Annals of Oncology 11: 53-58, 2000.
© 2000 Klimer Academic Publishers. Printed in the Netherlands.
Original article
Relapses of childhood anaplastic large-cell lymphoma:
Treatment results in a series of 41 children -
a report from the French Society of Pediatric Oncology
L. Brugieres,1 P. Quartier,1 M. C. Le Deley,2 H. Pacquement,3 Y. Perel,4 C. Bergeron,5
C. Schmitt,6 J. Landmann,7 C. Patte,1 M. J. Terrier-Lacombe,8 G. Delsol9 & O. Hartmann1
Departments of Pediatric Oncology, 'Statistics, sPathology, Institut Gustave-Roussy, Villejuif 3Pediatric Oncology, Institut Curie, Paris,
4
Pediatrics, Hopital Pellegrin, Bordeaux, 5Pediatric Oncology, Centre Leon Berard, Lyon, 6Pediatric Hemalology and Oncology,
Hopitald'enfants, Nancy, ''Pediatric Onco-Hemalology, Hopital Trousseau, Paris, 9Pathology, CHUPurpan, Toulouse, France
Summary
Purpose: to study response to chemotherapy and the outcome
of children treated for a relapsed anaplastic large-cell lym-
phoma (ALCL) and to evaluate the role of bone marrow
transplantation (BMT) in these patients.
Patients and methods: Clinical data concerning the 41
relapses that occurred in 119 patients with ALCL enrolled in 3
consecutive studies since 1975 were analysed. First-line treat-
ment consisted of intensive chemotherapy according to the
COPAD protocol for the first series of 12 patients treated
between 1975 and 1989 and to the SFOP (French Society of
Pediatric Oncology) HM protocols for the 30 patients treated
between 1989 and 1997. Twenty-eight patients were treated with
CV(B)A (CCNU, vinblastine, ara-C with or without bleo-
mycin), and the others with miscellaneous protocols for recur-
rent disease. Fifteen patients underwent autologous BMT and
1 allogeneic BMT while in CR2.
Introduction
Anaplastic large-cell lymphoma (ALCL) accounts for
only 10%-15% of all childhood non-Hodgkin's lympho-
mas [1, 2]. Like the other childhood lymphomas, ALCL
are highly chemo-sensitive with complete remission
rates ranging from 66%—100% with various multiagent
chemotherapy regimens in adult [3-11] and childhood
[12-15] series. However, in most of the series, 20%-40%
of the patients develop recurrent disease. As the disease
is rare, reports on the treatment and outcome of ALCL
relapses are limited in number and usually concern
small series of patients [4-6, 13, 15]. Furthermore, the
second-line treatment is often heterogeneous and follow-
up usually short. Data concerning treatment intensifi-
cation with bone marrow or stem-cell transplantation
(BMT) for ALCL relapses are also limited and hetero-
geneous with respect to the status of the disease at
the time of BMT and to conditioning regimens [16-20].
This study analyses the outcome of 41 children treated in
France for a relapsed ALCL between 1975 and 1997.
Results: Thirty-six of forty-one (88%) patients achieved
CR2. With a median follow-up of 5 years, 12 patients died, 9
of their disease and 29 patients are alive in CR2 (20 patients),
CR3 (5 patients), CR4 (2 patients), CR5 (1 patient) or CR6
(1 patient). Overall and disease-free survival are respectively
69% (53%-82%) and 44% (29%-61%) at three years. In uni-
variate analysis, patients treated with ABMT while in CR2 did
not appear to have a better outcome than the other. Remarkably,
a long-lasting remission was obtained in 8 of 13 patients treated
with weekly vinblastine for a relapse including 6 relapses
occurring after ABMT.
Conclusions: Relapsed ALCL are highly chemosensitive but
over 40% of the patients experience several relapses. Prolonged
conventional chemotherapy based on vinblastine might, in some
cases, be as efficient as short intensive treatment with ABMT.
Key words: ABMT, anaplastic large-cell lymphoma, children,
relapse, vinblastine
Patients and methods
Patients
We analysed the data on all consecutive relapses that occurrred in
three series of patients treated for ALCL between 1975 and 1997. The
first group of patients were first diagnosed as having malignant histio-
cytosis which, after review of histopathologic material, were reclassi-
fied as ALCL. They were treated between 1975 and 1988 with the
COPAD protocol in the Pediatrics department at the Institute Gustave
Roussy [21]. The second and third series of patients were treated at
several institutions of the French Society of Pediatric Oncology
(SFOP) and enrolled in two multicentric prospective SFOP studies,
HM89 and HM91 for newly diagnosed childhood ALCL [22]. Of the
119 patients included in these 3 series, 41 children relapsed and they
constitute the study population. The main patient characteristics are
shown in Table 1.
The histopathologic material was reviewed in the reference labo-
ratory for the HM studies for the 41 patients included in the study. The
diagnosis of ALCL was based on the morphologic and immunologic
criteria of the R.E.A.L. Classification for non-Hodgkin's lymphomas
[23]. The positivity for B-cell markers excluded the diagnosis of ALCL.
Immunohistochemistry was performed on routine sections and on
frozen sections, when available, by applying a panel of monoclonal
and polyclonal antibodies [24],
54

Table I. Main characteristics of the 41 patients included in the study Table 2. Protocols CVBA and CVA.
for recurrent ALCL.
CVBAa
Age at diagnosis (months) CCNU 100 mg/m2 p.o. Dl
Median Vinblastine 6 mg/m2 i.v. Dl, 15,22
Range 17-190 Bleomycin 20 mg/m2 i.v. Dl, 15,22
Sex Ara-C (replaces bleomycin when
Male 17 a total dose of 200 mg/m 2 of
Female 24 bleomycin is reached) 100 mg/m2 i.v. Dl-5
Immunophenotype CVAa
CD30 41 positive/41 tested CCNU 100 mg/m2 p.o. Dl
EMA 40 positive/40 tested Vinblastine 6 mg/m2 i.v. Dl,8, 15,22
ALK. 36 positive/39 tested Ara-C 100 mg/m2 i.v. Dl-5
T 23 positive/31 tested
Null 8 positive/31 tested ' Courses every six weeks for 12 months.
Stage at diagnosis according to St. Jude's
classification
I —II 6 Response assessment
III-IV 35
First-line treatment Complete remission (CR) was defined as the complete disappearance
COPAD 12 of all lesions for at least four weeks. Partial response (PR) was defined
HM89 8 as a regression of more than 50% of all the tumor sites without the
HM91 21 appearance of new lesions. Progressive disease (PD) was defined as an
Time to relapse increase in measurable disease or by the appearance of any new lesion.
Median delay (months post diagnosis) 10 months (1.6-58)
COPAD 6 months (1.6-58)
HM 89 and 91 10 months (7-55) Statistical analysis
Relapse on treatment 9 patients
Relapse within 12 months 24 patients Overall survival rates were estimated using the Kaplan-Meier method
Site of relapse [25] from the date of the first relapse to death or to the date of the last
Lymph node 38 observation for the patients who were still alive. Disease-free survival
Skin 9 rates (DFS) were estimated from the date of the first relapse to the time
Bone marrow 6 of documented failure (date of the relapse for patients who did not
Lung 5 achieve a second CR, the time of the second relapse or the time of
CNS 1 death for the others) or to the date of the last observation for those in
Other (spleen, kidney, pericardium, soft second CR. Follow-up data were updated on 1 March 1998. Statistical
tissue) differences in DFS were tested by the two-tailed log-rank test. As the
Type of relapse number of patients included in this study is rather small, only four
Local 10 factors were tested in univariate analysis: recurrence occurring during
New localisations 14 or after treatment, time to relapse less or more than 12 months, first-
Local and new localisations 17 line treatment and ABMT in CR2.

First-line treatment
The first group of patients were treated with a 12-18-month chemo-
therapy regimen combining vincristine, doxorubicin, cyclophospha-
mide, prednisone and intrathecal methotrexate [21]. For the second
and third groups of patients, the same drugs were combined with high-
dose methotrexate and etoposide for the HM89 protocol and with
high-dose methotrexate, etoposide, bleomycin and vinblastine in the
HM91 protocol [22]. The duration of the treatment was seven to eight
months for these latter groups. No patient had high-dose chemo-
therapy with autologous bone marrow transplantation at first complete
remission (CR) except for one in the HM91 series whose disease
progressed during first-line treatment
Second-line treatment
The second-line chemotherapy protocols were somewhat heterogene-
ous since the choice of the treatment for relapse was left to each center.
However, in the first two series of patients, the protocol suggested for
relapses was the CVBA, combination which had previously been tested
for relapsed lymphoma in the Pediatrics department at Institut
Gustave Roussy (Table 2). The treatment suggested for relapses for the
HM91 series, was CVA (Table 2). Intensification with a high-dose
regimen and autologous bone marrow (or peripheral stem cell) trans-
plantation (ABMT) was strongly recommended for patients in second
remission (CR2) in this third series.
Results
First relapses
Overall, 36 of 41 patients achieved a CR. One patient is
not evaluable for response to second-line chemotherapy
since he underwent resection of the entire tumor mass
for the diagnosis of the relapse before the beginning of
chemotherapy. Among the 40 patients who are evaluable
for response, 35 (88%) achieved a CR following various
chemotherapy regimens: 25 with CVA or CVBA, 2 with
high-dose ara-C VP16 according to the CYVE protocol
[26], 3 with vinblastine and 5 with other regimens. Five
patients did not achieve CR and died of progressive
disease seven to twenty-two months after the first re-
lapse (median 16 months). The CR rate did not vary
significantly according to the first-line chemotherapy
previously used. It was 92% (11 of 12) for patients
treated with COPAD, 88% (7 of 8) for patients treated
with HM89 and 90% (17 of 20) for patients treated with
HM91 (P = 0.95). After the second CR, 15 patients
underwent ABMT after 2-4 months of conventional
 55

41 relapsed ALCL alone for 6-18 months. Overall, 7 patients (including 4

patients given vinblastine after a relapse from BMT) are
5 NR (death 36CR2 alive disease-free and had no further relapse with a
i
I follow-up of 10-48 months (median 30 months) since
15ABMTatCR2 20CV|B!Atol2ra
1rat>'asS.iefor12n the beginning of vinblastine treatment. Among them, 2
1 i f
i are still on therapy whereas vinblastine treatment has
9CCR2 5 seasrd reiapses Itaccfe* j 11CCR2 1 10 seccrd relapses been stopped since 15-36 months (median 27 months) in
ir.afnFU18ir.or.tiis medial FU102 mon9is|
the other five patients. Only one of these long-term
,—I
Idath 3CR3
1— H
! 5 deaths 2CR3
survivors had had ABMT after a remission induced by
1CR4 1CR4 vinblastine.
1CR5
1CR6
Treatment intensification with ABMT
Figure I. Outcome of 41 children with relapsed ALCL.

Overall, 15 patients underwent myelo-ablative therapy

with BMT in CR2 (2 patients). All but one of these
chemotherapy and 21 patients were treated with conven- patients had received the HM91 protocol for first-line
tional chemotherapy alone (CV(B)A for 20 patients and treatment. Conditioning regimens were heterogeneous
vinblastine for one) for 12-18 months. Overall, 20 pa- and included total body irradiation (TBI) in nine pa-
tients are still in continuous complete remission with a tients, busulfan in three patients and neither TBI nor
median follow-up of 5 years (2 months - 21 years), 1 busulfan in three patients. Fourteen patients had autolo-
patient died of sepsis after an allogeneic bone marrow gous BMTor peripheral stem cell transplantation (PSCT)
transplant and 15 had a second relapse occurring 2-79 and one allogeneic BMT. One died of toxicity, five
months (median 13 months) after the first one, 5 of them relapsed four to twenty-one months after BMT (median
despite ABMT performed in CR2. 16 months) and nine are in continuous CR with 2 months
to 7.5 years of follow-up (median 18 months) post BMT.
Second, third andfurther relapses Six other patients underwent myelo-ablative therapy
with ABMT in PR2 (two patients), PR3 (one patient) or
Overall, 10 of 15 patients achieved a CR3 with various CR3 (three patients). All 3 patients treated in PR died of
regimens, 3 were treated with local radiation therapy disease progression within 10 months after BMTand 2/3
and 3 others underwent ABMT while in CR3. Five patients treated in CR3 relapsed again.
patients did not achieve a CR and died. Among the 10 Among the patients who relapsed post BMT, 6 were
patients who achieved a CR3, 5 had a third relapse treated with low-dose chemotherapy (vinblastine (4 pa-
including 2/3 patients treated with radiotherapy and tients), oral methotrexate (1 patient), oral vepeside (1
2/3 patients who had received ABMT in CR3. patient)) and are alive with no evidence of disease 10-52
Overall, among the patients who relapsed twice, 6 died months after the last relapse (median 44 months).
and 9 are alive in third (5 patients), fourth (2 patients),
fifth (1 patient) and sixth remission (1 patient) with a Survival
median follow-up of 40 months (10 months - 7 years)
since the last relapse. These nine long-term survivors do Overall, with a median follow-up of 5 years (2 months -
not differ from the overall population in terms of the 21 years), 3 patients died of toxicity, 9 patients died of
duration of the first remission and the percentage of their disease in first (6 patients), second (3 patients) or a
exclusively nodal recurrent disease. further relapse (1 patient) and 29 patients are alive in
CR2 (20 patients), CR3 (5 patients), CR4 (2 patients),
Vinblastine treatment CR5 (1 patient) and CR6 (1 patient) (Figure 1).
Overall and disease-free survival rates are respec-
It is noteworthy that 12 patients were treated with tively 69% (53%-82%) and 44% (29%-61%) at three
weekly vinblastine for 6-18 months for afirst(4 patients), years (Figure 2).
second (5 patients), third (1 patient), fifth (2 patients)
relapse including 6 relapses which occurred after high- Prognostic factors
dose chemotherapy and ABMT. Vinblastine was given at
a dose of 6 mg/m2 and combined with steroids for 0.5-2 In the univariate analysis (Table 3) two factors were
months in two cases. One patient failed to respond and found to be associated with a higher risk of failure: an
died early and one patient is not evaluable for response interval of less than 12 months between the diagnosis
since he was in CR after the biopsy and before the and the relapse and first-line treatment with the HM
beginning of vinblastine. Ten patients achieved a CR protocols. On the contrary, the occurrence of the relapse
following vinblastine treatment (six had only localized during or after treatment and a treatment including
nodal involvement and four disseminated disease). Fol- ABMT after a second CR (Figure 3) appeared to have
lowing this CR, 3 patients were given high-dose chemo- no effect on the outcome.
therapy and ABMT and 8 were treated with vinblastine
56

Table 3. Univariate analysis of disease-free survival.

Characteristics Patients Events DFS at three P

80%-
years (%)

60%-
On/off treatment
Relapse on treatment 9 5 44(19-73) 0.23a
\ Relapse off treatment 32 16 43(25-62)
40%- 1 Time to relapse
Early relapse (< 12 m) 24 16 28(14-50) 0.01b
Late relapse (> 12 m) 17 5 68(16-78)
Overall survival
20%- First-line treatment
— Disease-free survival COPAD 12 5 58(32-81) 0.02c
HM89orHM91 29 16 30(14-52)
0%- 1 1 1 1 1- 1 1 1 1 1 1 1 ABMTinCR2
9 10 11 12
Years after first relapse Yes 15 6 45(20-73) 0.55d
No 21 10 52(31-73)
At risk
a
41 31 22 20 19 16 13 12 11 6 Adjusted on first-line treatment.
b
Adjusted on first-line treatment and ABMT.
-41 23 13 12 11 10 9 c
Adjusted on the time to relapse ( > or < 12 months).
d
Figure 2. Overall and disease-free survival of 41 children with relapsed Ajusted on the time to relapse (> or < 12 months). For this analysis,
ALCL. only patients who achieved a CR2 were taken into account.

UU70 "
especially the indications for ABMT, have been subject
to considerable changes according to the period.
80%-
h no BMT in CR2, 1 = 21

— BMT in CR2, n =15

Although riddled with heterogeneity in several respects
including the combination of single-institution data
with data from a multicentric study, the relapses in these
60%- three series of patients allowed a comparison of the
results of treatment according to both first-line therapy
40%- and second-line treatment.
One of the major results of this study is that it
20% Adjusted logrank, p = 0 55
demonstrates the high response rate achieved in patients
treated for a recurrent ALCL: over 85% achieved a
second CR. This response rate does not appear to have
0% ii i i i i i i —I 1 1
0 1 2 3 4 5 6 7 8 9 10 11 12 differed according tofirst-linetreatment.
Years after first relapse
However, more than 40% of the patients who achieved
At risk a second CR experienced a second relapse. Nonetheless,
21 14 9 9 9 9 9 7 7 4 4 2 1
the response rate was still quite high in patients treated
15 9 4 3 2 1
for multiple relapses and the high percentage of survivors
Figure 3. Disease-free survival of patients treated with or without is strikingly different from the results usually reported for
ABMTatCR2.
relapsed non-Hodgkin's lymphoma since the overall two-
year survival rate of the patients in this combined series
Discussion is 69% (53%—82%) with a median follow-up offiveyears.
One of the questions raised by this study is whether
Relapses are not rare events in ALCL patients treated consolidation with high-dose regimen and ABMT is
with intensive multiagent regimens [4-8, 12-15]. In most efficient in avoiding further relapses in patients who
of the series reported to date, there is a marked differ- achieve a a CR with second-line treatment. The useful-
ence between OS and DFS because patients live for ness of these modalities has been reported for several
prolonged periods after a relapse [4-6, 11, 12, 14]. In all years for non-Hodgkin's lymphomas at relapse [27-31]
of these referenced reports, the number of patients or at first CR for high-risk adult patients [9, 32]. Data
treated for a relapse was quite small and the treatments concerning the value of this procedure in ALCL are very
were heterogeneous. Moreover, most of the patients scarce [9, 16-19] even-though some authors recommend
reported were treated with megatherapy in second CR. using ABMT at first CR in adult patients with high-risk
It is therefore difficult to assess the optimal treatment ALCL [9, 32, 33]. Recently, Fanin et al. reported a series
for relapsed ALCL and to estimate the role of mega- of 64 patients with ALCL treated with ABMT in 25
therapy in these children on the basis of these data. centers of the European Group for Blood and Marrow
The present study was designed to evaluate the re- Transplantation (EBMT) [20]. In this study (including
sponse rate and the long-term outcome of patients treated several patients of the present study), the 10-year overall
for recurrent ALCL. As it is a retrospective study span- survival of the whole population is 70%. However, only
ning over two decades, the treatment modalities, and 6 of 15 patients transplanted in CR after a relapse

maintained the CR over time. In the present study, the
three-year DFS of patients treated with ABMT in CR
is rather good (45%, 20%-73%). In univariate analysis,
it was not, however, statistically different from the DFS
of patients treated without ABMT in second CR (52%,
31%—73%). Comparison of the outcome of the patients
treated with or without ABMT should, however, be inter-
preted with caution because the indications for BMT
varied according to the treatment period. Patients who
did not undergo BMT in second CR were mostly those
treated before 1991 with COPAD or the HM89 protocol
asfirst-linetreatment whereas almost all the patients who
relapsed after HM91 chemotherapy underwent ABMT
in second CR. The long-lasting CR obtained with con-
ventional low-dose chemotherapy in six of eight patients
who relapsed after BMT also suggests that prolonged
conventional chemotherapy might be as efficient as
short intensive treatment comprising ABMT in some
patients. Whether one conditioning regimen has an edge
over another in terms of efficiency cannot be answered
in this series given the heterogeneity of the treatments
received by the patients. As a major drawback of mega-
therapy is transplant-related morbidity or mortality in
patients who could be cured with conventional treat-
ment, the latter therapy should be preferred for first
relapses. However, to evaluate the contribution of
ABMT to the treatment of relapsed ALCL, prospective
studies will have to be undertaken in high-risk patients,
i.e., those who relapse very early or who experience
second relapses after failure of prolonged conventional
chemotherapy.
An unexpected result of this study was the excellent
outcome of children treated with weekly vinblastine.
Vinblastine can be administered over extended periods
of time because of its low toxicity and in the early sixties,
several papers reported prolonged remissions of various
malignancies following long-term treatment with weekly
vinblastine [34]. The most important results were those
reported for Hodgkin's disease, a lymphoma which
shares several pathological and clinical aspects with
ALCL [35]. In a review published in 1973 [36], Carter,
summarizing 20 previous papers, reported a response
rate of 68% in 682 patients treated with vinblastine
alone for Hodgkin's disease. More recently, several
authors [37, 38] have reported the efficacy of weekly
vinblastine for relapsed Hodgkin's disease. In these
studies, long-lasting remissions were obtained in heavily
pretreated patients, some of whom had undergone bone
marrow transplantation [38]. However, in these studies,
vinblastine was continuously given until disease progres-
sion since the first reports suggested that relapse should
occur if maintenance treatment was discontinued [34,
39]. It may not be the case in our study since several
patients are in continuous complete remission several
months after the end of vinblastine. These results in
heavily pretreated patients suggest that maintenance
treatment with vinblastine could be useful as first-line
treatment in high-risk patients. As ALCL is rare in
children, evaluation of the efficacy of such strategies for
57
first-line treatment and of the optimal treatment for
relapses will only be possible through large international
randomized studies.
Acknowledgements
This work was supported by the ARC (Association pour
la Recherche contre le Cancer).
Acknowledgments to L. Saint Ange for editing the
manuscript.
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Received 5 June 1999; accepted 2 December 1999.
Correspondence to:
L. Brugieres, MD
Department of Pediatrics
Institut Gustave Roussy
39, rueCamilleDesmoulins
94805 Villejuif
France
E-mail: brugiere@igr.fr