From: A clinician perspective on the treatment of chronic myeloid leukemia in the chronic phase
Key trial information | Key efficacy | Key safety |
---|---|---|
2G TKIs | Â | Â |
Radotinib: 2G TKI with activity against native and kinase-domain mutant BCR::ABL, currently undergoing testing to assess efficacy in CML-CP with failure or intolerance to prior TKI therapy [106] | ||
RERISE (NCT01511289) [107]: phase 3 trial comparing radotinib with imatinib in patients with ND CML-CP in the Republic of Korea, Indonesia, the Philippines, and Thailand | MMR at 12 months (primary endpoint):  Radotinib 300 mg BID 52% (P = 0.0044 vs. imatinib)  Radotinib 400 mg BID 46% (P = 0.0342 vs. imatinib)  Imatinib 30% CCyR at 12 months (secondary endpoint):  Radotinib 300 mg BID 91% (P = 0.0120 vs. imatinib)  Radotinib 400 mg BID 82% (not significant vs. imatinib)  Imatinib 77% | Grade 3–4 neutropenia was the most frequently reported hematologic AE:  Radotinib 300 mg 19%  Radotinib 400 mg 23%  Imatinib 32% |
Phase 3 multinational (Republic of Korea, Turkey, Russian Federation, and Ukraine) trial to assess efficacy in CML-CP with failure or intolerance to prior TKI therapy (NCT03459534; currently recruiting) | Data not yet available. | Data not yet available. |
Flumatinib: imatinib derivative that displays increased efficacy over imatinib in Chinese patients with ND CML-CP with a similar safety profile [96] | ||
FESTnd (NCT02204644) [96]: phase 3 trial: flumatinib vs. imatinib in ND CML-CP | MMR at 6 months (primary endpoint):  Flumatinib 34%, imatinib 18% (P = 0.0006) EMR at 3 months (secondary endpoint):  Flumatinib 82%, imatinib 53% (P < 0.0001) | All-grade AEs more frequent in flumatinib arm:  Diarrhea (n = 79/196, 40%)  Alanine transaminase elevation (n = 51/196, 26%) All-grade AEs more frequent in imatinib arm:  Edema (n = 70/198, 35%)  Pain in extremities (n = 49/198, 25%)  Rash (n = 28/198, 14%)  Neutropenia  Thrombocytopenia  Anemia  Hypophosphatemia |
NCT04677439: currently recruiting patients to a phase 4 trial in China: efficacy and safety of flumatinib in patients with Ph + CML-CP post-imatinib failure | Data not yet available. | Data not yet available. |
3G TKIs | Â | Â |
Vodobatinib: novel 3G TKI with limited off-target activity effective against native and mutated BCR::ABL [108] | ||
NCT02629692: multinational phase 1/2 trial in ponatinib-treated and naive patients with CML-CP who failed ≥ 3 TKIs (or fewer, if not eligible for other approved 3G TKIs) to determine MTD and RP2D [97] | MTD (primary endpoint): 204 mg Efficacy (secondary endpoint):  MMR: 3/16 in ponatinib-treated and 4/15 in ponatinib-naive patients  MCyR: 5/16 in ponatinib-treated patients  CCyR: 3/15 in ponatinib-naive patients  Disease progression: 2/16 in ponatinib-treated and 4/15 in ponatinib-naive patients | TEAEs grade ≥ 3 reported in > 1 ponatinib-treated patient:  2 (13%) each of neutropenia, amylase increase, and thrombocytopenia TEAEs grade ≥ 3 reported in 7 (47%) ponatinib-naive patients:  1 of each: anemia, pneumonia, neutropenia, gout, hypokalemia and thrombocytopenia, dementia, amnesia, and increased liver and pancreatic enzymes |
Olverembatinib: a novel, broad-spectrum BCR::ABL1 TKI active against T315I mutations [98] | ||
Phase 1 dose escalation/expansion trial assessing safety, preliminary efficacy, and pharmacokinetic and dynamic properties in Chinese patients with TKI-resistant CML-CP/AP [99] | CHR within 3 cycles (primary endpoint):  CML-AP: 58% (n = 7/58) MCyR ≥ 3 cycles (primary endpoint):  CML-CP: 54% (n = 21/58) | ≥ 1 grade 3–4 TRAE:  44 (63%) of all patients Dose-limiting toxicities:  2/3 patients in 60 mg cohort |
Phase 1 dose escalation/expansion trial to determine maximum tolerated dose and dose-limiting toxicity in Chinese patients with TKI-resistant CML-CP/AP [98] | CHR:  CML-CP: 95% (n = 52/55)  CML-AP: 85% (n = 11/13) CCyR:  CML-CP: 61% (n = 49/81)  CML-AP: 36% (n = 5/14) | Most common grade ≥ 3 AEs in > 10% patients:  Thrombocytopenia (n = 50/101, 50%)  Leukopenia (n = 20/101, 20%)  Anemia (n = 12/101, 12%) |
4G TKI | Â | Â |
PF-114: potent 4G TKI selective against native BCR::ABL and BCR::ABL harboring the T315I mutation [109] | ||
NCT02885766: phase 1 trial in patients with CML-CP/AP failing ≥ 2 TKIs or with BCR::ABL1 T315I with ≥ 6 months’ therapy to determine MTD and dose-limiting toxicity. Interim analysis at ≥ 6 months [101] | MTD (primary endpoint):  600 mg Dose-limiting toxicity (primary endpoint):  600 mg manifesting as grade 3 psoriasis-like skin lesions MCyR:  6/11 patients receiving 300 mg dose  4/12 patients with the BCR::ABL1 T315I mutation | Discontinuations due to progression:  n = 18/51 (35%) Discontinuations due to AEs:  n = 6/51 (12%) Reversible grade 3 skin toxicity (psoriasis-like skin lesions):  11 patients ≥ 400 mg dose |
STAMP inhibitor | Â | Â |
Asciminib: novel, first-in-class STAMP inhibitor that binds to the myristoyl pocket of BCR::ABL [91] | ||
NCT03106779: multicenter phase 3 trial comparing asciminib and bosutinib in patients with CML-CP previously treated with ≥ 2 TKIs [110] | MMR at 24 weeks (primary endpoint)  Asciminib 26%; bosutinib 13% (P = 0.029) | Grade ≥ 3 TRAEs reported in 51% asciminib- and 61% bosutinib-treated patients 1 patient died due to treatment-related serious AE in the bosutinib arm |