In the Journals

Dasatinib improves outcomes vs. imatinib for pediatric ALL subset

Ching-Hon Pui, MD
Ching-Hon Pui

Dasatinib appeared more effective than imatinib mesylate for treatment of children with Philadelphia chromosome-positive acute lymphoblastic leukemia, according to results of a randomized phase 3 clinical trial published in JAMA Oncology.

In addition, the dasatinib (Sprycel, Bristol-Myers Squibb) regimen provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation, researchers noted.

“There were no randomized trials to compare the efficacy of first-generation and second-generation ABL tyrosine kinase inhibitors for patients with Ph+ALL,” Ching-Hon Pui, MD, pediatric hematologist-oncologist in the department of oncology at St. Jude Children’s Research Hospital, told Healio. “However, previous research showed that dasatinib at 80 mg/m² per day yielded promising results. We therefore asked our Chinese colleagues to conduct this research because they have an adequate number of patients to address this important question.”

The prospective Chinese Children’s Cancer Group study ALL-2015 included 189 children (median age, 7.8 years; interquartile range [IQR], 5.2-11.3; 72% male) with Ph+ALL treated across 20 hospitals in China.

Researchers randomly assigned the children to the second-generation dual ABL/SRC TKI dasatinib (n = 92) at a daily dose of 80 mg/m² or the first-generation ABL TKI imatinib mesylate (n = 97) at a daily dose of 300 mg/m². All children had been treated with dexamethasone for 4 days followed by remission induction with prednisone acetate, vincristine, daunorubicin hydrochloride and pegaspargase on days 5 to 28, and cyclophosphamide, cytarabine and mercaptopurine on days 29 to 35.

EFS served as the primary endpoint. OS, relapse and death associated with adverse events served as additional endpoints.

Median follow-up was 26.4 months (IQR, 16.3-34.1).

At 4 years, the dasatinib group achieved an EFS rate of 71% (95% CI, 56.2-89.6) and an OS rate of 88.4% (95% CI, 81.3-96.1) compared with an EFS rate of 48.9% (95% CI, 32-74.5; P = .005) and an OS rate of 69.2% (95% CI, 55.6-86.2; P = .04) for the imatinib group.

Moreover, 4-year cumulative risk for any relapse was 19.8% (95% CI, 4.2-35.4) in the dasatinib group vs. 34.4% (95% CI, 15.6-53.2) in the imatinib group (P = .01).

Although 4-year cumulative risk for an isolated CNS relapse appeared lower with dasatinib (2.7%; 95% CI, 0-8.1) than with imatinib (8.4%; 95% CI, 1.2-15.6), researchers did not observe a significant difference in cumulative risk for any CNS relapse, including isolated plus combined with hematologic (10.1%; 95% CI, 0-23.3 vs. 9.4%; 95% CI, 1.9-19.9) or cumulative risk for death in remission (5.6%; 95% CI, 0.8-10.4 vs. 4.3%; 95% CI, 0.2-8.4).

Results of the intention-to-treat analysis showed factors associated with inferior EFS in the dasatinib group included leukocyte cell count of at least 100 × 103/L at diagnosis, CNS3 status, high-risk classification, and increased minimal residual disease on days 19 and 46.

Researchers observed no differences in the frequency of severe adverse events between the two treatment groups. The most common adverse effects included infections and pancreatitis. Five fatal infections occurred in each group; however, no deaths could be attributed directly to either TKI.

The researchers noted several study limitations, including the fact that some children abandoned study treatment due to economic constraints, the perception of incurability, severe adverse effects and concern over late complications.

“With the availability of third-generation ABL TKI bispecific antibodies, such as blinatumomab [Blincyto, Amgen] and BCL-2 inhibitors, we will now conduct research to see if they can improve outcomes and [reduce] toxicity,” Pui told Healio.

Karen Rabin, MD, PhD
Karen R. Rabin

Although the early outcome data supporting use of the dasatinib-based regimen for Ph+ALL appear promising, key questions remain, including the optimal chemotherapy backbone for standard-risk patients, Karen R. Rabin, MD, PhD, director of the leukemia program at Baylor College of Medicine, wrote in an accompanying editorial.

“As noted by [Pui] and colleagues, a less intensive backbone regimen may be particularly beneficial in countries where treatment refusal and abandonment remain substantial challenges,” Rabin wrote “Ultimately, the goal of targeted therapy is to maximize antileukemic efficacy while minimizing treatment-related toxic effects, as stated at the start of TKI era more than 2 decades ago. The evolution of treatment for Ph+ALL since that time highlights both successes and challenges in realizing these goals. Further studies are needed to address remaining questions relating to the optimal choice of TKI [and] chemotherapy backbone, as well as the role of hematopoietic stem cell transplant, immunotherapies and non-TKI targeted therapies in the management of Ph+ALL.” – by Jennifer Southall

For more information:

Ching-Hon Pui, MD, can be reached at St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105; email: ching-hon.pui@stjude.org.

Disclosures: Pui reports advisory board roles with Adaptive Biotechnologies Inc. and Bristol-Myers Squibb, and receiving honoraria and reimbursement for travel expenses from Amgen. Please see the study for all other authors’ relevant financial disclosures. Rabin reports no relevant financial disclosures.

Ching-Hon Pui, MD
Ching-Hon Pui

Dasatinib appeared more effective than imatinib mesylate for treatment of children with Philadelphia chromosome-positive acute lymphoblastic leukemia, according to results of a randomized phase 3 clinical trial published in JAMA Oncology.

In addition, the dasatinib (Sprycel, Bristol-Myers Squibb) regimen provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation, researchers noted.

“There were no randomized trials to compare the efficacy of first-generation and second-generation ABL tyrosine kinase inhibitors for patients with Ph+ALL,” Ching-Hon Pui, MD, pediatric hematologist-oncologist in the department of oncology at St. Jude Children’s Research Hospital, told Healio. “However, previous research showed that dasatinib at 80 mg/m² per day yielded promising results. We therefore asked our Chinese colleagues to conduct this research because they have an adequate number of patients to address this important question.”

The prospective Chinese Children’s Cancer Group study ALL-2015 included 189 children (median age, 7.8 years; interquartile range [IQR], 5.2-11.3; 72% male) with Ph+ALL treated across 20 hospitals in China.

Researchers randomly assigned the children to the second-generation dual ABL/SRC TKI dasatinib (n = 92) at a daily dose of 80 mg/m² or the first-generation ABL TKI imatinib mesylate (n = 97) at a daily dose of 300 mg/m². All children had been treated with dexamethasone for 4 days followed by remission induction with prednisone acetate, vincristine, daunorubicin hydrochloride and pegaspargase on days 5 to 28, and cyclophosphamide, cytarabine and mercaptopurine on days 29 to 35.

EFS served as the primary endpoint. OS, relapse and death associated with adverse events served as additional endpoints.

Median follow-up was 26.4 months (IQR, 16.3-34.1).

At 4 years, the dasatinib group achieved an EFS rate of 71% (95% CI, 56.2-89.6) and an OS rate of 88.4% (95% CI, 81.3-96.1) compared with an EFS rate of 48.9% (95% CI, 32-74.5; P = .005) and an OS rate of 69.2% (95% CI, 55.6-86.2; P = .04) for the imatinib group.

Moreover, 4-year cumulative risk for any relapse was 19.8% (95% CI, 4.2-35.4) in the dasatinib group vs. 34.4% (95% CI, 15.6-53.2) in the imatinib group (P = .01).

Although 4-year cumulative risk for an isolated CNS relapse appeared lower with dasatinib (2.7%; 95% CI, 0-8.1) than with imatinib (8.4%; 95% CI, 1.2-15.6), researchers did not observe a significant difference in cumulative risk for any CNS relapse, including isolated plus combined with hematologic (10.1%; 95% CI, 0-23.3 vs. 9.4%; 95% CI, 1.9-19.9) or cumulative risk for death in remission (5.6%; 95% CI, 0.8-10.4 vs. 4.3%; 95% CI, 0.2-8.4).

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Results of the intention-to-treat analysis showed factors associated with inferior EFS in the dasatinib group included leukocyte cell count of at least 100 × 103/L at diagnosis, CNS3 status, high-risk classification, and increased minimal residual disease on days 19 and 46.

Researchers observed no differences in the frequency of severe adverse events between the two treatment groups. The most common adverse effects included infections and pancreatitis. Five fatal infections occurred in each group; however, no deaths could be attributed directly to either TKI.

The researchers noted several study limitations, including the fact that some children abandoned study treatment due to economic constraints, the perception of incurability, severe adverse effects and concern over late complications.

“With the availability of third-generation ABL TKI bispecific antibodies, such as blinatumomab [Blincyto, Amgen] and BCL-2 inhibitors, we will now conduct research to see if they can improve outcomes and [reduce] toxicity,” Pui told Healio.

Karen Rabin, MD, PhD
Karen R. Rabin

Although the early outcome data supporting use of the dasatinib-based regimen for Ph+ALL appear promising, key questions remain, including the optimal chemotherapy backbone for standard-risk patients, Karen R. Rabin, MD, PhD, director of the leukemia program at Baylor College of Medicine, wrote in an accompanying editorial.

“As noted by [Pui] and colleagues, a less intensive backbone regimen may be particularly beneficial in countries where treatment refusal and abandonment remain substantial challenges,” Rabin wrote “Ultimately, the goal of targeted therapy is to maximize antileukemic efficacy while minimizing treatment-related toxic effects, as stated at the start of TKI era more than 2 decades ago. The evolution of treatment for Ph+ALL since that time highlights both successes and challenges in realizing these goals. Further studies are needed to address remaining questions relating to the optimal choice of TKI [and] chemotherapy backbone, as well as the role of hematopoietic stem cell transplant, immunotherapies and non-TKI targeted therapies in the management of Ph+ALL.” – by Jennifer Southall

For more information:

Ching-Hon Pui, MD, can be reached at St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105; email: ching-hon.pui@stjude.org.

Disclosures: Pui reports advisory board roles with Adaptive Biotechnologies Inc. and Bristol-Myers Squibb, and receiving honoraria and reimbursement for travel expenses from Amgen. Please see the study for all other authors’ relevant financial disclosures. Rabin reports no relevant financial disclosures.