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Too much of a good thing? An in vitro study with dual Src/ABL kinase inhibitor and blinatumomab suggests some combination treatments for Ph+ ALL may not work well together

Apr 22, 2021
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Disease summary and treatment with tyrosine kinase inhibitors

The most common cytogenic abnormality in adult patients with acute lymphoblastic leukemia (ALL) is the Philadelphia chromosome (Ph), which increases with age and occurs in up to 50% of ALL that is diagnosed in individuals ≥50 years.1

The development of the BCR-ABL tyrosine kinase inhibitor (TKI) imatinib and second-generation TKIs to treat Ph+ ALL (and chronic myeloid leukemia) has measurably improved overall survival and other response measures.2,3

Treatment with blinatumomab, a bispecific T-cell engager4

Although treating Ph+ ALL with TKIs has dramatically improved a previously bleak outlook for patients with Ph+ ALL, new combinations or alternate therapies are needed for patients with relapsed/refractory disease.

The idea of combining a targeted TKI with the recently approved bispecific T-cell engager blinatumomab would seem to have potential. However, the dual Src/ABL inhibitors dasatinib and ponatinib are known to inhibit the Src family kinases that are important in T-cell receptor signaling, while nilotinib, an ABL inhibitor, does not appear to exhibit the same impact on tyrosine kinases.

A recent study by Jessica Leonard, published in Blood in February 2021, investigated in vitro the impact on the efficacy of combining blinatumomab with the ABL inhibitors imatinib and nilotinib, as well as with the with dual Src/ABL inhibitors dasatinib and ponatinib.4

Study design4

Peripheral blood mononuclear cells (PBMCs) were obtained from five healthy volunteers and from five patients with Ph+ ALL. The Ph+ ALL samples included three samples from newly diagnosed patients and two from patients with relapsed Ph+ ALL.

The primary approved TKIs included in this study are outlined in Table 1.2,3

Table 1. TKIs used in the study

TKI

Administration route

Indication(s)

Imatinib2

Oral

In combination with chemotherapy in adults with R/R Ph+ ALL

In combination with chemotherapy in pediatric patients with newly diagnosed Ph+ ALL

Dasatinib2

Oral

In combination with chemotherapy in adults with Ph+ ALL with resistance or intolerance to prior therapy

In combination with chemotherapy in pediatric patients aged ≥1 year with newly diagnosed Ph+ ALL

Ponatinib2

Oral

Adult patients with T3151-positive Ph+ ALL

Nilotinib3

Oral

Adult and pediatric patients aged ≥1 year with newly diagnosed Ph+ CML in CP

Adult patients with CP and AP Ph+ CML resistant to or intolerant to prior therapy that included imatinib

Pediatric patients aged ≥1 year with Ph+ CML in CP and resistant or intolerant to prior TKI therapy

ALL, acute lymphoblastic leukemia; AP, accelerated phase; CML, chronic myeloid leukemia; CP, chronic phase; Ph, Philadelphia chromosome; R/R, relapsed/refractory; TKI, tyrosine kinase inhibitor.

PBMCs were labeled and cultured in a dose-escalating manner as shown in Table 2.

Table 2. Dosing schedule*

Exposure type

Culture conditions

One 5-day cycle of continual exposure

No stimulation;
10 nM blinatumomab alone;
or 10 nM blinatumomab in combination with 5 nM to 500 nM imatinib, dasatinib, ponatinib, or nilotinib

One 5-day cycle of intermittent exposure

2 hours with 10 nM blinatumomab and 10 nM dasatinib, followed by removal of media and replacement with 10 nM blinatumomab only for 22 hours

*Data from Leonard, et al.4

Study results4

Treatment with dasatinib and ponatinib decreases CD3+ T-cell proliferation and the elimination of CD19+ B cells after blinatumomab stimulation in vitro.

PBMCs isolated from healthy donors and patients with ALL showed T-cell proliferation after 5 days with 10 nM blinatumomab. In the presence of imatinib and nilotinib, there continued to be T-cell proliferation. By contrast, no T-cell proliferation was observed if the cells were treated with either dasatinib or ponatinib.

In healthy donors this finding was further validated by the lack of CD19+ B-cell clearance in the presence of dasatinib and ponatinib. By contrast, there was clearance of the CD19+ B cells in samples obtained from newly diagnosed patients with ALL despite inhibition of T-cell proliferation, which was most likely due to the effect of dasatinib and ponatinib against the ABL kinase.

When investigating the patient sample with ALL cells containing the T315I mutation, which confers resistance to ABL-kinase inhibitors, the addition of dasatinib inhibited T-cell proliferation and prevented clearance of CD19+ B cells. Unsurprisingly, dasatinib alone did not eliminate CD19+ blast cells containing the T315I mutation, which indicates that the dasatinib-induced inhibition of blinatumomab is due to its effect on normal T cells.

Treatment with dasatinib and ponatinib decreases production of IFN-g and phosphorylation of LCK.

The activation of blinatumomab leads to the production of cytokines, including IFN-g. Treatment of PBMCs with blinatumomab led to a significant increase in production of IFN-g compared with unstimulated controls in both healthy donor and patient samples. The addition of imatinib or nilotinib did not affect the production of IFN-g in either healthy PBMCs or Ph+ ALL samples. Again, by contrast, both dasatinib and ponatinib completely suppressed the IFN-g secretion induced by stimulations with blinatumomab.

The addition of dasatinib or ponatinib to the cultures inhibited phosphorylation of LCK but there was no such effect by nilotinib and imatinib.

Summary4

The results gathered in this limited study suggest that combining the targeted antibody blinatumomab with the dual Src/ABL inhibitors dasatinib and ponatinib may reverse or reduce the effects of blinatumomab by inhibiting T-cell functioning, most likely due to inhibition of the T-cell receptor signaling molecule LCK. Only a randomized trial using a TKI together with blinatumomab would help to determine the impact on blast cell elimination in patients with Ph+ ALL. However, the immunomodulating effects of dual Src/ABL inhibitors should be taken into consideration when combining them with immunotherapies.

  1. Liu-Dumlao T, Kantarjian H, Thomas DA, et al. Philadelphia-positive acute lymphoblastic anemia: Current treatment options. Curr Oncol Rep. 2012;14(5):387-394. DOI: 10.1007/s11912-012-0247-7

  2. Leukemia & Lymphoma Society. Ph-positive ALL therapy. https://www.lls.org/leukemia/acute-lymphoblastic-leukemia/treatment/ph-positive-all-therapy. Accessed Apr 6, 2021.

  3. Nilotinib [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2020.

  4. Leonard JT, Kosaka Y, Malla P, et al. Concomitant use of a dual Src/ABL kinase inhibitor eliminates the in vitro efficacy of blinatumomab in Ph+ ALL. Blood. 2021;137(7):939-944. DOI: 10.1182/blood.2020005655

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