Inhibitor may benefit certain ALL patients

PHILADELPHIA—Results of preclinical research suggest the BCL-2 inhibitor ABT-199 (venetoclax) may be effective in certain pediatric patients with acute lymphoblastic leukemia (ALL).

In xenograft models of various ALL subtypes, ABT-199 produced an objective response rate below 30%.

However, additional analyses unearthed information that could potentially help us identify which ALL patients might respond to the drug.

Santi Suryani, PhD, of the Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues presented this research at the AACR Annual Meeting 2015 (abstract 3276*). The work was supported by AbbVie, one of the companies developing ABT-199.

Dr Suryani and her colleagues decided to investigate ABT-199 in pediatric ALL after observing mixed results with the BCL-2/BCL-W/BCL-XL inhibitor ABT-263 (navitoclax).

ABT-263 delayed ALL progression in nearly all of the xenograft models the team tested and produced a 61% response rate. However, the drug also induced BCL-XL-mediated thrombocytopenia.

As ABT-199 doesn’t target BCL-XL, the researchers thought the drug might produce similar responses as ABT-263 without inducing thrombocytopenia.

“When ABT-199 came into the picture, we were very excited,” Dr Suryani said. “We thought, ‘This is a wonder drug. This will cure pediatric ALL.’”

To test this hypothesis, the team compared ABT-199 (100 mg/kg x 21 days) and vehicle control in 19 pediatric ALL patient-derived xenografts, including infant mixed-lineage leukemia (MLL) ALL (n=4), B-cell precursor (BCP) ALL (n=5), BCP-ALL categorized as Ph-like (n=4), T-cell ALL (n=4), and early T-cell precursor (ETP) ALL (n=2).

ABT-199 significantly delayed progression in 12 xenografts (63%) for periods ranging from 0.4 days to 28 days. And the drug produced objective responses in 5 xenografts (26%).

Responses occurred in MLL-ALL, BCP-ALL, and Ph-like BCP ALL, but not T-cell ALL or ETP-ALL. Complete responses were seen in MLL-ALL (n=1) and BCP-ALL (n=2), and partial responses occurred in MLL-ALL (n=1) and Ph-like BCP-ALL (n=1).

As the response rate with ABT-263 was more than double that of ABT-199 (61% vs 26%), the researchers found the results with ABT-199 “a little bit disappointing,” according to Dr Suryani.

“But we thought, ‘That’s okay. That already tells us the science behind it—that pediatric ALL is probably more BCL-XL-dependent, rather than BCL-2-dependent,’” she said. “We wondered if there was any way we could come up with a predictive biomarker so we could select patients who will benefit from this treatment.”

With that in mind, the researchers evaluated the link between protein expression and response. They looked at BCL-2 and BCL-XL, as well as a range of other proteins, including BCL-W, MCL1, BAK1, and BAX, among others.

And they found that high BCL-XL and low BCL-2 expression were significantly associated with ABT-199 resistance.

The researchers are still investigating ways to guide treatment with ABT-199 in ALL. They are also hoping to improve responses by administering the drug in combination with other agents.

*Information in the abstract differs from that presented at the meeting.

PHILADELPHIA—Results of preclinical research suggest the BCL-2 inhibitor ABT-199 (venetoclax) may be effective in certain pediatric patients with acute lymphoblastic leukemia (ALL).

In xenograft models of various ALL subtypes, ABT-199 produced an objective response rate below 30%.

However, additional analyses unearthed information that could potentially help us identify which ALL patients might respond to the drug.

Santi Suryani, PhD, of the Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues presented this research at the AACR Annual Meeting 2015 (abstract 3276*). The work was supported by AbbVie, one of the companies developing ABT-199.

Dr Suryani and her colleagues decided to investigate ABT-199 in pediatric ALL after observing mixed results with the BCL-2/BCL-W/BCL-XL inhibitor ABT-263 (navitoclax).

ABT-263 delayed ALL progression in nearly all of the xenograft models the team tested and produced a 61% response rate. However, the drug also induced BCL-XL-mediated thrombocytopenia.

As ABT-199 doesn’t target BCL-XL, the researchers thought the drug might produce similar responses as ABT-263 without inducing thrombocytopenia.

“When ABT-199 came into the picture, we were very excited,” Dr Suryani said. “We thought, ‘This is a wonder drug. This will cure pediatric ALL.’”

To test this hypothesis, the team compared ABT-199 (100 mg/kg x 21 days) and vehicle control in 19 pediatric ALL patient-derived xenografts, including infant mixed-lineage leukemia (MLL) ALL (n=4), B-cell precursor (BCP) ALL (n=5), BCP-ALL categorized as Ph-like (n=4), T-cell ALL (n=4), and early T-cell precursor (ETP) ALL (n=2).

ABT-199 significantly delayed progression in 12 xenografts (63%) for periods ranging from 0.4 days to 28 days. And the drug produced objective responses in 5 xenografts (26%).

Responses occurred in MLL-ALL, BCP-ALL, and Ph-like BCP ALL, but not T-cell ALL or ETP-ALL. Complete responses were seen in MLL-ALL (n=1) and BCP-ALL (n=2), and partial responses occurred in MLL-ALL (n=1) and Ph-like BCP-ALL (n=1).

As the response rate with ABT-263 was more than double that of ABT-199 (61% vs 26%), the researchers found the results with ABT-199 “a little bit disappointing,” according to Dr Suryani.

“But we thought, ‘That’s okay. That already tells us the science behind it—that pediatric ALL is probably more BCL-XL-dependent, rather than BCL-2-dependent,’” she said. “We wondered if there was any way we could come up with a predictive biomarker so we could select patients who will benefit from this treatment.”

With that in mind, the researchers evaluated the link between protein expression and response. They looked at BCL-2 and BCL-XL, as well as a range of other proteins, including BCL-W, MCL1, BAK1, and BAX, among others.

And they found that high BCL-XL and low BCL-2 expression were significantly associated with ABT-199 resistance.

The researchers are still investigating ways to guide treatment with ABT-199 in ALL. They are also hoping to improve responses by administering the drug in combination with other agents.

*Information in the abstract differs from that presented at the meeting.

PHILADELPHIA—Results of preclinical research suggest the BCL-2 inhibitor ABT-199 (venetoclax) may be effective in certain pediatric patients with acute lymphoblastic leukemia (ALL).

In xenograft models of various ALL subtypes, ABT-199 produced an objective response rate below 30%.

However, additional analyses unearthed information that could potentially help us identify which ALL patients might respond to the drug.

Santi Suryani, PhD, of the Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues presented this research at the AACR Annual Meeting 2015 (abstract 3276*). The work was supported by AbbVie, one of the companies developing ABT-199.

Dr Suryani and her colleagues decided to investigate ABT-199 in pediatric ALL after observing mixed results with the BCL-2/BCL-W/BCL-XL inhibitor ABT-263 (navitoclax).

ABT-263 delayed ALL progression in nearly all of the xenograft models the team tested and produced a 61% response rate. However, the drug also induced BCL-XL-mediated thrombocytopenia.

As ABT-199 doesn’t target BCL-XL, the researchers thought the drug might produce similar responses as ABT-263 without inducing thrombocytopenia.

“When ABT-199 came into the picture, we were very excited,” Dr Suryani said. “We thought, ‘This is a wonder drug. This will cure pediatric ALL.’”

To test this hypothesis, the team compared ABT-199 (100 mg/kg x 21 days) and vehicle control in 19 pediatric ALL patient-derived xenografts, including infant mixed-lineage leukemia (MLL) ALL (n=4), B-cell precursor (BCP) ALL (n=5), BCP-ALL categorized as Ph-like (n=4), T-cell ALL (n=4), and early T-cell precursor (ETP) ALL (n=2).

ABT-199 significantly delayed progression in 12 xenografts (63%) for periods ranging from 0.4 days to 28 days. And the drug produced objective responses in 5 xenografts (26%).

Responses occurred in MLL-ALL, BCP-ALL, and Ph-like BCP ALL, but not T-cell ALL or ETP-ALL. Complete responses were seen in MLL-ALL (n=1) and BCP-ALL (n=2), and partial responses occurred in MLL-ALL (n=1) and Ph-like BCP-ALL (n=1).

As the response rate with ABT-263 was more than double that of ABT-199 (61% vs 26%), the researchers found the results with ABT-199 “a little bit disappointing,” according to Dr Suryani.

“But we thought, ‘That’s okay. That already tells us the science behind it—that pediatric ALL is probably more BCL-XL-dependent, rather than BCL-2-dependent,’” she said. “We wondered if there was any way we could come up with a predictive biomarker so we could select patients who will benefit from this treatment.”

With that in mind, the researchers evaluated the link between protein expression and response. They looked at BCL-2 and BCL-XL, as well as a range of other proteins, including BCL-W, MCL1, BAK1, and BAX, among others.

And they found that high BCL-XL and low BCL-2 expression were significantly associated with ABT-199 resistance.

The researchers are still investigating ways to guide treatment with ABT-199 in ALL. They are also hoping to improve responses by administering the drug in combination with other agents.

*Information in the abstract differs from that presented at the meeting.