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Ponatinib and Blinatumomab for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: updated results


Ponatinib ( Iclusig ) and Blinatumomab ( Blyncito ) are both highly effective therapies for Philadelphia chromosome-positive ( Ph+ ) acute lymphoblastic leukemia ( ALL ).
The combination of these two agents may offer an effective chemotherapy-free strategy in these patients.

Researchers have evaluated the efficacy and safety of Ponatinib and Blinatumomab in patients with newly diagnosed ( ND ), relapsed / refractory ( R/R ) Ph+ acute lymphoblastic leukemia ( Ph+ ALL ) or chronic myeloid leukemia in lymphoid blast phase ( CML-LBP ).

For patients with newly diagnosed Ph+ ALL, the primary endpoint was the complete molecular response ( CMR ) rate.
For patients with R/R Ph+ ALL, the primary endpoint was the complete response / incomplete hematologic recovery [ CR/CRi ] rate.
Secondary endpoints included safety, event-free survival ( EFS ) and overall survival ( OS ).

In this phase II study, adults with newly diagnosed Ph+ ALL, relapsed / refractory Ph+ ALL, or CML-LBP were eligible.
Patients were required to have a performance status of 2 or less, total bilirubin 2x or less the upper limit of normal ( ULN ), and ALT and AST 3x or less the ULN.

Patients with uncontrolled cardiovascular disease or clinically significant central nervous system ( CNS ) comorbidities ( except for CNS leukemia ) were excluded.

Patients received up to 5 cycles of Blinatumomab as a continuous infusion at standard doses.
Ponatinib 30mg daily was given during cycle 1 and was decreased to 15mg daily once complete molecular response was achieved.
After 5 cycles of Blinatumomab, Ponatinib was continued for at least 5 years.
Twelve doses of prophylactic IT chemotherapy with alternating Cytarabine and Methotrexate were administered.

Between 2/2018 to 1/2022, 55 patients were treated ( 35 with ND Ph+ ALL, 14 with R/R Ph+ ALL and 6 with CML-LBP ).

Among the 35 patients with ND Ph+ ALL, 12 were in complete response at enrollment ( including 2 patients in CMR ).
22 of the 23 evaluable patients ( 96% ) achieved CR/CRi.
One patient died on day 18 from intracranial hemorrhage in the setting of chemotherapy administered prior to enrollment.

After one cycle, 21/33 patients ( 64% ) have achieved complete molecular response, and 28/33 patients ( 85% ) have achieved complete molecular response at any time.
11 of 15 tested patients ( 73% ) also became MRD-negative by an NGS assay with sensitivity of 1x10-6.

CR/CRi was achieved in 12/13 ( 92% ) evaluable patients with R/R Ph+ acute lymphoblastic leukemia.
Complete molecular response was achieved in 10 patients ( 71% ) after cycle 1 and in 11 patients ( 79% ) overall.
5 of 6 patients with CML-LBP have achieved CR/CRi, and 1 patient has achieved partial response ( PR ) as best response.
2 patients ( 40% ) have achieved complete molecular response.

In the ND Ph+ ALL cohort, 1 of 34 patients who received at least 1 full cycle died in complete response; the other 33 are in ongoing hematologic remission.
Only one patient underwent stem cell transplant ( SCT ) in first remission for persistently detectable BCR/ABL1 transcripts.
Among 13 responding patients in the R/R Ph+ ALL cohort, 6 proceeded to stem cell transplant, 4 did not undergo SCT and subsequently relapsed, 1 died in complete response, and 2 are in ongoing remission without SCT.

In the CML-LBP cohort, 3 of the 5 responding patients subsequently relapsed.

The median follow-up is 11 months ( range, 1-46+ ).

For ND Ph+ ALL, the 2-year EFS and OS are both 93%. There were no relapses or leukemia-related deaths in this cohort.

In the R/R Ph+ ALL cohort, the 2-year EFS rate was 42% and the 2-year OS rate was 61%.

In the CML-LBP cohort, the 2-year EFS was 33% and the 2-year OS was 60%.

The treatment was well-tolerated, and most toxicities were grade 1-2 and consistent with the known toxicities of the two agents.

Two patients discontinued Ponatinib due to toxicity ( 1 due to stroke and 1 due to deep vein thrombosis [ DVT ] ). One patient discontinued Blinatumomab due to persistent grade 2 tremor.

In conclusion, the chemotherapy-free regimen of simultaneous Ponatinib and Blinatumomab is safe and effective in patients with Ph+ acute lymphoblastic leukemia.
For patients with newly diagnosed Ph+ acute lymphoblastic leukemia, stem cell transplant does not appear to be needed in first remission. ( Xagena )

Short N et al, European Hematology Association ( EHA ) Meeting, 2022

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