Outcomes of allogeneic hematopoietic cell transplantation in adults with fusions associated with Ph-like ALL

Abstract

Allogenic hematopoietic cell transplantation (alloHCT) is a well-established curative modality for adults with high-risk ALL; yet large data describing alloHCT outcomes in Philadelphia (Ph)-like ALL is lacking. We retrospectively analyzed archived DNA samples from consecutive adults with B-cell Ph-negative ALL who underwent alloHCT in complete remission (CR) (n= 127) at our center between 2006 and 2020. Identification of fusions associated with Ph-like were performed using accumulative results from RNAseq, conventional cytogenetics, FISH, and whole genome array studies. Fusions associated with Ph-like were detected in 56 (44%) patients, of whom 38 were carrying CRLF2r; and the rest (n=18) were non-CRLF2r. Compared to other non-Ph-like (n=71), patients with fusions associated with Ph-like ALL were more frequently Hispanic (P=0.008), less frequently carried high-risk cytogenetics (P<0.001), and more likely to receive blinatumomab prior to HCT (P=0.019). With the median follow-up of 3.5 years, patients with Ph-like ALL fusions had comparable post-transplant outcomes compared to other B-cell ALL: 3-year relapse-free survival (RFS) [41% vs. 44%, P=0.36], overall survival (OS) [51% vs. 50%, P=0.59] and relapse [37% vs. 31%, P=0.47]. In multivariable analysis, age (P= 0.023), disease status at the time of transplant (P<0.001), and donor type (P=0.015) influenced OS. RFS (primary endpoint) was significantly influenced by disease status (P<0.001) and conditioning regimen intensity (P=0.014). Relapse rate was associated with disease status (P=0.028) and conditioning regimen intensity (P=0.028). In conclusion, our data suggest that alloHCT consolidation results in similarly favorable survival outcomes in adult patients with Ph-like fusions and other high-risk B-cell ALL.

Characterization of Philadelphia-like Pre-B Acute Lymphoblastic Leukemia: Experiences in Mexican Pediatric Patients

“…Patients with Ph-like ALL show higher risks of induction failure, with high post-induction minimal residual disease levels when treated with conventional chemotherapy regimens. This poor early response translates into a lower overall survival [ 3 , 4 , 5 ]. However, preclinical studies and case reports indicate that Ph-like patients might benefit from clinical trials, including kinase inhibitors [ 1 ].…”

High response rates and transition to transplant after novel targeted and cellular therapies in adults with relapsed/refractory acute lymphoblastic leukemia with Philadelphia‐like fusions

“…Response to each of the three therapies as initial salvage cannot be determined accurately from this cohort since we included patients treated sequentially with novel therapies, whereby the majority of blinatumomab recipients were naïve for other novel drugs in contrast to InO and CAR T cells recipients who were more heavily pretreated and frequently had already failed blinatumomab. In addition, the rate of consolidation with allogeneic HCT was high among responders, and this may have abrogated the individual effect of novel therapy on remission durability among responders with Ph‐like fusions 5 …”

“…Philadelphia (Ph)‐like acute lymphoblastic leukemia (ALL) is a high‐risk genomic subgroup of B‐cell ALL that occurs across the lifespan and comprises up to 20% of all newly diagnosed adults with B‐cell ALL 1–6 . It is predominantly prevalent in Latinos, especially Guatemalans of Native American Ancestry 1,3,5,7,8 .…”

“…Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk genomic subgroup of B-cell ALL that occurs across the lifespan and comprises up to 20% of all newly diagnosed adults with B-cell ALL. [1][2][3][4][5][6] It is predominantly prevalent in Latinos, especially Guatemalans of Native American Ancestry. 1,3,5,7,8 Ph-like ALL encompasses several genetically defined subtypes; collectively, they are characterized by a gene expression profile similar to Ph-chromosome positive (Ph+) ALL, but they lack the BCR::ABL1 fusion.…”

“…[1][2][3][4][5][6] It is predominantly prevalent in Latinos, especially Guatemalans of Native American Ancestry. 1,3,5,7,8 Ph-like ALL encompasses several genetically defined subtypes; collectively, they are characterized by a gene expression profile similar to Ph-chromosome positive (Ph+) ALL, but they lack the BCR::ABL1 fusion. 2 The majority of Ph-like ALL cases harbor unique recurrent gene fusions, and rearrangements in the Cytokine Receptor Like Factor 2 (CRLF2) represent the most commonly encountered alterations, which are classically partnered with either IGH or P2RY8.…”