Ponatinib vs imatinib as a frontline treatment for patients with Ph+ ALL

Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL) is an aggressive form of the disease in which underlying genetic alterations impact treatment decisions. Historically, Ph+ ALL has been associated with poor prognosis; however, the introduction of tyrosine kinase inhibitors (TKI) targeting the BCR::ABL1 oncoprotein combined with standard or reduced-intensity chemotherapy has significantly improved the treatment response and long-term survival of patients with Ph+ ALL.

Imatinib is a first-generation TKI approved for adults with relapsed or refractory (R/R) Ph+ ALL. Ponatinib is a third-generation TKI approved for adults with R/R Ph+ ALL harboring the T315I mutation who are resistant to prior TKIs. Until now, the efficacy of ponatinib-based treatment for patients with Ph+ ALL has not been compared to imatinib-based treatments in head-to-head clinical trials. In this article, we summarize the results of a recent publication by Ribera et al.¹ comparing studies to evaluate the efficacy of ponatinib vs imatinib as a frontline treatment for Ph+ ALL.

Study design¹

Individual patient data for ponatinib from two studies, MD Anderson Cancer Center (NCT01424982) and GIMEMA LAL1811 (NCT01641107), and aggregate data for imatinib from published sources, including GRAAPH-2005 (NCT00327678), NCT00038610, and CSI57ADE10, were compared using matched-adjusted indirect comparison. Hazard ratios were calculated for overall survival (OS) and odds ratios for complete molecular response (CMR). The included studies are summarized in Table 1.

Table 1. Ponatinib and imatinib studies included in the MAIC^†*

CVAD, cyclophosphamide, vincristine, doxorubicin, and dexamethasone; MAIC, matching adjusted indirect comparison. *Adapted from Ribera, et al.1 †The MAIC only used data for the imatinib + hyper-CVAD arm. ‡Number of patients treated with imatinib + hyper-CVAD. § Total number of patients in the study.
	MDACC (N = 87)	GIMEMA LAL1811 (N = 44)	GRAAPH-2005 (N = 133‡/268§ )	NCT00038610 (N = 54)	CSI57ADE10 (N = 55)
Treatment	Ponatinib + hyper-CVAD	Ponatinib + steroids	Imatinib + reduced intensity chemotherapy or Imatinib + hyper-CVAD	Imatinib + hyper-CVAD	Imatinib monotherapy followed by age-adapted/intrathecal chemotherapy consolidation with imatinib
Study design	Single-center, open-label, single-arm, phase II	Multicenter, open-label, single-arm, phase II	Multicenter, randomized, open-label, two-arms, phase III	Single-center, open-label, single-arm, phase II	Multicenter, randomized, open-label, single-arm, phase II
Median follow-up duration	45.1 months	34.9 months	4.8 years	130 months	11.2 months

Results¹

Overall, ponatinib + hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) showed significantly prolonged OS and a higher CMR rate compared to imatinib + hyper-CVAD. Ponatinib + steroids also showed prolonged OS and a higher CMR rate compared with imatinib monotherapy induction + imatinib-containing consolidation. The comparative efficacy outcomes are summarized in Table 2 and Table 3.

Table 2. Relative efficacy of ponatinib versus imatinib (OS)*

CI, confidence interval; HR, hazard ratio; OS, overall survival. *Data from Ribera, et al.1 †HR with no censoring on stem cell transplantation ‡HR with censoring on stem cell transplantation
OS	MDACC vs GRAAPH-2005		MDACC vs NCT00038610		GIMEMA LAL1811 vs CSI57ADE10
	HR (95% CI)	p value	HR (95% CI)	p value	HR (95% CI)	p value
Unadjusted comparison	0.41 (0.25–0.68)	<0.001	0.42 (0.24–0.73)†	0.002	0.40 (0.20–0.81)	0.011
0.36 (0.20–0.63)‡	<0.001
Population-adjusted comparison	0.35 (0.17–0.74)	0.006	0.35 (0.18–0.70)†	0.003	0.24 (0.09–0.64)	0.004
0.30 (0.15–0.59)‡	0.001

Table 3. Relative efficacy of ponatinib versus imatinib (CMR)*

CMR, complete molecular response; OR, odds ratio; HR, hazard ratio. *Data from Ribera, et al.1
CMR	MDACC vs GRAAPH-2005		MDACC vs NCT00038610		GIMEMA LAL1811 vs CSI57ADE10
	OR (95% CI)	p value	OR (95% CI)	p value	OR (95% CI)	p value
Unadjusted comparison	12.34 (5.77–26.41)	<0.001	4.93 (2.13–11.39)	<0.001	7.65 (2.48–23.64)	<0.001
Population-adjusted comparison	12.11 (3.77–38.87)	<0.001	5.65 (2.02–15.76)	<0.001	6.20 (1.60–24.00)	0.008

Conclusion

This matched-adjusted indirect comparison analysis showed that ponatinib treatment was more effective compared with imatinib treatment in both high-dose therapy eligible and non-eligible patients with newly diagnosed or minimally treated Ph+ ALL. The findings from this analysis warrant further research comparing ponatinib-based and imatinib-based regimens.