Assessing Philadelphia-Like B-Cell ALL in a Largely Hispanic Population

Acute lymphoblastic leukemia (ALL) is a heterogenous malignancy with unique genetic drivers. Understanding these genetic drivers allows for further understanding of disease pathogenesis, prognosis, and development of treatments, and this also helps to predict the response patients may have to those treatments. Philadelphia chromosome (Ph)–like ALL is a subtype of Ph-like B-cell ALL (B-ALL) that contains a gene expression similar to Ph-positive ALL, with an important distinction where there is a lack of the BCR::ABL fusion gene. Ph-like ALL comprises approximately 20% to 30% of all adults with newly diagnosed Ph-like B-ALL in the United States.^1,2 Even though the incidence of Ph-like ALL varies among ethnic groups, there are studies that indicate it is predominantly prevalent in Hispanic and Latino populations.³ For example, at The University of Texas MD Anderson Cancer Center in Houston and City of Hope National Medical Center in Duarte, California, Latino patients represent approximately 60% to 80% of all patients with Ph-like ALL.2,3 One important linkage between the increased incidence of Ph-like ALL in Hispanic patients is an inherited GATA3 (rs3824662) gene polymorphism.³

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Due to the observation in previous studies and publications of an increased prevalence of Ph-like ALL and its similarity to Ph-like B-ALL, this study had the objective of further evaluating the clinical and genomic characteristics of Ph-like B-ALL in the Hispanic population. To successfully evaluate Ph-like B-ALL clinical and genomic characteristics in a predominantly Hispanic population, a retrospective chart review was used. The chart review consisted of patients with ALL at the USC Norris Comprehensive Cancer Center in Los Angeles, California, who received treatment from 2011 through 2023. Results from 3 different diagnostic techniques were used, including RNA sequencing, conventional cytogenetics, and fluorescence in situ hybridization with reflex gene fusion transcript analysis. These provided the identification of fusions that are associated with Ph-like B-ALL. The anchored multiplex polymerase chain reaction detected known and novel fusions, in addition to elevated gene expression levels. Significant evaluations also made in this study included the cumulative incidence of relapse (CIR), overall survival (OS), and event-free survival (EFS; relapse, treatment, failure, and death).

Results

A total of 253 patients were enrolled in this retrospective chart review, with a median age at diagnosis of 42 years (range, 18-80). The distribution of ALL subtypes consisted of 64 Ph-like (25.3%), 77 Ph-positive (30.4%), and 112 Ph-negative cases (44.3%). The majority of the participants were identified as Hispanic (n = 186; 73.5%), and the median follow-up duration was 27 months. Over a 3-year period, OS, EFS, and CIR were reported at 81.3%, 49.1%, and 39.9%, respectively.⁴

CRLF2-related mutations were identified in 44 (68.8%) Ph-like patients, comprising 9 with P2RY8-CRLF2 (14.0%), 24 with IGH-CRLF2 (37.5%), and 11 with other CRLF2 gene rearrangements (17.2%). Additionally, 19 Ph-like patients exhibited non-CRLF2 mutations, including 13 IGH (20.3%), 3 ABL1/2 (4.7%), 3 JAK2 (4.7%), and 1 EPOR rearrangement (1.6%).⁴

In comparison with patients who are Ph negative, those with Ph-like features were more prone to refractory disease (20.6% vs 6.2%; P = .006), had a higher necessity for blinatumomab (Blincyto; Amgen; 67.2% vs 39.3%; P < .001), and were accompanied by a nonsignificant tendency toward lower complete remission (CR) rates. Ph-like patients exhibited significantly poorer EFS while maintaining similar OS and CIR. Patients who were Ph positive displayed improved EFS compared with Ph-negative cases, similar OS, and a trend toward enhanced CIR. When adjusting for age, sex, and treatment type, Ph-like patients exhibited worse EFS (HR, 1.57; 95% CI, 1.03-2.41; P = .037), whereas patients who were Ph positive demonstrated improved EFS (HR, 0.56; 95% CI, 0.33-0.93; P = .026).⁴

In the subgroup analysis of Ph-like patients, cases with CRLF2-related mutations were associated with a poorer CIR (HR, 5.68; 95% CI, 1.91-16.9; P = .002), with OS (P = .99) and EFS (P = .18) remaining similar. PAX5 expression emerged as a predictor of unfavorable OS (HR, 8.89; 95% CI, 1.06-74.7; P = .044) and EFS (HR, 2.51; 95% CI, 1.09-5.77; P = .031), accompanied by a tendency toward increased CIR (HR, 2.30; 95% CI, 0.92-5.78; P = .075). In comparison with non-CRLF2 mutations, CRLF2 Ph-like cases exhibited a worse CIR (HR, 5.68; 95% CI, 1.91-16.9; P = .002). Relative to Ph-like patients achieving minimal residual disease (MRD) negativity during induction, those remaining MRD positive had a worse CIR (HR, 2.92; 95% CI, 1.23-6.94; P = .015) and EFS (HR, 4.32; 95% CI, 1.890-9.84; P < .001). However, after adjusting for blinatumomab administration, the effect diminished (CIR: P = .73; EFS: P = .28). No differences were observed in EFS (P = .34), CIR (P = .69), and OS (P = .36) between transplanted and nontransplanted Ph-like patients.⁴

Discussion

The findings of this study underscore the significance of Ph-like B-ALL as a high-risk subtype in adult B-ALL, characterized by compromised EFS and a notable incidence of treatment failure. The study revealed that CRLF2 translocation was identified as a significant factor associated with adverse outcomes within the Ph-like subgroup. Patients with CRLF2-related mutations demonstrated a higher CIR and poorer EFS, indicating the need for targeted therapeutic interventions tailored to this specific molecular profile. The observed trends in refractory disease and increased demand for blinatumomab in Ph-like patients compared with patients who are Ph negative emphasize the clinical challenges associated with managing this high-risk subgroup. The nonsignificant trend toward lower CR rates in Ph-like patients further underscores the complexity of achieving optimal treatment responses.

The identification of 253 patients, with a median age at diagnosis of 42 years, highlights the clinical relevance of exploring the characteristics and outcomes associated with Ph-like B-ALL. The clinical relevance associated with Ph-like B-ALL prompts for deeper delving into the molecular intricacies that underlie the pathogenesis of this subtype. Unraveling the molecular landscape may uncover novel therapeutic targets, paving the way for the development of more effective and targeted interventions. Moreover, a comprehensive exploration of patient characteristics may unveil potential biomarkers that could aid in early diagnosis and risk stratification.⁵ This study contributes not only to the quantitative understanding of survival outcomes but also to the qualitative appreciation of the challenges posed by Ph-like B-ALL. In doing so, a paradigm shift is prompted in the approach to diagnosis and management, emphasizing the imperative need to consider the intricate interplay between genetic aberrations, clinical manifestations, and treatment responses.

Conclusion

This retrospective study shed light on the high-risk nature of Ph-like B-ALL. The identification of CRLF2 translocation as a key determinant of adverse outcomes within the Ph-like subgroup underscores the importance of refining risk stratification and treatment approaches for this specific molecular subtype. This study contributes to the growing body of evidence supporting the need for personalized therapeutic strategies in the management of high-risk B-ALL subtypes. The identification of CRLF2 translocation as a prognostic marker prompts further investigation into its mechanistic implications and opens avenues for the development of targeted interventions aimed at improving outcomes for patients with Ph-like B-ALL.

How Does This Impact Pharmacists?

In light of the latest studies, the role of oncology pharmacists continues to evolve in areas such as stem cell transplant, hematology, and precision medicine. For instance, Ph-like ALL subtype encompasses a diverse array of genetic alterations involving various kinases, cytokine receptors, and signaling pathways. As a result, the role of the oncology pharmacist in managing Ph-like ALL has evolved in several key ways, such as understanding heterogeneity, interpreting genetic testing results, and navigating the targeted therapies.^4,6

The Role of the Pharmacist

In the dynamic landscape of hematological malignancies, with particular focus on Ph-like B-ALL, recent studies have uncovered critical insights that distinctly underscore the indispensable role of oncology pharmacists in clinical settings^4,6:

1. Precision medicine implementation in tyrosine kinase inhibitor (TKI) selection and management: The advent of targeted therapies, especially TKIs, necessitates the nuanced approach in treatment decisions for Ph-like ALL. Oncology pharmacists are pivotal in interpreting genomic data, advising on TKI selection, proficiently managing associated complexities, and ensuring optimal therapeutic outcomes.
2. Pharmacovigilance and adverse event management for blinatumomab: As novel therapies like blinatumomab gain prominence, pharmacovigilance becomes paramount. Oncology pharmacists play a critical role in monitoring therapy responses and identifying and managing adverse events such as cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome. Their expertise ensures the safe administration of these therapies, minimizing potential risks and optimizing patient safety.
3. Patient education and empowerment: Armed with intricate knowledge of TKIs and novel therapies, oncology pharmacists serve as educators, breaking down complex genetic findings and treatment intricacies for patient comprehension. This empowers patients to actively participate in their care plans and fosters a collaborative approach to treatment decisions.
4. Facilitating clinical trial access: Oncology pharmacists are instrumental in facilitating patient access to clinical trials exploring targeted therapies for Ph-like ALL, including those involving TKIs. They provide comprehensive information, enabling patients to make informed decisions about participating in trials that may offer innovative therapeutic options.
5. Collaborative care optimization in policy creation: Positioned at the intersection of health care teams, pharmacists actively engage in multidisciplinary discussions to formulate and implement policies that optimize the integration of TKIs and other novel therapies within comprehensive care plans. This ensures cohesive and standardized approaches to treatment strategies.
6. Continuous professional development: The rapidly evolving landscape of Ph-like ALL demands ongoing education for oncology pharmacists. Continuous professional development is imperative for staying abreast of emerging therapeutic modalities, including the latest advancements in TKI therapies, enabling pharmacists to provide state-of-the-art patient care.

References

1. Roberts KG, Gu Z, Payne-Turner D, et al. High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults. J Clin Oncol. 2017;35(4):394-401. doi:10.1200/JCO.2016.69.0073

2. Jain N, Roberts KG, Jabbour E, et al. Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. Blood. 2017;129(5):572-581. doi:10.1182/blood-2016-07-726588

3. Aldoss I, Gu Z, Afkhami M, Mokhtari S, Pullarkat V. Ph-like acute lymphoblastic leukemia in adults: understanding pathogenesis, improving outcomes, and future directions for therapy. Leuk Lymphoma. 2023;64(6):1092-1101. doi:10.1080/10428194.2023.2197538

4. Ashouri K, Hom B, Rahimi Y, et al. Philadelphia-like B-cell acute lymphoblastic leukemia in a largely Hispanic population: disease features and outcomes in the era of immunotherapy a single institutional study. Presented at: 2023 American Society of Hematology Annual Meeting & Exposition; December 9-12, 2023; San Diego, CA. Accessed December 11, 2023. https://ash.confex.com/ash/2023/webprogram/Paper190716.html

5. Bustin SA, Jellinger KA. Advances in molecular medicine: unravelling disease complexity and pioneering precision healthcare. Int J Mol Sci. 2023;24(18):14168. doi:10.3390/ijms241814168

6. Yadav V, Ganesan P, Veeramani R, Kumar VD. Philadelphia-like acute lymphoblastic leukemia: a systematic review. Clin Lymphoma Myeloma Leuk. 2021;21(1):e57-e65. doi:10.1016/j.clml.2020.08.011

About the Authors

Amir Ali, PharmD, BCOP, is a clinical pharmacist specialist at the University of Southern California (USC) Norris Comprehensive Cancer Center and an adjunct assistant professor of pharmacy practice at USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles.

Melissa Martinez is a class of 2024 PharmD candidate at the University of Southern California Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles.

Maryam Saheb Kashaf is a class of 2027 PharmD candidate at University of Southern California Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles.

Zyanya Rizzo is a class of 2027 PharmD candidate at University of Southern California Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles.