ALCL 99. International protocol for the treatment of childhood anaplastic large cell lymphoma

Transcription

1 ALCL 99 International protocol for the treatment of childhood anaplastic large cell lymphoma November 1999

2 1. BACKGROUND RESULTS OF THE DIFFERENT EUROPEAN NATIONAL PROTOCOLS BFM studies SFOP studies UK studies Italian study EUROPEAN INTERGROUP STUDY: COMPARISON OF THE DIFFERENT RESULTS AND PROGNOSTIC FACTORS EXPERIENCE OF VINBLASTINE PROPHYLAXIS OF CNS RELAPSE - COMPARISON OF DIFFERENT SCHEDULES TREATMENT FOR PATIENTS WITH CNS INVOLVEMENT MAIN OBJECTIVES OF THE TRIAL TYPE OF STUDY PARTICIPATING GROUPS PATIENT ELIGIBILITY ELIGIBILITY FOR THE STUDY ELIGIBILITY FOR RANDOMISATION First randomisation Second randomisation Parental (or patient) refusal of randomisation INITIAL STAGING HISTOPATHOLOGICAL DIAGNOSIS OBSERVATION OF TUMOUR EXTENSION BIOLOGY OTHER DEFINITION OF ORGAN INVOLVEMENT Skin involvement Mediastinal involvement Hepatic involvement Splenic involvement Lung involvement CNS involvement CLASSIFICATION OF THERAPEUTIC GROUPS Isolated skin lesions < 5 lesions Low risk group (LR) Standard risk group (SR) High risk group (HR) Patients with CNS involvement (CNS) TREATMENT TREATMENT PLAN Isolated skin disease usually < 5 lesions Group LR (Low risk group: stage 1 resected) Group SR (Standard risk group) Group HR (High risk group) Patients with CNS involvement (CNS) CHEMOTHERAPY DETAILS Pre-phase course (course P) -All patients Course A (A1, A2, A3) - standard or high risk patients Course B (B1, B2, B3) - standard or high risk patients Course AV (AV2, AV3) - high risk patients only Course BV (BV1, BV2, BV3) - high risk patients only Course AM (AM1, AM2, AM3) - standard or high risk patients Course BM (BM1, BM2, BM3) - standard or high risk patients Course AMV (AMV2, AMV3) - high risk patients only...24

3 Course BMV (BMV1, BMV2, BMV3) - high risk patients only Maintenance treatment with Vinblastine (Arm 2 and Arm 4) - high risk patients only DOSE MODIFICATIONS FOR TOXICITY Anaphylactic Reactions Nephrotoxicity Cardiotoxicity Hepatic toxicity Neurological toxicity DOSE MODIFICATIONS FOR YOUNG CHILDREN LESS THAN 10 KG EVALUATION ON TREATMENT EVALUATION Schedule of the evaluation Residual mass Echocadiography OFF TREATMENT FOLLOW UP Disease evaluation Late effects follow up (details to follow) REGISTRATION AND RANDOMISATION REGISTRATION TIME OF RANDOMISATION First randomisation (dose and mode of administration of MTX)- standard and high risk patients Second randomisation (addition of Vinblastine) - high risk patients only MODE OF RANDOMISATION STATISTICAL CONSIDERATIONS CRITERIA OF ASSESSMENT Main end point Secondary end points NUMBER OF SUBJECTS REQUIRED Randomisation of the Vinblastine treatment Randomisation of the Methotrexate treatment ANALYSIS Factorial design analysis Heterogeneity between national groups INTENT TO TREAT ANALYSIS INTERIM ANALYSIS OF EVENT FREE SURVIVAL STOPPING RULE (MONITORING TOXICITY) Relative excess of toxicity (comparison between arms MTX 1g/m_ / MTX 3g/m_ and comparison between arms with Vinblastine / without Vinblastine) Absolute excess of toxicity APPENDIX 1 CLINICAL STAGING SYSTEM ST JUDE S CLASSIFICATION ANN ARBOR STAGING CLASSIFICATION APPENDIX 2 PATHOLOGY GUIDELINES FOR ALCL PROTOCOL PATHOLOGY GOALS REQUIREMENTS FOR HANDLING TISSUE SPECIMENS DIAGNOSTIC CRITERIA FOR ALCL Morphology Immunophenotyping MATERIAL TO SUBMIT FOR CENTRAL PATHOLOGY REVIEW SPECIAL REQUIREMENT FOR TREPHINE BONE MARROW BIOPSY SPECIMENS BIOLOGY STUDIES AND TUMOUR TISSUE BANKING APPENDIX 3 BIOLOGICAL STUDIES APPENDIX 4 METHOD OF ADMINISTRATION OF HIGH DOSE METHOTREXATE...39

4 4.1. COURSES A, B, AV, BV WITH MTX AT 1G/M 2 OVER 24 HRS Hydration Methotrexate Drug interactions Folinic acid METHOTREXATE 3G/M 2 (COURSES AM, BM, AMV, BMV) Hydration Methotrexate Drug interactions Folinic acid Schedule for calculation of folinic acid rescue based on plasma MTX levels APPENDIX 5 RECOMMENDATIONS FOR SUPPORTIVE CARE VENOUS ACCESS SEPTRIN MUCOSITIS APPENDIX 6 GENERAL INFORMATION ON THE DRUGS USED IN THE PROTOCOL INTRAVENOUS AND ORAL DRUGS Vinblastine Cyclophosphamide Ifosfamide Dexamethasone Doxorubicin Methotrexate Etoposide (VP 16) Cytarabine Folinic acid (Leucovorin Calcium, Citrovorum Factor) INTRATHECAL DRUGS Hydrocortisone Sodium Succinate Methotrexate Cytarabine APPENDIX 7 ACUTE-TOXICITY DURING/AFTER ALCL 99 THERAPY APPENDIX 8 PARENT INFORMATION SHEET TREATMENT OF ANAPLASTIC LARGE CELL LYMPHOMA OF CHILDHOOD - STAGE 1 DISEASE TREATMENT OF ANAPLASTIC LARGE CELL LYMPHOMA OF CHILDHOOD - STANDARD RISK TREATMENT OF ANAPLASTIC LARGE CELL LYMPHOMA OF CHILDHOOD - HIGH RISK - FIRST RANDOMISATION TREATMENT OF ANAPLASTIC LARGE CELL LYMPHOMA OF CHILDHOOD - HIGH RISK SECOND RANDOMISATION APPENDIX 9 CONSENT FORM APPENDIX 10 BIBLIOGRAPHY APPENDIX 11 ORGANISATIONAL ASPECTS STATUS OF STUDY STEERING COMMITTEE DATA MONITORING COMMITTEE (DMC) THE PROTOCOL STUDY FORMS AND DATA COLLECTION CONFIDENTIALITY OF PATIENT DATA DATA QUALITY CONTROL DATA ANALYSIS AND MONITORING ADVERSE EVENTS PATHOLOGY REVIEW INSTITUTIONAL/LOCAL ETHICAL APPROVAL AND PATIENT CONSENT CONTACTS AND CORE COMMITTEE MEMBERS...66 BFM. Germany (Berlin-Frankfurt-Münster group)...66 BFM. Austria...66

5 BFM. Switzerland SFOP (Société Française d Oncologie Pédiatrique) Poland UKCCSG (United Kingdom Children s Cancer Study Group) AIEOP (Associazione Italiana di Ematologia ed Oncologia Pediatrica) NOPHO-NHL for the Scandinavian group Spain Belgium DCLSG (Dutch Childhood Leukemia Study Group)...69

6 This study is an international randomised phase III study for the treatment of childhood anaplastic large cell lymphomas. 1. Background Anaplastic large cell lymphoma represent approximately 10% of the childhood lymphomas. Identified separately in the mid-1980s, they correspond in the majority of cases to what used to be called malignant histiocytosis (1,2). On a clinical level they are characterised by peripheral, mediastinal or intra-abdominal lymph node involvement, by the frequency of B symptoms and by extra-nodal involvement, in particular skin and lung involvement (3).The diagnosis rests on morphological criteria and on the expression in the tumour cells of the antigens CD30 (Ki-1 or BERH2), EMA and of the IL2 receptor (4). The translocation t(2;5) (p23;q35) has been described in more than 80% of cases of anaplastic large cell lymphoma of childhood and can currently be detected by PCR and immunohistochemistry (5,6,7). This is found in the majority of T or null cell proliferations. There are rare B cell proliferations in which the histology is close to that of ALCL, but in most cases these are not associated with the translocation t(2;5) and their classification in the context of large cell anaplastic lymphomas is questioned (2). In fact, they are now considered as a morphologic variant of diffuse large B-cell lymphomas. One of the most difficult diagnoses is the putative but controversial Hodgkin s-like ALCL (2) Results of the different European national protocols BFM studies The results of the BFM studies on 87 patients treated with the protocols NHL-BFM-B 90 (protocols used for the treatment of B cell lymphomas) have been reported by A. Reiter in 1997 (8). All the patients received a prephase with Vincristine, Cyclophosphamide, Dexamethasone, then the treatment was stratified according to stage: Stage 1 and 2 resected received 3 courses: one course a (Methotrexate 500 mg/m 2 in continuous infusion over 24 hours, Ifosfamide 800 mg/m 2 x 5, VP mg/m 2 x 2, Cytarabine 150 mg/m 2 x 2, Dexamethasone 10 mg/m 2 x 5 and triple intrathecal treatment-prednisolone, Cytarabine and Methotrexate) and a course b (Dexamethasone, Methotrexate and Cytarabine, Cyclophosphamide 200 mg/m 2 x 5, Adriamycin 25 mg/m 2 x 2) followed by a second course a. ALCL - International protocol page 4

7 Stage 2 not resected and stage 3 received 6 courses (3 courses a and 3 courses b given alternately, the duration of treatment being approximately 4 months. A total dose of Adriamycin 150 mg/m 2, of Cyclophosphamide 3.4 g/m 2 and of Ifosfamide 12 g/m 2 was given. Stage 4 defined by the existence of multifocal bone disease and/or BM disease and/or CNS involvement received 2 courses AA (identical to course a but with a dose of Methotrexate of 5 g/m 2 and an injection of Vincristine), 2 courses BB (identical to b but with a dose of Methotrexate of 5 g/m 2 and an injection of Vincristine) and 2 courses of CC (Dexamethasone, Vincristine, Cytarabine 2 g/m 2 x4, Etoposide 150 mg/m 2 x3 and intrathecal therapy SFOP studies Since 1989, SFOP has organised 2 consecutive studies for ALCL patients (9). Study HM89 : January 1989 to December 1990 (18 patients) Intensive induction treatment of 1 COP (Vincristine, Cyclophosphamide, Prednisone) and 2 COPADM (Vincristine, Cyclophosphamide, Prednisone, Adriamycin, Methotrexate) and maintenance treatment consisting of 4 cycles of 2 courses VEM (VP16, Cyclophosphamide, Methotrexate) and VAD (Vincristine, Adriamycin). Duration - 8 months. Study HM91 : January 1991 to February 1997 (64 patients) Intensive induction treatment of 1 COP and 2 COPADM, then maintenance treatment consisting of 4 cycles of 2 courses: VEBBP (Vinblastine, VP16, Bleomycin, Prednisone). and sequence 1 (Methotrexate, Vincristine, Doxorubicin, Cyclophosphamide and Prednisone) Duration - 7 months UK studies From , most of the British patients were treated on the NHL B-Cell protocols(10). The majority, 41/50, were treated on the 902 protocol, equivalent to the SFOP LMB 89 group B protocol designed for B-cell lymphoma. These patients were patients with stage III and CNS negative stage IV. Intensive induction treatment was with COP and 2 COPADM. This was followed by 2 CYM (Methotrexate, Cytarabine) and a final COPADM. The duration of the treatment was about 5 months. Total dose of Adriamycin 180 mg/m 2 and of Cyclophosphamide 4.8 g/m Italian study The AIEOP protocol LNH 91 consists of an induction and consolidation similar to those of the protocol LSA2L2 of Wollner, followed by a maintenance treatment consisting of 7 cycles of 4 weekly courses given alternately: Cyclophosphamide-VP16 6MP - Methotrexate Cytarabine - VP16 ALCL - International protocol page 5

8 Vincristine - Dexamethasone The stages 3 and 4 received in addition triple intrathecal treatment every 6 weeks. The total duration of treatment was 24 months. With a median follow-up of 19 months the event-free survival reported in 1997 was 65% (11). However, several relapses occurred since that publication and significantly lowered the EFS (12) European intergroup study: comparison of the different results and prognostic factors In order to study prognostic factors, the data on 235 children enrolled in the BFM, SFOP and UKCCSG studies have been included in the European Intergroup Study of ALCL (13). Data on the Italian patients have not been included since the AIEOP protocol was very different to those of BFM, SFOP and UKCCSG. Among the 235 patients included in the study, 206 patients (88%) achieved a CR and 49 relapsed. The relapses occurred in the year following the diagnosis for 36 patients (74% of the relapses). The probability of survival and disease-free survival at 3 years of the whole population was 82% [76-86%] and 71% [64-76%] respectively, with a median follow-up of 47 months. The overall (OS) and event-free survival (EFS) appear significantly different between the three national groups. B.F.M. (93 pts) S.F.O.P. (82 pts) U.K.C.C.S.G. (60 pts) p 3-year EFS 79% [70-86%] 67% [56-77%] 55% [42-68%] year OS 90% [82-95%] 83% [73-91%] 64% [51-76%] < 10-5 Several factors seem to be associated with a higher risk of failure in univariate analysis: B-symptoms, mediastinal involvement, skin lesions, visceral involvement, high staging in the St Jude or Ann Arbor classification, or elevated LDH. Patients with bone lesions seem to have a better prognosis than others. Soft tissue masses do not worsen the prognosis. Multivariate analysis adjusted for country has permitted the highlighting of three poor prognostic factors: mediastinal involvement (relative risk of failure of 2.1 [ ] p = 0.004) ALCL - International protocol page 6

9 visceral involvement defined as lung, liver or spleen involvement (relative risk of failure of 2.1 [ ] p = 0.006) skin lesions (relative risk of failure of 1.9 [ ] p = 0.02) Based on the results of this Cox model, it is possible to define: A poor prognostic or high risk group (150 patients i.e. 64% with skin and/or mediastinal and/or visceral involvement) with a 3-year event free survival of 61% [53%-69%] and an overall survival of 76% [68%-82%] A good prognostic or standard risk group (85 patients i.e. 46% without skin or mediastinal or visceral involvement) with a 3-year event free survival of 87% [78-93%] and an overall survival of 92% [83%-96%] Only four patients had stage I completely resected disease before chemotherapy. All of them are alive and disease free after a short chemotherapy treatment. From these data, we can conclude that: 1. The best results are obtained with the BFM protocol which is less intensive than the French one, both in terms of duration and cumulative dose of Cyclophosphamide and Adriamycin. For this reason, a plan similar to the BFM has been adopted in the ALCL99 study for all patients. 2. The treatment should be stratified according to risk factors. For this study, patients with skin and/or mediastinal and/or visceral involvement are classed as a high risk group. 3. The very rare patients with a stage I completely resected may be treated with a short chemotherapy protocol Experience of Vinblastine The most commonly used second line treatment in France consists of combinations of either Vinblastine, CCNU and Bleomycin or Vinblastine, CCNU and Cytarabine. In these two protocols, Vinblastine is given weekly. In a French series of patients with ALCL (14), 25/28 patients treated with these protocols at relapse achieved a second remission and with a median follow-up of 30 months, 16 are still alive in CR with or without ABMT. Furthermore, a treatment of weekly Vinblastine alone for 6 months to 2 years (median 1 year) was administered to 13 French patients at first (4 pts), second (5 pts), third (2 pts), fifth (2 pts) relapse including 6 relapses after ABMT. 10/11 patients achieved CR and 8 are alive and disease-free with a median follow-up of 30 months since the beginning of Vinblastine ALCL - International protocol page 7

10 (including one patient who had had ABMT after Vinblastine induced remission). These promising results should be confirmed in a randomised clinical trial testing the impact of the early use of Vinblastine followed by a one-year maintenance treatment with Vinblastine on the EFS. Given the good EFS of the standard risk group, this trial will include only those patients with at least one risk factor of failure i.e. either skin and or visceral and or mediastinal involvement Prophylaxis of CNS relapse - Comparison of different schedules In the different European studies, CNS prophylaxis consisted either of Methotrexate 0.5 g/m 2 (BFM branch K1 or 2) or 5 g/m 2 (BFM branch K3) in a 24 hour infusion with intrathecal therapy, or in Methotrexate 3 g/m 2 in 3 hour infusion without intrathecal therapy (SFOP). In all these studies, primary CNS relapses were very rare. This study will compare these two doses and modes of administration of Methotrexate in a randomised trial, both in terms of efficacy and toxicity Treatment for patients with CNS involvement Initial CNS involvement was exceptional and usually treated according to a protocol designed for B-lymphoma with CNS involvement, usually with radiation therapy. 2. Main objectives of the trial The main aim of the study is to test the impact of adding Vinblastine during induction treatment and weekly as a maintenance treatment for a total of one year on the improvement of the event free survival of newly diagnosed high-risk ALCL patients. The second objective will be to compare the impact of a different dose and schedule of administration of Methotrexate currently used in the B.F.M. studies (1 g/m 2 over 24 hours with intrathecal) with those of the SFOP studies (3 g/m 2 over 3 hours without intrathecal) on event-free survival and prevention of CNS relapse. 3. Type of study The study includes: Registration of all the patients with newly diagnosed ALCL not included in the trial. A trial with two consecutive randomisations, as defined below: The trial is a multicentre international randomised trial using a factorial design. The first randomisation concerns the dose and schedule of administration of Methotrexate and the second, the addition of Vinblastine. After both randomisations, there will be four arms: ALCL - International protocol page 8

11 Arm 1 (reference arm): B.F.M.-K2 protocol (with Methotrexate 1 g/m 2 over 24 hours with intrathecal), Arm 2: B.F.M.-K2 protocol (with Methotrexate 1 g/m 2 over 24 hours with intrathecal) with the addition of Vinblastine for one year Arm 3: B.F.M.-K2 protocol but with Methotrexate 3 g/m 2 over 3 hours and without intrathecal Arm 4: B.F.M.-K2 protocol but with Methotrexate 3 g/m 2 over 3 hours and without intrathecal and with the addition of Vinblastine for one year. All the patients included in the study are eligible for the trial with the exception of those children whose disease has been completely resected and patients with CNS involvement. Standard risk patients defined as patients with no skin lesions, no mediastinal, liver, spleen or lung involvement are randomised between arms 1 and 3 (first randomisation only) whereas high risk patients are randomised between the four arms (both randomisations). Randomisation is stratified according to country and, for the question of the Vinblastine, to prognostic factors defined by the European Intergroup Study (13). The statistical tests will be conducted in a 2-sided form. 4. Participating groups ALCL 99 is an intergroup trial of several participating co-operative groups. These are: AIEOP: Associazione Italiana di Ematologia ed Oncologia Pediatrica German BFM: Berlin-Frankfurt-Münster group. Austrian BFM group. Swiss BFM group. SFOP: Société Française d Oncologie Pédiatrique UKCCSG: United Kingdom Children s Cancer Study Group Poland: Spain: DCLSG: Dutch Childhood Leukemia Study Group. Belgium: NOPHO-NHL for the Scandinavian group. These groups form the core collaborative group. Other national groups may join this study after discussion with the core group. Participating groups are expected: ALCL - International protocol page 9

12 To register all eligible patients, To provide diagnostic material for central review. All centres are expected to obtain approval for the study from their local research ethical committee according to their national policy. 5. Patient eligibility 5.1. Eligibility for the study ALCL diagnosed by local pathologist Slides available for national pathology review for all cases. If there are no slides (either cytological or histological) available for central review, the patient is not eligible except in the situation where the presence of t(2;5) is proven. No previous treatment (except for corticosteroids which should not have been given for more than 8 days). Age < 22 years. Appropriate Ethical Committee approval of the protocol. In all the participating groups, all the newly diagnosed ALCL cases should be registered in the database even if they fail to fulfil the criteria for randomisation or decline randomisation Eligibility for randomisation First randomisation Eligibility for the study (see above paragraph) Prephase commenced Not more than one week before the start of course A Potential follow-up of at least 36 months Signed informed consent No evidence of congenital immunodeficiency, AIDS, previous organ transplant or previous malignancy All stages of disease with the exception of: a. Isolated primary skin disease < 5 lesions. b. Completely resected stage I. c. CNS involvement (CSF + or cerebral tumour) ALCL - International protocol page 10

13 Second randomisation Eligibility for the study (see above paragraph) Review by the national pathologist for all cases without t(2;5) not fulfilling the classical criteria for diagnosis (typical histopathology, immunochemistry: CD30+, EMA+, NPM- ALK+ (if available), null or T-immunophenotype). Potential follow-up of at least 36 months Signed informed consent No evidence of congenital immunodeficiency, AIDS, previous organ transplant or previous malignancy High risk patients defined as patients either with: Biopsy proven skin lesion (except skin lesion overlying an involved node and isolated skin disease < 5 lesions), with mediastinal (X-ray or CT-scan) involvement, Liver (liver enlargement 5 cm and / or nodular liver), Spleen (spleen enlargement > 5cm and / or nodular spleen), or Lung (X-ray or CT-scan) involvement. With the exception of patients with CNS involvement (CSF + or cerebral /spinal tumour) First course A given No progressive disease after first course A Not more than one week before the start of second course Parental (or patient) refusal of randomisation Patients for whom the parents decline to be randomised for the methotrexate question can still be randomised for the vinblastine question. Those refusing randomisation should be treated on the reference arms, which are: MTX at 1 g/m 2 for the first randomisation (arms 1 and 2) No Vinblastine for the second randomisation (arms 1 and 3) 6. Initial staging 6.1. Histopathological diagnosis Histological diagnosis is essential. Wherever possible, tissue should be obtained fresh and delivered to the pathology laboratory for optimal handling for: Histology and cytology Immunophenotyping Cytogenetics ALCL - International protocol page 11

14 Storage of a tumour specimen at -80 C for subsequent molecular studies. Agreement for central review of the slides is necessary to enter in the study. A block or 10 unstained slides will be requested. Detail in Appendix Observation of tumour extension Detailed clinical examination with careful attention to : - general condition, including performance status according to ECOG s classification, fever over 38 C for at least 7 days, loss of weight >10%, - skin lesions, sometimes limited to a few pink macular papules. Please note skin lesions overlying an involved node are not considered as skin lesions. Biopsy of the suspect skin lesions X-ray of chest, PA and lateral Ultrasound scan abdomen/pelvis Abdomen, pelvis and chest CT scan (1 cm spacing) Bilateral BM aspirates and trephines, with immunohistochemistry with CD30 and E.M.A (please note bone marrow involvement is by morphological criteria only) CSF cytospin defined as either the presence of tumour cells identified morphologically or the presence of t(2;5) Cranial / Spinal MRI if neurological signs are present, or if the CSF shows presence of lymphoblasts Bone scan (and X-ray of any suspicious areas identified on bone scan ) Cytology of the pleural/ascitic fluid when appropriate Staging in the St Jude s and Ann Arbor s classifications (cf. Appendix 1) Pretreatment blood and marrow for minimal residual disease study (details in Appendix 3) 6.3. Biology Full blood count and film Electrolytes, urea, creatinine, uric acid, calcium, phosphorus, alkaline phosphatase, SGOT, SGPT GFR if there is any evidence of renal dysfunction LDH ALCL - International protocol page 12

15 6.4. Other Cardiac echo Clinical evaluation of pubertal status 6.5. Definition of organ involvement Skin involvement Skin involvement should always be comfirmed by biopsy Skin infiltration by continuous tumour growth arising from an involved node or soft tissue tumour is not considered as primary skin involvement Mediastinal involvement Mediastinal involvement should be confirmed by x-ray or CT scan. If the diagnosis can be reached by biopsy of other organs or lymph nodes a mediastinal biopsy is not necessary Hepatic involvement Liver is considered involved if The liver is palpable clinically or enlarged on imaging >5cm below the costal margin The liver is nodular in appearance on imaging Splenic involvement Spleen is considered involved if: The spleen is palpable clinically or enlarged on imaging >5cm below the costal margin The spleen is nodular in appearance on imaging Lung involvement Lung involvement should be confirmed by x-ray or CT scan. If the diagnosis can be reached by biopsy of other organs or lymph nodes a lung biopsy is not necessary CNS involvement CNS is considered involved if: Presence of lymphoma cells in the CSF Presence of t(2;5) in CSF Presence of a cranial nerve palsy Intra cerebral or spinal lesion as diagnosed by CT or MRI ALCL - International protocol page 13

16 6.6. Classification of therapeutic groups Isolated skin lesions < 5 lesions Isolated skin lesions (<5 lesions) is not considered a high risk factor. ALCL confined to skin is extremely rare in childhood and may represent a distinct form of the disease. Currently it is not clear whether patients with isolated skin disease and no extracutaneous manifestations need chemotherapy at all. Such patients should have careful staging, central pathology review of histology and discussed with the study coordinator before adopting a wait and see approach Low risk group (LR) Stage I disease completely resected Standard risk group (SR) No skin involvement No mediastinal involvement No liver, spleen or lung involvement High risk group (HR) Includes patients with any of the following features: Presence of biopsy proven skin lesions (except skin lesions overlying an involved node or isolated skin disease < 5 lesions) Presence of mediastinal involvement Presence of liver (liver enlargement 5 cm and / or nodular liver), spleen (spleen enlargement and / or nodular spleen) or lung involvement (biopsy is not necessary for obvious lesions) Patients with CNS involvement (CNS) See section ALCL - International protocol page 14

17 7. Treatment 7.1. Treatment plan Isolated skin disease usually < 5 lesions This probably represents a distinct biological entity, which is extremely rare in childhood. Such patients, whether disease is resected or not, probably do not require any chemotherapy providing careful evaluation and staging shows no evidence of disease elsewhere. It is proposed that these patients are followed closely for evidence of progressive disease and that they should be discussed with the study co-ordinator Group LR (Low risk group: stage 1 resected) Courses P A1 B1 A2 Total duration of treatment 10 weeks. Details see section 7.2.1, 7.2.2, Group SR (Standard risk group) All patients receive the prephase. The randomisation occurs before course A1. Pre-phase: P Randomisation Arm 1 MTX 1g/m 2-24 h + IT Arm 3 MTX 3g/m 2-3h no IT Course A: A1 AM1 Course B: B1 BM1 Course A: A2 AM2 Course B: B2 BM2 Course A: A3 AM3 Course B: B3 BM3 Remission evaluation M : MTX 3g/m 2 over 3 hrs without intrathecal ALCL - International protocol page 15

18 Group HR (High risk group) All patients receive the pre-phase. The first randomisation takes place before the course A1 between arms 1 and 3 and the second one before course B1 for non-progressive patients into one of the four arms: Pre-phase: P First Randomisation MTX 1g/m 2-24 h + IT MTX 3g/m 2-3h no IT Course A: A1 AM1 If no disease progression Second Randomisation Arm 1 Arm 2 (V) Arm 3 (M) Arm 4 (MV) Course B: B1 BV1 BM1 BMV1 Course A: A2 AV2 AM2 AMV2 Course B: B2 BV2 BM2 BMV2 Course A: A3 AV3 AM3 AMV3 Course B: B3 BV3 BM3 BMV3 Remission evaluation One year maintenance treatment? None Weekly Vinblastine If CR achieved None Weekly Vinblastine M : MTX 3g/m 2 over 3 hrs without intrathecal V : Addition of Vinblastine Patients included in the trial for the first question only i.e. dose and mode of administration of MTX, will be randomised between arm 1 and arm 3. Patients included in the trial for the second question only i.e. addition of Vinblastine or not, will be randomised between arm 1 and arm 2. Patients not included in the trial will be treated according to arm 1. ALCL - International protocol page 16

19 N.B Patients with disease progression after course 1 (A1 or AM1) should be discussed with the study coordinator and will be taken off study. Patients who are not in CR at the end of the induction therapy again should be discussed with the study coordinator Patients with CNS involvement (CNS) Initial CNS involvement is very rare. Treatment should be according BFM K3 or LMB89 group C according to the protocol currently used for lymphomas with CNS involvement in each group. CNS radiotherapy should be discussed according to the age and response to chemotherapy Chemotherapy details Pre-phase course (course P) -All patients This phase of treatment will be started as soon as the diagnosis is established with certainty. Days Dexamethasone Cyclophosphamide Intrathecal injection DEXAMETHASONE 5 mg/ m 2 /day in one daily dose IV or orally day 1 and 2 10 mg/m 2 /day (divided into BD doses) IV or orally days 3 to 5 CYCLOPHOSPHAMIDE 200 mg/m _ as a 60 minute infusion on days 1 and 2 INTRATHECAL Day 1 MTX ARA-C HSHC AGE 6mg 16 mg 4 mg <1 year 8 mg 20 mg 6 mg between 1 and 2 year 10 mg 26 mg 8 mg between 2 and 3 year 12 mg 30 mg 10 mg > 3 years HYDRATION Rate of 3000 mls/m 2 /day. Those patients with bulky disease may be at risk of metabolic problems associated with tumour lysis. Alkalinisation may be necessary. Allopurinol 300 mg/m 2 daily in 2 divided doses or uricozyme 1 ampoule /10kg /day 1 amp=1000units At least daily observation of biological parameters (electrolytes, calcium, phosphorus, urea) depending on tumour bulk. Limited evaluation of tumour response on day 5 based on clinical, radiological and ultrasound examination if necessary. ALCL - International protocol page 17

20 Course A (A1, A2, A3) - standard or high risk patients The course of A1 begins at day 6 of treatment. Subsequent courses, A2 and A3, start as soon as the peripheral counts have recovered with ANC 0.5 x 10 9 /l and platelets 50 x 10 9 /l and rising and patient is clinically well and free of fever for more than 3 days (from the BFM experience the median time from the start of the previous course is 21 days). Days Dexamethasone Methotrexate Intrathecal injection Ifosfamide Cytarabine Etoposide DEXAMETHASONE 10 mg/m 2 (divided into BD doses) from days 1 to 5 orally or iv METHOTREXATE 1 g/m 2 over 24 hours day 1 (10% of the dose in 30 minutes then 90% as a 23.5h infusion). See Appendix 4.1 for method of administration FOLINIC ACID INTRATHECAL IFOSFAMIDE 15 mg/m 2 i.v. 42, 48 and 54 hours after the beginning of MTX infusion Day 1 (2-4 hours after the beginning of Methotrexate infusion) MTX ARA-C HSHC AGE 6 mg 15 mg 4 mg <1 year 8 mg 20 mg 6 mg between 1 and 2 years 10 mg 26 mg 8 mg between 2 and 3 years 12 mg 30 mg 10 mg >3 years 800 mg/m 2 in 1 hour infusion days 1 to 5. On day 1 give before the start of MTX infusion. Mesna given as an iv bolus 330 mg/m 2 /dose at 0, 4 and 8 hours after Ifosfamide. CYTARABINE 150 mg/m 2 in 1 hour infusion every 12 hours on day 4 and 5. Total daily dose 300 mg/m 2 ETOPOSIDE 100 mg/m 2 in 2 hour infusion day 4 and 5 (after the infusion of Cytarabine). Dilution 0.4 mg/ml HYDRATION Note: Prophylactic GCSF is not recommended Specific alkaline hydration following Methotrexate for 48 hours (see Appendix 4.1). IV or oral hydration at a rate of 3000 mls/m 2 /day should then continue until 12 hours after the last dose of Ifosfamide. ALCL - International protocol page 18

21 Course B (B1, B2, B3) - standard or high risk patients Courses B1, B2 and B3 start as soon as the peripheral counts have recovered with ANC 0.5 x 10 9 /l and platelets 50 x 10 9 /l and rising and patient is clinically well and free of fever for more than 3 days (from the BFM experience the median time from the start of the previous course is 21 days). Days Dexamethasone Methotrexate Intrathecal injection Cyclophosphamide Doxorubicin DEXAMETHASONE METHOTREXATE FOLINIC ACID INTRATHECAL 10 mg/ m 2 (divided into BD doses) days 1 to 5 orally or iv 1 g/m 2 over 24 hours day 1:10% of the dose in 30 minutes then 90% as a 23.5hr infusion. (see Appendix 4.1 for method of administration) 15 mg/m 2 i.v. 42, 48 and 54 hours after the beginning of MTX infusion Day 1 (2-4 hours after the beginning of Methotrexate infusion) MTX ARA-C HSHC AGE 6 mg 16 mg 4 mg <1 year 8mg 20 mg 6 mg between 1 and 2 years 10 mg 26 mg 8mg between 2 and 3 years 12 mg 30 mg 10 mg >3 years CYCLOPHOSPHAMIDE 200 mg/m 2 as 60 minute infusion days 1 to 5. On day 1 give before the start of MTX infusion DOXORUBICIN 25 mg/m 2 in 1hour infusion days 4 and 5 HYDRATION Note: prophylactic GCSF is not recommended Specific alkaline hydration following Methotrexate for 48 hours (see Appendix 4.1). Hydration IV or PO at a rate of 3000 mls/m 2 /day should then continue until 12 hours after the last dose of Cyclophosphamide. ALCL - International protocol page 19

22 Course AV (AV2, AV3) - high risk patients only Courses AV2 and AV3 start as soon as the peripheral counts have recovered with ANC 0.5 x 10 9 /l and platelets 50 x 10 9 /l and rising and patient is clinically well and free of fever for more than 3 days (from the BFM experience the median time from the start of the previous course is 21 days). Days Dexamethasone Methotrexate Intrathecal injection Vinblastine Ifosfamide Cytarabine Etoposide DEXAMETHASONE 10 mg/m 2 (divided into BD doses) from days 1 to 5 METHOTREXATE 1 g/m 2 over 24 hours day 1: 10% of the dose in 30 minutes, then 90% as a 23.5h infusion. See Appendix 4.1 for method of administration FOLINIC ACID INTRATHECAL VINBLASTINE IFOSFAMIDE 15 mg/m 2 i.v. 42, 48 and 54 hours after the beginning of MTX infusion Day 1 (2-4 hours after the beginning of Methotrexate infusion) MTX ARA-C HC AGE 6 mg 16 mg 4 mg <1 year 8 mg 20 mg 6 mg between 1 and 2 years 10 mg 26 mg 8 mg between 2 and 3 years 12 mg 30 mg 10 mg >3 years 6 mg/m 2 ( 10 mg total dose) day 1 IV bolus 800 mg/m 2 in 1 hour infusion days 1 to 5. On day 1, give before the start of MTX infusion. Mesna given as an iv bolus 330 mg/m 2 /dose at 0, 4 and 8 hours after Ifosfamide. CYTARABINE 150 mg/m 2 in 1 hour infusion every 12 hours on day 4 and 5. Total daily dose 300 mg/m 2 ETOPOSIDE 100 mg/m 2 in 2 hour infusion day 4 and 5 (after the infusion of Cytarabine). Dilution 0.4 mg/ml HYDRATION Note: Prophylactic GCSF is not recommended Specific alkaline hydration following Methotrexate for 48 hours (see Appendix 4.1). IV or oral hydration at a rate of 3000 mls/m 2 /day should then continue until 12 hours after the last dose of Ifosfamide. ALCL - International protocol page 20

23 Course BV (BV1, BV2, BV3) - high risk patients only Courses BV1, BV2 and BV3 start as soon as the peripheral counts have recovered with ANC 0.5 x 10 9 /l and platelets 50 x 10 9 /l and rising and patient is clinically well and free of fever for more than 3 days (from the BFM experience the median time from the start of the previous course is 21 days). Days Dexamethasone Methotrexate Intrathecal injection Vinblastine Cyclophosphamide Doxorubicin DEXAMETHASONE 10 mg/ m 2 IV (divided into BD doses) days 1 to 5 METHOTREXATE 1 g/m 2 over 24 hours day 1: 10% of the dose in 30 minutes then 90% as a 23.5hr infusion. (see Appendix 4.1 for method of administration) FOLINIC ACID 15 mg/m 2 i.v. 42, 48 and 54 hours after the beginning of MTX infusion INTRATHECAL Day 1 (2-4 hours after the beginning of Methotrexate infusion) MTX ARA-C HC AGE 6 mg 16 mg 4 mg <1 year 8 mg 20 mg 6 mg between 1 and 2 years 10 mg 26 mg 8 mg between 2 and 3 years 12 mg 30 mg 10 mg >3 years VINBLASTINE 6 mg/ m 2 ( 10 mg total dose) IV bolus day 1 2 CYCLOPHOSPHAMIDE 200 mg/ m as 60 minute infusion days 1 to 5. On day 1 give before the start of the MTX infusion. DOXORUBICIN 25 mg/ m 2 in 1hour infusion day 4 and 5 HYDRATION Specific alkaline hydration following Methotrexate for 48 hours (see Appendix 4.1). Hydration PO or IV at a rate of 3000 mls/m 2 /day should then continue until 12 hours after the last dose of Cyclophosphamide. Note: Prophylactic GCSF is not recommended Course AM (AM1, AM2, AM3) - standard or high risk patients The course AM1 begins at D6 of treatment. ALCL - International protocol page 21

24 Courses AM2 and AM3 start as soon as the peripheral counts have recovered with ANC 0.5 x 10 9 /l and platelets 50 x 10 9 /l and rising and patient is clinically well and free of fever for more than 3 days (from the BFM experience the median time from the start of the previous course is 21 days). Days Dexamethasone Methotrexate Ifosfamide Cytarabine Etoposide DEXAMETHASONE 10 mg/m 2 (divided into BD doses) from days 1 to 5 METHOTREXATE 3 g/m 2 in 3 hour infusion day 1 (see Appendix 4.2 for method of administration) FOLINIC ACID 15 mg/m 2 orally or i.v every 6 hours for a total of 12 doses (or as required depending on Methotrexate levels. See Appendix 2 for further details). This begins 24 hours after start of MTX infusion. IFOSFAMIDE 800 mg/m 2 in 1 hour infusion days 1 to 5. On day 1, give before the start of MTX infusion. Mesna given as an iv bolus 330 mg/m 2 /dose at 0, 4 and 8 hours after Ifosfamide. CYTARABINE 150 mg/m 2 in 1 hour infusion every 12 hours on day 4 and 5. Total daily dose 300 mg/m_ ETOPOSIDE 100 mg/m 2 in 2 hour infusion day 4 and 5 (after the infusion of Cytarabine). Dilution 0.4 mg/ml HYDRATION Note: Prophylactic GCSF is not recommended Specific alkaline hydration following Methotrexate for 48 hours (see Appendix 4.2). IV or oral hydration at a rate of 3000 mls/m 2 /day should then continue until 12 hours after the last dose of Ifosfamide. ALCL - International protocol page 22

25 Course BM (BM1, BM2, BM3) - standard or high risk patients Courses BM1, BM2 and BM3 start as soon as the peripheral counts have recovered with ANC 0.5 x 10 9 /l and platelets 50 x 10 9 /l and rising and patient is clinically well and free of fever for more than 3 days (from the BFM experience the median time from the start of the previous course is 21 days). Days Dexamethasone Methotrexate Cyclophosphamide Doxorubicin DEXAMETHASONE 10 mg/m 2 (divided into BD doses) days 1 to 5 orally or iv METHOTREXATE 3 g/m 2 in 3 hour infusion day 1 (see Appendix 4.2 for method of administration) FOLINIC ACID 15 mg/m 2 orally or i.v. every 6 hours for a total of 12 doses (or as required depending on Methotrexate levels. See Appendix 2 for further details). This begins 24 hours after start of MTX infusion. CYCLOPHOSPHAMIDE 200 mg/m 2 as 60 minute infusion days 1 to 5. On day 1 give before the start of the MTX infusion DOXORUBICIN 25 mg/m 2 in 1hour infusion day 4 and 5 HYDRATION Note: Prophylactic GCSF is not recommended Specific alkaline hydration following Methotrexate for 48 hours (see Appendix 4.2). Hydration PO or IV at a rate of 3000 mls/m 2 /day should then continue until 12 hours after the last dose of Cyclophosphamide ALCL - International protocol page 23

26 Course AMV (AMV2, AMV3) - high risk patients only Courses AMV2 and AMV3 start as soon as the peripheral counts have recovered with ANC 0.5 x 10 9 /l and platelets 50 x 10 9 /l and rising and patient is clinically well and free of fever for more than 3 days (from the BFM experience the median time from the start of the previous course is 21 days). Days Dexamethasone Methotrexate Vinblastine Ifosfamide Cytarabine Etoposide DEXAMETHASONE 10 mg/m 2 (divided into BD doses) from days 1 to 5 orally or iv METHOTREXATE 3 g/m 2 in 3 hour infusion day 1 (see Appendix 4.2 for method of administration) FOLINIC ACID 15 mg/m 2 orally or i.v. every 6 hours for a total of 12 doses (or as required depending on Methotrexate levels. See Appendix 2 for further details). This begins 24 hours after start of MTX infusion. VINBLASTINE IFOSFAMIDE 6 mg/m 2 ( 10 mg total dose) day 1 IV bolus 800 mg/m 2 in 1 hour infusion days 1 to 5. On day 1, give before the start of MTX infusion. Mesna given as an iv bolus 330 mg/m 2 /dose at 0, 4 and 8 hours after Ifosfamide. CYTARABINE 150 mg/m 2 in 1 hour infusion every 12 hours on day 4 and 5. Total daily dose 300 mg/m_ ETOPOSIDE 100 mg/m 2 in 2 hour infusion day 4 and 5 (after the infusion of Cytarabine). Dilution 0.4 mg/ml HYDRATION Note: Prophylactic GCSF is not recommended Specific alkaline hydration following Methotrexate for 48 hours (see Appendix 4.2). IV or oral hydration at a rate of 3000 mls/m 2 /day should then continue until 12 hours after the last dose of Ifosfamide ALCL - International protocol page 24

27 Course BMV (BMV1, BMV2, BMV3) - high risk patients only Courses BMV1, BMV2 and BMV3 start as soon as the peripheral counts have recovered with ANC 0.5 x 10 9 /l and platelets 50 x 10 9 /l and rising and patient is clinically well and free of fever for more than 3 days (from the BFM experience the median time from the start of the previous course is 21 days). Days Dexamethasone Vinblastine Methotrexate Cyclophosphamide Doxorubicin DEXAMETHASONE 10 mg/ m 2 IV (divided into BD doses) days 1 to 5 VINBLASTINE 6 mg/ m 2 ( 10 mg total dose) IV bolus day 1 METHOTREXATE 3 g/m 2 in 3 hour infusion day 1 (see Appendix 4.2 for method of administration) FOLINIC ACID 15 mg/m 2 orally or i.v. every 6 hours for a total of 12 doses (or as required depending on Methotrexate levels. See Appendix 2 for further details). This begins 24 hours after start of MTX infusion. CYCLOPHOSPHAMIDE 200 mg/ m 2 in 1 hour infusion days 1 to 5. On day 1 give before the start of the MTX infusion. DOXORUBICIN 25 mg/ m 2 in 1hour infusion day 4 and 5 HYDRATION Note: Prophylactic GCSF is not recommended Specific alkaline hydration following Methotrexate for 48 hours (see Appendix 4.2). Hydration PO or IV at a rate of 3000 mls/m 2 /day should then continue until 12 hours after the last dose of Cyclophosphamide. ALCL - International protocol page 25

28 Maintenance treatment with Vinblastine (Arm 2 and Arm 4) - high risk patients only VINBLASTINE : 6 mg/m m 2 ( 10 mg total dose) IV bolus every week for a total duration of 1 year treatment starting 3 weeks after the beginning of the course BV3 (or BMV3). Dose modifications: A blood count should be carried out every 15 days and treatment stopped if the neutrophil count is < 0.5 x 10 9 /l or the platelets are < 50 x 10 9 /l. Vinblastine is recommenced once the neutrophil count is > 0.5 x 10 9 /l and the platelets are > 50 x 10 9 /l. The dose of Vinblastine should be reduced to 4 mg/m_ in case of prolonged cytopenia necessitating an interruption of more than 2 injections. If the next two courses are well tolerated, the standard dose of 6 mg/m 2 should be tried again. Neurological examination as part of clinical evaluation should be carried out monthly. It is suggested that the Vinblastine dose should be reduced to half (3 mg/m 2 ) if there is evidence of symptomatic peripheral neuropathy. In this situation please contact the study co-ordinator ALCL - International protocol page 26

29 Dose modifications for toxicity Anaphylactic Reactions For life threatening grade IV toxicity, secondary to Etoposide, discontinue all future Etoposide Nephrotoxicity For patients with a GFR by EDTA clearance of less than 60 ml/min/1.73 m 2 contact study coordinator for recommendations on further courses of high dose Methotrexate Cardiotoxicity Cardiac assessment with echocardiography should be carried out at least before treatment and at the end of treatment. If there is other evidence of cardiac dysfunction during treatment and a fractional shortening is < 28%, please discuss with the study co-ordinator Hepatic toxicity Prior to starting IV Methotrexate: if SGOT or SGPT is > 20 times normal of upper limits, contact the study co-ordinator for further recommendations. If the transaminases are between N x 10 and N x 20 wait 48 hours and recheck to ensure that the levels are decreasing. In cases of hyperbilirubinaemia/liver dysfunction, the dose of Vinblastine should be decreased. Please discuss with trial co-ordinator Neurological toxicity In case of recurrent seizures, which may be due to MTX or Vinblastine, the clinician should contact the study co-ordinator for consideration of drug modification during future cycles. In the event of symptomatic peripheral neuropathy, reduce the dose of Vinblastine by half and contact the study co-ordinator Dose modifications for young children less than 10 kg Drugs should be given at 2/3 /m 2 dose, or doses based on weight alone. Intrathecal doses are age specific. (See 9.5.1) ALCL - International protocol page 27

30 8. Evaluation 8.1. On treatment evaluation Schedule of the evaluation All easily accessible sites of initial disease must be assessed (either clinically or by standard planned X-ray or by ultrasound) before each course, until complete remission is achieved. A full assessment of complete remission (including all initially involved sites) must be performed as soon as there is no obvious site of disease. If this assessment has not been carried out before, it must be conducted after the third course B (B3, BV3, BM3 or BMV3). For patients with initial mediastinal involvement, CT scan (1 cm spacing) of the thorax must be repeated. A further repeat chest CT scan is not necessary after CR has been confirmed unless there is doubt about the mediastinum as seen on chest X-ray, or in the case of is relapse at another site Residual mass The presence of a residual mass at completion of treatment should not be considered as a failure in the majority of the cases if it is less than 30% of the initial tumour volume and should not imply any modifications of the treatment. In the German series, 13 patients had a residual mass at the end of the treatment, 10 were followed without evidence of progression (including one patient with local irradiation), one was lost to follow-up and two progressed. For patients showing a residual mediastinal mass, X-ray films including CT and MRI scans may be requested for central review Echocadiography Echocardiograms must be carried out before the start of treatment, and before course B Off treatment follow up Disease evaluation Two monthly clinical follow up with chest X-ray, abdominal ultrasound and imaging of initially involved sites for the first year. Four-monthly clinical review from the second to the third, six monthly from the third to the fifth year, followed by yearly follow up. ALCL - International protocol page 28

31 Late effects follow up (details to follow) Echocardiograms must be carried out, 3 months after the end of treatment and then every three years. Renal evaluation FSH and LH levels must be measured at the completion of puberty and any abnormality investigated. All patients who are eligible for the study will be evaluated and followed the same way, even if they are not included in the trial. 9. Registration and randomisation 9.1. Registration All the patients will be registered in the study, regardless of whether they are eligible for entry in the trial and randomisation. A registration fax must be sent within 5 days after the beginning of the pre-phase. If eligible for the trial, registration and first randomisation may be done together Time of randomisation First randomisation (dose and mode of administration of MTX)- standard and high risk patients Randomisation should be obtained for eligible patients within 3 to 5 days from the beginning of the pre-phase and no more than one week before the first course A Second randomisation (addition of Vinblastine) - high risk patients only Randomisation should be obtained for eligible patients (high-risk patients with no progression after course A1) and no more than one week before the second course Mode of randomisation Randomisation will be stratified according to: Country Prognostic factors, standard risk / High risk (for the first randomisation) Allocated treatment in the first randomisation (for the second randomisation) ALCL - International protocol page 29