ALL is the most common type of cancer in children with about two-thirds of newly diagnosed ALL patients being pediatric patients under the age of 18. The age distribution of ALL patients is bimodal with a peak incidence at around 2-5 years of age and another peak at 70 years of age with incidence rising after age 40. Survival rates are higher in children with more than 90% being cured after front-line therapy. The five-year survival rate for adult patients is around 40% with decreasing cure rates with increasing age.

A fraction of ALL is Philadelphia chromosome positive (Ph+) and amenable to treatment with a tyrosine kinase inhibitor (TKI). Approximately 3-4% of pediatric patients and 25% of adult patients are Ph+. The incidence of Ph+ ALL increases with age with over 50% of patients over 60 years old being Ph+. Three TKIs are currently approved for Ph+ ALL: first generation TKI Gleevec (imatinib), second generation TKI Sprycel (dasatinib) and third generation TKI Iclusig (ponatinib). Generic imatinib and generic dasatinib were launched in 2016 and 2024, respectively. In the US, Sprycel and Iclusig dominate the first-line market while in the EU, Gleevec dominates the first-line market with generic imatinib preferred over branded Gleevec.

In the US, Blincyto (blinatumomab), a bispecific antibody targeting CD19 and CD3, is approved for adult and pediatric B-cell ALL patients in both the first-line and relapsed/refractory setting. For first-line Ph-ve patients, Blincyto is approved for use in the consolidation phase of multiphase chemotherapy regardless of MRD status. This recent label expansion (approval granted in June 2024 in the US) has helped grow Blincyto market share.

Besponsa (inotuzumab ozagamicin) is an antibody-drug conjugate targeting CD22. Besponsa is used in the relapsed/refractory setting where it competes with Blincyto and CAR-T and has the advantage of targeting a different antigen. Besponsa is preferred in patients with high tumor burden or who have lost CD19 expression but retain CD22 expression. It is often used to induce remission prior to transplant and can be used to reduce disease burden prior to CAR-T therapy.

There are currently three autologous, CD19 targeted CAR-T therapies approved for relapsed/refractory ALL patients: first-to-market Kymriah (tisagenlecleucel), second-to-market Tecartus (brexucabtagene autoleucel) and third-to-market Aucatzyl (obecabtagene autoleucel). Kymriah is approved for pediatric patients and for patients <26 years of age while Tecartus and Aucatzyl are only approved for adult patients. Aucatzyl’s improved safety profile has allowed it to steal market share from Tecartus.

First-line treatments rely on intensive chemotherapy which is effective but is associated with toxicities that can prevent patients from receiving potentially curative therapies like allogeneic transplant or CAR-T therapy. Furthermore, the combined induction, consolidation and maintenance phase of these regimens can last several years significantly affecting the quality of life of patients. Reduced-intensity and chemotherapy-free regimens are needed for ALL.