Dasatinib with intensive chemotherapy in newly diagnosed pediatric patients with Ph+ ALL

Dasatinib is approved by the U.S. Food and Drug Administration (FDA) as a second-generation ABL-class tyrosine kinase inhibitor for the treatment of newly diagnosed adult patients with Philadelphia (Ph)-positive acute lymphoblastic leukemia (ALL). The phase II Children’s Oncology Group (COG) AALL0622 (NCT00720109) trial showed promising efficacy and safety of dasatinib in combination with the AALL0031 (NCT00022737)-based intensive chemotherapy backbone in a small cohort of pediatric patients with Ph+ ALL.

Here, we summarize the results of the open-label, single-arm, phase II study, CA180-372/COG AALL1122 (NCT01460160) , recently published by Hunger et al.¹ investigating the efficacy of dasatinib in combination with intensive chemotherapy in newly diagnosed pediatric patients with Ph+ ALL.

Study design

The CA180-372/COG AALL1122 study was a joint COG and European intergroup trial of post-induction treatment of Ph+ ALL (EsPhALL). Patients aged < 18 years with newly diagnosed Ph+ ALL and performance status of at least 60% received EsPhALL-based intensive chemotherapy plus dasatinib 60 mg/m² orally once daily from Day 15 of induction.

Minimal residual disease (MRD) was measured at three time points during therapy: at the end of induction 1A (the first four weeks of treatment), at the end of induction 1B (the second 4 weeks of treatment), and at the end of consolidation block three. Patients with MRD ≥ 0.05% after induction 1B or who remained MRD positive after receiving three consolidation blocks were classified as high risk and allocated to receive hematopoietic stem-cell transplantation in the first complete remission. The remaining patients were considered standard risk and received chemotherapy plus dasatinib for 2 years.

Endpoints

• Primary endpoint: 3-year event-free survival (EFS).
• This trial was to be considered positive if one of the following comparisons to historical controls were met:
  • A 3-year EFS superior to that of patients with Ph+ ALL treated in the high-risk group of AIEOP-BFM 2000 (NCT01117441) (estimated to be 52%)
  • A 3-year EFS non-inferior (with a margin of -5%) or superior (estimated to be 78%) to imatinib plus chemotherapy in the EsPhALL 2010 trial.

Results

Overall, 109 patients were included in the trial and 106 received dasatinib (three patients were excluded). Patient characteristics are shown in Table 1.

Table 1. Patient characteristics*

CNS, central nervous system; HSCT, hematopoietic stem-cell transplantation. *Adapted from Hunger et al.1
Characteristic, % (unless otherwise stated)	All treated patients (n = 106)
Median age at diagnosis, years	9.4
Male	54
Female	46
CNS status
CNS1 (no blasts)	71
CNS2 (< 5 blasts per µL)	24
CNS3 (≥ 5 blasts per µL)	5
Not available	1
Complete remission status
Yes	100
Risk status
Standard risk	82
High risk	18
Treatment received
Dasatinib and chemotherapy alone	86
HSCT in first complete remission	14

Outcomes

The trial met its primary efficacy endpoint.

• The 3-year EFS was superior in patients receiving dasatinib plus intensive chemotherapy when compared to the patients with Ph+ ALL treated in the high-risk group of AIEOP-BFM 2000 (p = 0.032) (Figure 1).
• The 3-year EFS was non-inferior (59.1% [90% confidence interval, 51.8 – 66.2], 90% confidence interval of the treatment difference was –3 to 17.2), but not superior to the 3-year EFS of the amended EsPhALL 2010 study with continuous imatinib and the same chemotherapy backbone (p = 0.27) (Figure 2).

EFS, event-free survival.

 

EFS, event-free survival; EsPhALL, European intergroup trial of post-induction treatment of Ph+ ALL.

Events

• Overall, 48 events occurred among the 106 treated patients, relapses (36%), remission deaths (8%), and second malignant neoplasm (1%).

• The most frequent adverse events were febrile neutropenia, blood infections, and Grade 4 sepsis, as shown in Table 2.
• There were nine deaths in remission due to infections (n = 5), transplantation related (n = 2), cardiac arrest (n = 1), or due to unknown cause (n = 1). No dasatinib-related deaths were recorded.

Table 2. The most frequent adverse events*

NR, not reported. Data are percentages of 106 patients. *Adapted from Hunger et al.1 †Events that were related to dasatinib were not included within events of any cause.
	Any cause†							Related to dasatinib
	Grade 1–2	Grade 3			Grade 4	Grade 5		Grade 1–2			Grade 3		Grade 4
Infections
Febrile neutropenia	1		78	10			0		1	21		2
Bacteremia	2		18	2			0		NR	NR		NR
Sepsis	0		9	25			1		0	3		3

MRD

Based on MRD analysis at the end of induction 1A, all 106 patients reached full remission. Immunoglobulin and T-cell receptor testing revealed that 35% of 86 patients were MRD-negative at the end of induction 1A; this number increased to 62% of 90 patients at the end of induction 1B, and to 89% of 85 patients at the end of consolidation block 3.

Conclusion

Dasatinib plus intensive chemotherapy showed promising efficacy with a manageable safety profile in newly diagnosed pediatric patients with Ph+ ALL. The 3-year EFS was similar to that of previous trials in patients with Ph+ ALL. To further improve the outcomes in children with Ph+ ALL, newer tyrosine kinase inhibitors represent potential strategies that could be investigated in the future trials.