Clinical trial NCT00317408: Combination Chemotherapy Followed By Stem Cell Transplant in Treating Young Patients With Progressive or Relapsed Anaplastic Large Cell Lymphoma
Official title: Treatment Protocol for Relapsed Anaplastic Large Cell Lymphoma of Childhood and Adolescence
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Lymphoma
Keywords: anaplastic large cell lymphoma
recurrent childhood anaplastic large cell lymphoma
stage III childhood anaplastic large cell lymphoma
stage IV childhood anaplastic large cell lymphoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-04-24
Enrollment: 96
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Primary purpose: TREATMENT

Brief summary: RATIONALE: Giving combination chemotherapy and total-body irradiation before a peripheral stem cell transplant that uses the patient's or a donor's stem cells, helps stop both the growth of cancer cells and the patient's immune system from rejecting the stem cells. When the stem cells are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving combination chemotherapy and total-body irradiation followed by a stem cell transplant may be an effective treatment for anaplastic large cell lymphoma.

PURPOSE: This clinical trial is studying how well combination chemotherapy followed by stem cell transplant works in treating young patients with progressive or relapsed anaplastic large cell lymphoma.

Detailed description: OBJECTIVES:

Primary

* Improve the probability of event-free survival in children and adolescents with early progression of anaplastic large cell lymphoma (ALCL) and/or relapse of ALCL with CD3-positive immunophenotype treated with reinduction combination chemotherapy followed by allogeneic or autologous stem cell transplantation.
* Determine whether a conditioning regimen comprising carmustine, etoposide phosphate, cytarabine, and melphalan (BEAM) (without total body irradiation) for autologous stem cell transplantation is an effective treatment for patients with relapsed CD3-negative ALCL occurring after the intensive phase of treatment.
* Determine the impact of vinblastine in patients with late relapse of CD3-negative ALCL who have not received vinblastine during frontline therapy.

Secondary

* Determine overall survival and treatment-related mortality in patients treated with these regimens.
* Determine acute and long-term toxicity in patients treated with these regimens.
* Determine the rate of acute and chronic graft-vs-host disease in patients treated with allogeneic stem cell transplantation.

OUTLINE: This is a multicenter, prospective, nonrandomized study. Patients are stratified according to time from initial diagnosis to progression/relapse, immunophenotype of lymphoma cells (CD3-positive + vs CD3-negative), stem cell donor availability (matched sibling donor vs 9/10 or 10/10 matched unrelated donor), and vinblastine during frontline therapy (yes vs no).

* Group 1 (early progression): Patients receive 1 course of ICM chemotherapy followed by 1 course of ICI chemotherapy.

  * ICM chemotherapy: Patients receive methotrexate, cytarabine, and prednisolone intrathecally (IT) on day 1, mitoxantrone hydrochloride IV over 5 hours on days 1 and 2, carboplatin IV continuously on days 2-5 and ifosfamide IV continuously on days 2-6.
  * ICI chemotherapy: Patients receive methotrexate, cytarabine, and prednisolone intrathecally on day 1, idarubicin IV over 4 hours on days 1 and 2, carboplatin IV continuously on days 2-5, and ifosfamide IV continuously on days 2-6.

Patients then proceed to allogeneic stem cell transplantation.

* Group 2 (relapsed disease and CD3-positive lymphoma cells): Patients are stratified according to stem cell donor availability (yes vs no).

  * Available donor: Patients receive 2 courses of CC chemotherapy and then proceed to allogeneic stem cell transplantation.
  * Unavailable donor : Patients receive 2 courses of CC chemotherapy comprising dexamethasone orally or IV on days 1-5, vindesine IV on day 1, cytarabine IV over 3 hours on days 1 and 2, etoposide phosphate IV over 2 hours on days 3-5, and methotrexate, cytarabine, and prednisolone IT on day 5. Patients then receive 1 course of CVA chemotherapy comprising oral lomustine on day 1, vinblastine IV on days 1, 8, 15, and 22, and cytarabine IV over 1 hour on days 1-5. Patients undergo leukapheresis for collection of autologous peripheral blood stem cells after the first and/or second course of CC chemotherapy. Patients then proceed to autologous stem cell transplantation.
* Group 3 (relapsed disease, CD3-negative immunophenotype, and received vinblastine during frontline therapy): Patients receive 2 courses of CC chemotherapy and 1 course of CVA chemotherapy as described above. Patients undergo leukapheresis for collection of autologous peripheral blood stem cells (PBSC) after the first and/or second course of CC chemotherapy. Patients then proceed to autologous stem cell transplantation.
* Group 4 (late relapse, CD3-negative immunophenotype, and did not receive vinblastine during frontline therapy): Patients receive vinblastine IV once weekly for 24 months. Patients with disease progression during or relapsed disease after vinblastine therapy undergo treatment as in group 3.
* Autologous stem cell transplantation (SCT): Patients receive a conditioning regimen comprising carmustine IV over 1 hour on day -7, etoposide phosphate IV over 1 hour and cytarabine IV over 30 minutes on days -6 to -3, and melphalan IV over 15 minutes on day -2. Patients undergo autologous SCT on day 0.
* Allogeneic SCT: Beginning 4-6 weeks after the start of the last chemotherapy course, patients receive 1 of the following conditioning regimens based on age:

  * Patients \> 2 years of age undergo total body irradiation on days -7 to -5 and receive thiotepa IV over 1 hour on day -4 and etoposide IV over 4 hours on day -3. Patients undergo allogeneic SCT on day 0.
  * Patients ≤ 2 years of age receive oral busulfan 4 times daily on days -8 to -5, thiotepa IV over 1 hour twice on day -4, and etoposide phosphate IV over 4 hours on day -3. Patients undergo allogeneic SCT on day 0.

Patients undergoing SCT from an unrelated donor also receive antithymocyte globulin IV over 4 hours on days -3 to -1.

All patients receive graft-versus-host (GVHD) prophylaxis as described below.

* GVHD prophylaxis: GVHD prophylaxis is administered as per donor status.

  * Matched sibling donor: Patients receive cyclosporine IV over 2 hours or orally on day -1 to 60 followed by a taper.
  * 10/10 or 9/10 matched unrelated donor: Patients receive cyclosporine IV over 2 hours or orally on days -1 to 100 followed by a taper, methotrexate IV on days 1, 3, and 6, and leucovorin calcium IV on days 2, 4, and 7.
  * Mismatched donor: Patients do not receive GVHD prophylaxis, however, CD3-positive lymphocytes are extracted from donor stem cells.

After completion of study treatment, patients are followed periodically for 10 years.

PROJECTED ACCRUAL: A total of 96 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically or cytologically confirmed anaplastic large cell lymphoma (ALCL)

  * Progressive disease OR first relapse
  * No second or subsequent relapse of ALCL
* Slides available for national central pathology review
* Availability of 1 of the following (for allogeneic stem cell transplantation only):

  * HLA-identical matched sibling donor
  * 10/10 HLA-matched nonsibling donor (related or unrelated)
  * 9/10 HLA-matched nonsibling donor (1-antigen-mismatched related or unrelated donor)
  * \< 9/10 HLA-mismatched donor (related or unrelated)

    * Stem cells may be obtained from unmanipulated bone marrow or peripheral blood stem cells after filgrastim (G-CSF) stimulation

PATIENT CHARACTERISTICS:

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* Adequate hepatic, renal, and cardiac function
* No HIV infection or AIDS
* No severe immunodeficiency
* No other prior malignancy
* No pre-existing disease or condition prohibiting study treatment

PRIOR CONCURRENT THERAPY:

* At least 2 months since prior chemotherapy or radiotherapy
* No significant pretreatment for first relapse
* No prior organ transplantation
* No concurrent participation in another clinical trial

Primary outcomes:
measure: Event-free survival as measured by the Kaplan-Meier method
Secondary outcomes:
measure: Proportion of patients who are treated on protocol among all patients who meet the inclusion criteria
measure: Overall survival
measure: Acute and long term toxicity
measure: Rate of acute and chronic graft-vs-host disease in patients with allogeneic stem cell transplantation
measure: Treatment related mortality
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: St. Anna Children's Hospital
city: Leuven
country: Belgium
facility: U.Z. Gasthuisberg
city: Brno
country: Czech Republic
facility: University Hospital Brno
city: Prague 5
country: Czech Republic
facility: Charles University Hospital
city: Lyon
country: France
facility: Centre Leon Berard
city: Aachen
country: Germany
facility: Kinderklinik - Universitaetsklinikum Aachen
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Berlin
country: Germany
facility: Helios Klinikum Berlin
city: Berlin
country: Germany
facility: Charite University Hospital - Campus Virchow Klinikum
city: Biefeld
country: Germany
facility: Evangelisches Krankenhauus Bielfeld
city: Bonn
country: Germany
facility: Kinderklinik der Universitaet Bonn
city: Braunschweig
country: Germany
facility: Staedtisches Klinikum - Howedestrase
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH
city: Cologne
country: Germany
facility: Kliniken der Stadt Koeln gGmbH - Kinderkrankenhaus Riehl
city: Cologne
country: Germany
facility: Children's Hospital
city: Cottbus
country: Germany
facility: Carl - Thiem - Klinkum Cottbus
city: Datteln
country: Germany
facility: Vestische Kinderklinik
city: Dortmund
country: Germany
facility: Klinikum Dortmund
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carus
city: Duesseldorf
country: Germany
facility: Universitaetsklinikum Duesseldorf
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt
city: Erlangen
country: Germany
facility: Universitaets - Kinderklinik
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe Universitaet
city: Freiburg
country: Germany
facility: Universitaetskinderklinik - Universitaetsklinikum Freiburg
city: Giessen
country: Germany
facility: Kinderklinik
city: Goettingen
country: Germany
facility: Universitaetsklinikum Goettingen
city: Greifswald
country: Germany
facility: Klinik und Poliklinik Fuer Kinder-und Jugendmedizin - Universitaetsklinikum Greifswald
city: Hamburg
country: Germany
facility: University Medical Center Hamburg - Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitaets-Kinderklinik Heidelberg
city: Herdecke
country: Germany
facility: Gemeinschaftskrankenhaus
city: Homburg
country: Germany
facility: Universitaetsklinikum des Saarlandes
city: Jena
country: Germany
facility: Universitaets - Kinderklinik
city: Karlsruhe
country: Germany
facility: Staedtisches Klinikum Karlsruhe gGmbH
city: Kassel
country: Germany
facility: Klinikum Kassel
city: Kiel
country: Germany
facility: University Hospital Schleswig-Holstein - Kiel Campus
city: Koblenz
country: Germany
facility: Klinikum Kemperhof Koblenz
city: Krefeld
country: Germany
facility: Klinikum Krefeld GmbH
city: Leipzig
country: Germany
facility: Universitaets - Kinderklinik
city: Ludwigshafen
country: Germany
facility: St. Annastift Krankenhaus
city: Luebeck
country: Germany
facility: Universitaets - Kinderklinik - Luebeck
city: Magdeburg
country: Germany
facility: Universitatsklinikum der MA
city: Mainz
country: Germany
facility: Johannes Gutenberg University
city: Mannheim
country: Germany
facility: Staedtisches Klinik - Kinderklinik
city: Marburg
country: Germany
facility: Universitaets - Kinderklinik
city: Minden
country: Germany
facility: Klinikum Minden
city: Muenster
country: Germany
facility: Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster
city: Munich
country: Germany
facility: Krankenhaus Muenchen Schwabing
city: Munich
country: Germany
facility: Dr. von Haunersches Kinderspital der Universitaet Muenchen
city: Neunkirchen
country: Germany
facility: Kinderklinik Kohlhof
city: Nuremberg
country: Germany
facility: Cnopf'sche Kinderklinik
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Regensburg
country: Germany
facility: Klinik St. Hedwig-Kinderklinik
city: Rostock
country: Germany
facility: Kinderklinik - Universitaetsklinikum Rostock
city: Saarbrucken
country: Germany
facility: Saarbrucker Winterbergkliniken
city: Schwerin
country: Germany
facility: Klinikum Schwerin
city: Siegen
country: Germany
facility: Kinderklink Siegen Deutsches Rotes Kreuz
city: St. Augustin
country: Germany
facility: Johanniter-Kinderklinik
city: Stuttgart
country: Germany
facility: Olgahospital
city: Trier
country: Germany
facility: Krankenanstalt Mutterhaus der Borromaerinnen
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
city: Ulm
country: Germany
facility: Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
city: Wiesbaden
country: Germany
facility: Dr. Horst-Schmidt-Kliniken
city: Wuerzburg
country: Germany
facility: Universitaets - Kinderklinik Wuerzburg
city: Wuppertal
country: Germany
facility: Helios Kliniken Wuppertal University Hospital
city: Dublin
country: Ireland
facility: Our Lady's Hospital for Sick Children Crumlin
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
city: Rotterdam
country: Netherlands
facility: Erasmus MC - Sophia Children's Hospital
city: Wroclaw
country: Poland
facility: Akademia Medyczna im. Piastow Slaskich
city: Goeteborg
country: Sweden
facility: Goeteborg University
city: Aarau
country: Switzerland
facility: Kantonspital Aarau
city: Basel
country: Switzerland
facility: Universitaets-Kinderspital beider Basel
city: Locarno
country: Switzerland
facility: Ospedale "la Carita", Locarno
city: Lucerne 16
country: Switzerland
facility: Kinderspital Luzern
city: St. Gallen
country: Switzerland
facility: Ostschweizer Kinderspital
city: Zurich
country: Switzerland
facility: University Children's Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
state: England
city: Bristol
country: United Kingdom
facility: Institute of Child Health at University of Bristol
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: England
city: Leeds
country: United Kingdom
facility: Leeds Cancer Centre at St. James's University Hospital
state: England
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: England
city: Liverpool
country: United Kingdom
facility: Royal Liverpool Children's Hospital, Alder Hey
state: England
city: London
country: United Kingdom
facility: Middlesex Hospital
state: England
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
state: England
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
state: England
city: Newcastle-Upon-Tyne
country: United Kingdom
facility: Sir James Spence Institute of Child Health at Royal Victoria Infirmary
state: England
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
state: England
city: Oxford
country: United Kingdom
facility: Oxford Radcliffe Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Children's Hospital - Sheffield
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden - Surrey
state: England
city: Belfast
country: United Kingdom
facility: Royal Belfast Hospital for Sick Children
state: Northern Ireland
city: Aberdeen
country: United Kingdom
facility: Royal Aberdeen Children's Hospital
state: Scotland
city: Edinburgh
country: United Kingdom
facility: Royal Hospital for Sick Children
state: Scotland
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Sick Children
state: Scotland
city: Cardiff
country: United Kingdom
facility: Childrens Hospital for Wales
state: Wales
Study officials:
affiliation: University Hospital Erlangen
name: Alfred Reiter, MD
role: STUDY_CHAIR
affiliation: Cambridge University Hospitals NHS Foundation Trust
name: Denise Williams, MD
References:
citation: Knorr F, Brugieres L, Pillon M, Zimmermann M, Ruf S, Attarbaschi A, Mellgren K, Burke GAA, Uyttebroeck A, Wrobel G, Beishuizen A, Aladjidi N, Reiter A, Woessmann W; European Inter-Group for Childhood Non-Hodgkin Lymphoma. Stem Cell Transplantation and Vinblastine Monotherapy for Relapsed Pediatric Anaplastic Large Cell Lymphoma: Results of the International, Prospective ALCL-Relapse Trial. J Clin Oncol. 2020 Dec 1;38(34):3999-4009. doi: 10.1200/JCO.20.00157. Epub 2020 Jul 30.