Spotlight on ponatinib in the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia: patient selection and perspectives

Figures & data

Table 1 Inhibition of kinases by different TKIs approved for the treatment of CML and/or ALL

Kinase	Imatinib	Dasatinib	Nilotinib	Bosutinib	Ponatinib
ABL1	X	X	X	X	X
T315I		X	X		X
FGFR		X	X		X
VEGFR			X		X
PDGFR	X	X	X	X	X
KIT	X	X	X		X
FLT3	X		X	X	X
SRC		X	X		X

Note: Over 50% inhibition is indicated by X.

Abbreviations: ALL, acute lymphoblastic leukemia; CML, chronic myeloid leukemia; TKIs, tyrosine kinase inhibitors; ABL1, abelson murine leukemia viral oncogene homolog 1; FGFR, fibroblast growth factor receptor; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; KIT, stem cell growth factor receptor; FLT3, fms-like tyrosine kinase 3; SRC, sarcoma kinase.

Figure 1 Overall survival (OS) of chronic phase CML patients resistant to IM, since IM initiation (A), since IM resistance (B), and since TKI2 initiation (C) in months according to T315I status (dashed line represents patients with T315I mutation, plain line represents patients without T315I mutation).

Notes: n, number of patients. Reproduced with permission from Nicolini FE, Ibrahim AR, Soverini S, et al. The BCR-ABLT315I mutation compromises survival in chronic phase chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitors, in a matched pair analysis. Haematologica. 2013;98(10):1510–1516.¹⁸
Abbreviations: CML, chronic myeloid leukemia; IM, imatinib; TKI, tyrosine kinase inhibitor.

Table 2 Summary of main clinical trials testing ponatinib in CML and ALL

Disease	Reference	Phase	Regimen	Study population	Outcomes	Vascular SEs	Most common SEs
CML	Cortes et al, NCT00660920^Citation15	I	2–60 mg daily	60, resistant to CML - 43, CP - 22, AP/BP - 12, T315I mutation	- CHR 98% MCyR 72% MMR 44% - CHR 36% MCyR 32% - CHR 100% MCyR 92%	HTN 24% MI, CVA, PVD, VTE 24%–48%	Rash (38%) GI SEs/pancreatitis (36%) Arthralgias (26%) Thrombocytopenia (25%)
	Cortes et al, NCT01207440^Citation16	II PACE	45 mg daily Dose reductions: 30 mg daily (patients without CMR) 15 mg daily (patients with CMR)	412, resistant or intolerant to other TKI - 267, CP - 83 AP - 62 BP	3-year OS 78% PFS 60% - MCyR 56% CCyR 46% MMR 34% - CHR 55% MCyR 39% - CHR 31% MCyR 23%	As in Phase I	As in Phase I
	Lipton et al, NCT01650805^Citation22	III EPIC	Ponatinib 45 mg daily (n=155) or imatinib 400 mg daily (n=152) until progression	307, newly diagnosed	MMR at 5 months 94%	MI 6%–9% CVA 3%–6% PVD 4%–6% VTE 3%–5% Five deaths	Pancreatitis 14% Thrombocytopenia 12% Rash 6%
	Jain et al, NCT01570868^Citation23	II	45 mg daily (n=43) 30 mg daily (n=8)	51, newly diagnosed	CCyR 94% MMR 50% CMR 55%	HTN 49% CVA 10%	Myelosuppression 29%
ALL	Cortes et al, NCT00660920^Citation15	I	2–60 mg daily	5	Not reported	As above	As above
	Cortes et al, NCT01207440^Citation16	II PACE	45 mg daily	32, resistant to two TKIs	CHR 41% MCyR 47% CCyR 38%	As above	As above
	Jabbour et al^Citation26	II	Hyper-CVAD plus - Cycle 1: Ponatinib 45 mg daily - Cycle 2 and beyond: - Ponatinib 30 mg daily (patients without CMR) - Ponatinib 15 mg daily (patients with CMR)	66, newly diagnosed	CCyR 100% MMR 97% CMR 77% alloHCT 17%	HTN (12%) Thrombotic events (6%) MI (5%) Two deaths	Infections (52%) LFT abnormalities (29%) Pancreatitis 18% Rash 14%

Abbreviations: ALL, acute lymphoblastic leukemia; alloHCT, allogeneic hematopoietic cell transplantation; AP, accelerated phase; BP, blast phase; CCyR, complete cytogenetic response; CHR, complete hematologic response; CML, chronic myeloid leukemia; CMR, complete molecular response; CP, chronic phase; CVA, cerebrovascular accident; CVAD, central venous access device; GI, gastrointestinal; HTN, hypertension; LFT, liver function test; MCyR, major cytogenetic response; MI, myocardial infarction; MMR, major molecular response; OS, overall survival; PFS, progression-free survival; PVD, peripheral vascular disease; SE, side effects; TKIs, tyrosine kinase inhibitors; VTE, venous thromboembolism.

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