Recap: Moffitt and Mayo Face-Off in CML Treatment Updates From ASH

ONCOLOGY® CompanionONCOLOGY® Companion, Volume 37, Supplement 3
Volume 37
Issue 3
Pages: 30-32

A panel of experts from Moffitt and Mayo discuss newly published data from the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition.

In a continuation of a Face-Off event featuring the Mayo Clinic and Moffitt Cancer Center going head to head in multiple myeloma, teams from the same institutions battled it out in the category of chronic myeloid leukemia (CML). This time, the presentations featured newly published data from the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition.

The panelists were Kendra Sweet, MD, a medical oncologist from Moffitt Cancer Center; Akriti Jain, MD, a hematologic oncology fellow at Moffitt Cancer Center; Talha Badar, MBBS, MD, a hematologic oncologist from the Mayo Clinic; Ricardo D. Parrondo, MD, a hematologic oncologist from the Mayo Clinic; and Ahmad Ghorab, MD, MSc, a hematology oncology fellow at the Mayo Clinic.


Updated results from the phase 3 ASCEMBL trial (NCT03106779) were presented at ASH 2022.1 The trial investigated asciminib (Scemblix) vs bosutinib (Bosulif) in patients with chronic phase-CML (CP-CML) who had previously received 2 or more tyrosine kinase inhibitors (TKIs). Patients were given 40 mg of asciminib twice a day vs 500 mg of bosutinib once a day. The treatment duration lasted 96 weeks or more along with survival follow-up.

The primary end point was major molecular response (MMR) at 24 weeks, and the secondary end point was MMR at 96 weeks.

In 97 patients who had BCR::ABL1 of 10% or more at baseline, 44.3% had an improved response of BCR::ABL1 of 10% or less at week 24, and 16.5% had MMR or better. In 60 patients who had BCR::ABL1 of 10% or less at baseline, 40.0% had MMR or better at week 24. Additionally, 23 patients who had BCR::ABL1 of more than 10% discontinued treatment at week 24.

Those who received asciminib achieved a BCR::ABL1 of 1% or less at week 96 and had resistance to prior TKIs.

A total of 47.2% (95% CI, 33.30%-61.36%) of patients who received 1 second-generation TKI and had a BCR::ABL1 of 1% or less at week 96 demonstrated resistance in the asciminib arm vs 23.5% (95% CI, 6.81%-49.90%) in the bosutinib arm. Similar results were observed in the asciminib arm for those receiving 2 or more second-generation TKIs but differed in the bosutinib cohort for 19.4% of patients (95% CI, 7.45%-37.47%).

Investigators noted that there were no independent predictive factors of early MMR by week 24 vs after week 24 based on the logistic regression analysis.

Moffitt Interrogates Mayo

SWEET: When would you use asciminib vs ponatinib [Iclusig]?

BADAR: We won’t be able to compare these 2 drugs but the FDA approval [for ponatinib] at this point in time is for patients with 2 prior TKIs or who had a T315I mutation.2 If you ask my opinion of an ideal setting, I will always prefer asciminib vs ponatinib based on better tolerability— especially in patients who have multiple comorbidities like hypertension and cardiovascular risk factors that could be detrimental to using ponatinib. Realistically, it’s not possible [to compare treatments] because of the payer issue of the high copay with these regimens, and most of the time I need to find some grants from the Leukemia & Lymphoma Society or some philanthropic services to provide therapy.

SWEET: Some of the data that you showed suggested that patients who had baseline BCR::ABL1 transcript levels of greater than 10% when they enrolled on trial [had] significantly lower response rates compared with those who had lower transcript levels at baseline. To me, this suggests that there [were] potentially some mutations at baseline in those patients that weren’t parsed out, but it potentially suggests maybe a BCRA-independent mechanism of resistance as well. What are your thoughts on ways to try to get around that as far as combinations moving forward? We have a lot of combinations with ATP inhibitors; are there any thoughts on ways to combine them or other ways to maybe get around some of that BCR::ABL1-independent mechanism of resistance?

BADAR: Multiple TKI and STAMP inhibitor combinations are being evaluated in clinical trials, [such as] asciminib with imatinib or asciminib, later incorporating the lorlatinib to improve the durability of response. Again, the questions become about the [adverse] effects and the insurance issues. How will the insurance company approve these 2 agents given together for the same indication to achieve a goal that hasn’t [been proven] to improve overall survival [OS]? We know that with MRR achievement, patients tend to do better and they’re more likely to achieve treatment-free remission, but so far, the data available; [don't seem] to improve OS. However, once you achieve a complete setting response then the survival is comparable.


The 3-year update from the phase 2 OPTIC trial (NCT02467270) was also presented at ASH 2022.3 The trial analyzed ponatinib in patients with CP-CML. The trial enrolled patients who were resistant to 2 or more TKIs or who were BCR::ABL1, T315I mutation positive. Patients were randomized 1:1:1 to ponatinib at 45 mg, 30 mg, or 15 mg daily. If patients achieved a BCR::ABL1 of 1% or less, they could be dose-reduced to the 15-mg group. In the 15-mg group, they could be reduced to 10 mg if adverse effects (AEs) were common. The primary end point was BCR::ABL1 of 1% or less at 12 months.

At 36 months, the BCR::ABL1 of 1% or less response rate in the 45-mg group was 60.2% (95% CI, 49.5%-70.2%), 39.8% (95% CI, 29.8%-50.5%) in the 30-mg group, and 39.6% (95% CI, 29.5%-50.4%) in the 15-mg group.

The 3-year progression-free survival (PFS) rate was 72.5% in the 45-mg group, 67.1% in the 30-mg group, and 69.7% in the 15-mg group. The probability of OS at 3 years was 87.4% in the 45-mg group, 87.0% in the 30-mg group, and 92.3% in the 15-mg group.

At 36 months, the BCR::ABL1 response rate was assessed based on mutation status at baseline. Those with a T315I mutation had a response rate of 64% in the 45-mg cohort, 25% in the 30-mg group, and 16% in the 15-mg group. For those who had mutations other than T315I, the response rates were 56% in the 45-mg group, 40% in the 20-mg group, and 50% in the 15-mg group. Those who had no mutation had response rates of 60% in the 45-mg group, 45% in the 30-mg group, and 45% in the 15-mg group.

Grade 3/4 treatment-emergent AEs (TEAEs) occurred in 67% of patients in the 45-mg group, 64% in the 30- mg group, and 63% in the 15-mg group. Grade 5 TEAEs occurred in 3% of patients in both the 45-mg and 15-mg groups, and in 1% of the 30-mg group.

Mayo’s Rapid Fire to Moffitt

PARRONDO: How do you decide which dosage to give to patients if they have cardiovascular risk factors and T315I mutations?

SWEET: I base the starting dose on their baseline pathologic complete response. If it is greater than 1%, I will start at 45 mg, but I am quick to dose reduce as soon as the BCR::ABL1 transcripts are less than 1%. I’m also aggressive as far as cardiovascular prevention. I start everyone—and I want to be clear that to my knowledge, there are no data to support this—on aspirin, and I [also] start everyone on lisinopril [Zestril]. I send everybody to our cardio-oncology clinic for baseline cardiac evaluation to see what can be done to mitigate risk. We’ve had good outcomes with this so far and, personally, I feel comfortable with our approach to using ponatinib, but in our practice, we have been quick to dose reduce from the beginning. We’ve seen less cardiovascular toxicity than what had been reported in a lot of the literature.

PARRONDO: What do you do about the inability to use anticoagulation medicine because of the mechanism of action of ponatinib?

SWEET: I start everyone, even those without baseline hypertension, [on lisinopril]. Most of them seem to still derive some benefit. Most people get a little bit of an increase in their blood pressure but if they don’t have any blood pressure [issues] at baseline, I will start them at a very low dose. We’ll get the cardiologists involved right off the bat, which is also crucial.

Key Efficacy Data of Vodobatinib

Next, results of a phase 1/2 trial (NCT02629692) were presented on the safety and efficacy of vodobatinib in patients with Philadelphia-positive CP-CML.4 The primary end points aimed to determine the maximum tolerated dose or phase 2 dose, safety and therapeutic activity, and pharmacokinetics.

Overall, the complete cytogenetic response (CCyR) was 16.3% at baseline, and 48.8% achieved a major cytogenetic response while on study. A response was not observed in 34.9% of patients. At baseline, MMR was observed in 2.3% of patients, 44.2% achieved MMR, and 53.5% did not have a molecular response.

At 24 months, the major cytogenetic response and MRR as a best response rate was 65.1% of patients and MMR was in 37.1%. The median total overall time to response was 7 months and the median overall time to MMR was 28.6 months. The median duration of CCyR was 15.3 months, and the median duration of MMR was 15.8 months.

The PFS rate at year 1 was 90.6% (95% CI, 76.8%-96.4%), 73.7% (95% CI, 57.7%-84.5%) at year 2, and 63.3% (95% CI, 45.2%-76.8%) at years 3 and 4, respectively.

The most common nonhematologic TEAEs that occurred included those involving the gastrointestinal, musculoskeletal, and connective tissue systems. The most common hematologic TEAE was thrombocytopenia.

Mayo on the Defensive

JAIN: Where can we see vodobatinib coming into play for these patients?

GHORAB: Vodobatinib is not active [in] patients with the T315I [mutation]. It will be [given] after the first- and second-generation [TKIs], especially in those patients who didn’t tolerate the first- or second-generation TKI, but unfortunately, for patients with a T315I [mutation], the only options we have are ponatinib and asciminib.

SWEET: What do you think it will take for this drug to be approved?

GHORAB: I would think of this in 2 ways: One is that a very small proportion of patients we see in our clinic are multidrug resistant or intolerant to ponatinib [or a similar] kind of therapy. Those small groups of patients would benefit from this. The other is [using vodobatinib in] combination with asciminib compared with other TKIs. Combining [these 2] may be a good strategy to improve deeper responses in first-line therapy, as we are looking for other second-generation TKI combinations. That would be an area to focus on.

When the results were tallied, the winner was the multiple myeloma team from Moffitt Cancer Center.


  1. Hughes T, Rea D, Boquimpani C, et al. Dynamics of response and response factors in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after ≥2 prior tyrosine kinase inhibitors (TKIs) in the phase 3 Ascembl study. Blood. 2022;140(suppl 1):6757-6759. doi:10.1182/blood-2022-169110
  2. U.S. FDA approves supplemental new drug application for Takeda’s ICLUSIG® (ponatinib) for adult patients with resistant or intolerant chronic-phase CML. News release. Takeda; December 18, 2020. Accessed January 31, 2023.
  3. Cortes JE, Deininger MW, Lomaia E, et al. Three-year update from the Optic trial: a dose-optimization study of 3 starting doses of ponatinib. Blood. 2022;140(suppl 1):1495-1497. doi:10.1182/blood-2022-157822
  4. Cortes JE, Saikia T, Kim D-W, et al. Efficacy and safety of vodobatinib in patients (pts) with chronic phase Philadelphia positive chronic myeloid leukemia (Ph+ CML): a sub group analysis by lines of tyrosine kinase inhibitor (TKI) therapy. Blood. 2022;140(suppl 1):205-207. doi:10.1182/blood-2022-166452
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