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

C. Palmi; E. Vendramini; D. Silvestri; G. Longinotti; D. Frison; G. Cario; C. Shochat; M. Stanulla; V. Rossi; A. M. Di Meglio; T. Villa; E. Giarin; G. Fazio; A. Leszl; M. Schrappe; G. Basso; A. Biondi; S. Izraeli; V. Conter; M. G. Valsecchi; G. Cazzaniga; G. Te Kronnie

doi:10.1038/leu.2012.101

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

C. Palmi
, E. Vendramini
, D. Silvestri
, G. Longinotti
, D. Frison
, G. Cario
, C. Shochat
, M. Stanulla
, V. Rossi
, A. M. Di Meglio
, T. Villa
, E. Giarin
, G. Fazio
, A. Leszl
, M. Schrappe
, G. Basso
, A. Biondi
, S. Izraeli
, V. Conter
, M. G. Valsecchi

G. Cazzaniga, G. Te Kronnie

University of Milan - Bicocca
University of Padua
Azienda Ospedaliera San Gerardo Monza
University Hospital Schleswig-Holstein
Tel Aviv University
Migal Galilee Technology Center Israel
Ospedali Riuniti di Bergamo

Research output: Contribution to journal › Article › peer-review

113 Scopus citations

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.

Original language	English
Pages (from-to)	2245-2253
Number of pages	9
Journal	Leukemia
Volume	26
Issue number	10
DOIs	https://doi.org/10.1038/leu.2012.101
State	Published - Oct 2012
Externally published	Yes

Bibliographical note

Funding Information:
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.

Funding

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.

Funders
CARIPARO Project of Excellence
Fondazione Tettamanti
Madeleine-Schickedanz-Kinderkrebsstiftung
Fondazione Città della Speranza
Leukaemia UK
Fondazione Cariplo
Ministero dell’Istruzione, dell’Università e della Ricerca
Israel Science Foundation
Associazione Italiana per la Ricerca sul Cancro
Deutsche Krebshilfe

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

CRLF2
Pediatric BCP-ALL
Prognosis

Access to Document

10.1038/leu.2012.101

Cite this

Palmi, C., Vendramini, E., Silvestri, D., Longinotti, G., Frison, D., Cario, G., Shochat, C., Stanulla, M., Rossi, V., Di Meglio, A. M., Villa, T., Giarin, E., Fazio, G., Leszl, A., Schrappe, M., Basso, G., Biondi, A., Izraeli, S., Conter, V., ... Te Kronnie, G. (2012). 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(10), 2245-2253. https://doi.org/10.1038/leu.2012.101

@article{a60051c6a8b744c299ef48d89717bbf5,

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

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.",

keywords = "CRLF2, Pediatric BCP-ALL, Prognosis",

author = "C. Palmi and E. Vendramini and D. Silvestri and G. Longinotti and D. Frison and G. Cario and C. Shochat and M. Stanulla and V. Rossi and \{Di Meglio\}, \{A. M.\} and T. Villa and E. Giarin and G. Fazio and A. Leszl and M. Schrappe and G. Basso and A. Biondi and S. Izraeli and V. Conter and Valsecchi, \{M. G.\} and G. Cazzaniga and \{Te Kronnie\}, G.",

note = "Funding Information: This study was supported by grants from: Fondazione Citt{\`a} 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.",

year = "2012",

month = oct,

doi = "10.1038/leu.2012.101",

language = "אנגלית",

volume = "26",

pages = "2245--2253",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Springer Nature",

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Palmi, C, Vendramini, E, Silvestri, D, Longinotti, G, Frison, D, Cario, G, Shochat, C, Stanulla, M, Rossi, V, Di Meglio, AM, Villa, T, Giarin, E, Fazio, G, Leszl, A, Schrappe, M, Basso, G, Biondi, A, Izraeli, S, Conter, V, Valsecchi, MG, Cazzaniga, G & Te Kronnie, G 2012, 'Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic leukemia', Leukemia, vol. 26, no. 10, pp. 2245-2253. https://doi.org/10.1038/leu.2012.101

TY - JOUR

T1 - Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic leukemia

AU - Palmi, C.

AU - Vendramini, E.

AU - Silvestri, D.

AU - Longinotti, G.

AU - Frison, D.

AU - Cario, G.

AU - Shochat, C.

AU - Stanulla, M.

AU - Rossi, V.

AU - Di Meglio, A. M.

AU - Villa, T.

AU - Giarin, E.

AU - Fazio, G.

AU - Leszl, A.

AU - Schrappe, M.

AU - Basso, G.

AU - Biondi, A.

AU - Izraeli, S.

AU - Conter, V.

AU - Valsecchi, M. G.

AU - Cazzaniga, G.

AU - Te Kronnie, G.

N1 - Funding Information: 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.

PY - 2012/10

Y1 - 2012/10

N2 - 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.

AB - 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.

KW - CRLF2

KW - Pediatric BCP-ALL

KW - Prognosis

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AN - SCOPUS:84867404417

SN - 0887-6924

VL - 26

SP - 2245

EP - 2253

JO - Leukemia

JF - Leukemia

IS - 10

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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Cite this