Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols: A retrospective analysis

Valentino Conter, Maria Grazia Valsecchi, Barbara Buldini, Rosanna Parasole, Franco Locatelli, Antonella Colombini, Carmelo Rizzari, Maria Caterina Putti, Elena Barisone, Luca Lo Nigro, Nicola Santoro, Ottavio Ziino, Andrea Pession, Anna Maria Testi, Concetta Micalizzi, Fiorina Casale, Paolo Pierani, Simone Cesaro, Monica Cellini, Daniela SilvestriGiovanni Cazzaniga, Andrea Biondi, Giuseppe Basso

Research output: Contribution to journalArticle

Abstract

Background: Early T-cell precursor acute lymphoblastic leukaemia was recently recognised as a distinct leukaemia and reported as associated with poor outcomes. We aimed to assess the outcome of early T-cell precursor acute lymphoblastic leukaemia in patients from the Italian Association of Pediatric Hematology Oncology (AIEOP) centres treated with AIEOP-Berlin-Frankfurt-Münster (AIEOP-BFM) protocols. Methods: In this retrospective analysis, we included all children aged from 1 to less than 18 years with early T-cell precursor acute lymphoblastic leukaemia immunophenotype diagnosed between Jan 1, 2008, and Oct 31, 2014, from AIEOP centres. Early T-cell precursors were defined as being CD1a and CD8 negative, CD5 weak positive or negative, and positive for at least one of the following antigens: CD34, CD117, HLADR, CD13, CD33, CD11b, or CD65. Treatment was based on AIEOP-BFM acute lymphoblastic leukaemia 2000 (NCT00613457) or AIEOP-BFM acute lymphoblastic leukaemia 2009 protocols (European Clinical Trials Database 2007-004270-43). The main differences in treatment and stratification of T-cell acute lymphoblastic leukaemia between the two protocols were that in the 2009 protocol only, pegylated L-asparaginase was substituted for Escherichia coli L-asparaginase, patients with prednisone poor response received an additional dose of cyclophosphamide at day 10 of phase IA, and high minimal residual disease at day 15 assessed by flow cytometry was used as a high-risk criterion. Outcomes were assessed in terms of event-free survival, disease-free survival, and overall survival. Findings: Early T-cell precursor acute lymphoblastic leukaemia was diagnosed in 49 patients. Compared with overall T-cell acute lymphoblastic leukaemia, it was associated with absence of molecular markers for PCR detection of minimal residual disease in 25 (56%) of 45 patients; prednisone poor response in 27 (55%) of 49 patients; high minimal residual disease at day 15 after starting therapy in 25 (64%) of 39 patients (bone marrow blasts ≥10%, by flow cytometry); no complete remission after phase IA in 7 (15%) of 46 patients (bone marrow blasts ≥5%, morphologically); and high PCR minimal residual disease (≥5 × 10-4) at day 33 after starting therapy in 17 (85%) of 20 patients with markers available. Overall, 38 (78%) of 49 patients are in continuous complete remission, including 13 of 18 after haemopoietic stem cell transplantation, with three deaths in induction, five deaths after haemopoietic stem cell transplantation, and three relapses. Severe adverse events in the 2009 study were reported in 10 (30%) of 33 patients with early T-cell precursor acute lymphoblastic leukaemia versus 24 (15%) of 164 patients without early T-cell precursor acute lymphoblastic leukaemia and life-threatening events in induction phase IA occurred in 4 (12%) of 33 patients with early T-cell precursor acute lymphoblastic leukaemia versus 7 (4%) of 164 patients without early T-cell precursor acute lymphoblastic leukaemia. No difference was seen in the subsequent consolidation phase IB of protocol I. Interpretation: Early T-cell precursor acute lymphoblastic leukaemia is characterised by poor early response to conventional induction treatment. Consolidation phase IB, based on cyclophosphamide, 6-mercaptopurine, and ara-at conventional (non-high) doses is effective in reducing minimal residual disease. Although the number of patients and observational time are limited, patients with early T-cell precursor acute lymphoblastic leukaemia treated with current BFM stratification and treatment strategy have a favourable outcome compared with earlier reports. The role of innovative therapies and haemopoietic stem cell therapy in early T-cell precursor acute lymphoblastic leukaemia needs to be assessed. Funding: None.

Original languageEnglish
Pages (from-to)e80-e86
JournalThe Lancet Haematology
Volume3
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

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T-Lymphoid Precursor Cells
Berlin
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Residual Neoplasm
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Stem Cell Transplantation
Prednisone
Cyclophosphamide
Disease-Free Survival
Flow Cytometry
Therapeutics
Bone Marrow
CD34 Antigens
Proto-Oncogene Proteins c-kit
Asparaginase
6-Mercaptopurine
Polymerase Chain Reaction
Investigational Therapies
Hematology

ASJC Scopus subject areas

  • Hematology

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Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols : A retrospective analysis. / Conter, Valentino; Valsecchi, Maria Grazia; Buldini, Barbara; Parasole, Rosanna; Locatelli, Franco; Colombini, Antonella; Rizzari, Carmelo; Putti, Maria Caterina; Barisone, Elena; Nigro, Luca Lo; Santoro, Nicola; Ziino, Ottavio; Pession, Andrea; Testi, Anna Maria; Micalizzi, Concetta; Casale, Fiorina; Pierani, Paolo; Cesaro, Simone; Cellini, Monica; Silvestri, Daniela; Cazzaniga, Giovanni; Biondi, Andrea; Basso, Giuseppe.

In: The Lancet Haematology, Vol. 3, No. 2, 01.02.2016, p. e80-e86.

Research output: Contribution to journalArticle

Conter, V, Valsecchi, MG, Buldini, B, Parasole, R, Locatelli, F, Colombini, A, Rizzari, C, Putti, MC, Barisone, E, Nigro, LL, Santoro, N, Ziino, O, Pession, A, Testi, AM, Micalizzi, C, Casale, F, Pierani, P, Cesaro, S, Cellini, M, Silvestri, D, Cazzaniga, G, Biondi, A & Basso, G 2016, 'Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols: A retrospective analysis', The Lancet Haematology, vol. 3, no. 2, pp. e80-e86. https://doi.org/10.1016/S2352-3026(15)00254-9
Conter, Valentino ; Valsecchi, Maria Grazia ; Buldini, Barbara ; Parasole, Rosanna ; Locatelli, Franco ; Colombini, Antonella ; Rizzari, Carmelo ; Putti, Maria Caterina ; Barisone, Elena ; Nigro, Luca Lo ; Santoro, Nicola ; Ziino, Ottavio ; Pession, Andrea ; Testi, Anna Maria ; Micalizzi, Concetta ; Casale, Fiorina ; Pierani, Paolo ; Cesaro, Simone ; Cellini, Monica ; Silvestri, Daniela ; Cazzaniga, Giovanni ; Biondi, Andrea ; Basso, Giuseppe. / Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols : A retrospective analysis. In: The Lancet Haematology. 2016 ; Vol. 3, No. 2. pp. e80-e86.
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author = "Valentino Conter and Valsecchi, {Maria Grazia} and Barbara Buldini and Rosanna Parasole and Franco Locatelli and Antonella Colombini and Carmelo Rizzari and Putti, {Maria Caterina} and Elena Barisone and Nigro, {Luca Lo} and Nicola Santoro and Ottavio Ziino and Andrea Pession and Testi, {Anna Maria} and Concetta Micalizzi and Fiorina Casale and Paolo Pierani and Simone Cesaro and Monica Cellini and Daniela Silvestri and Giovanni Cazzaniga and Andrea Biondi and Giuseppe Basso",
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TY - JOUR

T1 - Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols

T2 - A retrospective analysis

AU - Conter, Valentino

AU - Valsecchi, Maria Grazia

AU - Buldini, Barbara

AU - Parasole, Rosanna

AU - Locatelli, Franco

AU - Colombini, Antonella

AU - Rizzari, Carmelo

AU - Putti, Maria Caterina

AU - Barisone, Elena

AU - Nigro, Luca Lo

AU - Santoro, Nicola

AU - Ziino, Ottavio

AU - Pession, Andrea

AU - Testi, Anna Maria

AU - Micalizzi, Concetta

AU - Casale, Fiorina

AU - Pierani, Paolo

AU - Cesaro, Simone

AU - Cellini, Monica

AU - Silvestri, Daniela

AU - Cazzaniga, Giovanni

AU - Biondi, Andrea

AU - Basso, Giuseppe

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Background: Early T-cell precursor acute lymphoblastic leukaemia was recently recognised as a distinct leukaemia and reported as associated with poor outcomes. We aimed to assess the outcome of early T-cell precursor acute lymphoblastic leukaemia in patients from the Italian Association of Pediatric Hematology Oncology (AIEOP) centres treated with AIEOP-Berlin-Frankfurt-Münster (AIEOP-BFM) protocols. Methods: In this retrospective analysis, we included all children aged from 1 to less than 18 years with early T-cell precursor acute lymphoblastic leukaemia immunophenotype diagnosed between Jan 1, 2008, and Oct 31, 2014, from AIEOP centres. Early T-cell precursors were defined as being CD1a and CD8 negative, CD5 weak positive or negative, and positive for at least one of the following antigens: CD34, CD117, HLADR, CD13, CD33, CD11b, or CD65. Treatment was based on AIEOP-BFM acute lymphoblastic leukaemia 2000 (NCT00613457) or AIEOP-BFM acute lymphoblastic leukaemia 2009 protocols (European Clinical Trials Database 2007-004270-43). The main differences in treatment and stratification of T-cell acute lymphoblastic leukaemia between the two protocols were that in the 2009 protocol only, pegylated L-asparaginase was substituted for Escherichia coli L-asparaginase, patients with prednisone poor response received an additional dose of cyclophosphamide at day 10 of phase IA, and high minimal residual disease at day 15 assessed by flow cytometry was used as a high-risk criterion. Outcomes were assessed in terms of event-free survival, disease-free survival, and overall survival. Findings: Early T-cell precursor acute lymphoblastic leukaemia was diagnosed in 49 patients. Compared with overall T-cell acute lymphoblastic leukaemia, it was associated with absence of molecular markers for PCR detection of minimal residual disease in 25 (56%) of 45 patients; prednisone poor response in 27 (55%) of 49 patients; high minimal residual disease at day 15 after starting therapy in 25 (64%) of 39 patients (bone marrow blasts ≥10%, by flow cytometry); no complete remission after phase IA in 7 (15%) of 46 patients (bone marrow blasts ≥5%, morphologically); and high PCR minimal residual disease (≥5 × 10-4) at day 33 after starting therapy in 17 (85%) of 20 patients with markers available. Overall, 38 (78%) of 49 patients are in continuous complete remission, including 13 of 18 after haemopoietic stem cell transplantation, with three deaths in induction, five deaths after haemopoietic stem cell transplantation, and three relapses. Severe adverse events in the 2009 study were reported in 10 (30%) of 33 patients with early T-cell precursor acute lymphoblastic leukaemia versus 24 (15%) of 164 patients without early T-cell precursor acute lymphoblastic leukaemia and life-threatening events in induction phase IA occurred in 4 (12%) of 33 patients with early T-cell precursor acute lymphoblastic leukaemia versus 7 (4%) of 164 patients without early T-cell precursor acute lymphoblastic leukaemia. No difference was seen in the subsequent consolidation phase IB of protocol I. Interpretation: Early T-cell precursor acute lymphoblastic leukaemia is characterised by poor early response to conventional induction treatment. Consolidation phase IB, based on cyclophosphamide, 6-mercaptopurine, and ara-at conventional (non-high) doses is effective in reducing minimal residual disease. Although the number of patients and observational time are limited, patients with early T-cell precursor acute lymphoblastic leukaemia treated with current BFM stratification and treatment strategy have a favourable outcome compared with earlier reports. The role of innovative therapies and haemopoietic stem cell therapy in early T-cell precursor acute lymphoblastic leukaemia needs to be assessed. Funding: None.

AB - Background: Early T-cell precursor acute lymphoblastic leukaemia was recently recognised as a distinct leukaemia and reported as associated with poor outcomes. We aimed to assess the outcome of early T-cell precursor acute lymphoblastic leukaemia in patients from the Italian Association of Pediatric Hematology Oncology (AIEOP) centres treated with AIEOP-Berlin-Frankfurt-Münster (AIEOP-BFM) protocols. Methods: In this retrospective analysis, we included all children aged from 1 to less than 18 years with early T-cell precursor acute lymphoblastic leukaemia immunophenotype diagnosed between Jan 1, 2008, and Oct 31, 2014, from AIEOP centres. Early T-cell precursors were defined as being CD1a and CD8 negative, CD5 weak positive or negative, and positive for at least one of the following antigens: CD34, CD117, HLADR, CD13, CD33, CD11b, or CD65. Treatment was based on AIEOP-BFM acute lymphoblastic leukaemia 2000 (NCT00613457) or AIEOP-BFM acute lymphoblastic leukaemia 2009 protocols (European Clinical Trials Database 2007-004270-43). The main differences in treatment and stratification of T-cell acute lymphoblastic leukaemia between the two protocols were that in the 2009 protocol only, pegylated L-asparaginase was substituted for Escherichia coli L-asparaginase, patients with prednisone poor response received an additional dose of cyclophosphamide at day 10 of phase IA, and high minimal residual disease at day 15 assessed by flow cytometry was used as a high-risk criterion. Outcomes were assessed in terms of event-free survival, disease-free survival, and overall survival. Findings: Early T-cell precursor acute lymphoblastic leukaemia was diagnosed in 49 patients. Compared with overall T-cell acute lymphoblastic leukaemia, it was associated with absence of molecular markers for PCR detection of minimal residual disease in 25 (56%) of 45 patients; prednisone poor response in 27 (55%) of 49 patients; high minimal residual disease at day 15 after starting therapy in 25 (64%) of 39 patients (bone marrow blasts ≥10%, by flow cytometry); no complete remission after phase IA in 7 (15%) of 46 patients (bone marrow blasts ≥5%, morphologically); and high PCR minimal residual disease (≥5 × 10-4) at day 33 after starting therapy in 17 (85%) of 20 patients with markers available. Overall, 38 (78%) of 49 patients are in continuous complete remission, including 13 of 18 after haemopoietic stem cell transplantation, with three deaths in induction, five deaths after haemopoietic stem cell transplantation, and three relapses. Severe adverse events in the 2009 study were reported in 10 (30%) of 33 patients with early T-cell precursor acute lymphoblastic leukaemia versus 24 (15%) of 164 patients without early T-cell precursor acute lymphoblastic leukaemia and life-threatening events in induction phase IA occurred in 4 (12%) of 33 patients with early T-cell precursor acute lymphoblastic leukaemia versus 7 (4%) of 164 patients without early T-cell precursor acute lymphoblastic leukaemia. No difference was seen in the subsequent consolidation phase IB of protocol I. Interpretation: Early T-cell precursor acute lymphoblastic leukaemia is characterised by poor early response to conventional induction treatment. Consolidation phase IB, based on cyclophosphamide, 6-mercaptopurine, and ara-at conventional (non-high) doses is effective in reducing minimal residual disease. Although the number of patients and observational time are limited, patients with early T-cell precursor acute lymphoblastic leukaemia treated with current BFM stratification and treatment strategy have a favourable outcome compared with earlier reports. The role of innovative therapies and haemopoietic stem cell therapy in early T-cell precursor acute lymphoblastic leukaemia needs to be assessed. Funding: None.

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