table 21.2.
Table 21.2. CNS prophylaxis by induction treatment regimen
It is clear that at least two modalities are required
for adequate prophylaxis. Most trials have used a combination
of IT and cranial irradiation. However, an
approach combining high-dose IV methotrexate, cytarabine,
and dexamethasone in conjunction with 16
doses of IT methotrexate alternating with cytarabine
has been reported to greatly reduce the risk of CNS leukemia
[5, 67].
Analysis of multiple chemotherapy approaches
without cranial irradiation from a single institution
was published by Cortes et al. [5]. Patients at low risk
for CNS leukemia were given high-dose cytarabine
and intermediate-dose methotrexate. Their 5-year CNS
event-free rate was 85%, which compares favorably to
the historical 65% with no prophylaxis (p = 0.05).
Comparatively, for patients with high-risk CNS leukemia
who had no prophylaxis, the 5-year CNS eventfree
rate was 28%, compared to 67% with HDST, 70%
with HDST plus late (at the time of CR) IT, and 98%
(at 3-year EFS) with HDST and early (starting with induction
chemotherapy) IT [5]. This study emphasizes
the importance of early start of prophylaxis (i.e., at
the start of induction chemotherapy) and the use of a
risk-oriented approach for prophylaxis. In this study
risk was determined by the serum LDH level and the
percentage of cells in S + G2M phase in the bone marrow.
Mature B-cell ALL is by definition associated with
high risk for CNS disease. Between 10 to 40% of patients
Treatment regimen a
CNS prophylaxis
Low risk High risk
VAD High-dose systemic chemotherapy b
High-dose Systemic chemotherapy b
Modified VAD High-dose systemic chemotherapy c
Hyper-CVAD High-dose systemic e +IT(´ 4) chemotherapy f
High-dose systemic c +IT(´22) chemotherapy
High-dose systemic e +IT(´ 4) chemotherapy f
CNS, central nervous system; high-risk, mature B-cell immunophenotype, or the presence of either elevated serum levels of lactate dehydrogenase
or high proliferative index in the bone marrow (i.e., ³ 14% cells in S and G2M phase; all others were low risk); VAD, Vincristine, doxorubicin,
and dexamethasone; IT, intrathecal.
a IT started in complete response for patients on the modified VAD regimen and during induction for patients on the hyper-CVAD regimen.
b High-dose cytosine arabinoside (ara-C) (3 g/m 2 every 12 h for six doses) and moderate dose methotrexate (MTX) (400–1600 mg/m 2 ).
c High-dose ara-C (3 g/m 2 every 12 h for six doses).
d Ara-C 100 mg weekly ´ 8, then every other week ´ 8, then monthly ´ 6 (22 IT doses in 12 months).
e High-dose ara-C (3 g/m 2 every 12 h for four doses) and high-dose MTX (1 g/m 2 ).
f MTX 12 mg on day 2, ara-C 100 mg on day 8 with each hyper-CVAD or MTX/ara-C course. High-risk patients received 16 IT doses, low-risk
patients received four IT doses.