Highlights in ALL

During ASH 2024, Dr Guru Subramanian Guru Murthy from the Medical College of Wisconsin in Milwaukee chaired an oral abstract session discussing innovations in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) and early T-precursor ALL (ETP-ALL).

Over the last decade, the development of next generation tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL fusion gene revolutionized the treatment of Ph+ ALL. More recently, also the introduction of blinatumomab in the treatment paradigm for these patients has led to improved outcomes. Building on these two success stories, several studies are currently exploring combinations of a BCR-ABL TKI and blinatumomab. In the Gimema ALL2820 study, 133 newly diagnosed adult Ph+ ALL patients were treated with a steroid pre-phase followed by a 70-day induction with ponatinib followed by at least 2 cycles (maximum 5) of blinatumomab. By the end of the induction phase, 96% of these patients had obtained a complete hematologic remission (CHR). After 2 cycles of blinatumomab, an overall molecular response rate of 74% was reported. Importantly, these high response rates did not come at the cost of excessive toxicity, with a low rate of treatment discontinuation, including in elderly patients.¹

The efficacy and safety of the ponatinib-blinatumomab combination in this setting was further reinforced by the results of a phase II study conducted by the MD Anderson Cancer Center.² In this study, including 76 patients with newly diagnosed Ph+ ALL, the ponatinib-blinatumomab treatment resulted in a composite complete response (cCR: complete response [CR] and complete response with incomplete count recovery [CRi]) rate of 98%. After 1 cycle of blinatumomab, 96% of patients proved to be MRD-negative.² At 3-years, the event-free (EFS) and overall survival (OS) rates were reported at 78% and 88%, respectively. Overall, both this study and Gimema ALL2820 observed a very low rate of relapses, and a low rate of patients required a stem cell transplantation (SCT). Interestingly, in the MD Andersen study, a high white blood count at diagnosis (≥70k) and the presence of a VPREB1 deletion were shown to be associated with a higher risk for a disease relapse.²

A third study zooming in on Ph+ ALL evaluated the immunomodulatory effects of dasatinib and ponatinib when used in combination with blinatumomab. This study showed that a frontline treatment with dasatinib and blinatumomab induces a more profound NK, T-NK and Treg immune modulation than what was seen with ponatinib plus blinatumomab.³ However, whether this increased immunomodulation also leads to a better disease control remains unclear.

While the studies discussed above clearly demonstrate the potency of next generation BCR-ABL TKIs, a fourth abstract of the session illustrates that also the first generation TKI imatinib still has its place in the treatment of Ph+ ALL. In the GMALL Trial 08/2013 study, dose reduced induction and intensive consolidation in combination with imatinib followed by an allogeneic SCT resulted in high response rates.⁴ At the end of the induction phase, a cCR rate of 85% was reported, increasing to 94% after consolidation. While the molecular failure rate was relatively high at 81% at the end of induction, this reduced to 38% after consolidation. In total, 160 of the 176 patients enrolled in the study were able to move to an allogenic SCT. After 5 years of follow-up the OS among these patients was 76%.⁴

Finally, the oral abstract session also featured 2 interesting presentations in the field of ETP-ALL, a disease entity that is characterized by a poor outcome when treated with standard chemotherapy. In a first of these studies, 34 patients with newly diagnosed ETP-ALL were treated with a combination of venetoclax and a chemotherapy regimen consisting of homoharringtonine, cytarabine and G-CSF (HAG). Interestingly, all the response evaluable patients obtained a CR/CRi to this regimen, with 54.7% of patients having a blast level <5% in combination with MRD negativity.⁵

In a second study looking into ETP-ALL, the novel histone deacetylase inhibitor tucidinostat was combined with a pediatric-inspired chemotherapy schedule. The study enrolled 54 newly diagnosed ETP-ALL patients with a median age of 24 years. The CR/CRi rate after induction and consolidation was reported at 91%, with corresponding rates of MRD negativity of 65% and 87%.  After 40 months of follow-up, the median OS and EFS were not yet reached, with a 3-year OS and EFS rate of 71.5% and 67.7%, respectively.⁶

The results obtained with these two regimens in ETP-ALL are very promising and warrant further evaluation in a randomized-controlled setting in the years to come.