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Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3591-3598
By
From the Departments of Pediatric Oncology, Statistics, and
Pathology, Institut Gustave-Roussy, Villejuif, France; the Department
of Pediatric Oncology, Institut Curie, Paris, France; the Departments
of Pathology and of Pediatric Hematology and Oncology, CHU Purpan,
Toulouse, France; the Department of Pediatric Hematology, Hopital
Debrousse, Lyon, France; the Department of Pediatric Onco-Hematology,
Hopital Trousseau, Paris, France; and the Department of
Onco-Hematology, Hopital des Enfants Reine Fabiola, Bruxelles, Belgium.
The purpose of this study was (1) to investigate the efficacy of
chemotherapy regimens designed by the French Society of Pediatric Oncology for childhood anaplastic large-cell lymphoma (ALCL) and (2) to
identify prognostic factors in these children. Eighty-two children with
newly diagnosed ALCL were enrolled in two consecutive studies, HM89 and
HM91. The diagnosis of ALCL was based on immuno-morphological features
and all the cases but 2 were investigated using ALK1 antibody directed
to the NPM/ALK protein associated with the 2;5 translocation. Treatment
consisted of 2 courses of COPADM (methotrexate, cyclophosphamide,
doxorubicin, vincristine, and prednisone) and a maintenance treatment
of 5 to 7 months. Seventy-eight patients (95%) achieved a complete
remission and 21 relapsed. The probability of survival and event-free
survival at 3 years was of 83% (72% to 90%) and 66% (54% to 76%),
respectively, with a median follow-up of 49 months. In multivariate
analysis, visceral involvement, mediastinal involvement, and
lacticodeshydrogenase (LDH) level
THAT KI-1 ANAPLASTIC large-cell lymphoma
(ALCL) is a distinct clinico-pathologic entity has been debated for
several years, but its specific features are now well
established1-3 and this entity has been included in both
the updated Kiel classification4 and in the more recent
Revised European-American lymphoma (REAL) classification.5
This disease, covering most of the cases historically diagnosed as
malignant histiocytosis6,7 and some cases of Hodgkin's
disease and other types of non-Hodgkin's lymphoma, is characterized by
the proliferation of neoplastic lymphoid cells coexpressing several
activation antigens such as CD30 (Ki-1) and the epithelial membrane
antigen (EMA).6 With respect to lymphocyte lineage markers,
it is widely admitted that most of the cases are associated with a
T-cell or null cell immunophenotype.5 The existence of
sporadic cases of ALCL of the B-cell phenotype is still a debated
question.
The t(2;5) (p23;q35) translocation, resulting in the fusion of the
nucleophosmine gene (NPM) at 5q3 and the tyrosine kinase gene ALK at
2p23,8 was identified in this disease several years ago.9-11 However, the specificity of this translocation has
not been established, because it has occasionally been reported in other lymphomas, especially in a few cases of large B-cell lymphomas and pleiomorphic T-cell lymphomas.12-16
This disease accounts for only 10% to 15% of all childhood
non-Hodgkin's lymphomas.17,18 Because it is rare, the
optimal treatment has yet to be assessed. In most of the European
studies, ALCL is considered as an entity and treated either with a
short and intensive chemotherapy regimen, as in B-cell
lymphoma,19 or with more prolonged chemotherapy derived
from T-cell lymphoma protocols,20,21 whereas in the North
American studies, all the large-cell lymphomas are treated with the
same chemotherapy protocols regardless of the histologic subgroup and
immunophenotype.22,23
Based on our previous experience of patients in whom disease was
initially diagnosed as malignant histiocytosis and reviewed as ALCL and
treated with COPAD (cyclophosphamide, vincristine, prednisone,
doxorubicin) for first-line treatment and CCNU Bleomycin and
vinblastine for relapse,24 prospective studies have been designed by the French Society of Pediatric Oncology (SFOP) for children with ALCL since 1988. We report here a series of 82 children enrolled in two consecutive SFOP studies (HM89 and HM91) between 1988 and 1997.
Diagnosis
Inclusion
Staging The minimal investigations requested for staging were a physical examination, chest and nasopharyngeal x-rays, abdominal ultrasonography, a cranial computed tomography (CAT) scan, a complete blood count, two bone marrow aspirates, two bone marrow biopsies, examination of cerebrospinal fluid (CSF), a skeletal scintigraphy, and lacticodeshydrogenase (LDH) level measurement. An LDH level exceeding 800 UI/L, which is twofold the upper limit of the normal level in 70% of the centers, was considered pathologic.Chemotherapy Regimen Between August 1988 and December 1990, 18 patients were treated according to the HM 89 protocol; between January 1991 and February 1997, 64 patients were treated according to the HM 91 protocol. The schedules of these two protocols are detailed in Fig 1. Within each protocol, all patients received the same treatment whatever the stage, because the prognostic value of the stage had not been clearly demonstrated in the historical series of patients treated by COPAD.24 The total duration of the treatment was 8 months for HM89 and 7 months for HM91. No intrathecal therapy was administered either in HM89 or in HM91.
Response Criteria Complete remission (CR) was defined as the disappearance for at least 4 weeks of all tumor masses confirmed by clinical examination, x-rays, ultrasonography, and a normal bone marrow. A chest computerized tomography (CT) scan was not required to confirm remission of mediastinal or lung lesions. Any tumor residue detectable after the third course of induction therapy had to be removed surgically or the minimum requirement was a biopsy specimen. CR was confirmed only in the absence of tumor cells.Statistical Analysis Overall survival rates were estimated using the Kaplan-Meier method34 from the first day of chemotherapy to death or to the date of the last follow-up visit for patients who were still alive. Event-free survival (EFS) rates were estimated from the first day of chemotherapy to the time of documented failure (date of the beginning of treatment for patients whose disease progressed while they were on chemotherapy before achieving a CR, time of relapse, or time of death for the others) or to the date of the last follow-up visit for those in first CR. Follow-up data were updated as of June 1, 1997. Statistical differences in EFS were tested by the two-tail log-rank test, adjusted on the chemotherapy protocol.
Patient Characteristics Morphology and immunohistochemistry.
The distribution of cases according to the histologic subtypes and the
results of immunohistochemistry are shown in
Table 1. All cases were
positive for both CD30 and EMA, and ALK protein expression was found in
74 of 80 (93%) cases tested. Among the 6 cases proven to be
ALK
Cytogenetic analysis. The t(2;5) (p23;q35) translocation was demonstrated in 23 cases. An additional case showed a t(1;2) (q25;p23) translocation involving the same breakpoint on chromosome 2 as in the classic t(2;5) translocation. In 1 case, the karyotype showed complex chromosomal abnormalities with several structural rearrangements. The karyotype was normal in 5 cases, of which 4 were positive for the ALK1 antibody. Clinical features. The main clinical findings are given in Table 2. Ages ranged from 17 months to 17 years (median age, 10 years). The clinical presentation did not vary according to the immunophenotype or according to the histologic subtype, except for a borderline excess of B symptoms (P = .05) and visceral involvement (P = .06) in the patients with the lymphohistiocytic subtype.
Results of Treatment Remission. Seventy-eight patients (95%) achieved a CR, 68 (87%) of which achieved the CR within 3 months of the beginning of the treatment. Eight patients underwent surgery for a residual mass, which was completely necrotic in 7 cases. The last patient, who had viable cells in the resected residual tumor after the third course of chemotherapy, achieved a CR after further therapy and is alive with no evidence of disease and 60 months of follow-up. Four patients failed to achieve a CR. Three of them died 5 to 12 months after the diagnosis and the last one is still on therapy. Relapses. Twenty-one patients relapsed 7 to 49 months after diagnosis (median, 10 months). All but 2 relapses occurred within 2 years of the diagnosis. In 20 of 21 patients, the site of the relapse was the nodes, which were associated or not associated with other sites of disease. There were no first recurrences in the CNS. The site of relapse was restricted to the initial site of the disease in only 3 patients. Treatment for relapses was rather heterogeneous: 15 patients received carmustine, vinblastine, cytarabine, associated or not associated with bleomycin, and various treatments were administered to the others. A second remission was obtained in 17 of 21. Overall, 8 patients died 1 to 24 months from the first relapse and 13 patients are alive in second (7 patients), third (4 patients), or fourth remission (2 patients), with a median follow-up of 48 months (range, 5 to 93 months) since the first relapse. Survival. Median follow-up of this population is 49 months (range, 3 to 105 months). Eleven patients died of their disease 5 to 31 months after diagnosis. Overall and EFS rates are, respectively, 83% (72% to 90%) and 66% (54% to 76%) at 3 years (Fig 2).
Prognostic factors.
The results of the univariate analysis are shown in Tables 1 and 2. In
the Cox regression analysis, three parameters were found to be
predictive of a higher risk of failure: a mediastinal mass (RR = 3.1 [1.2 B 8.0]), any visceral involvement (RR = 2.5 [1.0 to 6.5]), and
LDH
Outcome of the patients excluded from analysis.
With a median follow-up of 44 months, no difference was noted in the
3-year overall survival (86% [77% to 92%]) and EFS (69% [59% to
78%]) survival rates between the whole population of 112 patients
(including the patients excluded from analysis) and the study patients.
ALCL is now a widely recognized clinico-pathologic entity included in
the recent REAL of lymphoid neoplasms.5 However, several
areas of disagreement and controversies remain. One reason for these
disagreements may lie in the different criteria used for its diagnosis.
The criteria we considered mandatory for the diagnosis of ALCL, ie,
characteristic cells of the T or the null phenotype and coexpression of
CD30 and EMA antigens,26 are rather strict, which probably
explains the high percentage of cases (15%) in which the initial
diagnoses of ALCL was not confirmed after re-examination of slides by
the panel of pathologists. One of the most difficult diagnoses is the
putative but controversial Hodgkin's-like ALCL. Seven cases initially
diagnosed as Hodgkin's-like ALCL were subsequently diagnosed as
Hodgkin's disease after re-examination with immunohistochemistry. All
of these cases showed malignant cells with a typical phenotype
(CD30+, CD15+, EMA The authors are grateful to Lorna Saint Ange for editing the
manuscript.
Submitted February 24, 1998;
accepted July 15, 1998.
Address reprint requests to L. Brugières, MD, Department of
Pediatrics, Institut Gustave Roussy, 39, rue CamilleDesmoulins, 94805 Villejuif, France.
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This article has been cited by other articles:
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Top
Abstract
Introduction
800 UI/L were shown
to be predictive of a higher risk of failure. In conclusion, this type
of regimen demonstrated efficacy in childhood ALCL. However,
therapeutic results have to be improved for children with adverse
prognostic parameters such as visceral or mediastinal involvement or a
high LDH level.
, because the diagnosis of ALCL was rejected
after re-examination by the panel of pathologists. Seven of these
cases, initially diagnosed as Hodgkin's-like ALCL, were classified as
Hodgkin's disease rather than ALCL because of the phenotype of
malignant cells (CD30+, CD15+,
EMA
) and EFS (---) of the 82 patients enrolled in the HM89 and HM91 studies.
