Make Room for Asciminib and Ponatinib in the CP-CML Landscape


The question of the most optimal therapy for Philadelphia chromosome-positive chronic myeloid leukemia has come down to asciminib vs ponatinib.

For patients with Philadelphia chromosome-positive chronic myeloid leukemia (CP-CML), there is an unanswered question of which approved therapy is the most optimal. The question has come down to asciminib (Scemblix®; Novartis) and ponatinib (Iclusig®; Takeda Oncology).1

During a presentation at the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022), Jorge Cortes, MD, director, Georgia Cancer Center at Augusta University in Augusta, Georgia, explained that both asciminib and ponatinib are adequate therapies for patients with CP-CML and discussed the data supporting each therapy. He also explained the clinical circumstances that affected drug choice.

“I evaluate each patient individually and decide what might be the best choice for each patient in those circumstances. I use both drugs frequently and I feel very comfortable prescribing both of them,” Cortes told The SOHO Daily News, in an interview. “We have 2 excellent drugs for patients who have received multiple prior TKIs [tyrosine kinase inhibitors] or who have T315I mutations. Both offer very good efficacy and an acceptable toxicity profile with the current schedules. We want to learn more about each of them and ideally have a randomized trial, but both have a role in this setting depending on the unique patient circumstances.”

Ponatinib in CP-CML

Ponatinib was evaluated in the phase 2 PACE trial (NCT01207440) in patients with CP-CML and acute lymphoblastic leukemia. Ponatinib achieved durable and clinically meaningful responses that were irrespective of dose reductions in the study.2

In 270 patients with CP-CML treated with a 45 mg once daily starting dose of ponatinib, 60% achieved major cytogenetic responses (MCyR) at any time. Fifty-four percent of those who achieved a complete response (CR) at any time also achieved complete cytogenetic responses (CCyR).

MCyR were observed in 60% of patients and major molecular responses (MMR) were seen in 40% of patients, and 24% had a 4.5-log molecular response.

Notably, molecular, and cytogenetic responses occurred rapidly and were durable. The results show that 82% of patients who achieved MCyr and 59% of those who achieved an MMR had response lasting 5 years. The median duration of response for patients who had an MCyr or MMR had not been reached at the time of the assessment.

A Kaplan-Meier estimate in the PACE trial predicted that showed the 5-year progression-free survival (PFS) rate with ponatinib to be 53%, and the estimated 5-year overall survival (OS) rate was 73%.

The most common treatment-emergent adverse events (TEAEs) shown with ponatinib were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). In terms of grade 3 and 4 TEAEs, the most common events were thrombocytopenia (35%), neutropenia (17%), hypertension (14%), increased lipase (13%), abdominal pain (10%), and anemia (10%).

Cortes also highlighted results from the phase 3 OPTIC study (NCT02467270), which showed a high response rate and robust survival outcomes in patients with CP-CMLA who are resistant to second-generation BCR-ABL1 tyrosine kinase inhibitor therapy.

Asciminib in CP-CML

Results from the phase 3 ASCEMBL trial (NCT03106779) support the use of asciminib for the treatment of patients with CML-CP who are resistant or intolerant to 2 or more prior TKIs.3

The study randomized 233 patients with CP-CML to receive either asciminib 40 mg twice daily or bosutinib (Bosulif®; Pfizer) 500 mg once daily.

At a median follow-up of 14.9 months, the MMR rate at 24 weeks was 25.5% in the asciminib arm compared with 13.2% in the bosutinib arm. After the MMR was adjusted for MCyR at baseline, the difference between the 2 arms was 12.2% (95% CI, 2.19%-22.30%; 2-sided P = .029).

The response benefit observed with asciminib was consistent across the demographic and prognostic subgroups in the study, including line of therapy and prior treatment with a TKI.

Any-grade adverse events (AEs) were observed in 89.7% of the asciminib arm compared with 96.1% of the bosutinib. Grade ≥ 3 AEs occurred in 50.6% of patients in the asciminib group compared with 60.5% of the bosutinib group. Treatment-related AEs were seen in 63.5% of the asciminib arm vs 88.2% of the bosutinib arm.

When to Use Each Drug

Cortes explained that the standard drugs to combine with in CP-CML are third-generation TKIs, and there is a role of the novel mechanism of asciminib and ponatinib conducive to combination with TKIs.1

“Both ponatinib and asciminib [TB1] are excellent drugs and we should take advantage of their potential in appropriate patients to offer the best possible outcome for those who have already experienced resistance to 2 or more TKIs or who have T315I, Cortes told The SOHO Daily News.

For ponatinib, Cortes said there is a benefit for patients with T315I and those whose disease is in an advanced phase.

Asciminib is most useful for patients with arterial occlusive events, according to Cortes.

“The introduction of asciminib is the most recent advanced to CML therapy and it has offered, and excellent additional option for patients with multiply refractory or intolerant CML in CP. We also continue learning about the role of additional molecular abnormalities in genes associated with other cancers. This is an area of active research where we still have much work to do to understand the role of these mutations and how to address them,” Cortes said.

Aside from asciminib and ponatinib, there are patients with CP-CML in need of novel therapies, according to Cortes.

“Despite the many treatment options, most patients still cannot discontinue therapy successfully, so we need to find better ways to increase the number of eligible patients and the success rate upon discontinuation. My impression is that this will come more from combination therapy than from other TKIs,” he said.


Cortes JE. Ponatinib or Asciminib for Multiresistant Patients? Presented at: 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022); September 28-October 1, 2022; Houston TX.

Cortes JE, Kim D, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018; 132 (4): 393–404. doi: 10.1182/blood-2016-09-739086

Reu D, Mauro MJ, Boquimpani C, et al. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood .2021;138 (21): 2031–2041. doi: 10.1182/blood.2020009984

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