Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges

Abstract

The Philadelphia (Ph) chromosome, resulting from the t(9;22)(q34;q11) translocation, can be found in chronic myeloid leukemia (CML) as well as in a subset of acute lymphoblastic leukemias (ALL). The deregulated BCR-ABL1 tyrosine kinase encoded by the fusion gene resulting from the translocation is considered the pathogenetic driver and can be therapeutically targeted. In both CML and Ph-positive (Ph+) ALL, tyrosine kinase inhibitors (TKIs) have significantly improved outcomes. In the TKI era, testing for BCR-ABL1 transcript levels by real-time quantitative polymerase chain reaction (RQ-PCR) has become the gold standard to monitor patient response, anticipate relapse, and guide therapeutic decisions. In CML, key molecular response milestones have been defined that draw the ideal trajectory towards optimal long-term outcomes. Treatment discontinuation (treatment-free remission, TFR) has proven feasible in a proportion of patients, and clinical efforts are now focused on how to increase this proportion and how to best select TFR candidates. In Ph+ ALL, results of trials with second- and third-generation TKIs are challenging the role of intensive chemotherapy and even that of allogeneic stem cell transplantation. Additional weapons are offered by the recently introduced monoclonal antibodies. In patients harboring mutations in the BCR-ABL1 kinase domain, prompt therapeutic reassessment and individualization based on mutation status are important to regain response and prevent disease progression. Next-generation sequencing is likely to become a precious tool for mutation testing because of the greater sensitivity and the possibility to discriminate between compound and polyclonal mutations. In this review, we discuss the latest advances in treatment and monitoring of CML and Ph+ ALL and the issues that still need to be addressed to make the best use of the therapeutic armamentarium and molecular testing technologies currently at our disposal.

Ponatinib in the Treatment of Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Leukemia: Recommendations of a German Expert Consensus Panel with Focus on Cardiovascular Management

“…In Ph+ ALL, the incorporation of TKIs in conventional chemotherapeutic approaches has significantly improved depth and duration of responses and is now considered standard of care. With improved remission rates, a higher proportion of patients can be referred to alloSCT in first remission, and the 5-year OS in Ph+ ALL has increased with rates ranging from 38 to 71% depending on age group [26]. Relapses are often attributed to TKI resistance mutations, which are found in approximately 70–80% of imatinib-resistant patients [27-29].…”

Practical guidance for the management of acute lymphoblastic leukemia in the adolescent and young adult population

“…114 Allogeneic HCT in Ph+ ALL As for Ph-ALL, the role of HCT in Ph+ ALL patients is changing in relation to the efficacy of TKI associations with low-dose chemotherapy and new immunotherapeutic approaches. 83 MRD status and genomic characterization at diagnosis are key factors in this decision-making process, 78,83,115,116 especially with the most effective combinations tested upfront to date, such as ponatinib-chemotherapy 78 and dasatinib-blinatumomab, 79…”

“…As reviewed extensively elsewhere, trials with new agents targeting different ALL subsets and molecular variants were performed successfully in advanced ALL, and are flourishing in frontline studies. [118][119][120] Among them, it is worth mentioning several North-American and European immunotherapy studies with rituximab (targeting CD20 antigen), [53][54][55] blinatumomab (bispecific CD19 × CD3 T-cell engager antibody), and inotuzumab ozogamicin (anti-CD22 drug-antibody conjugate) for CD20, CD19, and CD22-positive, Ph+, and Ph-ALL, respectively; a variety of TKI-based trials for Ph-like ALL 83 ; and the evaluation of several other small molecules (such as BCL2 inhibitors in KMT2A-rearranged ALL, ETP ALL, etc.) and of CAR T cells, at present mainly in relapsed/refractory states and MRD+ ALL.…”

Patient-Initiated Discontinuation of Tyrosine Kinase Inhibitor for Chronic Myeloid Leukemia

“…With the increased acceptance and uptake of attempting TFR in routine clinical practice, recommendations for the minimal requirements for treatment discontinuation have been proposed by both European and North American experts groups [13,14]. Similarities exist between these two sets of criteria although there remains limited consensus on the requirements for TKI treatment duration or depth and stability of the molecular remission prior to attempting TFR [15]. Both sets of guidelines concur on the importance of instigating frequent molecular monitoring so that molecular relapse can be rapidly captured prompting reintroduction of TKI.…”