Acute Leukemias - Republican Scientific Medical Library

142 Chapter 10 · Recent Clinical Trials in Acute Lymphoblastic Leukemia by the Cancer and Leukemia Group B
fully by the German ALL study group for patients with
L3 ALL [16]. The major differences between the 9251
regimen and Hoelzer’s are the use of etoposide instead
of teniposide and the use of cytarabine as a continuous
infusion for 48 h rather than as subcutaneous injections.
We enrolled 92 adults with Burkitt leukemia or lymphoma
and studied two cohorts to evaluate the efficacy
of intensive chemotherapy with and without cranial radiation
for CNS prophylaxis. Prophylactic cranial radiation
(2400 cGy) and 12 doses of triple intrathecal chemotherapy
were given to the first cohort of patients
[14]. A subsequent group underwent the same chemotherapy,
except intrathecal therapy was reduced to six
doses and radiotherapy was given only to those at high
risk [15].
The median follow-up is 6.8 years in cohort 1 and 4.1
years in cohort 2. Toxicity was significant with all patients
having severe myelosuppression and most patients
having grade 3 or 4 mucositis. Three occurrences
of transverse myelitis, two severe neuropathies, three
cases with aphasia, and one of blindness were documented
in the first cohort of 52 patients. In the subsequent
cohort of 40 patients, there were none of these occurrences
and patients experienced less neurologic toxicity
overall (61% vs. 26%, p=0.001). Responses were similar
(74% CR overall), and the 3-year event-free survival
(EFS) from diagnosis was 52% (95% confidence interval,
38–65%) for the first cohort and 45% (29–60%) for the
second. The DFS rates were 66% and 67%, respectively.
We concluded that intensive, short-duration chemotherapy
with less intensive CNS prophylaxis controlled this
sanctuary site with little neurotoxicity and may be curative
for adults with Burkitt leukemia or lymphoma.
10.7 CALGB Study 19802
Aggressive combination chemotherapy for adults with
ALL has resulted in CR rates of 70–90%, but overall survival
(OS) remains at 30–40%. We hypothesized that
early dose intensification of daunorubicin (Dnr) and cytarabine
(Ara-C) may improve DFS and that aggressive
high dose intravenous (IV), oral, and intrathecal (IT)
methotrexate (MTX) could replace cranial radiotherapy
(RT) for CNS prophylaxis. The CALGB undertook a
phase II study (19802) to examine these issues [17, 18].
Treatment consisted of 6 monthly courses of intensive
therapy followed by 18 months of maintenance therapy.
Five drugs (cyclophosphamide [Cy], Dnr, prednisone,
vincristine, l-asparaginase) were given with G-CSF support
for remission induction as in study 9111. In patients
< 60 years old, the Dnr dose in the induction module A
was increased in cohorts from 45 mg/m 2 /day on days 1,
2, and 3 (used in prior CALGB ALL studies) to 60 and
then to 80 mg/m 2 daily for 3 days. In patients ³60 yrs
old, Cy was omitted from module A, and Dnr was increased
from 30 to 60 mg/m 2 /day for 3 days. Cy plus
high-dose Ara-C, and CNS prophylaxis with IV, oral,
and IT MTX were introduced in later treatment modules
for all patients. No cranial RT was given.
Between 1999 and 2001, 163 adults with untreated
ALL (FAB L1 and L2) were enrolled on study. The median
age was 41 years (range 16 to 82); 61% were male. The
median white blood cell (WBC) count at presentation
was 10 050/ll (range 500 to 348500). A large proportion,
43% (42/97) of centrally reviewed and evaluable cases,
had poor risk cytogenetics as defined in prior CALGB
studies [19]. Seventy-eight percent (127/163) of patients
(95% CI, 71–84%) achieved a CR, comparable to CR
rates (81–85%) achieved in three prior CALGB studies
with lower doses of Dnr. By age, the CR rates were
91% (43/47) for patients < 30 years, 78% (65/83) for patients
30–59 years, and 58% (19/33) for patients ³60
years. There were 11% induction deaths and 11% induction
failures due to refractory ALL. Thirty-nine patients
< 60 years received Dnr at 60 mg/m 2 ; two of these patients
(5%) died during induction and two (5%) had refractory
disease. These results were similar when compared
to eight (9%) induction deaths and 11 (12%) with
refractory disease among the 91 patients who received
Dnr at 80 mg/m 2 . Thirteen high-risk patients had an allogeneic
SCT in first CR and 12 more underwent transplantation
after relapse.
With a median follow-up of 2.4 years for survivors,
63/163 (39%) are alive and 44/127 (35%) are in continuous
CR. Relapses have occurred in 66 (52%) patients; of
these, eight (5%) had isolated CNS relapses. The median
DFS is 1.5 years (95% CI, 1.0–1.9) and the median OS is
1.6 years (95% CI, 1.2–2.4). Age > 60 years impacted adversely
on DFS. Of interest, neither poor-risk cytogenetics
nor presenting WBC > 30000/ll significantly affected
DFS. Both older age and adverse cytogenetics
were associated with shorter OS.
In conclusion, intensification of Dnr during treatment
of adult ALL is feasible, and the postremission
therapy piloted in CALGB 19802 was generally well tolerated
and could be given in the outpatient setting. To
date, intensified Dnr has not resulted in an improve-