Javier Pinilla-Ibarz MD, PhD
Ponatinib is most likely the most powerful tyrosine kinase inhibitor (TKI) approved for the relapsed or refractory chronic myeloid leukemia (CML) after two lines of therapy. In the original PACE study, ponatinib showed deep and durable responses, but arterial occlusive events (AOE) emerged as notable adverse events. Post hoc analyses indicated that AOEs were dose dependent and recommendations to lower the dose from 45 mg to 30 mg after achieving complete cytogenic response (CCR) and to 15 mg after achieving major molecular response (MMR) were used in an attempt to minimize the cardiovascular toxicities. The question remained regarding the optimal dose of ponatinib in terms of efficacy and toxicity. Cortes et al ( Blood 2021 Aug 18.) reported the results of the OPTIC trial where patients with chronic phase CML (CP-CML), resistant/intolerant to at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1T315I mutation, were randomized 1:1:1 to receive 3 different doses of ponatinib daily (45, 30, or 15 mg). Patients who received 45 mg or 30 mg daily reduced their dose to 15 mg upon achievement of response ( BCR-ABL1IS transcript levels ≤1%). The primary endpoint ( BCR-ABL1IS transcript levels ≤1%) was achieved at 12 months in 44.1%, 29.0%, and 23.1% in the 3 cohorts, respectively. Independently confirmed grade 3/4 treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 3 cohorts, respectively. In conclusion, the optimal benefit:risk outcomes occurred with the 45 mg starting dose reduced to 15 mg upon achievement of response.
New drugs with alternative mechanisms of action are always welcome for the treatment of resistant or intolerant CP-CML. Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with the potential to overcome resistance or intolerance to approved TKIs. Rea et al (Blood 2021 Aug 18) reported the results of the ASCEMBL trial that compare 40 mg twice daily asciminib vs. bosutinib in patients with CP-CML refractory to >2 previous lines of therapy. The rates of MMR at week 24 in patients receiving asciminib and bosutinib were 25.5% and 13.2%, respectively (difference 12.2%; P = .029). The bosutinib arm, compared to the asciminib arm, had a more frequent occurrence of grade 3 or higher adverse events (AE; 60.5% vs. 50.6%) and AEs leading to treatment discontinuation (21.1% vs. 5.8%). This will be another important alternative for CP-CML patients failing 2 lines of therapy; however, it is still unclear if the drug may be superior to ponatinib in the same setting.
In the new era of COVID-19, patients with hematologic malignancies are at an increased risk of SARS-CoV-2 disease (COVID-19) and an adverse outcome. However, is unclear if this can be seen across the board in all type of hematologic malignancies, as a low mortality rate has been described in patients with CP-CML, suggesting that TKIs may have a protective role against severe COVID-19. Bonifacio et al ( Cancer Med 2021 Aug 31) conducted a cross-sectional study of 564 consecutive patients with CML who were tested for anti-SARS-CoV-2 IgG/IgM antibodies at their first outpatient visit between May and early November 2020 in 5 hematologic centers representative of 3 Italian regions. Interestingly, the serological prevalence of SARS-CoV-2 infection in patients with CML after the first pandemic wave was similar to that in the general population. The data confirm mild SARS-CoV-2 infection in patients with CML and suggest that patients with CML succeed to mount an antibody response after exposure to SARS-CoV-2 similar to the general population.