Published Ahead of Print on September 8, 2009 as 10.1200/JCO.2008.20.1764 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2008.20.1764

JOURNAL OF CLINICAL ONCOLOGY

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Single-Drug Vinblastine As Salvage Treatment for Refractory or Relapsed Anaplastic Large-Cell Lymphoma: A Report From the French Society of Pediatric Oncology Laurence Brugie`res, Helene Pacquement, Marie-Cecile Le Deley, Guy Leverger, Patrick Lutz, Catherine Paillard, Andre Baruchel, Didier Frappaz, Brigitte Nelken, Laurence Lamant, and Catherine Patte From the Department of Pediatric Oncology, Biostatistics and Epidemiology Unit, Institut Gustave Roussy, Villejuif; University Paris de Sud, Department of Pediatric Oncology, Institut Curie; Department of Pediatric Hematology, Hoˆpital Armand Trousseau, Universite´ Pierre et Marie Curie; Department of Pediatric Hematology, Hoˆpital Saint Louis, Paris; Department of Pediatric Hematology, Hoˆpital Hautepierre, Strasbourg; Pediatric Department, Hoˆtel Dieu, Clermont-Ferrand; Institut of Pediatric Onco-Hematology, Lyon; Department of Pediatric Hematology, Hoˆpital Jeanne de Flandre, Lille; and Department of Pathology, Hoˆpital Purpan, Toulouse, France. Submitted September 22, 2008; accepted April 1, 2009; published online ahead of print at www.jco.org on September 8, 2009. Supported by the Société Françase des Cancers de L’Enfant/French Society for Pediatric Oncology (SFCE/SFOP), the Association Cent pour Sang la Vie, and the Institut Gustave Roussy, France. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Laurence Brugie`res, Department of Pediatric Oncology, Institut Gustave Roussy, 94805 Villejuif, France; e-mail: [email protected]. © 2009 by American Society of Clinical Oncology 0732-183X/09/2799-1/$20.00 DOI: 10.1200/JCO.2008.20.1764

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Purpose To evaluate the efficacy of vinblastine for relapsed/refractory anaplastic large-cell lymphoma (ALCL). Patients and Methods Data were reviewed on all 36 patients included prospectively in the French database for pediatric ALCL who were treated with vinblastine (6 mg/m2/wk) for resistant primary disease (one), a first relapse (15), or subsequent relapses (20). Fifteen patients had undergone hematopoietic stem-cell transplantation (HSCT) for a previous relapse. Results Six patients were not evaluable for response, 25 (83%) of 30 evaluable patients achieved a complete remission (CR), and five experienced progressive disease. Among the 31 patients who achieved a CR with vinblastine or before its initiation, six patients were treated with HSCT and 25 with vinblastine alone (median duration, 14 months). Overall, nine of 25 patients treated with vinblastine alone have remained in CR (median, 7 years since the end of treatment), and 16 patients have relapsed. Vinblastine was still efficient for subsequent relapses. With a median follow-up of 9.2 years, 12 patients have died (four as a result of toxicity after HSCT and eight as a result of disease), and 24 patients are alive (15 following treatment with single-agent vinblastine for the last event). Five-year overall survival is 65% (95% CI, 48% to 79%), and 5-year event-free survival is 30% (95% CI, 17% to 47%). Conclusion Vinblastine is highly efficient in relapsed ALCL and may produce durable remissions. The optimal treatment duration still has to be assessed. These results should be borne in mind when designing future phase II studies with the targeted therapies directed against anaplastic lymphoma kinase. J Clin Oncol 27. © 2009 by American Society of Clinical Oncology

INTRODUCTION

Anaplastic large-cell lymphoma (ALCL) is a rare disease in children. In more than 90% of the patients, it is associated with the t(2;5) translocation resulting in the expression of the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM/ALK).1 In most pediatric series, event-free survival (EFS) rates are between 65% and 75% with conventional chemotherapy, and thus disease progresses in 25% to 35% of patients during or after front-line chemotherapy and requires additional treatment.2-10 The treatment of relapsed ALCL is still a matter of debate. Induction therapy followed by high-dose chemotherapy and autologous or allogeneic hematopoeitic stem-cell transplantation (HSCT) after a second complete

remission (CR) is the standard treatment for relapsed lymphomas in children and is currently used by most groups as first-line treatment for relapsed ALCL.11-18 Unlike other lymphomas, ALCLs are usually still chemosensitive at relapse, and most patients can achieve a second remission and undergo high-dose chemotherapy. However, some proportion of patients will relapse again and will require further treatment. In a previous study from the French Society for Pediatric Oncology (SFOP), we showed that some of these high-risk patients can be rescued with prolonged weekly vinblastine therapy.12 The purpose of this study was to review the data for all the children treated in France with vinblastine for relapsed ALCL to better assess the role of this drug in this group of patients. © 2009 by American Society of Clinical Oncology

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PATIENTS AND METHODS Patients treated for ALCL between 1975 and 2005 were included prospectively in the SFOP database for childhood ALCL. We extracted data from this database on all patients who had resistant primary disease or who had relapsed. Data concerning these patients were reviewed to identify those who had received weekly vinblastine, with or without steroids, for refractory disease, a first relapse, or subsequent events. Patients who had received vinblastine as part of a multidrug regimen were not selected. Detailed data on second-line treatment and the outcome of these patients were collected retrospectively from medical files. All patients or their parents gave their consent for data registration in the French pediatric ALCL database. Confirmation of the diagnosis of ALCL was based on morphology and immunophenotyping. Slides from these patients were centrally reviewed and, whenever possible, restained for ALK for patients diagnosed before the availability of the ALK antibody. Patients were reclassified according to the WHO classification.19 Histology confirmed the diagnosis of relapsed ALCL in all patients. The treatment of ALCL relapses was not standardized over the whole study period. Vinblastine was initially recommended for patients with multiple relapses, relapses occurring after HSCT, or for patients in poor clinical condition at the initiation of treatment of a relapse. Since the end of the 1990s, vinblastine has been used in some centers to treat patients at first relapse. The recommended dose was 6 mg/m2/wk. There was no standardized treatment duration. Patients who had not previously received HSCT were considered eligible for this procedure after the remission induced by vinblastine if their clinical condition allowed it. A CR was defined as the disappearance of disease from all initially involved sites for at least 4 weeks. EFS was defined from the beginning of vinblastine therapy to the time of failure (progression, subsequent relapse, second malignancy, or death) or to the last follow-up visit for patients in continuous CR. Overall survival (OS) was estimated from the date of the beginning of vinblastine therapy to death, whatever the cause, or the date of the last follow-up visit for patients last seen alive. Survival rates (EFS, OS) were estimated using the Kaplan-Meier method with Rothman’s 95% CIs.20 Median follow-up was estimated using Schemper’s method.21 EFS rates were estimated by considering the whole series and then excluding patients who received HSCT after the first vinblastine-induced CR to avoid overestimating the results related to vinblastine due to a possible effect of HSCT.

RESULTS

Patients Among the patients included prospectively in the SFOP database for childhood ALCL between 1975 and 2005, 85 had resistant primary disease or relapsed after first-line treatment. Among them, 36 patients were treated with weekly vinblastine either for the first relapse or for a subsequent event and are included in the present series. Twelve of these patients were included in our previous study, which focused on the outcome of ALCL relapses in childhood.12 Median age at diagnosis was 6 years.2-15 All 36 patients showed positive staining for CD30, 35 of 35 patients tested showed positivity for ALK, and 24 of 36 patients expressed at least one T-cell marker, including 14 patients with CD3 expression. According to the WHO classification (available for 28 patients), the distribution of subtypes was as follows: common type (n ⫽ 16), lymphohistiocytic (n ⫽ 2), small-cell variant (n ⫽ 4), mixed (n ⫽ 5), and Hodgkin’s-like (n ⫽ 1). All patients had previously been treated with intensive chemotherapy, most of them according to COPAD (cyclophosphamide, vincristine, prednisolone, doxorubicin),22 HM protocols,2 or the ALCL99 protocol.23 2

© 2009 by American Society of Clinical Oncology

As detailed in Table 1, the status of disease at the beginning of vinblastine therapy was resistant primary disease (n ⫽ 1), first relapse (n ⫽ 15), second relapse (n ⫽ 15), third relapse (n ⫽ 2), or fifth relapse (n ⫽ 3). Fifteen patients had a localized relapse (peripheral lymph nodes associated with skin lesions in two patients), and 21 patients had a disseminated relapse. The interval between the diagnosis and the first relapse was less than 12 months in 22 patients. Vinblastine treatment was started at a median of 21 months after the initial diagnosis (range, 5 months to 13 years) and at a median interval of 3 months since the last treatment (range, 0 to 11 years). Fifteen patients had received high-dose chemotherapy with autologous (n ⫽ 14) or allogeneic (n ⫽ 1) HSCT as consolidation therapy for the treatment of a previous relapse, with BEAM (carmustine, etoposide, aracytine, melphalan)24 (n ⫽ 7), a conditioning regimen that included total-body irradiation (n ⫽ 3), or busulfan (n ⫽ 5). First Vinblastine Treatment Most patients received vinblastine at 6 mg/m2/wk. In some patients, the dose had to be reduced to 4 mg/m2/wk after a few weeks because of hematologic toxicity. In 22 patients, vinblastine was given weekly for the total duration of treatment, whereas in 14 patients, the injections were spaced out to twice a month and then once a month after 2 to 12 months. Steroids were combined with vinblastine during the first weeks of treatment in 15 patients. Response Six patients had no measurable disease after surgical excision of the entire tumor mass to confirm the relapse. Among the 30 patients in whom response was evaluable, five experienced early disease progression and 25 achieved a CR (overall CR rate, 83%; 95% CI, 65% to 94%): 11 of the 15 patients who received vinblastine plus steroids and 14 of the 15 patients who received vinblastine alone. Outcome After the First Vinblastine Treatment Among the patients who achieved a CR either with vinblastine or before its initiation, 25 received prolonged vinblastine therapy alone for 7 to 39 months (median, 14 months), whereas six were subsequently treated with either autologous (n ⫽ 4) or allogeneic (n ⫽ 2) HSCT after 1 to 8 months of vinblastine (Fig 1). Overall, nine of 25 patients treated with vinblastine alone are still in continuous CR. Two are still undergoing treatment, whereas treatment has been stopped for more than 2 years (median, 7.5 years) in the other seven patients. Sixteen patients relapsed again, two during vinblastine treatment and 14 after a median interval of 4 months after the end of vinblastine therapy (range, 1 to 29 months). Among the six patients treated with HSCT after a CR, two are alive in continuous remission, one died as a result of toxicity, and three relapsed again. All but one of the five nonresponders died. The fifth patient was rescued with prolonged oral etoposide and is alive and disease-free with 14 years of follow-up. Treatment of Subsequent Relapses Treatments for subsequent relapses are listed in Table 1. Twelve of the 19 patients who developed a subsequent relapse were treated again with vinblastine. All but one achieved a CR again. Among them, seven patients were re-treated with protracted vinblastine alone over a median duration of 30 months (range, 26 months to 10 years). One patient relapsed a few months after the end of vinblastine treatment JOURNAL OF CLINICAL ONCOLOGY

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Single-Drug Vinblastine As Salvage Treatment in ALCL

Table 1. Outcome According to Patient Characteristics and Treatment Prior History

Present Relapse/Progression and Treatment

Outcome

Time to First Relapse Duration of Event (No. of Patient First-Line or Progression Previous Status at the Type of Response VLB HSCT months from No. Treatment (months) HSCT Beginning of VLB Relapse to VLB (months) After CR the end of VLB) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

HM91 HM91 HM97 HM91 HM91 HM91 HM91 ALCL99 HM91 HM97 COPAD HM91 HM91 ALCL99 HM91 ALCL99 HM97 COPAD HM91 HM91 HM91 HM97 HM97 HM91 Other COPAD HM91 ALCL99 ALCL99 Other ALCL99 ALCL99 ALCL99 COPAD HM91 ALCL99

8 10 12 7 12 19 9 9 1.5 13 4 7 24 6 10 9 7 6 55 16 19 11 8 8 36 60 7 16 14 5 6 6 13 6 23 11

Auto

Auto

Auto Auto

Auto Auto Auto

Auto

Auto Auto Auto Auto Allo

Auto Auto

1st relapse 2nd relapse 1st relapse 1st relapse 2nd relapse 1st relapse 2nd relapse 1st relapse Prim R 1st relapse 5th relapse 1st relapse 1st relapse 2nd relapse 2nd relapse 1st relapse 1st relapse 2nd relapse 1st relapse 2nd relapse 2nd relapse 1st relapse 1st relapse 2nd relapse 5th relapse 2nd relapse 3rd relapse 2nd relapse 2nd relapse 3rd relapse 1st relapse 2nd relapse 1st relapse 5th relapse 2nd relapse 2nd relapse

D D D D D D L D D L L D L L L L D D L L L D L D D L D D D L D L D D D L

PD PD PD PD PD CR CR CR CR NE NE CR CR CR NE NE CR CR CR CR CR CR NE CR CR CR CR CR CR CR CR CR CR CR CR CR

0.5 1 1 1.5 2. 5 1 1.5 6 6 7 8 3 9 9 11.5 12 12 12 12 12 12 12 14 15 18 18 18 24 24 24 24 ⱖ 24 30 36 39 ⱖ9

Auto Auto Allo Allo Auto Auto

Treatment and Time of Subsequent Relapse

Progression Progression Progression Progression Progression

Etoposide (18 months)

Relapse (6.5)

BCNU

Relapse (3) Relapse (21) Relapse (0) Relapse (1) Relapse (0)

VLB relapse (24 months) Methotrexate (18 months) MOPP COPADM-Allo Vinorelbine-Allo

Relapse (16) Relapse (1) Relapse (5)

CC-Allo VLB (26 months) VLB relapse (9 years)

Relapse (1) Relapse (3) Relapse (4) Relapse (1) Relapse (2)

VLB-CC-Allo VLB-CC-Allo VLB-CC-Allo VLB (30 months) VLB (30 months)

Relapse (27) Relapse (33) Relapse (11)

VLB-Allo VLB (60 months) VLB (ⱖ 8 months)

Relapse (13) Relapse (21)

MOPP VLB (60 mo)

Outcome

Follow-Up

DOD DOD DOD DOD CR CR DOD CR DOT CR CR DOD DOT DOT CR CR CR CR AWD CR CR DOT DOD CR CR CR CR CR CR CR CR CR CR DOD CR CR

0.5 months 2 months 4 months 3 months ⱖ 12 years ⱖ 13.5 years 11 months ⱖ 22 months 8 months ⱖ 6 years ⱖ 9 years 5 months 14 months 24 months ⱖ 13 years ⱖ 7 years ⱖ 9 years ⱖ 9 years ⱖ 9 years ⱖ 14 years ⱖ 11 years 21 months 42 months ⱖ 9 years ⱖ 8 years ⱖ 13 years ⱖ 10 years ⱖ 5 years ⱖ 5 years ⱖ 12 years 3.5 years 25 months ⱖ 6 years 4.5 years ⱖ 12 years ⱖ 9 months

Abbreviations: HSCT, hematopoietic stem-cell transplantation; VLB, vinblastine; CR, complete response; HM, French protocols for pediatric ALCL2; D, diffuse; PD, progressive disease; DOD, death as a result of disease; Auto, autologous HSCT; L, localized; BCNU, carmustine; ALCL, anaplastic large-cell lymphoma; Allo, allogeneic HSCT; Prim R, resistant primary disease; DOT, death as a result of toxicity; NE, not evaluable; COPAD, cyclophosphamide, vincristine, prednisolone, doxorubicin; MOPP, mechlorethamine, vincristine, procarbazine, prednisone; COPADM, vincristine, prednisone, cyclophosphamide, doxorubicin, and methotrexate; CC, dexamethasone, vindesine, aracytine, etoposide, according to the Berlin-Frankfurt-Mu¨nster (BFM) protocol18; AWD, alive with disease.

and the other six are alive and disease-free. It has been 2 to 7 years since treatment was stopped in five patients, and the last one is still being treated with weekly vinblastine. Survival Overall, 12 patients died (four as a result of toxicity after HSCT, eight as a result of disease), 23 are alive and disease-free with a median follow-up of 6 years since the last relapse, and one patient is alive with disease.Amongthepatientswhoarealiveanddisease-free,15weretreated with vinblastine alone for the last event, only nine of them being continuously disease-free since the start of vinblastine treatment. The median follow-up was 9.2 years from the initiation of vinblastine treatment. Considering the whole population, EFS was 69% (95% CI, 53% to 82%) at 1 year and 30% (95% CI, 17% to 47%) at 5 years; OS was 83% (95% CI, 68% to 92%) at 1 year and 65% (95% CI, 48% to 79%) at 5 years (Fig 2). After excluding the six patients treated with HSCT after the first vinblastine-induced CR, results are similar www.jco.org

for the 30 patients treated with vinblastine alone; 5-year EFS was 30% (95% CI, 16% to 49%) and 5-year OS was 65% (95% CI, 47% to 80%). Toxicity Data on toxicity were not collected prospectively. Although doses were reduced in some patients due to hematologic toxicity, vinblastine was well tolerated and no patient had to discontinue the drug because of toxicity. To date, no severe cumulative problems related to vinblastine have been reported. DISCUSSION

This study of 36 patients treated with weekly vinblastine for relapsed or resistant ALCL demonstrates that this drug is highly efficient in this setting with a CR rate of 83%. Furthermore, 5 years after the start of vinblastine, 30% of the patients treated with vinblastine alone remained in CR, with all but two having stopped their treatment for © 2009 by American Society of Clinical Oncology

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36 patients treated by VLB

31 remissions

5 progressions

6 before VLB(NE) 25 after VLB (CR)

25 VLB alone Median 14 mo

9 CR

16 relapses

7 VLB alone Median 30 mo

6 CR

1 relapse AWD

2 CR

3 CR

3 DOT

1 DOT

2 other CT No SCT

7 alloSCT after CT+/- VLB

1 DOD

1 CR

3 relapses

2 CT

1 CR

2 DOD

4 DOT

1 CT

6 HSCT

1 VLB

1 DOD

1 relapse CR

Fig 1. Patient flow chart. VLB, vinblastine; NE, not evaluable; CR, complete remission; HSCT, hematopoietic stem-cell transplantation; CT, chemotherapy; mo, months; AWD, alive with disease; DOD, death as a result of disease progression; DOT, death as a result of toxicity; SCT, stem-cell transplantation; alloSCT, allogeneic SCT.

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© 2009 by American Society of Clinical Oncology

alone were similar to EFS and OS of the whole population. It is noteworthy that among the 25 patients who received protracted vinblastine therapy, only two relapsed while on therapy, whereas 14 patients relapsed shortly after the end of therapy, raising the question of its optimal duration. We cannot answer this question with our data. However, it is noteworthy that among the patients who developed a relapse after the end of vinblastine therapy, it was still possible to obtain a long-lasting CR with vinblastine alone in six of eight patients with a median treatment duration of 30 months. This finding supports the hypothesis that more than 2 years of vinblastine therapy might be more efficient than a shorter duration to induce long-term remission in this disease. The efficacy of single-agent vinblastine is well known in Hodgkin’s disease,26-29 whereas it has been considered a minor drug against non-Hodgkin’s lymphoma for years.30 Few clinical data are

100

Survival Probability (%)

more than 2 years. Additionally, re-treatment with vinblastine in patients who relapsed after the discontinuation of treatment was still efficient in most cases, yielding a 5-year OS rate of 65% for the whole population. One limit of this study is that it is an observational study on a small series of patients. However, we must emphasize that all consecutive patients reported prospectively in the French pediatric database for ALCL are included in the present series. Our study was not designed to evaluate the toxicity of this treatment, which was previously assessed, notably in Langerhans cell histiocytosis25 and in relapsed Hodgkin’s disease.26 In studies in which vinblastine was given at 6 mg/m2/wk, toxicity was mainly hematologic with mild leucopenia in 34% of patients and a low incidence of extrahematologic toxicity. The CR rate obtained with vinblastine in these heavily pretreated patients compares favorably with the CR rates obtained with multiagent chemotherapy following first-line treatment in previously published series of childhood ALCL.4,5,9,23 Because vinblastine was administered with steroids in 41% of the patients, it is difficult to assess the respective contribution of vinblastine and steroids in those patients. However, it is noteworthy that among patients with evaluable disease, 14 of 15 patients who did not receive steroids achieved a CR with single-agent vinblastine. The effect of vinblastine was more difficult to assess in the six patients who underwent resection of the tumor mass before vinblastine therapy. It is noteworthy that the remission was maintained throughout vinblastine therapy in all six patients, whereas three of them relapsed after its discontinuation. Because this treatment was not given according to a preestablished protocol, the duration of vinblastine therapy and the indication of HSCT after CR varied according to the period of treatment and with the centers. To avoid the risk of overestimating the efficacy of vinblastine, the results were analyzed after exclusion of the six patients who received HSCT after a vinblastine-induced CR. This analysis confirmed that EFS and OS of the 30 patients treated with vinblastine

80 60 Overall survival Event-free survival

40 20

0

2

No. at risk 36 36

4

6

8

10

12

Time Since Initiation of Vinblastine (years) 25

22

17

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11

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Fig 2. Overall and event-free survival curves from the beginning of vinblastine treatment. JOURNAL OF CLINICAL ONCOLOGY

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Single-Drug Vinblastine As Salvage Treatment in ALCL

available on the use of vinblastine in ALCL patients. The efficacy of this drug in ALCL is supported by in vitro data comparing the efficacy of 11 antineoplastic agents against four cell lines established from pediatric ALCL patients.31 In that report, vinblastine was shown to be the most effective in three of four cell lines. We cannot rule out the notion that the efficacy of the treatment in our patients might be related to the mode of administration of the drug (repeated administration of the drug for a prolonged period) and that comparable results might be obtained by any kind of maintenance treatment. This hypothesis is supported by the fact that two patients in this series were rescued with other drugs (oral methotrexate in one patient and oral etoposide in another one) after failure of prolonged vinblastine. Because ALK overexpression has been shown to be associated with a host immune reaction,32 we can hypothesize that the low hematologic toxicity of vinblastine treatment might be one of the reasons for its efficacy. Unfortunately, this hypothesis was not tested in the present series. The results of this study are particularly interesting because most of the participants were high-risk patients with several previous relapses and treatments including previous HSCT in 41%. Furthermore, the short interval (less than 12 months) between the initial diagnosis and the first relapse observed in 61% of the patients is recognized as a poor prognostic factor.12,17 In this series, several patients with one or several poor prognostic factors are long-term survivors after treatment with vinblastine alone, but we could not perform a prognostic factor analysis because of the limited size of the series and the heterogeneity of the patients’ disease status at the initiation of vinblastine therapy. The major question raised by these data is whether this treatment will definitively cure patients or whether it only postpones relapses. It is difficult to answer this question because a number of patients developed late relapses. However, in this series, several patients who have stopped their treatment for more than 5 years may be considered potentially cured. The role of vinblastine in the treatment of relapsed ALCL still has to be defined. Given its low toxicity, its indication in relapses occurring after HSCT is indisputable. Conversely, its role at the time of the first relapse still has to be established. The effectiveness of allogeneic HSCT in patients with chemoresistant disease or multiple relapses was recently evidenced by several investigators, with 5-year EFS around 75% in small series of patients with high-risk relapses.13,17,18 The risk of further relapses after these procedures is well below that following single-agent vinblastine treatment. However, allogeneic HSCT is associated with a high rate of short- and long-term toxicity and a high rate of toxicity-related mortality.13 We must emphasize that one third of the deaths in our series were related to toxicity after HSCT. Furthermore, the 5-year OS rate of 65% observed in this small series of REFERENCES 1. Morris SW, Kirstein MN, Valentine MB, et al: Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 263:1281-1284, 1994 2. Brugie`res L, Deley MC, Pacquement H, et al: CD30(⫹) anaplastic large-cell lymphoma in children: Analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood 92:3591-3598, 1998 www.jco.org

patients treated with vinblastine compares favorably with the results obtained with allogeneic HSCT. The risks associated with allogeneic HSCT must be balanced in each patient with the constraints of prolonged intravenous vinblastine, and this highly toxic procedure should probably be restricted to patients with high-risk failures such as refractory disease during therapy. The ongoing international prospective study for children and adolescents with ALCL relapses conducted by the European Intergroup for Childhood Non-Hodgkin’s Lymphoma should provide data that will enable us to define the respective role of these two procedures in relapsed ALCL, in the not too distant future. The result of this study also raises the issue of the role of vinblastine for initial treatment of ALCL. Several ongoing studies have been designed to assess whether adding maintenance vinblastine therapy to first-line chemotherapy could reduce the risk of relapse in high-risk patients. However, the optimal duration of such maintenance therapy has yet to be determined. Finally, in this lymphoma, which in most of the patients is associated with the t(2.5) translocation, targeted therapies directed against the ALK will probably be available within a short period of time.33 The efficacy and the safety of single-agent vinblastine will have to be kept in mind when designing phase II studies with these new drugs. In conclusion, we have shown that single-agent vinblastine may be effective in relapsed ALCL, leading to durable remissions. A prospective trial is warranted to define the role of this drug in relapsed ALCL and the optimal treatment duration in this setting. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS Conception and design: Laurence Brugie`res, Helene Pacquement Provision of study materials or patients: Laurence Brugie`res, Helene Pacquement, Guy Leverger, Patrick Lutz, Catherine Paillard, Andre Baruchel, Didier Frappaz, Brigitte Nelken, Laurence Lamant, Catherine Patte Collection and assembly of data: Laurence Brugie`res, Helene Pacquement, Marie-Cecile Le Deley Data analysis and interpretation: Laurence Brugie`res, Marie-Cecile Le Deley, Catherine Patte Manuscript writing: Laurence Brugie`res, Marie-Cecile Le Deley Final approval of manuscript: Laurence Brugie`res, Helene Pacquement, Marie-Cecile Le Deley, Guy Leverger, Patrick Lutz, Catherine Paillard, Andre Baruchel, Didier Frappaz, Brigitte Nelken, Laurence Lamant, Catherine Patte

3. Reiter A, Schrappe M, Tiemann M, et al: Successful treatment strategy for Ki-1 anaplastic large-cell lymphoma of childhood: A prospective analysis of 62 patients enrolled in three consecutive Berlin-Frankfurt-Munster group studies. J Clin Oncol 12:899-908, 1994 4. Seidemann K, Tiemann M, Schrappe M, et al: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: A report of the Berlin-FrankfurtMu¨nster Group Trial NHL-BFM 90. Blood 97:36993706, 2001

5. Williams DM, Hobson R, Imeson J, et al: Anaplastic large cell lymphoma in childhood: Analysis of 72 patients treated on The United Kingdom Children’s Cancer Study Group chemotherapy regimens. Br J Haematol 117:812-820, 2002 6. Laver JH, Kraveka JM, Hutchison RE, et al: Advanced-stage large-cell lymphoma in children and adolescents: Results of a randomized trial incorporating intermediate-dose methotrexate and highdose cytarabine in the maintenance phase of the APO regimen: A Pediatric Oncology Group phase III trial. J Clin Oncol 23:541-547, 2005

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Acknowledgment The authors are indebted to all the children and parents who participated in this study; to Nathalie Bouvet, Institut Gustave-Roussy, Villejuif, France, for database management; to Lorna Saint Ange for editing; to K. Yacouben, MD, Hoˆpital Robert Debre´, Paris; V. Gandemer, MD, Centre Hospitalier Régional Sud, Rennes; A. Robert, MD, Hoˆpital des enfants, Centre Hospitalier Universitaire de Toulouse, Toulouse; O. Lejars, MD, Hoˆpital de Clocheville - Centre Hospitalier Universitaire, Tours; and F. Bauduer, MD, Hoˆpital de la Coˆte Basque, Bayonne, for providing data about their patients.

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