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Effectiveness of Intensified Rotational Combination Chemotherapy for Late
Hematologic Relapse of Childhood Acute Lymphoblastic Leukemia
By Gaston K. Rivera, Melissa M. Hudson, Qing Liu, Ely Benaim, Raul C. Ribeiro, William M. Crist, and Ching-Hon Pui
Relapsed acute lymphoblastic leukemia (ALL) usually carries
a dire prognosis. We evaluated the effectiveness and longterm complications of intensive rotational combination chemotherapy for late hematologic relapse (median, 16 months
after elective cessation of therapy) among 34 children and
young adults (ages 4 t o 23 years). Concurrent central nervous system (CNS) relapse was present in 3 cases and testicular relapse in 4. Secondary therapy comprised an intensive
five-drug reinduction (6 weeks) followed by continuation
treatment with four drug pairs, rotated weekly in 4-week
cycles over 120 weeks. Intrathecal chemotherapy (methotrexate, hydrocortisone, cytarabine) was given three times
during reinduction and every 8 weeks during continuation.
Treatment was electively discontinued at week 120 in the
absence of detectable disease. Thirty-three patients (97%)
attained a second complete remission. At a median followup of 9.3 years (range, 4.5 t o 11.4). estimates of 5-year sec-
ond event-free and overall survival (+SE) are 65% f 8% and
79% f 7%. respectively. Eleven patients had a second relapse (9 marrow, 2 testicular) and one developed secondary
myeloid leukemia. There have been no CNS relapses or
deaths in remission. Treatment was well-tolerated and was
given largely on an outpatient basis. Late effects are primarily endocrinologic; one child had a second malignant solid
tumor (presumed related t o initial radiation therapy) that
was treated successfully. Intensive treatment with alternating non-cross-resistant drug pairs for late hematologic relapses of ALL is effective and well-tolerated, and produces
results similar t o those achieved in patients with newly diagnosed ALL. Event-free survival compares favorably with reports of other relapse regimens, including those incorporating bone marrow transplantation.
0 1996 b y The American Society of Hematology.
T
mia was diagnosed when leukemic blast cells were identified in
Wright-stained centrifuged samples of cerebrospinal fluid (CSF),
regardless of the CSF mononuclear cell count. This study was approved by the hospital‘s institutional review board, and written informed consent was obtained from patients, parents, or guardians,
as appropriate.
Twenty-nine patients had received primary multiagent chemotherapy for ALL on St Jude Total Therapy Studies IX and X,which
have been described in detail previo~sly.~.~
Five children were initially treated elsewhere: 2 on protocols of the Childrens Cancer
Groupl”l’ and 3 with combination chemotherapy similar to St Jude
protocols. Briefly, initial therapy was based on postremission standard-dose 6-mercaptopurine and methotrexate in 7 cases; antimetabolite-based therapy with periodic high-dose methotrexate intensification in 13; standard-dose antimetabolites and postremission
intensification with anthracyclines and epipodophyllotoxins in 10;
periodic teniposide (VM-26) and cytarabine pulses in 2; and rotational combination chemotherapy including cyclophosphamide and
epipodophyllotoxins in 2. CNS therapy comprised 18 to 24 Gy cranial irradiation plus intrathecal methohxate in 20 cases and highdose intravenous methotrexate (1 g/mz)plus intrathecal methotrexate
followed by leucovorin rescue in 14 cases.
Treatment. The RI1 treatment schedule is illustrated in Table
1.Reinduction therapy comprised five drugs (prednisone, vincristine,
L-asparaginase, VM-26, cytarabine) administered over a 6-week period at full scheduled dosages, regardless of blood counts. Triple
HE OPTIMAL TREATMENT for relapsed childhood
acute lymphoblastic leukemia (ALL) remains contro-
versial. However, there is agreement that late hematologic
relapses are associated with a better treatment outcome than
relapses during or soon after treatment. In fact, the length
of first hematologic remission has consistently emerged as
the most important predictor of second remission duration
after both hematologic and extramedullary relapse^."^ It is
unclear, however, for how long one should retreat these
patients, and what guidelines should be used for second elective cessation of therapy, particularly in view of reports of
second relapses occumng several years after apparently successful secondary therapy.’,* Long-term follow-up is clearly
necessary to evaluate the effectiveness, and the associated
morbidity, of any treatment regimen for relapsed ALL.
Our previous institutional protocol for patients with late
marrow relapses yielded an estimated 5-year second eventfree survival of 31% (SE 17%). Twelve of the 26 patients
treated on this protocol appear to be cured (4in third remission), 12 to 15 years after the diagnosis of r e l a p ~ e .We
~
hypothesized that further intensification of both reinduction
and continuation chemotherapy would improve these results.
Here we report the encouraging responses to a treatment
regimen based on this premise. At a median follow-up of
more than 9 years, it appears that at least two thirds of
patients treated for late hematologic relapse will be longterm survivors. A parallel trial for children with isolated
central nervous system (CNS) relapse has been described
separately.6
MATERIALS AND METHODS
Between February 1983 and May 1990, a total of 34 patients
with late hematologic relapses of ALL were treated on the St Jude
Children’s Research Hospital “R11” protocol. To participate in this
mal, patients were required to have been off therapy for at least 6
months and to be in first hematologic relapse. Patients who had
previously experienced an isolated CNS relapse (n = 2) or who had
a combined marrow and CNS (n = 3) or testicular relapse (n = 4)
were also eligible. The diagnosis of hematologic relapse was based
on detection of greater than 25% leukemic blast cells in bone marrow
(BM) aspirates, using previously described techniques.’ CNS leukeBlood, Vol 88, NO3 (August 1). 1996: pp 831-837
From the Departments of Hematology-Oncology, Pathology and
Laboratory Medicine, and Biostatistics, St Jude Children’s Research
Hospital; and the Department of Pediatrics, University of Tennessee,
Memphis, College of Medicine, Memphis, TN.
Submitted December 22, 1995; accepted March 26, 1996.
Supported by Grants No. P30 CA-21765 and POI CA-20180from
the National Cancer Institute, Bethesda, MD, and the American
Lebanese Syrian Associated Charities (ALSAC), Memphis, TN.
Address reprint requests to Gaston K. Rivera, MO, St Jude Children’s Research Hospital, 332 N Lauderdale, Memphis, TN 38105.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accorahce with 18 U.S.C.section 1734 solely to
indicate this fact.
0 1996 by The American Society of Hematology.
0006-4971/96/8803-04$3.00/0
831
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832
RIVERA ET AL
Table 1. Treatment for Late Hematologic Relapse of ALL
~~
Reinduction (weeks 1 to 6)
Vincristine
1.5 mg/mz IV weekly x 6
Prednisone
40 mglm' orally daily x 42
Asparaginase
10,000 U/mZIM on days 1,3,5, 15, 17,
Teniposide
Cytarabine
Triple IT therapy
19,29, 31,33
200 mglm' IV on days 8, 22, 36
300 mglm' on days 8,22,36
Days 1, 22, 43 (or weekly x 6 in
patients with combined marrow and
CNS relapse). Doses follow:
Patient AQe
Methotrexate
Hydrocortisone
Cytarabine
< 1 yr
1-3 yr
> 3 yr
6 mg
12 mg
18 mg
8 mg
16 mg
24 mg
12 mg
24 mg
36 mg
Continuation therapy (drug pairs 1-4in sequence every 4 weeks for
120 weeks)
(1) Etoposide
Cyclophosphamide
(2) Methotrexate
Mercaptopurine
(3)Teniposide
Cytarabine
(4)Prednisone
Vincristine
300 mg/mz IV
300 mg/m2 IV
40 mg/mz orally
75 mg/m2/dorally x 7
150 mg/mz IV
300 mg/mz IV
40 mglm'ld orally x 7
1.5 mg/m' IV weekly
Triple IT therapy every 8 weeks
Abbreviations: IV, intravenous; IM, intramuscular: IT, intrathecal.
intrathecal therapy (methotrexate, hydrocortisone, and cytarabine)
was given on days 1, 22, and 43 (plus days 8 and 15 for patients
with combined marrow and CNS relapse). On day 43, a BM aspirate
was performed to evaluate response. The four patients who had
combined marrow and testicular relapses received 20 to 24 Gy bilateral gonadal irradiation (10 to 12 fractions over 14 to 16 days) after
induction of hematologic remission.
Continuation treatment, administered for 120 weeks after documentation of hematologic remission, was based on the use of multiple agents in rapid succession to avoid the development of drug
resistance." Eight drugs were given in four pairs (etoposide [VP-16]
+ cyclophosphamide, 6-mercaptopurine + methotrexate, teniposide
[VM-261 + cytarabine, and prednisone + vincristine) in weekly
rotation for 4 weeks, with the rotation restarted at week 5. All
patients received triple intrathecal chemotherapy every 8 weeks
throughout continuation. Doses of all drugs except prednisone and
vincristine were omitted if the absolute phagocyte count (polymorphonuclear cells + early myeloid cells + monocytes) was less than
0.5 X 109L or the platelet count was less than 50 X 109L, or if
grade IIYIV stomatitis occurred. BM aspirates were obtained every
4 months and CSF examinations were done every 8 weeks. Chemotherapy was stopped if there was no evidence of disease after 120
weeks of continuation treatment. The three patients with combined
marrow and CNS relapse received craniospinal irradiation (cranial
24 Gy, spinal 15 Gy in 16 fractions over 21 days) at week 120,
before second elective cessation of therapy. None of these three
patients had received preventive radiation during first remission.
After therapy was discontinued. patients were seen for follow-up
clinic visits every 4 months during the first year, every 6 months
during the second year, and yearly thereafter. Examinations focused
on possible late effects of treatment (eg, endocrine or neuropsychologic deficits) as well as the patients' continued leukemia-free status.
Sraristical merhods. Second event-free survival (EFS) was defined as the interval from date of second remission to relapse in any
site, life-threatening second-malignancy, or death (EFS was zero
for patients whose disease did not enter remission). Second overall
survival was defined as the time from diagnosis of first marrow
relapse to death from any cause or to date of last contact. Final
follow-up data for patients who were free of failure were obtained
in February 1995. Life tables and Kaplan-Meier curves were constructed for second EFS and survival.'' The Cox proportional hazards
model14 was used to examine the following potential predictors of
EFS: sex, age at initial diagnosis, age at first marrow relapse, leukocyte count at initial diagnosis, site of relapse (marrow alone I'
combined), duration of first hematologic remission, epipodophyllotoxin-intensified versus antimetabolite-based therapy, and prior cranial irradiation. Each prognostic factor was evaluated individually
by a Cox univariate analysis because of the small number of events.
These analyses showed no significant differences; hence, the P values were not adjusted for multiple significance tests. However. it
should be pointed out that the lack of statistical significance does
not necessarily mean that these factors do not have any prognostic
value. Because of small sample sizes. these tests have limited statistical power. For example, a two-sided comparison of any two subgroups of equal size has 42% power to distinguish a 5-year EFS
rate of 70% from a rate of 50% at the .OS significance level.
RESULTS
Characteristics of the 34 patients treated for late BM relapses of ALL, and summaries of their clinical course, are
presented in Table 2. At initial diagnosis, these patients
ranged in age from 1 to 1 1 years (median, 4); age at relapse
ranged from 4 to 23 years (median, 9). There were slightly
more male than female patients. Thirty-three patients were
white and 1 (case 1) was black. The median white blood
cell count was 10 X IO9& at initial diagnosis and 5.1 X IOy/
L at relapse.
The first hematologic remission in this group of patients
had lasted 36 to 216 months (median, 45). The time since
completion of initial therapy was 7 to 179 months (median,
16). Morphologic and immunophenotypic features of leukemic cells were similar at diagnosis and relapse in all cases.
CDIO' B-lineage ALL was identified in 19 cases tested at
both diagnosis and relapse and in 9 cases tested only at
relapse. Six of 22 patients studied had a favorable DNA
index (>1.16) at both initial diagnosis and relapse.
Of the 34 patients enrolled, 33 (97%) had attained complete hematologic remission at the end of the 6-week reinduction therapy. One patient died of Escherichia coli septicemia in the third week of reinduction therapy. At a median
follow-up of 9.3 years (range, 4.5 to 11.4), the estimated 5year second EFS is 65% 2 8% and the estimated 5-year
overall survival is 79% ~ 7 (Fig
% 1). Nine patients have had
second marrow relapses, diagnosed 16 to 60 months after
second remission (median, 40); 2 have had testicular relapses
(41 and 54 months, respectively. after second remission):
and 1 patient died of secondary myeloid leukemia. Only 3
of the 1 I relapses occurred during continuation therapy. Of
the 3 patients who had combined marrow and CNS relapse
at enrollment, 2 remain well 3 and 10 years, respectively,
after C N S radiation and second cessation of chemotherapy.
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THERAPY FOR RELAPSED ALL
833
Table 2. Initial Treatment and Responses to Secondary Therapy
Duration 1st
Remission (mo)
Initial Treatment
Patient
No./Sex
Age (yr;
Dx/Relapse)
11M
2lM
3/F
4/M
7111
8112
811 1
411 1
11114
417
519
216
419
317
416
6110
9/13
5/F
6lF
7lM
8lM
9/F
1O/F*
11/F
12/M
13lF
14lM
15lF
16lF
17/M
18/M
19/M
20/M
21/M
22lM
23/M
24/F*
25/M
26lM
271F
28/M
29/F
3O/F
31/M
32lM
33lM
34/M
WBC
X
10s/L
(OX)
38
9
28
3
4
25
1.7
99
318
216
115
10115
4123
519
217
26
12/16
10119
215
419
519
211 1
7117
Epipo
CRT
1.2
-I+
-I+
+I-
18 Gy
18 Gy
-1-I+
+I-/+
+/-I+
+/+
+/+I+/-I+
-1-I+
-I+
-I+
-I+
+I-
24 Gy
18 Gy
0.5
1.o
1.4
1.o
1.o
1.o
1.o
1.0
1.17
1.o
87
49
10
9
79
21
2.3
6.5
10
2.6
7
28
76
292
70
21
4.2
5.4
2
2.8
6.5
1.7
20
11
7.4
311 1
12118
316
114
12/17
HDMTW
-
5
217
DI
(Ox)
-
1.o
1.o
1.o
1.17
1.o
-
1.19
-
1.o
-
1.17
-
1.o
-
36
44
40
79
36
39
40
40
-
18 Gy
18 Gy
24 Gy
50
49
36
47
45
58
93
62
38
38
50
59
45
42
54
216
42
62
39
45
113
38
63
44
111
128
18 Gy
24 Gy
18 Gy
18 Gy
24 Gy
18 Gy
-
-
+/+/-I+
-1+/-1+/+
+I+
-1-1-I+
-1+/+/-
1.14
1.o
Total
24 Gy
48 Gy
-
24 Gy
24 Gy
24 Gy
18 Gy
18 Gy
18 Gy
-
Off Therapy
8
16
10
49
8
12
15
11
21
8
7
17
16
30
63
33
8
7
21
30
14
14
24
179
14
18
12
16
81
13
35
7
83
99
Responsa to Secondary Therapy
Other Relapse
Sites
Type of
Failure
Duration 2nd
Remission (mo)
Current
Status
18
60
139+
16
137+
40
53
131+
128+
128+
53
124+
123+
119+
119+
117+
113+
112+
38
47
108+
98+
97 +
0
41
92t
91 +
9
DOD
DOD
NED
DOD
NED
NEDt
DOD
NED
NED
NED
DOD
NED
NED
NED
NED
NED
NED
NED
DOD
DOD
NED
NED
NED
DOD
NED*
NED
NED
Died
NED
NED
NED*
DOD
NED
NED
88+
84+
54
21
63+
56+
Abbreviations: Dx, diagnosis; WBC, white blood count; DI, DNA index; CRT, cranial radiation therapy; HDMTX, high-dose MTX; Epipo,
epipodophyllotoxins; HR, hematologic relapse; IF, induction failure; TA, testicular relapse; AML, acute myeloid leukemia; NED, no evidence of
disease; DOD, died of disease.
Patients 10 and 24 were previously treated for an isolated CNS relapse but had remained in hematologic remission.
t Patient survives 8 years after allogeneic BMT.
Patients 25 and 31 are alive and in complete remission 3 years and 4 years, respectively, after testicular relapse.
*
1
78+m
............
\
0.8
="
4
2
,_................. "
0.4
0.2
E9 f Us(
62*149b
0.8
t
1
0
..........
kM,
-
EFS
2
4
6
8
10
12
nan
Fig 1. Kaplan-Meier estimates of second EFS and overall survival
in 34 patients following late hematologic relapse of acute lymphoblastic leukemia.
Three of the 4 patients with combined marrow and testicular
relapses remain in continuous second remission for 6 , 8 , and
10 years, respectively, after testicular radiation therapy and
secondary chemotherapy.
Twenty-four patients (71%) are long-term survivors: 21
of these 24 are in continuous second hematologic remission.
The length of the second remission exceeded that of the first
remission in 19 cases. There have been no CNS relapses or
deaths in remission. The two patients whose second remission ended with testicular relapse remain in complete remission after third elective cessation of therapy. Only one child
survives after a second hematologic relapse, which followed
second elective cessation of therapy. This patient (no. 6 in
Table 2) received an allogeneic BM transplant in third hematologic remission, 8 years ago, and has been well since that
time.
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RIVERA ET AL
834
Analysis using the Cox proportional hazards model
showed no significant impact on second EFS by any of the
potential prognostic factors examined (sex, age at diagnosis,
age at relapse, white blood cell count at diagnosis, DNA
index at diagnosis, duration of first remission, combined v
isolated BM relapse, and prior epipodophyllotoxin-intensified v antimetabolite-based therapy). However, given the
sample size and limited power to detect differences between
subgroups, the absence of statistical significance should not
be equated with lack of clinical relevance.
Acute toxicity. During reinduction therapy, 96% of
planned chemotherapy doses were administered. As expected, all patients developed profound myelosuppression.
The median time to hematopoietic recovery after completion
of reinduction therapy was 8 days (range, 1 to 18). In addition to the 1 case of fatal bacterial septicemia, 1 patient
developed Aspergillus sinusitis but recovered with antifungal
treatment. Stomatitis was infrequent. Eight patients required
hospitalization (1 to 2 weeks duration) for febrile neutropenia and 10 received blood products. Seven patients required insulin for hyperglycemia secondary to treatment with
prednisone and L-asparaginase. Two patients had L-asparaginase-associated cerebrovascular accidents; one of these patients has residual hemiparesis and the other recovered completely.
Continuation therapy was well tolerated, and the majority
of treatment was administered on an outpatient basis. Myelosuppression was the most frequent cause of omitted chemotherapy doses (8% of planned doses). Platelet and absolute
phagocyte counts recovered to acceptable levels within 1
week in 95% of myelosuppressive episodes. Hospital admissions were rare and usually brief, and few nonhematologic
toxicities were observed. Grade 11-111 stomatitis occurred in
12 patients and was easily reversible; there were no instances
of grade IV stomatitis. Moderate hypersensitivity reactions
to epipodophyllotoxins (15 patients) were reversed with antihistamines, and no patient developed anaphylaxis.
Late effects. Of the 24 long-term survivors (13 males,
11 females), 21 reported average or above-average academic
progress through high school (Table 3). Three of these 21
(all treated with cranial radiotherapy) received tutoring for
minor academic difficulties. Three patients, including patient
30, who has constitutional trisomy 21, have required placement in special education classes for learning disabilities
that predated the diagnosis of leukemia. Only 1 of the 10
patients who had serial neuropsychiatric evaluations showed
a decline in functioning after treatment that included total
body irradiation and BM transplantation (BMT). Other than
the residual hemiparesis mentioned previously, no significant
neurologic or psychologic problems have been identified
among the long-term survivors.
Reduced growth velocity was identified in 14 individuals,
11 of whom received cranial radiotherapy as primary CNS
therapy (n = 8) or relapse therapy (n = 3). Thirteen of these
patients have reached their adult heights: five have short
adult stature (ie, height at or below the fifth percentile),
including the patient with trisomy 21. Three of these five
patients had received cranial radiation as primary preventive
therapy and one was treated with craniospinal radiation for
Table 3. Late Toxicity After Therapy
Finding
Neuropsychologic
Normal cognitive function
Required tutoring
Developmental delay
Moderate
Severe*
Hemiparesis
Endocrinologic
Thyroid function
Normal
Hypothyroid
Growth
Normal
Reduced growth velocityt
Short adult stature
Fertility
Males (n = 13)
Hypogonadal
Unknown
Females (n = 11)
Regular menses
Ovarian failure
Pregnancies
No. Patients (%)
21 (88)
3
3 (12)
2
1
1
23 (96)
1 (4)
10 (42)
14 (58)
5/13$
4 (31)
9 (69)
10 (91)
1 (9)
3 (27)
Infectious
Chronic hepatitis B and C
1 (4)
Orthopedic
Avascular necrosis and slipped capital femoral
epiphysis
1 (4)
Second malignancy
Acute myeloid leukemia
Mucoepidermoid carcinoma
2 (8)
1
1
Developmental delay predated leukemia diagnosis.
t Three patients are Currently on growth hormone therapy.
Only 13 patients have achieved adult height.
*
a combined CNS and hematologic relapse. Three boys, all
of whom underwent cranial irradiation during their initial
treatment, are receiving growth hormone therapy for reduced
growth velocity. Five female and five male survivors are
obese (increased body mass index for age). Hypothyroidism
has been identified in only 1patient, who was treated with 24
Gy cranial radiation. Pubertal development has progressed
normally in 10 female survivors, all of whom are menstruating regularly. The young woman in third remission after
allogeneic BMT has ovarian failure. Two female long-term
survivors have delivered healthy full-term infants and one
is currently pregnant. Four young men are hypogonadal as
a consequence of testicular radiotherapy.
One patient has chronic active hepatitis B and C, following
36 donor exposures over a 5-year period. Another has avascular necrosis of the left hip and slipped capital femoral
epiphysis.
Two patients developed a second malignant neoplasm.
One died of secondary acute myeloid leukemia, which was
diagnosed 9 months after the start of continuation therapy.
The second, a young woman previously treated with cranial
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THERAPY FOR RELAPSED ALL
radiation, developed a parotid mucoepidermoid carcinoma
67 months after the initial diagnosis of ALL. She remains
in continuous hematologic remission and has had no recurrence of the radiation-related tumor after parotidectomy.
DISCUSSION
In this prospective study, intensive rotational combination
chemotherapy was highly effective in treating patients who
developed late hematologic relapses of childhood ALL. With
long-term follow-up (median, 9.3 years), the estimated 5year second EFS is 65% (SE 8%). Thus, two thirds of these
patients are probably cured of their leukemia. These results
are superior to those of our prior relapse trial (5-year second
EFS 3 1%)5 and a parallel Pediatric Oncology Group study
(4-year second EFS 37%),15both of which used a less intensive three-drug reinduction therapy. Although direct comparisons are not possible in view of differences in patient populations and treatment histories, these results are similar to
those from studies of high-dose chemotherapy, total body
irradiation, and allogeneic BMT for patients in second remission after a late hematologic relapse.16
Uderzo et all6 recently reported a large series of pediatric
patients with hematologic relapses of ALL in which allogeneic BMT was superior to chemotherapy among those children who had a short first remission. However, the data did
not demonstrate superiority of allografts in children with an
initial remission of 30 or more months (relative risk [RR]
= .94; P = .92, 95% confidence interval [CI], 0.30 to 2.96).
Barrett et all7 used the criteria of age and leukocyte count
at diagnosis, sex, immunophenotype, and length of first remission to match 76 patients enrolled in Pediatric Oncology
Group chemotherapy relapse protocols with children who
underwent BMT in a variety of institutions. Overall, BMT
produced a significantly superior 5-year leukemia-free survival (40% [SE 3%] v 17% [SE 3%], P < .01). However, this
difference was less marked for patients who had a prolonged
initial remission (5-year leukemia-free survival, 32% [SE
6%] for the chemotherapy-treated patients and 53% [SE 7%]
for the transplant group; P value not given). Therefore, the
investigators suggested that, in patients with long initial remissions, it might be reasonable to defer transplantation until
a subsequent relapse occurred. Investigators from the BerlinFrankfurt-Munster group have reported a 7-year second EFS
of 47% (SE 12%) for 27 patients treated with allogeneic
transplantation for late marrow relapse,” an outcome no
better than that in our chemotherapy-treated patients. Taken
together, the available data suggest an approach based on
intensified chemotherapy for patients with late marrow relapses, with allogeneic marrow transplant reserved for patients who relapse early or who have specific high-risk features such as the Philadelphia chromosome.
Some leukemia specialists recommend autologous marrow transplants for patients with relapsed ALL in second
or subsequent hematologic remission. The Boston group’’
recently reported a 3-year EFS (median follow-up, 3.3 years)
of 50% (SE 9%) for 31 patients treated with high-dose chemotherapy, total body irradiation, and infusion of antibodytreated autologous marrow in second hematologic remission.
Patients in this study (which also included children in third
835
or subsequent relapse) had a first remission duration of at
least 24 months and a B-progenitor CD19+/CDlO+immunophenotype. Our findings suggest that similar results could
be obtained with chemotherapy alone in children with these
features who are in first hematologic relapse after a prolonged initial remission.
Regardless of the duration of prior remission, effective
CNS preventive therapy at relapse is essential, as hematologic relapse apparently nullifies the effects of initial therapy
for subclinical meningeal leukemia. However, the specific
therapy must be selected carefully, in view of the potential
for severe neurotoxicity.” We previously reported that prolonged periodic administration of intrathecal chemotherapy
effectively prevented CNS relapses during second hematologic remission, even in the context of less intensive postremission therapy.’ The Berlin-Frankfurt-Munster group recommends that all children with late hematologic relapse
receive 12 to 18 Gy cranial irradiation combined with shortterm intrathecal chemotherapy. In their 1987 relapse study,
estimated 6-year second EFS rates were 46% for patients
who received cranial irradiation versus 18% for those who
did not.” However, to our knowledge, the late sequelae of
these therapies have not been reported.
None of our patients treated with multiple courses of triple
intrathecal therapy, without craniospinal radiation, ended
second remission with a CNS relapse. Craniospinal radiation
was used only for the 3 patients who had combined marrow
and CNS relapses (2 of whom survive, without long-term
neurotoxicity, at 3 and 10 years posttreatment, respectively).
Pharmacokinetic studies at St. Jude have demonstrated good
CNS penetration of intravenous epipodophyllotoxins,22
which may be an additional factor in preventing meningeal
relapses. Hence, we recommend that cranial irradiation be
reserved for the small percentage of patients who have overt
CNS leukemia at the time of hematologic relapse.
The treatment program described here was well tolerated,
permitting delivery of chemotherapy as scheduled and thus
enhancing dose intensity. Most therapy was delivered on an
outpatient basis. There were no deaths from acute toxicity
during continuation therapy. Long-term follow-up to detect
late failures and treatment sequelae is mandatory in studies
of therapy for relapsed childhood ALL. Late effects, particularly severe organ
and secondary malignan~ies,~~
are a major concern, but data on sequelae are often unavailable when treatment results are reported. For these reasons,
we chose to follow our patients for a minimum of e 5 years
before reporting treatment outcome.
When this study was designed, the carcinogenic potential
of the topoisomerase I1 inhibitors had not been d e ~ c r i b e d . ~ ~
Fortunately, however, irradiation was restricted to patients
with extramedullary disease, anthracyclines were not used,
and the epipodophyllotoxins were administered every 2
weeks-a schedule that has since been associated with a
lower risk of secondary leukemia compared with more frequent administration.26The one case of secondary acute myeloid leukemia in our series was diagnosed only 9 months
after second remission induction and may have been related
to the patient’s initial treatment, which comprised alkylating
agents, anthracyclines, epipodophyllotoxins, and CNS irradi-
From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
RIVERA ET AL
836
ation. A second patient has been successfully treated for a
parotid mucoepidermoid carcinoma, presumed to have resulted from cranial radiation therapy during initial treatment.
Other cumulative long-term sequelae in this series primarily
comprise endocrinopathies and learning problems. These
deficits are unfortunate, but must be viewed in the context
of the overall outcome of this treatment regimen and the
absence of deaths from toxicity during postremission therapy.
We failed to identify patient or treatment characteristics
that were predictive of second remission duration. Similarities among our patients in terms of potential predictive features such as immunophenotype and duration of first remission (>36 months in all cases), along with the relatively
small sample size and overall good results, may account
for the absence of statistically significant findings. Although
there is no statistical evidence that the type of prior therapy
affected outcome, it is worth noting the excellent long-term
outcome of 10 of 13 patients initially treated with antimetabolite-based therapy that included high-dose methotrexate intensification.
The use of rapidly rotated drug pairs, most given parenterally, represented a marked departure from the then-standard
postremission treatment (ie, standard-doses, primarily oral,
of 6-mercaptopurine and methotrexate). Once adequate tolerance was established, we extended this approach to the treatment of newly diagnosed patients in St Jude Total Therapy
Study XI-a protocol that was very successful, especially
among higher-risk patients2' These observations underscore
the importance of relapse studies in developing effective
new therapies for leukemia. We have also found this relapse
therapy highly effective in the treatment of isolated CNS
relapses, especially in patients initially treated with antimetabolite-based therapy, with a 5-year second EFS of 68%
(SE IO%).'
Useful modifications of the chemotherapy regimen described here (in addition to parenteral versus oral methotrexate), might include substitution of dexamethasone for prednisone because of its better CNS penetration." and/or
postremission intensification using high-dose L-asparaginase." A second course of reinduction treatment to reinforce
remission might also be of benefit.",'" Other possibilities
include high-dose intravenous chemotherapy with methotrexate, cytarabine, or both. However, doses and schedules
must be carefully planned, especially in patients who have
received prior CNS radiation therapy, to decrease the risk
of neurotoxicity.
With current information, it remains difficult to determine
the optimal time for second cessation of therapy. In this
study, 8 of the I 1 relapses occurred after elective cessation
of therapy. Thus, it appears that, in about one fourth of our
patients, this therapy was not sufficiently intensive or was
stopped too soon. These clinical findings, along with the
inherent biologic differences in leukemic cell growth properties, suggest the need to consider individualized treatment
intensity and duration. To address this issue, we have begun a
prospective study of the predictive value of minimal residual
disease detection. If these studies prove to be reliably predictive, it may be possible to identify patients who require
extended or alternative therapies.
Our experience suggests that patients with late hematologic relapses of ALL can be effectively treated with chemotherapy, which should be as intensive as that used in newly
diagnosed patients with high-risk leukemia, and that CNS
radiation therapy can be reserved for patients who develop
overt meningeal relapse. We prefer to consider allogeneic
BMT only for patients who have an early first relapse (or
relapse after prolonged initial remission and subsequent retreatment), or who have known high-risk features such as
the Philadelphia chromosome.
The results obtained with this therapy for late relapses of
ALL are not markedly different from those achieved in trials
for newly diagnosed ALL, and compare favorably with other
reports of treatment for patients in second remission. The
intensive relapse therapy was generally well-tolerated and
may be particularly well-suited for late relapses following
antimetabolite-based therapy -an approach currently used by
several groups in the United States and elsewhere to treat
children with intermediate- or better-risk B-progenitor ALL.
ACKNOWLEDGMENT
We thank Christy Wright, ELS, for helpful comments and editorial
review.
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From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
1996 88: 831-837
Effectiveness of intensified rotational combination chemotherapy for
late hematologic relapse of childhood acute lymphoblastic leukemia
GK Rivera, MM Hudson, Q Liu, E Benaim, RC Ribeiro, WM Crist and CH Pui
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