Recommendations for treatment of chronic-phase CML with treatment resistance or intolerance in the third line
| Clinical category . | Case example . | Relevant data . | Comment . | Strength of evidence and urgency for further clinical trials . |
|---|---|---|---|---|
| Asciminib preferred | ||||
| Intolerance to previous TKI therapy. Molecular response achieved | Patient who has received imatinib, nilotinib, and dasatinib and developed significant intolerance or toxicity to each TKI | Phase 1 asciminib study; ASCEMBL, 42% MMR at 6 mo in intolerant cohort | ASCEMBL supports superiority of asciminib over bosutinib in this setting. Very limited role for ponatinib in this setting. Other TKIs may also be appropriate depending on individual circumstances | Good level of evidence. Less urgent priority for further clinical trials |
| Treatment failure (failure to achieve mol targets) but responsive disease (eg, BCR::ABL1 ≤10% or in MCyR) | >1% BCR::ABL1 after 12 mo of imatinib, still >1% after further 6 mo of nilotinib | ASCEMBL, patients in MCyR achieved 46% MMR by 6 mo | These patients are TKI sensitive and may benefit from the greater potency and tolerability of asciminib compared with the current 2-G TKI they are receiving. May be safer option than ponatinib | More data needed. High priority for randomized study of ponatinib vs asciminib |
| Ponatinib preferred | ||||
| BCR::ABL1 >10% (IS) | No cytogenetic and/or molecular response after 6 mo of imatinib followed by 6 mo of nilotinib, patient being considered for an allograft | In OPTIC, patients >10% BCR::ABL1 at study entry (45-mg group) 51% achieved MMR by 3 y In ASCEMBL, patients >10% BCR::ABL1 at baseline: 17% MMR at 24 wk | Both TKIs active in this setting; ponatinib may have an advantage because of its activity against other kinases that might be contributing to resistance pathways | More data needed. OPTIC and ASCEMBL have very different trial designs and follow-up. High priority for randomized study of ponatinib vs asciminib indicated. Combination TKI + asciminib may also be effective |
| Both asciminib and ponatinib may be acceptable | ||||
| T315I mutation | Poor response to 1st-line dasatinib and loss of response after 12 mo with 70% T315I mutation | OPTIC: 60% achieved MMR on ponatinib 45-mg arm by 3 y CABL001X2101: asciminib 200 mg twice a day: 41% MMR after 24 wk | Unclear whether efficacy is superior for either ponatinib vs asciminib. Tolerability may also be similar at the asciminib 200-mg twice daily dose | Longer follow-up needed for asciminib. High priority for randomized study of ponatinib vs asciminib |
| Non-T315I kinase domain mutations | Poor response to 1st-line nilotinib and loss of response after 12 mo with E255K mutation | Non-T315I mutation data incomplete. Only 13% of ASCEMBL patients had a history of kinase domain mutations | Data pending for individual mutations. F359 may confer resistance to asciminib; higher dose of 200 mg twice a day may be necessary | More data needed on individual mutations; preference may depend on specific mutation. Low frequency of specific mutation and clinical heterogeneity a challenge for clinical studies |
| Neither asciminib nor ponatinib particularly effective | ||||
| Compound kinase domain mutations | Poor response to 1st-line dasatinib and loss of response after 12 mo with compound T315I/E255K mutation | Clinical data suggesting lack of efficacy for ponatinib Only 3 patients in ASCEMBL had multiple mutations | In vitro evidence that combination of asciminib plus ponatinib may be effective in this setting (see text) | No clinical evidence. Exploratory trials of combination ponatinib plus asciminib indicated. Asciminib combined with other TKIs may also be effective |
| TKI resistance in the setting of marked cytopenia | Patient who has failed 2 or more TKIs with extended interruptions for severe neutropenia and thrombocytopenia | No published data | This is one of the most challenging settings; an allograft may be the only effective therapy | No evidence exists. Exploratory trials indicated |
| Clinical category . | Case example . | Relevant data . | Comment . | Strength of evidence and urgency for further clinical trials . |
|---|---|---|---|---|
| Asciminib preferred | ||||
| Intolerance to previous TKI therapy. Molecular response achieved | Patient who has received imatinib, nilotinib, and dasatinib and developed significant intolerance or toxicity to each TKI | Phase 1 asciminib study; ASCEMBL, 42% MMR at 6 mo in intolerant cohort | ASCEMBL supports superiority of asciminib over bosutinib in this setting. Very limited role for ponatinib in this setting. Other TKIs may also be appropriate depending on individual circumstances | Good level of evidence. Less urgent priority for further clinical trials |
| Treatment failure (failure to achieve mol targets) but responsive disease (eg, BCR::ABL1 ≤10% or in MCyR) | >1% BCR::ABL1 after 12 mo of imatinib, still >1% after further 6 mo of nilotinib | ASCEMBL, patients in MCyR achieved 46% MMR by 6 mo | These patients are TKI sensitive and may benefit from the greater potency and tolerability of asciminib compared with the current 2-G TKI they are receiving. May be safer option than ponatinib | More data needed. High priority for randomized study of ponatinib vs asciminib |
| Ponatinib preferred | ||||
| BCR::ABL1 >10% (IS) | No cytogenetic and/or molecular response after 6 mo of imatinib followed by 6 mo of nilotinib, patient being considered for an allograft | In OPTIC, patients >10% BCR::ABL1 at study entry (45-mg group) 51% achieved MMR by 3 y In ASCEMBL, patients >10% BCR::ABL1 at baseline: 17% MMR at 24 wk | Both TKIs active in this setting; ponatinib may have an advantage because of its activity against other kinases that might be contributing to resistance pathways | More data needed. OPTIC and ASCEMBL have very different trial designs and follow-up. High priority for randomized study of ponatinib vs asciminib indicated. Combination TKI + asciminib may also be effective |
| Both asciminib and ponatinib may be acceptable | ||||
| T315I mutation | Poor response to 1st-line dasatinib and loss of response after 12 mo with 70% T315I mutation | OPTIC: 60% achieved MMR on ponatinib 45-mg arm by 3 y CABL001X2101: asciminib 200 mg twice a day: 41% MMR after 24 wk | Unclear whether efficacy is superior for either ponatinib vs asciminib. Tolerability may also be similar at the asciminib 200-mg twice daily dose | Longer follow-up needed for asciminib. High priority for randomized study of ponatinib vs asciminib |
| Non-T315I kinase domain mutations | Poor response to 1st-line nilotinib and loss of response after 12 mo with E255K mutation | Non-T315I mutation data incomplete. Only 13% of ASCEMBL patients had a history of kinase domain mutations | Data pending for individual mutations. F359 may confer resistance to asciminib; higher dose of 200 mg twice a day may be necessary | More data needed on individual mutations; preference may depend on specific mutation. Low frequency of specific mutation and clinical heterogeneity a challenge for clinical studies |
| Neither asciminib nor ponatinib particularly effective | ||||
| Compound kinase domain mutations | Poor response to 1st-line dasatinib and loss of response after 12 mo with compound T315I/E255K mutation | Clinical data suggesting lack of efficacy for ponatinib Only 3 patients in ASCEMBL had multiple mutations | In vitro evidence that combination of asciminib plus ponatinib may be effective in this setting (see text) | No clinical evidence. Exploratory trials of combination ponatinib plus asciminib indicated. Asciminib combined with other TKIs may also be effective |
| TKI resistance in the setting of marked cytopenia | Patient who has failed 2 or more TKIs with extended interruptions for severe neutropenia and thrombocytopenia | No published data | This is one of the most challenging settings; an allograft may be the only effective therapy | No evidence exists. Exploratory trials indicated |
Examples of clinical scenarios where asciminib or ponatinib may be indicated are given.
For detailed data from the OPTIC,20 ASCEMBL,10 and CABL001X21019 studies, please refer to the text and references.
MCyR, major cytogenetic response.