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Acute Leukemias

Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic leukemia

Leukemia volume 26, pages 2245–2253 (2012)Cite this article

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Abstract

Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has achieved an 80% cure rate as a result of a risk-adapted therapy largely based on minimal residual disease (MRD) monitoring. However, relapse is still the most frequent adverse event, occurring mainly in the patients with intermediate MRD levels (intermediate risk, IR), emphasizing the need for new prognostic markers. We analyzed the prognostic impact of cytokine receptor-like factor 2 (CRLF2) over-expression and P2RY8-CRLF2 fusion in 464 BCP-ALL patients (not affected by Down syndrome and BCR-ABL negative) enrolled in the AIEOP-BFM ALL2000 study in Italy. In 22/464 (4.7%) samples, RQ-PCR showed CRLF2 over-expression (⩾20 times higher than the overall median). P2RY8-CRLF2 fusion was detected in 22/365 (6%) cases, with 10/22 cases also showing CRLF2 over-expression. P2RY8-CRLF2 fusion was the most relevant prognostic factor independent of CRLF2 over-expression with a threefold increase in risk of relapse. Significantly, the cumulative incidence of relapse of the P2RY8-CRLF2+ patients in the IR group was high (61.1%±12.9 vs 17.6%±2.6, P<0.0001), similar to high-risk patients in AIEOP-BFM ALL2000 study. These results were confirmed in a cohort of patients treated in Germany. In conclusion, P2RY8-CRLF2 identifies a subset of BCP-ALL patients currently stratified as IR that could be considered for treatment intensification.

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Acknowledgements

This study was supported by grants from: Fondazione Città della Speranza (Padova), Fondazione Tettamanti (Monza), Associazione Italiana Ricerca sul Cancro (AIRC; to GteK, GB, GiC, AB and MGV), CARIPARO Project of Excellence (to GteK, EV and DF), MIUR (to AB and GB), Fondazione Cariplo (to AB and GiC), Deutsche Krebshilfe (to GuC, MSt and MSc), Madeleine-Schickedanz-Kinderkrebsstiftung (to GuC, MSt and MSc), Israel Science Foundation Legacy Program and Children with Leukaemia UK (to SI). We thank Simona Songia, Lilia Corral, Valentina Carrino, Eugenia Mella (Monza), Elena Seganfreddo and Katia Polato (Padova) for AIEOP MRD monitoring; Silvia Bungaro and Marta Galbiati (Monza) for cytogenetics and FISH; all medical doctors of the AIEOP and BFM centers.

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Author notes

  1. C Palmi, E Vendramini, M G Valsecchi, G Cazzaniga and G te Kronnie: These authors contributed equally to this work.

Authors and Affiliations

  1. Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano Bicocca, Ospedale San Gerardo, Monza, Italy

    C Palmi, G Longinotti, V Rossi, T Villa, G Fazio & G Cazzaniga

  2. Department of Pediatrics, Laboratory of Oncohematology, Università di Padova, Padova, Italy

    E Vendramini, D Frison, A M Di Meglio, E Giarin, A Leszl, G Basso & G te Kronnie

  3. Centro di Biostatistica per l’Epidemiologia Clinica, Università di Milano Bicocca, Monza, Italy

    D Silvestri & M G Valsecchi

  4. Clinica Pediatrica, Università di Milano Bicocca, Ospedale San Gerardo, Monza, Italy

    D Silvestri, A Biondi & V Conter

  5. Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

    G Cario, M Stanulla & M Schrappe

  6. Sheba Medical Center, Tel Hashomer, Ramat Gan and Tel Aviv University, Tel Aviv, Israel

    C Shochat & S Izraeli

  7. Migal-Galilee Bio-Technology Center, Kiryat-Shmona, Israel

    C Shochat

  8. Pediatria, Ospedali Riuniti, Bergamo, Italy

    V Conter

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  1. C Palmi
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Corresponding author

Correspondence to G Cazzaniga.

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The authors declare no conflict of interest.

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Author contributions

CP, GL, EV, DF and CS performed the molecular analyses on CRLF2 aberrations and additional genetic mutations; CP, EV and SI collaborated in writing the manuscript; DS and MGV collected the Trial data and performed all the statistical analyses; AMDM and AL performed cytogenetic analyses; VR, GF and TV represent the team that performed Trial molecular and MRD analyses; GB and AB supervised the research; EG performed DNA/RNA extraction and cell banking; VC is responsible of the AIEOP ALL2000 study; MSc, MSt and GuC provided the data of the BFM-G patients; GiC and GtK designed the study, supervised the research, analyzed data and wrote the manuscript.

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Palmi, C., Vendramini, E., Silvestri, D. et al. Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic leukemia. Leukemia 26, 2245–2253 (2012). https://doi.org/10.1038/leu.2012.101

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