Impact of P190 and P210 BCR::ABL1 Chimeric Protein on Outcomes of Acute Lymphoblastic Leukemia at a Tertiary Center
Authors: Mohamed Ahmed N , Patel Meera , Zureigat Hadil , Nurse Daniel P. , Haddad Sara F , Zabor Emily C. , Bedelu Yohana B. , Chen Mark Jinan , Nakitandwe Joy , Molina John C. , Balderman Sophia , Jain Akriti G. , Singh Abhay , Mukherjee Sudipto , Gerds Aaron T. , Carraway Hetty E. , Advani Anjali S. , Mustafa Ali Moaath K. 
Published: December 2024

Background: The Philadelphia chromosome (Ph) is the most common cytogenetic abnormality in adult acute lymphoblastic leukemia (ALL) and results in three principal BCR::ABL1 fusion chimeric proteins: P190, P210, or P230. Due to poor response to conventional chemotherapy, Ph+ ALL was associated with poor outcomes. Since the introduction of tyrosine kinase inhibitors, outcomes have dramatically improved for this subset of patients. This analysis explores associations between BCR::ABL1 status (P190 vs P210 vs unmutated) and outcomes in ALL.

Methods: We conducted a single-center retrospective cohort study to investigate how BCR::ABL1 status impacts overall survival (OS), event-free survival (EFS), and the clinical response rate for ALL in adult patients (≥18 years) treated at Cleveland Clinic from 01/2017 to 08/2023. Baseline variables collected include demographics, comorbidities, ALL subtypes, cytogenetics, BCR::ABL1 status, next-generation sequencing, performance status, all treatment lines and responses, and follow-up data. Response to first-line treatment included composite complete response (CCR) (complete response (CR) + complete response with incomplete count recovery (CRi)) and measurable residual disease through flow cytometry (MRD-FC). Complete cytogenetic response at first response was defined as complete cytogenetic remission. BCR::ABL1 PCR response was assessed based on the difference in PCR level at baseline (day 0) and at response assessment (~day +30) and tested with Wilcoxon rank-sum. EFS was defined from the date of diagnosis to the date of refractoriness, progression, or death. OS was defined from the date of diagnosis to the date of death. The Kaplan-Meier method estimated survival probabilities, and the log-rank test was used to test for differences according to BCR::ABL1 status. Univariable and multivariable regression were used as appropriate.

Results: Out of 161 ALL patients treated during the study period, atotal of 148 patients were tested for BCR::ABL1 fusion at baseline, of those 119/148 (80%) had no BCR::ABL1 fusion ((Ph- ALL)), 11/148 (7.4%) had p210 mutation (P210+ ALL) and 18/148 (12.2%) had p190 mutation (P190+ ALL). The median ages for the three groups were 51, 57, and 64 years (P=0.07). B-subtype ALL was seen in 71%, 82%, and 100% of the Ph- ALL, P210+ ALL, and P190+ ALL groups, respectively (P&lt;0.01). TP53 mutation was seen exclusively in 11 patients of the Ph- ALL group (P&lt;0.01). IKZF1 deletions were seen in 3.9%, 0%, and 28% in Ph- ALL, P210+ ALL, and P190+ ALL groups, respectively (P=0.02).

On multivariable logistic regression, P210+ ALL (odds ratio (OR): 1.2, 95%CI: 0.23-9.21), and P190+ ALL (OR: 3.91, 95%CI: 0.85-30.7) were not more likely to have a CCR compared to Ph- ALL (reference) (P=0.2) to initial therapy. Similarly, there was no difference in cytogenetic remission between the three groups on multivariable regression (P=0.9). However, P210+ ALL was less likely to be in an MRD-FC negative state (OR:0.15, 95%CI: 0.01-0.92) compared to P190+ ALL (OR:4.26, 95%CI: 0.97-29.7) and Ph- ALL (reference). At response assessment, the BCR::ABL1 PCR dropped to ~ 2% in the P210+ ALL and &lt;0.01 in the P190+ ALL groups (both P&lt;0.05).

The median follow-up time for the study groups was 24.3 months (range: 0.5 - 74.3). On the multivariable Cox proportional hazards model, there was no difference in OS between P210+ ALL (Hazard ratio (HR: 0.88, 95%CI: 0.29-2.63), P190+ ALL (HR: 0.96, 95%CI: 0.44-2.09), or Ph- ALL (reference) (P&gt;0.9). Similarly, there was no difference in EFS between the comparison groups. When comparing Ph+ ALL (P190+P210) with Ph- ALL, there was no difference in response rate, OS, or EFS (P&gt;0.05).

Conclusions: Our findings show that Ph+ ALL patients had similar survival and responses to first-line therapy compared to Ph- ALL, though those with P210 were less likely to be in an MRD-negative state. Moreover, the average decrease in BCR::ABL1 PCR transcript was less in P210+ ALL, without compromise in their long-term survival compared to P190 +ALL and Ph- ALL. The poor prognosis historically associated with Ph+ ALL has improved with the introduction of tyrosine kinase inhibitor use.