Treatment and outcome of Philadelphia chromosome-positive acute lymphoblastic leukemia in adults after relapse

ABSTRACT

Introduction

Despite the significant progress that has been made over the last years in the front-line treatment of Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL), relapses are frequent and their treatment remains a challenge, especially among patients with resistant BCR-ABL1 mutations.

Areas covered

This manuscript reviews available data for the treatment of adult patients with relapsed/refractory Ph-positive ALL, with a focus on the role of tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and immunotherapy.

Expert opinion

Although a majority of patients with first relapsed Ph-positive ALL respond to subsequent salvage chemotherapy plus TKI combination, their outcomes remain poor. The main predictor of survival is the achievement of major molecular response anytime during the morphological response. More treatment strategies to improve survival are under investigation. Monoclonal antibodies and bispecific antibody constructs hold considerable promise in improving the outcomes of patients with relapsed ALL including Ph-positive ALL.

KEYWORDS:

• Acute lymphoblastic leukemia
• Philadelphia chromosome
• blinatumomab
• inotuzumab ozogamicin
• CAR-Ts

Article highlights

• Although the introduction of TKIs in the treatment of Ph chromosome-positive ALL has led to significant improvement in the outcomes of these patients, relapse remains clinically challenging because of the frequent association with resistance substitutions in the ABL kinase domain.

• The third-generation TKI ponatinib has been shown highly active in heavily pretreated patients with Ph-positive ALL, including patients with the BCR-ABL T315I mutation. However, there is no evidence of a real sustained response with TKIs at the time of relapse.

• Recently, several immunotherapeutic agents have been introduced for treatment of relapsed or refractory Ph-positive ALL. Inotuzumab ozogamicin and blinatumomab gave encouraging data and increased the probability of receiving subsequent allogeneic HSCT. CD19-specific CAR-T cells were effective regardless of tumor burden or prior receipt of HSCT and can be used as a definite treatment in some patients.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This included employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received research support from Celgene, Incyte and Amgen, and honoraria (adboards) from Novartis, Incyte, Celgene, Sun Pharma, Roche and Amgen. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper received no funding.