Acute Leukemias - Republican Scientific Medical Library

270 Chapter 21 · Central Nervous System Involvement in Adult Acute Lymphocytic Leukemia
expected in adults. In one study, all 18 patients who had
an isolated CNS recurrence eventually had a recurrence
in the BM or died despite responding to treatment for
CNS disease but with no change in systemic therapy
[6]. This suggests that even when the disease is not
readily identified in the blood or BM at the time of
CNS relapse, there is residual disease. Indeed, Neale et
al. [72] identified molecular evidence of minimal residual
disease in BM from four of six patients with T-cell
ALL and seemingly isolated CNS recurrence. Goulden
et al. [73] found evidence of minimal residual disease
by polymerase chain reaction analysis in BM from 12
of 13 children with B-lineage ALL who were otherwise
considered to have isolated extramedullary disease.
Using intensive systemic reinduction regimens together
with IT with or without cranial irradiation at
the time of isolated CNS relapse has resulted in remarkably
improved results. With intensive regimens, children
who had isolated CNS recurrences had a better survival
compared with patients who had BM recurrences.
Ribeiro et al. [74] treated 20 children who had isolated
CNS recurrences with triple IT therapy given weekly for
at least 4 weeks, until two consecutive CSF examinations
showed no CNS disease, and then every 6 weeks.
In addition, patients received cranial irradiation (the
cranium was treated with 2400 rads and spine with
1500 rads) and systemic chemotherapy. Five drugs systemic
reinduction treatment included standard dose
prednisone, vincristine, and asparaginase plus teniposide
and cytarabine. After reinduction therapy, continuation
therapy consisted of four drug pairs (etoposide
plus cyclophosphamide, methotrexate plus mercaptopurine,
teniposide plus cytarabine, and vincristine plus
prednisone) administered sequentially every 5 weeks.
All patients achieved CR and the estimated 5-year EFS
rate was 70%. A similar approach was used by Ritchey
et al. [75] in 83 patients (median age 4.1 years) who
had isolated recurrences. All patients achieved second
CR, and the 4-year event free survival rate was 71%.
Thus, patients with “isolated” CNS disease should receive
systemic reinduction chemotherapy together with
IT. With this strategy, children with isolated CNS relapse
have a significant probability of being cured and this
group constitutes indeed a favorable subset among
those with CNS relapse.
The experience in adults has not been as favorable.
In a recent series from MDACC [76] thirty-two adult patients
with CNS recurrence were analyzed. The timing
of CNS recurrences were: 17 patients isolated (53%),
eight patients after BM recurrence (24%), and seven patients
simultaneous BM and CNS recurrence (21%).
Seventeen patients (53%) had no neurologic symptoms
at the time of CNS recurrence and their diagnosis was
made on a routine lumbar puncture. The majority of
patients (88%) were treated with VAD (vincristine,
adriamycin, and dexamethasone) regimen for induction
and the rest received Hyper-CVAD. All patients received
IT to treat the CNS recurrence. The majority received
alternating IT agents twice weekly until CSF was negative,
although the specific sequence and frequency of
administration varied. The IT agents used were cytarabine
in all 32 patients, methotrexate in 26 patients, hydrocortisone
in 19 patients, and thiotepa in one patient.
The 15 patients with cranial palsies or motor and sensory
deficits also received cranial irradiation. IT was effective
in achieving a CNS CR in 30 patients (94%), but
10 patients (31%) had a second CNS recurrence. However,
the median survival was only 6 months. Only
28% of patients were alive at 1 year, and only 6% were
alive at 4 years. This single institution study demonstrated
that adults patients with ALL and isolated CNS
recurrence had a slightly better outcome compared to
others with CNS recurrence concomitant or after BM relapse.
However, the prognosis for isolated CNS recurrence
clearly is worse for adults than for children. Isolated
CNS recurrences occur much earlier in adults than
in children. This may be due at least in part to the earlier
occurrence of CNS relapse in adults. The median
duration of first CR in the MDACC series was 21 weeks,
compared with 2 years in children with isolated CNS recurrence,
and only 15–17% had a first CR duration of
< 1 year [75, 77]. A short CR duration has been proposed
as the single most important prognostic variable for
children with isolated CNS recurrence [75]. Thus, CNS
relapse confers a very poor prognosis to adult patients,
even in the setting of isolated CNS relapse and despite
the use of systemic chemotherapy at the time of relapse.
New approaches are needed for this setting.
Bone marrow transplantation (BMT) is unfortunately
also ineffective in the management of CNS leukemia.
Thompson et al. [78] reported the probability of
CNS relapse was 52% for patients with a history of
and/or active CNS disease at the time of BMT. The probability
was 17% for patients receiving IT Mtx after BMT,
although IT significantly increased the risk of leukoencephalopathy.
However, in a study by van Besien et al.
[79] all four patients with active CNS disease at the time
of BMT, and 16 of 20 with history of CNS disease re-