Adults with Philadelphia Chromosome–Like Acute Lymphoblastic Leukemia: Considerations for Allogeneic Hematopoietic Cell Transplantation in First Complete Remission

Abstract

A B S T R A C T Philadelphia chromosomeÀlike (Ph-like) acute lymphoblastic leukemia (ALL) is a subset of high-risk B cell ALLs. A large proportion of Ph-like ALL cases carry activating kinase mutations that could potentially allow them to be targeted by tyrosine kinase inhibitors. Ph-like ALL is not an uncommon entity, especially among adults, with a frequency exceeding 20%, including in older patients (>60 years old) with ALL. Ph-like ALL is associated with inferior outcomes across all ages, and studies have consistently shown a higher incidence of persistent postinduction minimal residual disease in patients carrying Ph-like ALL compared with other subgroups of ALL, and this translates into inferior leukemia-related outcomes. The inferior outcome of conventional chemotherapy for Ph-like ALL in adults raises the fundamental question of whether all adults with Ph-like ALL require an allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR1) regardless of other presenting features and treatment response parameters. Here we present and discuss several scenarios in which adults with Ph-like ALL underwent or were considered for HCT in CR1 for various reasons. Although the decision to proceed with HCT was clear and indisputable in some of these situations, in others we struggled with the decision to transplant in CR1 because of the lack of published data regarding the efficacy of allogeneic HCT as consolidation for Ph-like ALL. We emphasize the urgent need for developing well-designed studies to address this important question.

CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways

“…BCR-ABL1 is the most frequent fusion found concurrent with CRLF2 abnormalities; this condition confers an aggressive disease progression with clones resistant to treatment with ABL inhibitors [18,19]. CRLF2 rearrangements and overexpression are commonly determined in the BCR-ABL1-like B-ALL subtype, but not in B-ALL patients with recurrent gene fusions, who are not screened for CRLF2 abnormalities [10,[12][13][14][15][16][17][18][19]. This exclusion criterion could underestimate the frequency of patients with the coexistence of recurrent gene fusions, and CRLF2 rearrangements and overexpression.…”

“…According to our literature review, the coexistence of BCR-ABL1 fusion with CRLF2 rearrangements and overexpression could be more common in Mexican American patients (see supplementary material, Table S1). Therefore, it is essential to consider that ethnicity could influence these findings [13,18,19]. Another related fact is that the incidence of childhood B-ALL in Mexicans (79.8/million) is much higher compared to other populations [36,37], and Hispanic children have worse outcomes and the lowest survival rates [33,38,39].…”

“…In addition, overrepresentation of CRLF2 rearrangements and overexpression has been observed in the B-ALL Hispanic population [7]. Besides the natural history of each genetic subtype of B-ALL, the Mexican population's genetic background may impact patients' recurrence with the coexistence of CRLF2 abnormalities and recurrent gene fusions [7,18,19]. Further studies in a higher number of Mexican B-ALL patients and in non-Hispanic B-ALL populations must be performed to prove this hypothesis.…”

“…Notably, CRLF2 rearrangements concurrent with BCR-ABL1 confer to patients' resistance to the ABL pathway inhibitors; furthermore, some of these patients have been diagnosed as BCR-ABL1-like [18]. Interestingly, the coexistence of recurrent gene fusions with CRLF2 rearrangements in the same blast has been observed mostly in patients of Hispanic and Mexican American origin [18,19].…”

Philadelphia chromosome‐like acute lymphocytic leukemia: Perspectives on diagnosis

“…At this time, no standardized treatment approach has been developed for individuals with Ph‐L ALL, but it is an area of active investigation. Currently, patients with Ph‐L ALL who achieve remission and have persistently high levels of MRD+ are being recommended for allogeneic transplant in first remission due to the high risk of relapse with standard treatment approaches . One of the hopes for the future is that targeted kinase inhibitors and/or targeted immune therapies can be incorporated into frontline therapy for these patients and enhance relapse free survival rates.…”