Dual BCR::ABL1 Inhibition Shows Promise in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Philadelphia chromosome-positive (Ph+) leukemia¹  has long presented a formidable clinical challenge despite significant advances in tyrosine kinase inhibitor (TKI) therapy. At the heart of this disease lies the BCR::ABL1 fusion protein, a constitutively active oncogenic driver resulting from the characteristic chromosomal translocation.

The therapeutic landscape for Ph+ leukemias was revolutionized with imatinib, the first TKI to directly target their fusion protein.^2,3  Second-generation TKIs such as dasatinib and nilotinib delivered further clinical benefits through enhanced potency and reduced resistance profiles. Recent results from a phase I trial⁴  offer compelling evidence that simultaneously targeting BCR::ABL1 through two distinct mechanisms may represent a significant therapeutic advancement for patients with Ph+ acute lymphoblastic leukemia (ALL).

The development of TKIs began with imatinib, initially discovered by screening compounds against various protein kinases to inhibit the ATP-binding site.⁵  These type 1 TKIs evolved into second-generation agents that achieved faster and deeper remissions.

A breakthrough came in 2017⁶  with the successful development of a novel class of BCR::ABL1 inhibitors. In its normal state, wild-type ABL1 remains inactive when its myristoylated N-terminus binds to a specific myristoyl-binding pocket within the kinase domain. However, this regulatory mechanism is lost in the BCR::ABL1 fusion, as the myristoylated N-terminal region is replaced by BCR sequence, resulting in constitutive kinase activation. Asciminib was rationally designed to bind directly to this myristoyl-binding pocket, inducing an inactive conformation of the fusion kinase — a fundamentally different approach from ATP-competitive inhibitors. Asciminib showed activity as monotherapy in heavily pretreated patients or those with T315I mutations.⁷ 

In their phase I study, Marlise R. Luskin, MD, MSCE, and colleagues evaluated the combination of dasatinib (a type I ATP-competitive TKI) with asciminib (an allosteric inhibitor) plus prednisone in 24 adult patients with Ph+ leukemia. The cohort consisted of 22 patients newly diagnosed with Ph+ ALL, as well as two patients with chronic myeloid leukemia in lymphoid blast crisis (CML-LBC).

The patient population had a median age of 64.5 years, with 50% being 65 years old or older. Using a 3+3 design, the investigators escalated asciminib from 40 mg to 80 mg to 160 mg daily while maintaining fixed doses of dasatinib (140 mg daily) and prednisone (60 mg/m² daily for days 1-24, followed by a taper through day 32).

The efficacy outcomes were encouraging for a phase I study. Among patients with de novo ALL, complete hematologic remission rates at days 28 and 84 were 84% and 100%, respectively. By day 84, all evaluable patients achieved complete cytogenetic remission. Furthermore, 89% of patients achieved measurable residual disease (MRD) negativity (<0.01%) by multicolor flow cytometry. Molecularly, 74% of patients achieved a molecular response 3 (<0.1%) and 26% reached a molecular response 4 (<0.01%). Nearly all patients (95%) achieved at least a two-log reduction in BCR::ABL1 transcripts by day 84.

The regimen demonstrated excellent tolerability with no treatment-related mortality. Complete hematologic recovery was achieved in most patients by day 28 and in all patients by day 45. The most common adverse event was pleural effusion (n=7), likely related to dasatinib, which typically resolved with dose reductions. Low-grade increases in amylase and lipase occurred frequently but were clinically insignificant. Notably, no vaso-occlusive events were observed — a significant advantage over ponatinib, the only TKI effective against T315I mutations.

Eight patients proceeded to allogeneic hematopoietic cell transplantation (HCT), with no relapses observed at a median follow-up of 495 days. Four of these patients received bridging therapy with blinatumomab and dasatinib before HCT.

Among patients who continued on dual TKI therapy without HCT or other consolidation, three experienced relapses between 283 and 1,260 days from registration. Of the five patients who experienced clinical progression or molecular recurrence and underwent mutational analysis, only one developed a T315I mutation. Importantly, no treatment-emergent alterations were observed in myristoyl-binding site residues or in positions previously associated with resistance to asciminib monotherapy.

For the two patients with relapsed/refractory CML-LBC, one achieved a molecular response to less than 0.1% by day 84 but progressed after 248 days, while the other achieved only a molecular response 2 as a best response before progressing by day 83 with the acquisition of T315I and Q252H mutations.

This study demonstrates that dual BCR::ABL1 inhibition with dasatinib and asciminib is both feasible and highly effective in newly diagnosed Ph+ ALL, particularly in older patients who may not tolerate intensive chemotherapy regimens. The impressive rates of molecular response and MRD negativity, combined with the favorable toxicity profile, position this approach as a promising option for Ph+ ALL treatment. The investigators are now exploring the addition of blinatumomab to this regimen in an expansion cohort. This innovative approach of simultaneously targeting two distinct binding sites on BCR::ABL1 represents a significant advancement in our therapeutic arsenal against Ph+ ALL.

Dr. Furlan indicated no relevant conflicts of interest.