PROGNOSTIC SIGNIFICANCE OF IKZF1 ALTERATIONS IN ADULT B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA. POTENTIAL OF HARMONY ALLIANCE BIG DATA ANALYSIS FOR PRECISON MEDICINE
Author(s): ,
Jordi Ribera
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
,
Mireia Morgades
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
,
Lurdes Zamora
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
,
Susana Vives
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
,
Montserrat Batlle
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
,
Anna Torrent
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
,
Eduardo Cerello Chachap
Affiliations:
Israelita Albert Einstein – Dayan-Daycoval Family Hematology and Oncology Center,Sao Paulo,Brazil
,
Olga Garcia
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
,
Mar Mallo
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
,
Isabel Granada
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
,
Neus Ruiz-Xivillé
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
,
Nuri de Haro
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
,
Rosa Coll
Affiliations:
ICO-Hospital Josep Trueta,Girona,Spain
,
Santiago Mercadal
Affiliations:
ICO-Hospital Duran i Reynals,Hospitalet de Llobregat,Spain
,
Lourdes Escoda
Affiliations:
ICO-Hospital Joan XXIII,Tarragona,Spain
,
Pau Montesinos
Affiliations:
Hospital Universitari i Politècnic La Fe,València,Spain
,
Inés Gómez-Seguí
Affiliations:
Hospital Universitari i Politècnic La Fe,València,Spain
,
Marta Pratcorona
Affiliations:
Josep Carreras Leukaemia Research Institute, Hospital de Sant Pau,Barcelona,Spain
,
Josep Nomdedeu
Affiliations:
Josep Carreras Leukaemia Research Institute, Hospital de Sant Pau,Barcelona,Spain
,
Mar Tormo
Affiliations:
Hospital Clínico Universitario,València,Spain
,
Joaquín Martínez-López
Affiliations:
Hospital Universitario Doce de Octubre,Madrid,Spain
,
Pere Barba
Affiliations:
Hospital Universitari Vall d'Hebrón,Barcelona,Spain
,
Jordi Esteve
Affiliations:
Hospital Clínic,Barcelona,Spain
,
José González-Campos
Affiliations:
Hospital Universitario Virgen del Rocío,Sevilla,Spain
,
Juana Ciudad
Affiliations:
Hospital Universitario de Salamanca, Universidad de Salamanca, IBMCC (CSIC/USAL), IBSAL and CIBERONC,Salamanca,Spain
,
Celia González-Gil
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
,
Eulàlia Genescà
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
,
Francesc Solé
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
,
Evarist Feliu
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
,
Alberto Orfao
Affiliations:
Hospital Universitario de Salamanca, Universidad de Salamanca, IBMCC (CSIC/USAL), IBSAL and CIBERONC,Salamanca,Spain
,
Jesús María Hernández-Rivas
Affiliations:
Hospital Universitario de Salamanca, Universidad de Salamanca, IBMCC (CSIC/USAL), IBSAL and CIBERONC,Salamanca,Spain
Josep Maria Ribera
Affiliations:
Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona,Badalona,Spain
EHA Library. Ribera J. 06/12/20; 294292; EP373
Jordi Ribera
Jordi Ribera
Contributions
Abstract

Abstract: EP373

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background

The use of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) has contributed to increase survival, especially in children and AYA. However, although being the strongest prognostic factor in ALL, MRD is not predictive and precise enough as one third of patients with good MRD response at the end of induction relapse and need alternative therapies, whose effectiveness is again evaluated by MRD.

Aims

In an attempt to identify prognostic markers not covered by MRD, the Spanish PETHEMA Group has sent a proposal to the HARMONY Alliance on behalf of the EWALL Group. This proposal was approved by HARMONY on September 2019. Ten European adult ALL study groups (UKALL, NOPHO, GIMEMA, CLSG, HOVON, GRAALL, GMALL, PALG, RALL and PETHEMA) will participate by sending datasets to HARMONY. As the primary objective of this proposal is to evaluate if IKZF1 alterations have prognostic significance independent of MRD, the key inclusion criteria is that patients must have been treated within clinical trials with MRD determinations. 

Methods
Herein we present a pilot study including patients from PETHEMA protocols analyzed by MLPA and/or SNP array. MRD was centrally measured by multiparemtric flow cytometry.

Results

One hundred and fifty-two adult BCP ALL patients (110 Ph-negative and 42 Ph+, median age 40 [15-72] years) were included. Ph+ ALL patients showed significantly older age (52 [20;72] vs. 36 [15;68] years, p<0.001) and higher frequency of IKZF1 deletions (26/42 [62%] vs. 36/109 [33%], p=0.001) than those with Ph-negative ALL. The profile of deletions significantly differed between both groups, with homozygous and dominant negative (DN) heterozygous deletions (i.e., Ik6) being significantly more prevalent in the Ph+ than in the Ph-negative subset. Interestingly, the presence of IKZF1 partial gene deletions (DN and loss of exons 2 or 8 leading to haploinsufficiency) was significantly more prevalent among patients with CD34+ ALL than in patients with CD34- ALL (22/25 partial IKZF1 and CD34+ vs. 3/25 IKZF1 partial and CD34-, p=0.009). Regarding treatment response, IKZF1 deletions were not markers of resistance neither for CR achievement nor for achieving low MRD level (<0.01%) at the end of induction (End-Ind) in the whole series. Ph-negative patients with low End-Ind MRD showed better overall survival (OS) than MRD+ individuals (5-year OS 52% [36%;68%] vs. 32% [16%;48%], p=0.076). Patients with IKZF1 deletions or with IKZF1plus signature did not show significantly lower OS than patients without these abnormalities. Ph-negative ALL patients with IKZF1 partial gene deletions significantly experienced more relapses than those without Ikaros losses, while patients with whole gene deletions experienced similar relapse probability than WT individuals (81% [41%;95%] partial vs. 43% [30%;56%] WT vs. 18% [2%;46%] whole gene, p=0.009). When combining IKZF1 status and MRD, patients with IKZF1 partial losses and low MRD levels showed a 5-year CIR of 79% (6%;98%)(Figure). All patients with IKZF1 partial deletions died due to disease progression (5-year Non-relapse mortality 0% partial  vs. 17% [9%;27%] WT, p=0.065). Multivariable analysis in Ph-negative subset identified age, WBC count and End-Ind MRD as independent prognostic factors for OS while for CIR showed WBC (significant) and IKZF1 partial gene deletions showed a trend towards higher risk of relapse (p=0.100).

Conclusion

This pilot study does not show an independent influence of IKZF1 deletion on outcome of adult Ph-negative ALL patients, despite this deletion was associated with higher relapse probability. 

Session topic: 01. Acute lymphoblastic leukemia - Biology & Translational Research

Keyword(s): B cell acute lymphoblastic leukemia, Ikaros, MRD

Abstract: EP373

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background

The use of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) has contributed to increase survival, especially in children and AYA. However, although being the strongest prognostic factor in ALL, MRD is not predictive and precise enough as one third of patients with good MRD response at the end of induction relapse and need alternative therapies, whose effectiveness is again evaluated by MRD.

Aims

In an attempt to identify prognostic markers not covered by MRD, the Spanish PETHEMA Group has sent a proposal to the HARMONY Alliance on behalf of the EWALL Group. This proposal was approved by HARMONY on September 2019. Ten European adult ALL study groups (UKALL, NOPHO, GIMEMA, CLSG, HOVON, GRAALL, GMALL, PALG, RALL and PETHEMA) will participate by sending datasets to HARMONY. As the primary objective of this proposal is to evaluate if IKZF1 alterations have prognostic significance independent of MRD, the key inclusion criteria is that patients must have been treated within clinical trials with MRD determinations. 

Methods
Herein we present a pilot study including patients from PETHEMA protocols analyzed by MLPA and/or SNP array. MRD was centrally measured by multiparemtric flow cytometry.

Results

One hundred and fifty-two adult BCP ALL patients (110 Ph-negative and 42 Ph+, median age 40 [15-72] years) were included. Ph+ ALL patients showed significantly older age (52 [20;72] vs. 36 [15;68] years, p<0.001) and higher frequency of IKZF1 deletions (26/42 [62%] vs. 36/109 [33%], p=0.001) than those with Ph-negative ALL. The profile of deletions significantly differed between both groups, with homozygous and dominant negative (DN) heterozygous deletions (i.e., Ik6) being significantly more prevalent in the Ph+ than in the Ph-negative subset. Interestingly, the presence of IKZF1 partial gene deletions (DN and loss of exons 2 or 8 leading to haploinsufficiency) was significantly more prevalent among patients with CD34+ ALL than in patients with CD34- ALL (22/25 partial IKZF1 and CD34+ vs. 3/25 IKZF1 partial and CD34-, p=0.009). Regarding treatment response, IKZF1 deletions were not markers of resistance neither for CR achievement nor for achieving low MRD level (<0.01%) at the end of induction (End-Ind) in the whole series. Ph-negative patients with low End-Ind MRD showed better overall survival (OS) than MRD+ individuals (5-year OS 52% [36%;68%] vs. 32% [16%;48%], p=0.076). Patients with IKZF1 deletions or with IKZF1plus signature did not show significantly lower OS than patients without these abnormalities. Ph-negative ALL patients with IKZF1 partial gene deletions significantly experienced more relapses than those without Ikaros losses, while patients with whole gene deletions experienced similar relapse probability than WT individuals (81% [41%;95%] partial vs. 43% [30%;56%] WT vs. 18% [2%;46%] whole gene, p=0.009). When combining IKZF1 status and MRD, patients with IKZF1 partial losses and low MRD levels showed a 5-year CIR of 79% (6%;98%)(Figure). All patients with IKZF1 partial deletions died due to disease progression (5-year Non-relapse mortality 0% partial  vs. 17% [9%;27%] WT, p=0.065). Multivariable analysis in Ph-negative subset identified age, WBC count and End-Ind MRD as independent prognostic factors for OS while for CIR showed WBC (significant) and IKZF1 partial gene deletions showed a trend towards higher risk of relapse (p=0.100).

Conclusion

This pilot study does not show an independent influence of IKZF1 deletion on outcome of adult Ph-negative ALL patients, despite this deletion was associated with higher relapse probability. 

Session topic: 01. Acute lymphoblastic leukemia - Biology & Translational Research

Keyword(s): B cell acute lymphoblastic leukemia, Ikaros, MRD

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