Asciminib in the Treatment of Philadelphia Chromosome-Positive Chronic Myeloid Leukemia: Focus on Patient Selection and Outcomes

Figures & data

Table 1 Efficacy of Asciminib by Months 6 and 12

		CML-CP (N=141)
		Resistant/Intolerant, Non-T315I (n=113; Median Follow-Up, 72 Weeks)^a			Resistant/Intolerant, T315I Mutation Present (n=28; Median Follow-Up, 37 Weeks)^a
Treatment Response to Asciminib (%)		Overall	Response Achieved	Response Maintained	Overall	Response Achieved	Response Maintained
CHR		–	92	–	–	88	–
MCyR^b		77	60	87	60	55	80
CCyR^b		70	54	87	44	41	67
MMR^c (in all patients)	6 months	37	24	95	25	21	100
	12 months	48	36	95	28	24	100
MMR (in patients treated with ≤2 TKIs)	6 months	52	33	80	40	33	100
	12 months	60	47	80	44	38	100
MMR (in patients treated with >2 TKIs)	6 months	32	22	100	10	10	0
	12 months	44	34	100	11	11	0
MMR in patients with resistance to/ intolerance of prior ponatinib	6 months	41	23	100	14	14	0
	12 months	57	40	100	17	17	0

Notes: ^aNumber of patients who received ≥1 dose of asciminib. ^bCalculation of patients in whom cytogenetic responses were achieved is based on patients not in respective cytogenetic response categories at baseline. ^cMMR rates by 6 or 12 months were defined as the percentage of patients whose best molecular response by a specific visit was at least MMR. A patient who achieved MMR but then lost this response at or before a particular visit would still be classified as having obtained MMR by that specific time point. From Hughes TP, Mauro MJ, Cortes JE, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. N Engl J Med. 381:2315–232, Copyright © (2019). Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.⁵⁶

Abbreviations: CCyR, complete cytogenetic response; CHR, complete hematologic response; CML-CP, chronic phase chronic myeloid leukemia; MCyR, major cytogenetic response; MMR, major molecular response (BCR::ABL1^IS ≤0.1% on the International Scale); TKI, tyrosine kinase inhibitor.

Figure 1 ASCEMBL study design.

Notes: ^aMust meet lack of efficacy criteria based on the 2013 ELN recommendations for second-line TKI therapy. ^bPatients who discontinued bosutinib treatment due to intolerance or any reason other than lack of efficacy were not allowed to switch to asciminib. Adapted from Blood, volume 138, Rea D, Mauro MJ, Boquimpani et al A Phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Page numbers: 2031–2041, copyright 2021, with permission from Elsevier.⁵⁹

Abbreviations: ABL1, Abelson tyrosine kinase 1; BCR, breakpoint cluster region; CML-CP, chonic myeloid leukemia in chronic phase; ELN, European LeukemiaNet; IS, International Scale; MCyR, major cytogenetic response; CCyR, complete cytogenetic response rate; MMR, major molecular response (BCR::ABL1IS ≤0.1%); TKI, tyrosine kinase inhibitor.

Figure 2 Risk difference (95% CI) for MMR at week 96 from subgroup analyses.

Notes: ^aPatients with T315I and V299L BCR::ABL1 mutations or a nonevaluable mutation assessment were excluded from the subgroup analysis. Reproduced from Hochhaus A, Rea D, Boquimpani et al Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL. Leukemia. Mar 2023;37(3):617–626. Creative Commons.⁶³

Abbreviations: ABL1, Abelson tyrosine kinase 1; BCR, breakpoint cluster region; CI, confidence interval; IS, international scale; TKI, tyrosine kinase inhibitor.

Table 2 Most Frequent Adverse Events (≥10% of Patients in Any Treatment Arm) by Week 24

Event, n (%)^a	Asciminib 40 mg BID (n=156)		Bosutinib 500 mg QD (n=76)
	All Grades	Grade ≥3	All Grades	Grade ≥3
No. of patients with ≥1 adverse event	140 (89.7)	79 (50.6)	73 (96.1)	46 (60.5)
Thrombocytopenia^b	45 (28.8)	34 (21.8)	14 (18.4)	7 (9.2)
Neutropenia^c	34 (21.8)	28 (17.9)	16 (21.1)	11 (14.5)
Headache	25 (16.0)	3 (1.9)	10 (13.2)	0
Diarrhea	18 (11.5)	0	54 (71.1)	8 (10.5)
Hypertension	18 (11.5)	9 (5.8)	3 (3.9)	3 (3.9)
Nausea	18 (11.5)	1 (0.6)	35 (46.1)	0
Fatigue	16 (10.3)	0	7 (9.2)	1 (1.3)
Rash	11 (7.1)	0	18 (23.7)	3 (3.9)
Vomiting	11 (7.1)	2 (1.3)	20 (26.3)	0
Abdominal pain	7 (4.5)	0	11 (14.5)	1 (1.3)
Increased ALT	6 (3.8)	1 (0.6)	21 (27.6)	11 (14.5)
Increased AST	6 (3.8)	1 (0.6)	16 (21.1)	5 (6.6)

Notes: ^aNumbers represent counts of patients. A patient with multiple severity grades for a given adverse event is only counted under the maximum grade; Medical Dictionary for Regulatory Activities version 23.0, Common Terminology Criteria for Adverse Events version 4.03. ^bIncludes thrombocytopenia and decreased platelet count. ^cIncludes neutropenia, decreased neutrophil count, and febrile neutropenia. Reprinted from Blood, 138, Rea 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. 2031–2041, Copyright (2021), with permission from Elsevier.⁵⁹

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; QD, once daily.

Table 3 Ongoing Trials of Asciminib in CML

Line of Therapy	Trial			Study Design	Phase	Primary Outcome Measure
Any	NCT04216563^Citation68			Adults aged ≥18 years with CML-CP to receive asciminib while receiving standard of care dasatinib or nilotinib whether as initial therapy or after prior TKI	2	Rate of molecular response at 12 months
3L+	AIM4CML^Citation69 NCT04666259			Adults aged ≥18 years with CML-CP with/without T315I to receive asciminib monotherapy (CML-CP with T315I mutation treated with ≥1 TKI)	3b	AEs and serious AEs up to 24 weeks
	NCT04795427^Citation70			Adults aged ≥18 years with CML-CP without T315I to receive asciminib monotherapy or best available treatment of investigator’s choice	2	MMR at week 24
	Combination	NCT02081378^Citation71		Adults aged ≥18 years with CML-CP with/without T315I to receive asciminib ± nilotinib, dasatinib, or imatinib (CML-CP with T315I mutation treated with ≥1 TKI with no other effective therapy available)	1	Dose -limiting toxicities during the first cycle of treatment
	ASC4OPT^Citation72 NCT04948333			Adults aged ≥18 years with CML-CP without T315I to receive asciminib monotherapy	3	MMR at 48 weeks with no MMR at baseline
2L	ASC4KIDS^Citation73 NCT04925479 *Pediatrics study			Adults aged ≥1 and <18 years with CML-CP without T315I to receive asciminib monotherapy	1/pediatric formulation 2/adult formulation	Pharmacokinetic parameters AUClast, AUCtau, Cmax, Tmax, and Ctrough for 52 weeks
	ASC2ESCALATE^Citation74 NCT05384587			Adults aged ≥18 years with CML-CP without T315I to receive asciminib monotherapy starting at 80 mg QD with possible dose escalation	2	MMR rate from baseline to 12 months
	Combination	ASC4MORE^Citation75 NCT03578367		Adults aged ≥18 years with CML-CP treated with continued 1L imatinib for ≥1 year who have not achieved DMR to receive imatinib + asciminib (add-on) vs asciminib monotherapy vs switch to nilotinib	2	MR^4.5 between asciminib + imatinib vs imatinib monotherapy
		TFR	NCT04838041^Citation76	Adults aged ≥18 years with CML-CP with either the b3a2 (e14a2) or b2a2 (e13a2) variants that give rise to the p210 BCR::ABL1 protein who relapsed after prior attempt at TFR with imatinib treated with asciminib + imatinib	2	One-year “second” TFR after 12 months of combination therapy
1L			NCT05413915^Citation77	Adults aged ≥18 years with CML-CP treated with 1L imatinib for >4 years and in DMR for at least 12 months prior to randomization to receive asciminib (add-on) vs continued imatinib, followed by an attempt at TFR	3	Event-free survival from randomization until 12 months after TKI discontinuation
		FASCINATION^Citation78 NCT03906292		Adults aged ≥18 years with CML-CP to receive asciminib 12 weeks after the start of imatinib, nilotinib, or dasatinib and after recovery of hematopoiesis or no therapy so far 6 weeks after diagnosis	2	MR^4 at 12 months and MR^4.5 at 36 months
	ASC4FIRST^Citation79 NCT04971226			Adults aged ≥18 years with CML-CP to receive asciminib vs investigator-selected TKI (imatinib, nilotinib, bosutinib, or dasatinib)	3	MMR at week 48
	ASC4START^Citation80 NCT05456191			Adults aged ≥18 years with CML-CP to receive asciminib vs nilotinib	3	Time to discontinuation of study treatment due to AEs
	NCT05143840^Citation81			Adults aged ≥18 years with CML-CP to receive asciminib, and patients who have not achieved a response after 24 months will be offered nilotinib as an add-on therapy	2	DMR Exploratory objective: safety and efficacy of nilotinib add-on to asciminib in patients who have not achieved MR^4.5

Abbreviations: 1L, first line; 2L, second line; 3L+, third line and beyond; AE, adverse event; AUC_last, area under the curve from time zero to the last measurable concentration sampling time; AUC_tau, area under the curve calculated to the end of a dosing interval at steady state; C_max, maximum observed plasma drug concentration after oral dose administration; CML-CP, chronic phase chronic myeloid leukemia; C_trough, minimal concentration before the next dose is administered; DMR, deep molecular response; QD, once daily; TFR, treatment-free remission; TKI, tyrosine kinase inhibitor; T_max, time to peak concentration.

Hughes TP, Mauro MJ, Cortes JE, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. N Engl J Med. 2019;381:2315–2326. doi:10.1056/NEJMoa1902328

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 PubMed Web of Science ®Google Scholar

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