Page 12 - 2021_06-Haematologica-web

Editorials
Philadelphia chromosome-like acute lymphoblastic leukemia. Still a pending matter
Josep-Maria Ribera
Clinical Hematology Department, ICO-Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Badalona and Universitat Autònoma de Barcelona, Spain
E-mail: JOSEP-MARIA RIBERA - jribera@iconcologia.net doi:10.3324/haematol.2020.270645
New genetic abnormalities affecting risk assess- ment and patient stratification have been reported in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) defining novel subtypes. Some of these subtypes have been included in the most recent World Health Organization classification.1 Almost 10 years ago, two independent studies identified a subset of pediatric ALL characterized by a specific gene expression profile similar to that of Philadelphia (Ph) chromosome-positive ALL.2,3 This novel ALL subtype, called Ph-like ALL or BCR-ABL1-like ALL, is a frequent ALL subtype that com- prises up to 15% of pediatric BCP-ALL. Its incidence reaches 25% in adolescents and young adults and 20% in adults and it is generally recognized as being associated with a poor prognosis at any age.4
Ph-like ALL is characterized by multiple genetic aberra- tions that converge on tyrosine kinase and cytokine receptor signaling pathways.5 According to the signaling pathway involved several subgroups have been defined. These include CRLF2 rearrangements or mutations, fusions involving ABL-class genes, Ras signaling path- ways and other less common fusions. Alterations in the CRLF2 gene are the most frequent and result in overex- pression of this gene and an increase of CRLF2 protein expression. Aberrant CRLF2 expression frequently co- occurs with JAK activating mutations or other mutations deregulating JAK/STAT signaling (e.g., IL7R mutations). Deregulation of JAK/STAT signaling may also be due to JAK2 or EPOR rearrangements or additional alterations
activating other JAK/STAT signaling genes. In turn, the subgroup of ABL-class fusions involving ABL1, ABL2, CSF1R and PDGFRB accounts for 15-20% of Ph-like ALL cases.
Since kinase-activating alterations are frequent in Ph- like ALL and most converge on clinically actionable sig- naling, there is great interest in the early identification of Ph-like patients, with the aim of improving the prognosis with the use of tyrosine kinase inhibitors (TKI). However, identification of Ph-like ALL is currently challenging, and appropriate assays are not yet available for use as routine diagnostic approaches.6
In this issue of Haematologica, Chiaretti et al. screened 88 BCP-ALL cases negative for the major fusion genes (BCR-ABL1, ETV6-RUNX1, TCF3-PBX1 and KTM2A) enrolled in the pediatric-inspired, measurable residual dis- ease (MRD)-driven GIMEMA LAL1913 front-line proto- col for adults with Ph-negative ALL in order to assess response to the treatment and prognosis.7 Twenty-eight of these 88 cases (31.8%) showed the Ph-like phenotype. Screening for Ph-like ALL was performed successfully using the “BCR/ABL1-like predictor” developed by the GIMEMA Group.8 This model is based on the identifica- tion of nine genes specifically overexpressed by adult Ph- like ALL cases and uses their expression values together with CRLF2 transcript quantification by real time quanti- tative polymerase chain reaction to build this predictive tool. This study showed that Ph-like patients had a lower complete response rate, event-free survival and disease-
Table 1. Clinical trials either specific for Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL patients) or including patients with Ph-like ALL*.
NCT number
02883049
02723994 03117751
02420717
03571321
03643276
02716233
03007147
03564470
Group
COG
COG SJCRH
MDACC
University of Chicago
AIEOP/BFM
Assistance Publique - Hôpitaux de Paris
COG
EsPhALL Nanfang Hospital
Guangzhou
Schedule
Dasatinib Ruxolitinib
Ruxolitinib
Dasatinib Ruxolitinib
Dasatinib
Ruxolitinib
Ruxolitinib
Bortezomib
Blinatumomab Imatinib
Imatinib
Chidamide
Dasatinib
Phase N patients planned or enrolled
3 5,956
2 170 2/3 1,000
2 92 1 15 3 5,000
3 1,578
3 700
2 120
Age (yrs)
1-30
1-21 1-18
≥10 18-39 ≤17
1-18
2-21
14-55
Status
Active, not recruiting
Recruiting Recruiting
Active, not recruiting Recruiting Recruiting
Recruiting
Recruiting
Unknown
1514
*Clinicaltrials .gov. accessed on November 28, 2020. COG: Children’s Oncology Group; SJCRH: Saint Jude Childrens Research Hospital; MDACC: MD Anderson Cancer Center; AIEOP: Associazione Italiana di Ematologia e Oncologia Pediatrica; BFM: Berlin-Frankfurt-Münster; EsPhALL: European PhALL Consortium; yrs: years.
haematologica | 2021; 106(6)