Current and future management of Ph/BCR-ABL positive ALL

Abstract

Following the introduction of targeted therapy with tyrosine kinase inhibitors (TKI) at the beginning of the past decade, the outcome of patients with Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) has dramatically improved. Presently, the use of refined programs with first/second generation TKI’s and chemotherapy together with allogeneic stem cell transplantation allow up to 50% of all patients to be cured. Further progress is expected with the new TKI ponatinib, overcoming resistance caused by T315I point mutation, other targeted therapies, autologous transplantation in molecularly negative patients, therapeutic monoclonal antibodies like inotuzumab ozogamicin and blinatumomab, and chimeric antigen receptor-modified T cells. Ph+ ALL could become curable in the near future even without allogeneic stem cell transplantation, minimizing the risk of therapy-related death and improving greatly the quality of patients’ life.

Keywords::

• acute lymphoblastic leukemia
• BCR-ABL rearrangement
• experimental therapy
• MRD monitoring
• Philadelphia chromosome
• prognosis
• therapy

Financial & competing interests disclosure

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 includes 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.

Key issues

• Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is defined by the presence of the Philadelphia chromosome, t(9;22), or the corresponding BCR-ABL gene rearrangement, in a B-cell precursor acute leukemia.

• The BCR-ABL fusion gene plays a fundamental pathogenetic role, encoding for an abnormal tyrosine kinase (TK) protein with leukemogenetic properties.

• Although seen at any age, the incidence of Ph+ ALL increases with aging, which makes treatment problematic in many frail/elderly patients (>55 years).

• Ph+ ALL was traditionally a very high-risk disease until imatinib, the first TK inhibitor (TKI), was available in the early 2000s.

• Sensitivity to TKIs is not universal, and can be impaired by several resistance mechanisms including TK domain point mutations, particularly T315I.

• After imatinib, second-generation TKIs dasatinib and nilotinib were introduced, they have greater potency and can overcome several point mutations except T315I. The newest TKI ponatinib seems effective against T315I.

• The current treatment paradigm consists of a combined chemotherapy-TKI induction (several schedules available), resulting in 90–100% remission rate, followed by allogeneic stem cell transplantation (SCT), which is curative in about two-thirds of the cases.

• Both overall and post-transplantation outcomes are largely dependent on the achievement of a good/complete molecular remission; thus, monitoring and treatment of minimal residual disease and underlying TK point mutations is crucial.

• The standard treatment strategy in TKI era allows 40–50% of all patients with Ph+ ALL to achieve cure.

• Selected clinical series have reported survival probabilities of 40–50% at 3+ years even in older patients and patients excluded from allogeneic SCT.

• To reduce treatment toxicities and risk of non-relapse mortality, induction chemotherapy schedules should be de-intensified, and minimal residual disease-negative patients should be considered for programs alternative to allogeneic SCT, like autologous SCT or new targeted therapies.

• New targeted therapies with non-TKIs, monoclonal antibodies (inotuzumab ozogamicin, blinatumomab) and chimeric antigen receptor-modified T cells are entering the clinical arena and will contribute to further increase survival rates.

Notes