[ICKSH 2025] ‘Ph-like ALL treatment paradigm shifting toward molecularly guided immuno- and targeted therapy’

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-cell precursor ALL, first identified in 2009.

Although it lacks the BCR::ABL1 fusion gene characteristic of Philadelphia chromosome-positive ALL, it exhibits a similar gene expression profile and is associated with poor prognosis. Its prevalence increases with age, affecting up to 25 percent of adolescents and young adults (AYA) with ALL.

During the International Congress of the Korean Society of Hematology (ICKSH) 2025, held at Grand Walkerhill Seoul from March 27 to 29, Professor Thai Hoa Tran of the University of Montreal presented a session, titled, “Diagnosis and treatment of Ph-like in children and young adults.” In his lecture, he provided an in-depth look into the molecular diversity of Ph-like ALL and the current challenges in both its diagnosis and treatment.

“Ph-like ALL is not a single disease — it represents a heterogeneous group defined by kinase-activating alterations, and that makes diagnosis quite complicated,” Tran said.

According to the landmark study by Roberts et al. (NEJM, 2014), over 90 percent of Ph-like ALL cases harbor structural alterations in kinase genes, with CRLF2 rearrangements and JAK/STAT pathway fusions being the most frequent.

Tran underscored the limitations of current diagnostic access.

“Ideally, every center would use NGS-based fusion panels to detect the wide array of rearrangements, but cost and infrastructure remain real-world barriers,” he said.

As a more feasible interim approach, he recommended that combining sequencing for ABL-class fusions with FISH testing for CRLF2 alterations to maximize detection while balancing resources.

On the treatment front, Professor Tran noted that while tyrosine kinase inhibitors (TKIs), including JAK inhibitors, are biologically appealing, their survival benefit has yet to be conclusively proven in frontline settings.

“We don’t yet have definitive evidence that adding targeted agents improves outcomes in newly diagnosed patients — that’s where ongoing trials come in,” he said.

He highlighted the potential of immunotherapies such as blinatumomab and inotuzumab, which have shown high remission and MRD-negative rates in relapsed/refractory patients.

“These therapies are redefining our approach to high-risk ALL,” he said. “Their integration into upfront regimens is the next frontier.”

Currently, the Children’s Oncology Group (COG) is running prospective trials such as AALL1732 (testing blinatumomab plus inotuzumab in ABL-class fusion-negative patients) and AALL1521 (investigating ruxolitinib in CRLF2/JAK-mutated disease).