Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a high-risk subtype of ALL, historically associated with poor outcomes. The introduction of tyrosine kinase inhibitors (TKIs) has dramatically changed its therapeutic landscape. Current optimization strategies focus on integrating TKIs with chemotherapy, immunotherapy, and, in selected cases, allogeneic stem cell transplantation (allo-HSCT), while tailoring treatment according to minimal residual disease (MRD) status and patient characteristics.

Induction therapy now commonly consists of a TKI combined with corticosteroids and/or reduced-intensity chemotherapy, aiming to achieve remission with lower toxicity compared to traditional intensive regimens. Commonly used TKIs include imatinib, dasatinib, and ponatinib, with the latter being preferred in cases with the T315I mutation due to its broader activity.

Consolidation therapy is designed to eradicate residual disease. Achieving MRD negativity is the primary goal, as it strongly predicts long-term survival. Strategies include continued TKI administration combined with short chemotherapy blocks or novel agents such as blinatumomab, a CD19-targeted bispecific T-cell engager. Allo-HSCT remains an important option for younger, fit patients, especially those with persistent MRD or high relapse risk. However, accumulating evidence suggests that deep and durable remissions may be achievable without transplantation when combining TKIs with immunotherapies.

Maintenance therapy typically involves prolonged TKI treatment, often for at least two to three years, with ongoing MRD monitoring to guide adjustments.

In the relapsed or refractory setting, therapeutic options expand to include next-generation TKIs such as ponatinib, immunotherapies including blinatumomab and the CD22-targeted antibody-drug conjugate inotuzumab ozogamicin, and chimeric antigen receptor T-cell (CAR-T) therapies targeting CD19, which have shown promising results in heavily pretreated patients.

The core principles of treatment optimization in Ph+ ALL include:

1. MRD-directed decision-making, as MRD negativity is the strongest predictor of favorable outcomes.

2. Reducing treatment-related toxicity, particularly in elderly or frail patients, by minimizing intensive chemotherapy and incorporating TKIs with immunotherapy.

3. Individualizing the role of allo-HSCT, reserving it primarily for patients with persistent MRD, high-risk features, or early relapse.

4. Integrating novel agents such as blinatumomab, inotuzumab, and CAR-T therapies earlier in the treatment course to improve long-term survival and potentially reduce the need for transplantation.

In summary, modern management of Ph+ ALL emphasizes TKI-based regimens, MRD-guided therapeutic decisions, and the incorporation of targeted immunotherapies. While allo-HSCT remains relevant for selected patients, emerging evidence suggests that long-term remission may increasingly be achievable without transplantation, especially when potent TKIs and immunotherapies are combined. This evolving paradigm reflects a shift toward personalized, less toxic, and more effective treatment strategies for Ph+ ALL.