Leukemia, Myelodysplasia, Transplantation

The Food and Drug Administration has approved ibrutinib for the treatment of patients with relapsed or refractory marginal zone lymphoma (MZL), the drug’s manufacturers report.

The approval marks the fifth indication for ibrutinib (Imbruvica) in just over 4 years, and ibrutinib is the first agent specifically approved for relapsed/refractory MZL, according to press releases issued by Janssen Biotech and Pharmacyclics, the two manufacturers that jointly developed and marketed the Bruton tyrosine kinase inhibitor.

hematologynews@frontlinemedcom.com

On Twitter @HematologyNews1

The Food and Drug Administration has approved ibrutinib for the treatment of patients with relapsed or refractory marginal zone lymphoma (MZL), the drug’s manufacturers report.

The approval marks the fifth indication for ibrutinib (Imbruvica) in just over 4 years, and ibrutinib is the first agent specifically approved for relapsed/refractory MZL, according to press releases issued by Janssen Biotech and Pharmacyclics, the two manufacturers that jointly developed and marketed the Bruton tyrosine kinase inhibitor.

hematologynews@frontlinemedcom.com

On Twitter @HematologyNews1

The Food and Drug Administration has approved ibrutinib for the treatment of patients with relapsed or refractory marginal zone lymphoma (MZL), the drug’s manufacturers report.

The approval marks the fifth indication for ibrutinib (Imbruvica) in just over 4 years, and ibrutinib is the first agent specifically approved for relapsed/refractory MZL, according to press releases issued by Janssen Biotech and Pharmacyclics, the two manufacturers that jointly developed and marketed the Bruton tyrosine kinase inhibitor.

hematologynews@frontlinemedcom.com

On Twitter @HematologyNews1

Inpatient palliative care can help maintain quality of life (QoL) in patients undergoing hematopoietic stem cell transplantation (HCT), based on the results of a randomized clinical trial to assess the effect of inpatient palliative care on patient and caregiver-reported outcomes while hospitalized for HCT and for 3 months after transplantation.

During the 2-week period following their transplants, patients who received inpatient palliative care experienced a 14.72-point decrease in QoL, compared with a 21.54-point decrease in QoL for those assigned to standard transplant care alone. The difference was statistically significant (JAMA. 2016;316[20]:2094-2103. doi:10.1001/jama.2016.16786).

In addition to the QoL results, Areej El-Jawahri, MD, of Massachusetts General Hospital in Boston, and coauthors, noted that “exploratory secondary outcomes also showed that patients in the palliative care group benefited, with less increase in their depression symptoms, lower anxiety symptoms, and less increase in symptom burden compared with those receiving standard transplant care.

“Thus, palliative care may help to lessen the decline in QoL experienced by patients during hospitalization for HCT, which has long been perceived as a natural aspect of the transplantation process.”

The study cohort comprised 160 adults with hematologic malignancies undergoing autologous/allogeneic HCT, and 94 caregivers.

A total of 81 patients were assigned to the intervention, and were seen by palliative care clinicians at least twice a week while they were hospitalized. The palliative care intervention focused on managing both physical and psychological symptoms, and those who were assigned to the standard care arm (n = 79) could also request to be seen by the palliative care team.

Quality of life was measured based on mean FACT-BMT score. In the palliative care group, the FACT-BMT score was 110.26 at hospitalization and 95.46 at 2 weeks after transplant (mean change, −14.72). For the standard care group, FACT-BMT score was 106.83 at hospitalization and 85.42 at 2 weeks after transplant (mean change, −21.54) The −6.82 difference between the group groups was statistically significant (95% CI, −13.48 to −0.16; P = .045).

When looking at secondary outcomes, those in the intervention group had lower mean depression scores at 2 weeks based on the HADS-D measure. For the intervention group, the mean baseline score was 3.95 and the mean week 2 score was 6.39. For the control group, the baseline score was 4.94 and the week 2 score was 8.86. The difference between the groups was 1.49 (95% CI, 0.20-2.78; P = .02). Depression scores remained lower in the intervention group at 3 months.

The intervention group also reported a decrease in anxiety symptoms, but the control group reported an increase in anxiety symptoms from baseline to week 2 on the HADS-A measure. The mean difference in score between the two groups was 1.92; (95% CI, 0.83-3.01; P less than .001). However, there was no significant difference between the two groups at 3 months after transplant.

The study was supported by the National Palliative Care Research Foundation and grant K24 CA 181253 from the National Cancer Institute. Dr. El-Jawahri reported no disclosures.

Inpatient palliative care can help maintain quality of life (QoL) in patients undergoing hematopoietic stem cell transplantation (HCT), based on the results of a randomized clinical trial to assess the effect of inpatient palliative care on patient and caregiver-reported outcomes while hospitalized for HCT and for 3 months after transplantation.

During the 2-week period following their transplants, patients who received inpatient palliative care experienced a 14.72-point decrease in QoL, compared with a 21.54-point decrease in QoL for those assigned to standard transplant care alone. The difference was statistically significant (JAMA. 2016;316[20]:2094-2103. doi:10.1001/jama.2016.16786).

In addition to the QoL results, Areej El-Jawahri, MD, of Massachusetts General Hospital in Boston, and coauthors, noted that “exploratory secondary outcomes also showed that patients in the palliative care group benefited, with less increase in their depression symptoms, lower anxiety symptoms, and less increase in symptom burden compared with those receiving standard transplant care.

“Thus, palliative care may help to lessen the decline in QoL experienced by patients during hospitalization for HCT, which has long been perceived as a natural aspect of the transplantation process.”

The study cohort comprised 160 adults with hematologic malignancies undergoing autologous/allogeneic HCT, and 94 caregivers.

A total of 81 patients were assigned to the intervention, and were seen by palliative care clinicians at least twice a week while they were hospitalized. The palliative care intervention focused on managing both physical and psychological symptoms, and those who were assigned to the standard care arm (n = 79) could also request to be seen by the palliative care team.

Quality of life was measured based on mean FACT-BMT score. In the palliative care group, the FACT-BMT score was 110.26 at hospitalization and 95.46 at 2 weeks after transplant (mean change, −14.72). For the standard care group, FACT-BMT score was 106.83 at hospitalization and 85.42 at 2 weeks after transplant (mean change, −21.54) The −6.82 difference between the group groups was statistically significant (95% CI, −13.48 to −0.16; P = .045).

When looking at secondary outcomes, those in the intervention group had lower mean depression scores at 2 weeks based on the HADS-D measure. For the intervention group, the mean baseline score was 3.95 and the mean week 2 score was 6.39. For the control group, the baseline score was 4.94 and the week 2 score was 8.86. The difference between the groups was 1.49 (95% CI, 0.20-2.78; P = .02). Depression scores remained lower in the intervention group at 3 months.

The intervention group also reported a decrease in anxiety symptoms, but the control group reported an increase in anxiety symptoms from baseline to week 2 on the HADS-A measure. The mean difference in score between the two groups was 1.92; (95% CI, 0.83-3.01; P less than .001). However, there was no significant difference between the two groups at 3 months after transplant.

The study was supported by the National Palliative Care Research Foundation and grant K24 CA 181253 from the National Cancer Institute. Dr. El-Jawahri reported no disclosures.

Inpatient palliative care can help maintain quality of life (QoL) in patients undergoing hematopoietic stem cell transplantation (HCT), based on the results of a randomized clinical trial to assess the effect of inpatient palliative care on patient and caregiver-reported outcomes while hospitalized for HCT and for 3 months after transplantation.

During the 2-week period following their transplants, patients who received inpatient palliative care experienced a 14.72-point decrease in QoL, compared with a 21.54-point decrease in QoL for those assigned to standard transplant care alone. The difference was statistically significant (JAMA. 2016;316[20]:2094-2103. doi:10.1001/jama.2016.16786).

In addition to the QoL results, Areej El-Jawahri, MD, of Massachusetts General Hospital in Boston, and coauthors, noted that “exploratory secondary outcomes also showed that patients in the palliative care group benefited, with less increase in their depression symptoms, lower anxiety symptoms, and less increase in symptom burden compared with those receiving standard transplant care.

“Thus, palliative care may help to lessen the decline in QoL experienced by patients during hospitalization for HCT, which has long been perceived as a natural aspect of the transplantation process.”

The study cohort comprised 160 adults with hematologic malignancies undergoing autologous/allogeneic HCT, and 94 caregivers.

A total of 81 patients were assigned to the intervention, and were seen by palliative care clinicians at least twice a week while they were hospitalized. The palliative care intervention focused on managing both physical and psychological symptoms, and those who were assigned to the standard care arm (n = 79) could also request to be seen by the palliative care team.

Quality of life was measured based on mean FACT-BMT score. In the palliative care group, the FACT-BMT score was 110.26 at hospitalization and 95.46 at 2 weeks after transplant (mean change, −14.72). For the standard care group, FACT-BMT score was 106.83 at hospitalization and 85.42 at 2 weeks after transplant (mean change, −21.54) The −6.82 difference between the group groups was statistically significant (95% CI, −13.48 to −0.16; P = .045).

When looking at secondary outcomes, those in the intervention group had lower mean depression scores at 2 weeks based on the HADS-D measure. For the intervention group, the mean baseline score was 3.95 and the mean week 2 score was 6.39. For the control group, the baseline score was 4.94 and the week 2 score was 8.86. The difference between the groups was 1.49 (95% CI, 0.20-2.78; P = .02). Depression scores remained lower in the intervention group at 3 months.

The intervention group also reported a decrease in anxiety symptoms, but the control group reported an increase in anxiety symptoms from baseline to week 2 on the HADS-A measure. The mean difference in score between the two groups was 1.92; (95% CI, 0.83-3.01; P less than .001). However, there was no significant difference between the two groups at 3 months after transplant.

The study was supported by the National Palliative Care Research Foundation and grant K24 CA 181253 from the National Cancer Institute. Dr. El-Jawahri reported no disclosures.

Saccharomyces cerevisiae
as it buds before dividing
Image by Carolyn Larabell

L-asparaginase derived from baker’s yeast has shown early promise for treating acute lymphoblastic leukemia (ALL), according to researchers. 

The team isolated L-asparaginase from Saccharomyces cerevisiae and found the enzyme could kill ALL cells in vitro, while largely sparing healthy control cells.

Gisele Monteiro de Souza, PhD, of the University of São Paulo in São Paulo, Brazil, and her colleagues detailed these findings in Scientific Reports.

“In this study, we characterized the enzyme L-asparaginase from S cerevisiae,” Dr Souza said. “The results show this protein can efficiently annihilate leukemia cells with low cytotoxicity to healthy cells.”

She and her colleagues conducted this study in search of alternatives to L-asparaginase extracted from bacteria (Escherichia coli and Erwinia chrysanthemi).

“Our goal in this project wasn’t to produce the enzyme, but rather to find a new source of the biodrug in microorganisms for use in patients who develop resistance to the bacterial enzyme,” said study author Marcos Antonio de Oliveira, of São Paulo State University in São Vicente, Brazil.

To this end, the researchers isolated fungi from several different Brazilian environments as well as marine and land environments in Antarctica. According to Oliveira, these organisms often secrete asparaginase into the extracellular medium in response to a shortage of nitrogen.

“This lowers the cost of purifying the molecule for drug production, an important factor from an industrial standpoint,” he said.

The group also used bioinformatics tools to mine information on the genomes of several microorganisms from international databases.

In this way, they identified a gene responsible for producing an enzyme that closely resembles the enzymes found in E coli and E chrysanthemi, but with a number of advantages, in the genome of S cerevisiae.

The gene of interest from L-asparaginase was cloned, and the researchers used genetic engineering to make E coli express large amounts of the enzyme originally found in yeast.

“We were able to obtain the recombinant protein,” said study author Iris Munhoz Costa, of the University of São Paulo.

“We then performed studies to characterize its secondary structure and identify important regions called catalytic sites. Finally, we evaluated its efficacy in vitro.”

The enzyme was tested in 3 different cell lines: ALL cells incapable of producing asparagine at normal levels (MOLT4), another ALL cell line capable of producing asparagine at normal levels (REH), and non-malignant control cells (HUVECs).

These 3 cell lines were subdivided into 2 groups. One was treated with L-asparaginase derived from E coli enzyme, and the other was treated with L-asparaginase from yeast.

“The bacterial enzyme killed about 90% of the MOLT4 human leukemia cells and displayed low toxicity to the healthy HUVEC cells, killing only 10%,” Dr Souza said.

“The yeast enzyme killed between 70% and 80% of the MOLT4 cells and displayed less than 10% toxicity for HUVEC cells. Neither was significantly effective against REH cells.”

In her view, the results are encouraging, in contrast with those of studies performed with the same enzyme in the 1970s. At that time, the tests involved a version of the protein extracted directly from yeast and containing many impurities.

The group’s next step is to perform new in vitro trials with different cell types to evaluate the immune response and toxicity. If the results are positive, the first tests in animals may be next.

The researchers are also studying possible modifications that could be made to the molecule’s structure to increase antitumor activity and extend the enzyme’s half-life.

Saccharomyces cerevisiae
as it buds before dividing
Image by Carolyn Larabell

L-asparaginase derived from baker’s yeast has shown early promise for treating acute lymphoblastic leukemia (ALL), according to researchers. 

The team isolated L-asparaginase from Saccharomyces cerevisiae and found the enzyme could kill ALL cells in vitro, while largely sparing healthy control cells.

Gisele Monteiro de Souza, PhD, of the University of São Paulo in São Paulo, Brazil, and her colleagues detailed these findings in Scientific Reports.

“In this study, we characterized the enzyme L-asparaginase from S cerevisiae,” Dr Souza said. “The results show this protein can efficiently annihilate leukemia cells with low cytotoxicity to healthy cells.”

She and her colleagues conducted this study in search of alternatives to L-asparaginase extracted from bacteria (Escherichia coli and Erwinia chrysanthemi).

“Our goal in this project wasn’t to produce the enzyme, but rather to find a new source of the biodrug in microorganisms for use in patients who develop resistance to the bacterial enzyme,” said study author Marcos Antonio de Oliveira, of São Paulo State University in São Vicente, Brazil.

To this end, the researchers isolated fungi from several different Brazilian environments as well as marine and land environments in Antarctica. According to Oliveira, these organisms often secrete asparaginase into the extracellular medium in response to a shortage of nitrogen.

“This lowers the cost of purifying the molecule for drug production, an important factor from an industrial standpoint,” he said.

The group also used bioinformatics tools to mine information on the genomes of several microorganisms from international databases.

In this way, they identified a gene responsible for producing an enzyme that closely resembles the enzymes found in E coli and E chrysanthemi, but with a number of advantages, in the genome of S cerevisiae.

The gene of interest from L-asparaginase was cloned, and the researchers used genetic engineering to make E coli express large amounts of the enzyme originally found in yeast.

“We were able to obtain the recombinant protein,” said study author Iris Munhoz Costa, of the University of São Paulo.

“We then performed studies to characterize its secondary structure and identify important regions called catalytic sites. Finally, we evaluated its efficacy in vitro.”

The enzyme was tested in 3 different cell lines: ALL cells incapable of producing asparagine at normal levels (MOLT4), another ALL cell line capable of producing asparagine at normal levels (REH), and non-malignant control cells (HUVECs).

These 3 cell lines were subdivided into 2 groups. One was treated with L-asparaginase derived from E coli enzyme, and the other was treated with L-asparaginase from yeast.

“The bacterial enzyme killed about 90% of the MOLT4 human leukemia cells and displayed low toxicity to the healthy HUVEC cells, killing only 10%,” Dr Souza said.

“The yeast enzyme killed between 70% and 80% of the MOLT4 cells and displayed less than 10% toxicity for HUVEC cells. Neither was significantly effective against REH cells.”

In her view, the results are encouraging, in contrast with those of studies performed with the same enzyme in the 1970s. At that time, the tests involved a version of the protein extracted directly from yeast and containing many impurities.

The group’s next step is to perform new in vitro trials with different cell types to evaluate the immune response and toxicity. If the results are positive, the first tests in animals may be next.

The researchers are also studying possible modifications that could be made to the molecule’s structure to increase antitumor activity and extend the enzyme’s half-life.

Saccharomyces cerevisiae
as it buds before dividing
Image by Carolyn Larabell

L-asparaginase derived from baker’s yeast has shown early promise for treating acute lymphoblastic leukemia (ALL), according to researchers. 

The team isolated L-asparaginase from Saccharomyces cerevisiae and found the enzyme could kill ALL cells in vitro, while largely sparing healthy control cells.

Gisele Monteiro de Souza, PhD, of the University of São Paulo in São Paulo, Brazil, and her colleagues detailed these findings in Scientific Reports.

“In this study, we characterized the enzyme L-asparaginase from S cerevisiae,” Dr Souza said. “The results show this protein can efficiently annihilate leukemia cells with low cytotoxicity to healthy cells.”

She and her colleagues conducted this study in search of alternatives to L-asparaginase extracted from bacteria (Escherichia coli and Erwinia chrysanthemi).

“Our goal in this project wasn’t to produce the enzyme, but rather to find a new source of the biodrug in microorganisms for use in patients who develop resistance to the bacterial enzyme,” said study author Marcos Antonio de Oliveira, of São Paulo State University in São Vicente, Brazil.

To this end, the researchers isolated fungi from several different Brazilian environments as well as marine and land environments in Antarctica. According to Oliveira, these organisms often secrete asparaginase into the extracellular medium in response to a shortage of nitrogen.

“This lowers the cost of purifying the molecule for drug production, an important factor from an industrial standpoint,” he said.

The group also used bioinformatics tools to mine information on the genomes of several microorganisms from international databases.

In this way, they identified a gene responsible for producing an enzyme that closely resembles the enzymes found in E coli and E chrysanthemi, but with a number of advantages, in the genome of S cerevisiae.

The gene of interest from L-asparaginase was cloned, and the researchers used genetic engineering to make E coli express large amounts of the enzyme originally found in yeast.

“We were able to obtain the recombinant protein,” said study author Iris Munhoz Costa, of the University of São Paulo.

“We then performed studies to characterize its secondary structure and identify important regions called catalytic sites. Finally, we evaluated its efficacy in vitro.”

The enzyme was tested in 3 different cell lines: ALL cells incapable of producing asparagine at normal levels (MOLT4), another ALL cell line capable of producing asparagine at normal levels (REH), and non-malignant control cells (HUVECs).

These 3 cell lines were subdivided into 2 groups. One was treated with L-asparaginase derived from E coli enzyme, and the other was treated with L-asparaginase from yeast.

“The bacterial enzyme killed about 90% of the MOLT4 human leukemia cells and displayed low toxicity to the healthy HUVEC cells, killing only 10%,” Dr Souza said.

“The yeast enzyme killed between 70% and 80% of the MOLT4 cells and displayed less than 10% toxicity for HUVEC cells. Neither was significantly effective against REH cells.”

In her view, the results are encouraging, in contrast with those of studies performed with the same enzyme in the 1970s. At that time, the tests involved a version of the protein extracted directly from yeast and containing many impurities.

The group’s next step is to perform new in vitro trials with different cell types to evaluate the immune response and toxicity. If the results are positive, the first tests in animals may be next.

The researchers are also studying possible modifications that could be made to the molecule’s structure to increase antitumor activity and extend the enzyme’s half-life.

SAN DIEGO – Patients with chronic lymphocytic leukemia at risk for early relapse were about 85% less likely to progress on lenalidomide maintenance therapy compared with placebo, based on an interim analysis of the randomized phase III CLLM1 study.

After a typical follow-up time of 17.5 months, median durations of progression-free survival were not reached with lenalidomide and were 13 months with placebo, for a hazard ratio of 0.15 (95% confidence interval, 0.06-0.35). These results were “statistically significant, robust, and reliable in favor of lenalidomide,” Anna Fink, MD, said at the 2016 meeting of the American Society of Hematology. Several patients in the lenalidomide arm also converted to minimal residual disease (MRD) negativity, added Dr. Fink of University Hospital Cologne (Germany).

The study included patients whose CLL responded at least partially to front-line chemoimmunotherapy, but who were at high risk of progression – minimal residual disease levels were at least 10^–2, or were between 10^–4 and 10^–2 in patients who also had an unmutated IGHV gene status or del(17p) or TP53 mutations at baseline. Among 89 patients who met these criteria, 60 received lenalidomide maintenance and 20 received placebo.

The initial lenalidomide cycle consisted of 5 mg daily for 28 days. To achieve MRD negativity, clinicians increased this dose during subsequent cycles to a maximum of 15 mg daily for patients who were MRD negative after cycle 12, 20 mg for patients who were MRD negative after cycle 18, and 25 mg for patients who remained MRD positive. Median age was 64 years, more than 80% of patients were male, and the median cumulative illness rating was relatively low at 2, ranging between 0 and 8.

A total of 37% of patients had a high MRD level and 63% had an intermediate level. For both cohorts, lenalidomide maintenance significantly prolonged progression-free survival, compared with placebo, with hazard ratios of 0.17 and 0.13, respectively. Patients received a median of 11 and up to 40 cycles of lenalidomide, but a median of only 8 cycles of placebo.

In all, 43% of lenalidomide patients and 72% of placebo patients stopped maintenance. Nearly a third of those who discontinued lenalidomide did so because of adverse events, but 45% of patients who stopped placebo did so because of progressive disease, Dr. Fink said. Lenalidomide was associated with more neutropenia, gastrointestinal disorders, nervous system disorders, and respiratory and skin disorders than was placebo, but the events were usually mild to moderate in severity, she added.

The three deaths in this study yielded no treatment-based difference in rates of overall survival. Causes of death included acute lymphoblastic leukemia (lenalidomide arm), progressive multifocal leukoencephalopathy (placebo), and Richter’s syndrome (placebo). Venous thromboembolic events were uncommon because patients were given low-dose aspirin or anticoagulant therapy, Dr. Fink noted.

“Lenalidomide is a feasible and efficacious maintenance option for high-risk CLL after chemoimmunotherapy,” she concluded. The low duration of progression-free survival in the placebo group confirms the prognostic utility of assessing risk based on MRD, which might be useful in future studies, she added.

The German CLL Study Group sponsored the trial. Dr. Fink disclosed ties to Mundipharma, Roche, Celgene, and AbbVie.

SAN DIEGO – Patients with chronic lymphocytic leukemia at risk for early relapse were about 85% less likely to progress on lenalidomide maintenance therapy compared with placebo, based on an interim analysis of the randomized phase III CLLM1 study.

After a typical follow-up time of 17.5 months, median durations of progression-free survival were not reached with lenalidomide and were 13 months with placebo, for a hazard ratio of 0.15 (95% confidence interval, 0.06-0.35). These results were “statistically significant, robust, and reliable in favor of lenalidomide,” Anna Fink, MD, said at the 2016 meeting of the American Society of Hematology. Several patients in the lenalidomide arm also converted to minimal residual disease (MRD) negativity, added Dr. Fink of University Hospital Cologne (Germany).

The study included patients whose CLL responded at least partially to front-line chemoimmunotherapy, but who were at high risk of progression – minimal residual disease levels were at least 10^–2, or were between 10^–4 and 10^–2 in patients who also had an unmutated IGHV gene status or del(17p) or TP53 mutations at baseline. Among 89 patients who met these criteria, 60 received lenalidomide maintenance and 20 received placebo.

The initial lenalidomide cycle consisted of 5 mg daily for 28 days. To achieve MRD negativity, clinicians increased this dose during subsequent cycles to a maximum of 15 mg daily for patients who were MRD negative after cycle 12, 20 mg for patients who were MRD negative after cycle 18, and 25 mg for patients who remained MRD positive. Median age was 64 years, more than 80% of patients were male, and the median cumulative illness rating was relatively low at 2, ranging between 0 and 8.

A total of 37% of patients had a high MRD level and 63% had an intermediate level. For both cohorts, lenalidomide maintenance significantly prolonged progression-free survival, compared with placebo, with hazard ratios of 0.17 and 0.13, respectively. Patients received a median of 11 and up to 40 cycles of lenalidomide, but a median of only 8 cycles of placebo.

In all, 43% of lenalidomide patients and 72% of placebo patients stopped maintenance. Nearly a third of those who discontinued lenalidomide did so because of adverse events, but 45% of patients who stopped placebo did so because of progressive disease, Dr. Fink said. Lenalidomide was associated with more neutropenia, gastrointestinal disorders, nervous system disorders, and respiratory and skin disorders than was placebo, but the events were usually mild to moderate in severity, she added.

The three deaths in this study yielded no treatment-based difference in rates of overall survival. Causes of death included acute lymphoblastic leukemia (lenalidomide arm), progressive multifocal leukoencephalopathy (placebo), and Richter’s syndrome (placebo). Venous thromboembolic events were uncommon because patients were given low-dose aspirin or anticoagulant therapy, Dr. Fink noted.

“Lenalidomide is a feasible and efficacious maintenance option for high-risk CLL after chemoimmunotherapy,” she concluded. The low duration of progression-free survival in the placebo group confirms the prognostic utility of assessing risk based on MRD, which might be useful in future studies, she added.

The German CLL Study Group sponsored the trial. Dr. Fink disclosed ties to Mundipharma, Roche, Celgene, and AbbVie.

SAN DIEGO – Patients with chronic lymphocytic leukemia at risk for early relapse were about 85% less likely to progress on lenalidomide maintenance therapy compared with placebo, based on an interim analysis of the randomized phase III CLLM1 study.

After a typical follow-up time of 17.5 months, median durations of progression-free survival were not reached with lenalidomide and were 13 months with placebo, for a hazard ratio of 0.15 (95% confidence interval, 0.06-0.35). These results were “statistically significant, robust, and reliable in favor of lenalidomide,” Anna Fink, MD, said at the 2016 meeting of the American Society of Hematology. Several patients in the lenalidomide arm also converted to minimal residual disease (MRD) negativity, added Dr. Fink of University Hospital Cologne (Germany).

The study included patients whose CLL responded at least partially to front-line chemoimmunotherapy, but who were at high risk of progression – minimal residual disease levels were at least 10^–2, or were between 10^–4 and 10^–2 in patients who also had an unmutated IGHV gene status or del(17p) or TP53 mutations at baseline. Among 89 patients who met these criteria, 60 received lenalidomide maintenance and 20 received placebo.

The initial lenalidomide cycle consisted of 5 mg daily for 28 days. To achieve MRD negativity, clinicians increased this dose during subsequent cycles to a maximum of 15 mg daily for patients who were MRD negative after cycle 12, 20 mg for patients who were MRD negative after cycle 18, and 25 mg for patients who remained MRD positive. Median age was 64 years, more than 80% of patients were male, and the median cumulative illness rating was relatively low at 2, ranging between 0 and 8.

A total of 37% of patients had a high MRD level and 63% had an intermediate level. For both cohorts, lenalidomide maintenance significantly prolonged progression-free survival, compared with placebo, with hazard ratios of 0.17 and 0.13, respectively. Patients received a median of 11 and up to 40 cycles of lenalidomide, but a median of only 8 cycles of placebo.

In all, 43% of lenalidomide patients and 72% of placebo patients stopped maintenance. Nearly a third of those who discontinued lenalidomide did so because of adverse events, but 45% of patients who stopped placebo did so because of progressive disease, Dr. Fink said. Lenalidomide was associated with more neutropenia, gastrointestinal disorders, nervous system disorders, and respiratory and skin disorders than was placebo, but the events were usually mild to moderate in severity, she added.

The three deaths in this study yielded no treatment-based difference in rates of overall survival. Causes of death included acute lymphoblastic leukemia (lenalidomide arm), progressive multifocal leukoencephalopathy (placebo), and Richter’s syndrome (placebo). Venous thromboembolic events were uncommon because patients were given low-dose aspirin or anticoagulant therapy, Dr. Fink noted.

“Lenalidomide is a feasible and efficacious maintenance option for high-risk CLL after chemoimmunotherapy,” she concluded. The low duration of progression-free survival in the placebo group confirms the prognostic utility of assessing risk based on MRD, which might be useful in future studies, she added.

The German CLL Study Group sponsored the trial. Dr. Fink disclosed ties to Mundipharma, Roche, Celgene, and AbbVie.

Hartmut Döhner, MD
Photo courtesy of
University Hospital Ulm

Research published in Nature Genetics suggests a knowledge bank

can reveal the optimal treatment for patients with acute

myeloid leukemia (AML), although more research is needed before such

banks can be used in the clinic.

Researchers built a knowledge

bank using data from 1540 AML patients enrolled in clinical

trials in Germany and Austria.

The bank includes information on genetic features, treatment, and outcomes for each patient.

The researchers used this information to develop models that could predict a patient’s likelihood of remission, relapse, and mortality.

The team then validated those results using data from patients in The Cancer Genome Atlas.

The researchers estimate that up to 1 in 3 AML patients would be prescribed a different treatment regimen if physicians used the knowledge bank approach rather than current practice.

“The knowledge bank approach makes far more detailed and accurate predictions about the likely future course of a patient with AML than what we can make in the clinic at the moment,” said study author Peter Campbell, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.

“Current guides use a simple set of rules based on only a few genetic findings. For any given patient, using the new tool, we can compare the likely future outcomes under a transplant route versus a standard chemotherapy route. This means that we can make a treatment choice that is personally tailored to the unique features of that particular patient.”

However, the researchers said the knowledge bank approach requires further testing before it can be used to prescribe treatment in AML clinics.

“Our analysis reveals that knowledge banks of up to 10,000 patients would be needed to obtain the precision needed for routine clinical application,” said study author Moritz Gerstung, PhD, of the European Bioinformatics Institute in Hinxton, UK.

“Building knowledge banks is not easy,” added author Hartmut Döhner, MD, of the University of Ulm in Germany. “To get accurate treatment predictions, you need data from thousands of patients and all tumor types.”

“Furthermore, such knowledge banks will need continuous updating as new therapies become approved and available. As genetic testing enters routine clinical practice, there is an opportunity to learn from patients undergoing care in our health systems. Our paper gives the first real evidence that the approach is worthwhile, how it could be used, and what the scale needs to be.”

Hartmut Döhner, MD
Photo courtesy of
University Hospital Ulm

Research published in Nature Genetics suggests a knowledge bank

can reveal the optimal treatment for patients with acute

myeloid leukemia (AML), although more research is needed before such

banks can be used in the clinic.

Researchers built a knowledge

bank using data from 1540 AML patients enrolled in clinical

trials in Germany and Austria.

The bank includes information on genetic features, treatment, and outcomes for each patient.

The researchers used this information to develop models that could predict a patient’s likelihood of remission, relapse, and mortality.

The team then validated those results using data from patients in The Cancer Genome Atlas.

The researchers estimate that up to 1 in 3 AML patients would be prescribed a different treatment regimen if physicians used the knowledge bank approach rather than current practice.

“The knowledge bank approach makes far more detailed and accurate predictions about the likely future course of a patient with AML than what we can make in the clinic at the moment,” said study author Peter Campbell, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.

“Current guides use a simple set of rules based on only a few genetic findings. For any given patient, using the new tool, we can compare the likely future outcomes under a transplant route versus a standard chemotherapy route. This means that we can make a treatment choice that is personally tailored to the unique features of that particular patient.”

However, the researchers said the knowledge bank approach requires further testing before it can be used to prescribe treatment in AML clinics.

“Our analysis reveals that knowledge banks of up to 10,000 patients would be needed to obtain the precision needed for routine clinical application,” said study author Moritz Gerstung, PhD, of the European Bioinformatics Institute in Hinxton, UK.

“Building knowledge banks is not easy,” added author Hartmut Döhner, MD, of the University of Ulm in Germany. “To get accurate treatment predictions, you need data from thousands of patients and all tumor types.”

“Furthermore, such knowledge banks will need continuous updating as new therapies become approved and available. As genetic testing enters routine clinical practice, there is an opportunity to learn from patients undergoing care in our health systems. Our paper gives the first real evidence that the approach is worthwhile, how it could be used, and what the scale needs to be.”

Hartmut Döhner, MD
Photo courtesy of
University Hospital Ulm

Research published in Nature Genetics suggests a knowledge bank

can reveal the optimal treatment for patients with acute

myeloid leukemia (AML), although more research is needed before such

banks can be used in the clinic.

Researchers built a knowledge

bank using data from 1540 AML patients enrolled in clinical

trials in Germany and Austria.

The bank includes information on genetic features, treatment, and outcomes for each patient.

The researchers used this information to develop models that could predict a patient’s likelihood of remission, relapse, and mortality.

The team then validated those results using data from patients in The Cancer Genome Atlas.

The researchers estimate that up to 1 in 3 AML patients would be prescribed a different treatment regimen if physicians used the knowledge bank approach rather than current practice.

“The knowledge bank approach makes far more detailed and accurate predictions about the likely future course of a patient with AML than what we can make in the clinic at the moment,” said study author Peter Campbell, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.

“Current guides use a simple set of rules based on only a few genetic findings. For any given patient, using the new tool, we can compare the likely future outcomes under a transplant route versus a standard chemotherapy route. This means that we can make a treatment choice that is personally tailored to the unique features of that particular patient.”

However, the researchers said the knowledge bank approach requires further testing before it can be used to prescribe treatment in AML clinics.

“Our analysis reveals that knowledge banks of up to 10,000 patients would be needed to obtain the precision needed for routine clinical application,” said study author Moritz Gerstung, PhD, of the European Bioinformatics Institute in Hinxton, UK.

“Building knowledge banks is not easy,” added author Hartmut Döhner, MD, of the University of Ulm in Germany. “To get accurate treatment predictions, you need data from thousands of patients and all tumor types.”

“Furthermore, such knowledge banks will need continuous updating as new therapies become approved and available. As genetic testing enters routine clinical practice, there is an opportunity to learn from patients undergoing care in our health systems. Our paper gives the first real evidence that the approach is worthwhile, how it could be used, and what the scale needs to be.”

Cancer patient receiving
chemotherapy
Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) regarding the new drug application (NDA) for an intravenous (IV) formulation of rolapitant.

An oral formulation of rolapitant, marketed as VARUBI®, is FDA-approved for use in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy in adults.

The NDA for rolapitant IV is for the same indication.

The FDA requested additional information regarding the in vitro method utilized to demonstrate comparability of drug product produced at the 2 proposed commercial manufacturers for rolapitant IV that were included in the NDA.

TESARO Inc., the company developing rolapitant IV, said it is working to provide the requested information.

The CRL did not identify concerns related to the safety or efficacy of rolapitant IV or request additional clinical studies. No concerns were raised regarding the active pharmaceutical ingredient, which is also used for VARUBI®.

TESARO identified potential deficiencies at the original contract manufacturer for rolapitant IV, secured a second drug product supplier, and included data from this manufacturer in the NDA.

During the NDA review, the FDA requested and TESARO provided in vitro data to demonstrate comparability of drug product made at the 2 manufacturing sites.

“TESARO is committed to bringing this new intravenous formulation of rolapitant to physicians and patients to enable additional flexibility and choice of antiemetic regimens, and we plan to address FDA’s questions expeditiously and complete this application, which we expect to enable approval in the first half of 2017,” said Mary Lynne Hedley, PhD, president and chief operating officer of TESARO.

Cancer patient receiving
chemotherapy
Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) regarding the new drug application (NDA) for an intravenous (IV) formulation of rolapitant.

An oral formulation of rolapitant, marketed as VARUBI®, is FDA-approved for use in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy in adults.

The NDA for rolapitant IV is for the same indication.

The FDA requested additional information regarding the in vitro method utilized to demonstrate comparability of drug product produced at the 2 proposed commercial manufacturers for rolapitant IV that were included in the NDA.

TESARO Inc., the company developing rolapitant IV, said it is working to provide the requested information.

The CRL did not identify concerns related to the safety or efficacy of rolapitant IV or request additional clinical studies. No concerns were raised regarding the active pharmaceutical ingredient, which is also used for VARUBI®.

TESARO identified potential deficiencies at the original contract manufacturer for rolapitant IV, secured a second drug product supplier, and included data from this manufacturer in the NDA.

During the NDA review, the FDA requested and TESARO provided in vitro data to demonstrate comparability of drug product made at the 2 manufacturing sites.

“TESARO is committed to bringing this new intravenous formulation of rolapitant to physicians and patients to enable additional flexibility and choice of antiemetic regimens, and we plan to address FDA’s questions expeditiously and complete this application, which we expect to enable approval in the first half of 2017,” said Mary Lynne Hedley, PhD, president and chief operating officer of TESARO.

Cancer patient receiving
chemotherapy
Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) regarding the new drug application (NDA) for an intravenous (IV) formulation of rolapitant.

An oral formulation of rolapitant, marketed as VARUBI®, is FDA-approved for use in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy in adults.

The NDA for rolapitant IV is for the same indication.

The FDA requested additional information regarding the in vitro method utilized to demonstrate comparability of drug product produced at the 2 proposed commercial manufacturers for rolapitant IV that were included in the NDA.

TESARO Inc., the company developing rolapitant IV, said it is working to provide the requested information.

The CRL did not identify concerns related to the safety or efficacy of rolapitant IV or request additional clinical studies. No concerns were raised regarding the active pharmaceutical ingredient, which is also used for VARUBI®.

TESARO identified potential deficiencies at the original contract manufacturer for rolapitant IV, secured a second drug product supplier, and included data from this manufacturer in the NDA.

During the NDA review, the FDA requested and TESARO provided in vitro data to demonstrate comparability of drug product made at the 2 manufacturing sites.

“TESARO is committed to bringing this new intravenous formulation of rolapitant to physicians and patients to enable additional flexibility and choice of antiemetic regimens, and we plan to address FDA’s questions expeditiously and complete this application, which we expect to enable approval in the first half of 2017,” said Mary Lynne Hedley, PhD, president and chief operating officer of TESARO.

Micrograph showing AML

New research suggests the protein SAMHD1 could be used to predict which

patients with acute myeloid leukemia (AML) will respond to treatment

with cytarabine.

Researchers found that response to cytarabine

was inversely correlated with SAMHD1 expression in AML cell lines, mouse

models of the disease, and adult patients with AML.

Jindrich Cinatl, PhD, of the University of Frankfurt in Germany, and his colleagues reported these findings in Nature Medicine.

The researchers first analyzed 13 AML cell lines and found that SAMHD1 reduces the cytotoxic effect of cytarabine. When the team depleted SAMHD1 in these cell lines, they were “markedly sensitized” to cytarabine.

The researchers also cultivated cytarabine-resistant AML cell lines and found that SAMHD1 levels increased along with cytarabine resistance. However, depleting SAMHD1 resensitized the cells to cytarabine. 

Investigation revealed that SAMHD1 removes the phosphate residues from the active form of cytarabine, Ara-CTP, and converts the drug to its inactive form, Ara-C.

The researchers then evaluated the role of SAMHD1 in AML in vivo. They transplanted SAMHD1-knockout AML cells and wild-type SAMHD1 AML cells into mice and treated the mice with cytarabine or phosphate-buffered saline.

Mice that received SAMHD1-knockout AML cells and cytarabine had significantly longer survival than mice that received wild-type SAMHD1 AML cells and cytarabine or either AML cell type plus phosphate-buffered saline.

Next, the researchers tested blasts isolated from the bone marrow of patients with therapy-naive AML.

The team found that basal SAMHD1 expression was significantly correlated with cytarabine IC₅₀ values. And depleting SAMHD1 diminished cytarabine IC₅₀ values by 3- to 15-fold.

Lastly, the researchers assessed whether SAMHD1 expression might be used to predict response to cytarabine-based therapy in patients with AML.

The team analyzed a cohort of 150 adult AML patients who had received 1 to 2 courses of induction therapy including cytarabine—either 2 cycles of 7+3 or 7+3 plus high-dose cytarabine in combination with mitoxantrone.

Analysis revealed that SAMHD1 expression was “markedly increased” among patients who did not achieve a complete remission (CR) at the end of induction.

Of the 112 patients who achieved a CR, 90 were scored as “SAMHD1 low,” and 22 were scored as “SAMHD1 high.” The CR rate was 44% in the SAMHD1-high cohort and 90% in the SAMHD1-low cohort.

In addition, the researchers found the level of SAMHD1 expression in blasts at patients’ initial diagnosis was predictive of event-free survival, relapse-free survival, and overall survival.

The team said these results suggest SAMHD1 could be used to guide treatment with cytarabine-based therapies in patients with AML.

Micrograph showing AML

New research suggests the protein SAMHD1 could be used to predict which

patients with acute myeloid leukemia (AML) will respond to treatment

with cytarabine.

Researchers found that response to cytarabine

was inversely correlated with SAMHD1 expression in AML cell lines, mouse

models of the disease, and adult patients with AML.

Jindrich Cinatl, PhD, of the University of Frankfurt in Germany, and his colleagues reported these findings in Nature Medicine.

The researchers first analyzed 13 AML cell lines and found that SAMHD1 reduces the cytotoxic effect of cytarabine. When the team depleted SAMHD1 in these cell lines, they were “markedly sensitized” to cytarabine.

The researchers also cultivated cytarabine-resistant AML cell lines and found that SAMHD1 levels increased along with cytarabine resistance. However, depleting SAMHD1 resensitized the cells to cytarabine. 

Investigation revealed that SAMHD1 removes the phosphate residues from the active form of cytarabine, Ara-CTP, and converts the drug to its inactive form, Ara-C.

The researchers then evaluated the role of SAMHD1 in AML in vivo. They transplanted SAMHD1-knockout AML cells and wild-type SAMHD1 AML cells into mice and treated the mice with cytarabine or phosphate-buffered saline.

Mice that received SAMHD1-knockout AML cells and cytarabine had significantly longer survival than mice that received wild-type SAMHD1 AML cells and cytarabine or either AML cell type plus phosphate-buffered saline.

Next, the researchers tested blasts isolated from the bone marrow of patients with therapy-naive AML.

The team found that basal SAMHD1 expression was significantly correlated with cytarabine IC₅₀ values. And depleting SAMHD1 diminished cytarabine IC₅₀ values by 3- to 15-fold.

Lastly, the researchers assessed whether SAMHD1 expression might be used to predict response to cytarabine-based therapy in patients with AML.

The team analyzed a cohort of 150 adult AML patients who had received 1 to 2 courses of induction therapy including cytarabine—either 2 cycles of 7+3 or 7+3 plus high-dose cytarabine in combination with mitoxantrone.

Analysis revealed that SAMHD1 expression was “markedly increased” among patients who did not achieve a complete remission (CR) at the end of induction.

Of the 112 patients who achieved a CR, 90 were scored as “SAMHD1 low,” and 22 were scored as “SAMHD1 high.” The CR rate was 44% in the SAMHD1-high cohort and 90% in the SAMHD1-low cohort.

In addition, the researchers found the level of SAMHD1 expression in blasts at patients’ initial diagnosis was predictive of event-free survival, relapse-free survival, and overall survival.

The team said these results suggest SAMHD1 could be used to guide treatment with cytarabine-based therapies in patients with AML.

Micrograph showing AML

New research suggests the protein SAMHD1 could be used to predict which

patients with acute myeloid leukemia (AML) will respond to treatment

with cytarabine.

Researchers found that response to cytarabine

was inversely correlated with SAMHD1 expression in AML cell lines, mouse

models of the disease, and adult patients with AML.

Jindrich Cinatl, PhD, of the University of Frankfurt in Germany, and his colleagues reported these findings in Nature Medicine.

The researchers first analyzed 13 AML cell lines and found that SAMHD1 reduces the cytotoxic effect of cytarabine. When the team depleted SAMHD1 in these cell lines, they were “markedly sensitized” to cytarabine.

The researchers also cultivated cytarabine-resistant AML cell lines and found that SAMHD1 levels increased along with cytarabine resistance. However, depleting SAMHD1 resensitized the cells to cytarabine. 

Investigation revealed that SAMHD1 removes the phosphate residues from the active form of cytarabine, Ara-CTP, and converts the drug to its inactive form, Ara-C.

The researchers then evaluated the role of SAMHD1 in AML in vivo. They transplanted SAMHD1-knockout AML cells and wild-type SAMHD1 AML cells into mice and treated the mice with cytarabine or phosphate-buffered saline.

Mice that received SAMHD1-knockout AML cells and cytarabine had significantly longer survival than mice that received wild-type SAMHD1 AML cells and cytarabine or either AML cell type plus phosphate-buffered saline.

Next, the researchers tested blasts isolated from the bone marrow of patients with therapy-naive AML.

The team found that basal SAMHD1 expression was significantly correlated with cytarabine IC₅₀ values. And depleting SAMHD1 diminished cytarabine IC₅₀ values by 3- to 15-fold.

Lastly, the researchers assessed whether SAMHD1 expression might be used to predict response to cytarabine-based therapy in patients with AML.

The team analyzed a cohort of 150 adult AML patients who had received 1 to 2 courses of induction therapy including cytarabine—either 2 cycles of 7+3 or 7+3 plus high-dose cytarabine in combination with mitoxantrone.

Analysis revealed that SAMHD1 expression was “markedly increased” among patients who did not achieve a complete remission (CR) at the end of induction.

Of the 112 patients who achieved a CR, 90 were scored as “SAMHD1 low,” and 22 were scored as “SAMHD1 high.” The CR rate was 44% in the SAMHD1-high cohort and 90% in the SAMHD1-low cohort.

In addition, the researchers found the level of SAMHD1 expression in blasts at patients’ initial diagnosis was predictive of event-free survival, relapse-free survival, and overall survival.

The team said these results suggest SAMHD1 could be used to guide treatment with cytarabine-based therapies in patients with AML.

First month’s supply of
venetoclax (US version)
Photo courtesy of Abbvie

The Australian Therapeutic Goods Administration (TGA) has approved the BCL-2 inhibitor venetoclax (Venclexta™, formerly ABT-199) for use in certain patients with chronic lymphocytic leukemia (CLL).

The drug is now approved to treat Australian patients with relapsed or refractory CLL who have 17p deletion or no other treatment options.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Now that venetoclax has been approved by the TGA, it can be registered on the Australian Register of Therapeutic Goods and legally marketed and sold in Australia.

To make the drug affordable to the Australian public, the manufacturer can apply to the Pharmaceutical Benefits Advisory Committee to have the cost of the drug subsidized by the Australian government on the Pharmaceutical Benefits Scheme (PBS).

Venetoclax is not listed on the PBS. Historically, the delay between TGA approval and PBS listing ranges from 14 months to 31 months for cancer drugs.

Phase 2 trials

Venetoclax has produced high objective response rates (ORR) in two phase 2 trials of CLL patients.

In one of these trials, researchers tested venetoclax in 107 patients with previously treated CLL and 17p deletion. The results were published in The Lancet Oncology in June 2016.

The ORR in this trial was 79%. At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival.

The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%, and the incidence of serious adverse events was 55%.

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the second trial, researchers tested venetoclax in 64 patients with CLL who had failed treatment with ibrutinib and/or idelalisib. Results from this trial were presented at the 2016 ASH Annual Meeting.

The ORR was 67%. At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival was 80%.

The incidence of adverse events was 100%, and the incidence of serious adverse events was 53%. No clinical TLS was observed, but 1 patient met Howard criteria for laboratory TLS.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

First month’s supply of
venetoclax (US version)
Photo courtesy of Abbvie

The Australian Therapeutic Goods Administration (TGA) has approved the BCL-2 inhibitor venetoclax (Venclexta™, formerly ABT-199) for use in certain patients with chronic lymphocytic leukemia (CLL).

The drug is now approved to treat Australian patients with relapsed or refractory CLL who have 17p deletion or no other treatment options.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Now that venetoclax has been approved by the TGA, it can be registered on the Australian Register of Therapeutic Goods and legally marketed and sold in Australia.

To make the drug affordable to the Australian public, the manufacturer can apply to the Pharmaceutical Benefits Advisory Committee to have the cost of the drug subsidized by the Australian government on the Pharmaceutical Benefits Scheme (PBS).

Venetoclax is not listed on the PBS. Historically, the delay between TGA approval and PBS listing ranges from 14 months to 31 months for cancer drugs.

Phase 2 trials

Venetoclax has produced high objective response rates (ORR) in two phase 2 trials of CLL patients.

In one of these trials, researchers tested venetoclax in 107 patients with previously treated CLL and 17p deletion. The results were published in The Lancet Oncology in June 2016.

The ORR in this trial was 79%. At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival.

The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%, and the incidence of serious adverse events was 55%.

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the second trial, researchers tested venetoclax in 64 patients with CLL who had failed treatment with ibrutinib and/or idelalisib. Results from this trial were presented at the 2016 ASH Annual Meeting.

The ORR was 67%. At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival was 80%.

The incidence of adverse events was 100%, and the incidence of serious adverse events was 53%. No clinical TLS was observed, but 1 patient met Howard criteria for laboratory TLS.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

First month’s supply of
venetoclax (US version)
Photo courtesy of Abbvie

The Australian Therapeutic Goods Administration (TGA) has approved the BCL-2 inhibitor venetoclax (Venclexta™, formerly ABT-199) for use in certain patients with chronic lymphocytic leukemia (CLL).

The drug is now approved to treat Australian patients with relapsed or refractory CLL who have 17p deletion or no other treatment options.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Now that venetoclax has been approved by the TGA, it can be registered on the Australian Register of Therapeutic Goods and legally marketed and sold in Australia.

To make the drug affordable to the Australian public, the manufacturer can apply to the Pharmaceutical Benefits Advisory Committee to have the cost of the drug subsidized by the Australian government on the Pharmaceutical Benefits Scheme (PBS).

Venetoclax is not listed on the PBS. Historically, the delay between TGA approval and PBS listing ranges from 14 months to 31 months for cancer drugs.

Phase 2 trials

Venetoclax has produced high objective response rates (ORR) in two phase 2 trials of CLL patients.

In one of these trials, researchers tested venetoclax in 107 patients with previously treated CLL and 17p deletion. The results were published in The Lancet Oncology in June 2016.

The ORR in this trial was 79%. At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival.

The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%, and the incidence of serious adverse events was 55%.

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the second trial, researchers tested venetoclax in 64 patients with CLL who had failed treatment with ibrutinib and/or idelalisib. Results from this trial were presented at the 2016 ASH Annual Meeting.

The ORR was 67%. At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival was 80%.

The incidence of adverse events was 100%, and the incidence of serious adverse events was 53%. No clinical TLS was observed, but 1 patient met Howard criteria for laboratory TLS.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

SAN DIEGO – More than 90% of the first patients with previously untreated chronic lymphocytic leukemia who received ibrutinib in an early study are alive and without disease progression 5 years later, investigators reported.

Among 31 treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) who were started on the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) in the phase Ib/II PCYC-1102/1103 study, the 5-year progression-free survival (PFS) rate was 92%, with the median PFS not reached. Estimated 5-year overall survival (OS) among these patients was also 92%, with the median not reached, Susan O’Brien, MD, of the University of California, Irvine, reported at the annual meeting of the American Society of Hematology.

The 5-year PFS rate for patients with relapsed/refractory disease who had received a median of four prior lines of therapy before starting on single-agent ibrutinib was 43%, with a median PFS of 52 months. In this group, the overall survival (OS) rate was 57%, with the median not reached.

“At 5 years of follow-up, there are very durable responses in treatment-naive and relapsed refractory patients. You saw that, in the treatment-naive group, there is, in fact, only one patient who has progressed so far,” Dr. O’Brien said.

In a separate study, investigators from the phase III RESONATE-2 trial reported updated safety and efficacy data showing that in first-line therapy for patients aged 65 years and older with CLL/SLL with active disease, ibrutinib was associated with significantly better PFS at 24 months, compared with chlorambucil.

In this study by Dr. O’Brien and colleagues, 31 patients with previously untreated CLL/SLL and 101 patients with relapsed/refractory disease (progression or no objective response within 24 months of starting on chemoimmunotherapy) were treated with oral ibrutinib once daily at doses of 420 mg or 840 mg until disease progression or unacceptable toxicity.

After 5 years of follow-up, 20 of the 31 treatment-naive patients (65%) and 30 of the 101 relapsed/refractory patients (30%) remained on ibrutinib therapy. The primary reasons for discontinuation among relapsed/refractory patients included progressive disease in 33%, adverse events in 21%, and investigator decision in 11%.

Best response rates in treatment-naive patients were 87% (29% complete response, 55% partial response, 3% partial response-L) and 89% in relapsed/refractory patients (10%, 76%, and 3%, respectively).

An analysis of survival by IGHV (immunoglobulin heavy chain variable) mutational status in patients with relapsed/refractory disease showed a 53% 5-year PFS rate among patients with mutated IGHV and a median PFS of 63 months, compared with 38% and 43 months for patients with unmutated IGHV. Respective 5-year overall survival rates were 66% (median OS, 63 months) and 55% (median not reached).

In an analysis of survival outcomes by chromosomal abnormalities detected by FISH (fluorescent in situ hybridization) among patients with relapsed/refractory disease, median PFS and OS rates were highest among patients with the 13q deletion, at 91% for both PFS and OS, compared with 80% for each in patients with trisomy 12, 33% and 61% for patients with deletion 11q, and 19% and 32% for patients with deletion 17p. In patients with no chromosomal abnormalities, the 5-year PFS rate was 66% (median not reached), and the 5-year OS rate was 83% (median not reached).

Among patients with complex karyotype, 90% of whom had relapsed refractory disease, the 5-year PFS rate was 36% (median 33 months), and the OS rate was 46% (median 57 months). In contrast, respective PFS and OS rates for patients without complex karyotype were 69% and 84%, with the median not reached in either survival category.

In multivariate analysis, only deletion 17p was identified as a significant predictor of PFS and OS.

Grade 3 or greater treatment-emergent adverse events occurred mostly frequently in the first year of therapy and declined thereafter. The most common grade 3 or greater events were hypertension, (26% of all patients), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%).

Paul M. Barr, MD, of the University of Rochester presented updated data from RESONATE-2, comparing ibrutinib with chlorambucil in patients 65 and older with newly diagnosed, active CLL/SLL.

At a median follow-up of 29 months, the rates of 2-year PFS were 89% for patients treated with ibrutinib (median PFS not reached) vs. 34% for chlorambucil (median PFS 15 months). This translated into a hazard ratio for ibrutinib of 0.121 (P less than .0001). The benefit of ibrutinib occurred without regard to IGHV status, and ibrutinib continues to demonstrate an OS benefit over chlorambucil with longer follow-up and crossover. Overall survival at 24 months was 95% for patients treated with ibrutinib (included 55 patients who were crossed over from chlorambucil) vs. 84% for patients treated with chlorambucil only.

“The depth of the responses has improved over time, now with 18% of patients achieving a CR with ibrutinib, and lastly, ibrutinib remains tolerable in this elderly population, with 79% of patients that are continuing on therapy,” Dr. Barr said.

Both studies were funded by Pharmacyclics. Dr. Barr and Dr. O’Brien disclosed serving as consultants to the company, and Dr. O’Brien further disclosed honoraria and research funding from Pharmacyclics.

SAN DIEGO – More than 90% of the first patients with previously untreated chronic lymphocytic leukemia who received ibrutinib in an early study are alive and without disease progression 5 years later, investigators reported.

Among 31 treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) who were started on the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) in the phase Ib/II PCYC-1102/1103 study, the 5-year progression-free survival (PFS) rate was 92%, with the median PFS not reached. Estimated 5-year overall survival (OS) among these patients was also 92%, with the median not reached, Susan O’Brien, MD, of the University of California, Irvine, reported at the annual meeting of the American Society of Hematology.

The 5-year PFS rate for patients with relapsed/refractory disease who had received a median of four prior lines of therapy before starting on single-agent ibrutinib was 43%, with a median PFS of 52 months. In this group, the overall survival (OS) rate was 57%, with the median not reached.

“At 5 years of follow-up, there are very durable responses in treatment-naive and relapsed refractory patients. You saw that, in the treatment-naive group, there is, in fact, only one patient who has progressed so far,” Dr. O’Brien said.

In a separate study, investigators from the phase III RESONATE-2 trial reported updated safety and efficacy data showing that in first-line therapy for patients aged 65 years and older with CLL/SLL with active disease, ibrutinib was associated with significantly better PFS at 24 months, compared with chlorambucil.

In this study by Dr. O’Brien and colleagues, 31 patients with previously untreated CLL/SLL and 101 patients with relapsed/refractory disease (progression or no objective response within 24 months of starting on chemoimmunotherapy) were treated with oral ibrutinib once daily at doses of 420 mg or 840 mg until disease progression or unacceptable toxicity.

After 5 years of follow-up, 20 of the 31 treatment-naive patients (65%) and 30 of the 101 relapsed/refractory patients (30%) remained on ibrutinib therapy. The primary reasons for discontinuation among relapsed/refractory patients included progressive disease in 33%, adverse events in 21%, and investigator decision in 11%.

Best response rates in treatment-naive patients were 87% (29% complete response, 55% partial response, 3% partial response-L) and 89% in relapsed/refractory patients (10%, 76%, and 3%, respectively).

An analysis of survival by IGHV (immunoglobulin heavy chain variable) mutational status in patients with relapsed/refractory disease showed a 53% 5-year PFS rate among patients with mutated IGHV and a median PFS of 63 months, compared with 38% and 43 months for patients with unmutated IGHV. Respective 5-year overall survival rates were 66% (median OS, 63 months) and 55% (median not reached).

In an analysis of survival outcomes by chromosomal abnormalities detected by FISH (fluorescent in situ hybridization) among patients with relapsed/refractory disease, median PFS and OS rates were highest among patients with the 13q deletion, at 91% for both PFS and OS, compared with 80% for each in patients with trisomy 12, 33% and 61% for patients with deletion 11q, and 19% and 32% for patients with deletion 17p. In patients with no chromosomal abnormalities, the 5-year PFS rate was 66% (median not reached), and the 5-year OS rate was 83% (median not reached).

Among patients with complex karyotype, 90% of whom had relapsed refractory disease, the 5-year PFS rate was 36% (median 33 months), and the OS rate was 46% (median 57 months). In contrast, respective PFS and OS rates for patients without complex karyotype were 69% and 84%, with the median not reached in either survival category.

In multivariate analysis, only deletion 17p was identified as a significant predictor of PFS and OS.

Grade 3 or greater treatment-emergent adverse events occurred mostly frequently in the first year of therapy and declined thereafter. The most common grade 3 or greater events were hypertension, (26% of all patients), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%).

Paul M. Barr, MD, of the University of Rochester presented updated data from RESONATE-2, comparing ibrutinib with chlorambucil in patients 65 and older with newly diagnosed, active CLL/SLL.

At a median follow-up of 29 months, the rates of 2-year PFS were 89% for patients treated with ibrutinib (median PFS not reached) vs. 34% for chlorambucil (median PFS 15 months). This translated into a hazard ratio for ibrutinib of 0.121 (P less than .0001). The benefit of ibrutinib occurred without regard to IGHV status, and ibrutinib continues to demonstrate an OS benefit over chlorambucil with longer follow-up and crossover. Overall survival at 24 months was 95% for patients treated with ibrutinib (included 55 patients who were crossed over from chlorambucil) vs. 84% for patients treated with chlorambucil only.

“The depth of the responses has improved over time, now with 18% of patients achieving a CR with ibrutinib, and lastly, ibrutinib remains tolerable in this elderly population, with 79% of patients that are continuing on therapy,” Dr. Barr said.

Both studies were funded by Pharmacyclics. Dr. Barr and Dr. O’Brien disclosed serving as consultants to the company, and Dr. O’Brien further disclosed honoraria and research funding from Pharmacyclics.

SAN DIEGO – More than 90% of the first patients with previously untreated chronic lymphocytic leukemia who received ibrutinib in an early study are alive and without disease progression 5 years later, investigators reported.

Among 31 treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) who were started on the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) in the phase Ib/II PCYC-1102/1103 study, the 5-year progression-free survival (PFS) rate was 92%, with the median PFS not reached. Estimated 5-year overall survival (OS) among these patients was also 92%, with the median not reached, Susan O’Brien, MD, of the University of California, Irvine, reported at the annual meeting of the American Society of Hematology.

The 5-year PFS rate for patients with relapsed/refractory disease who had received a median of four prior lines of therapy before starting on single-agent ibrutinib was 43%, with a median PFS of 52 months. In this group, the overall survival (OS) rate was 57%, with the median not reached.

“At 5 years of follow-up, there are very durable responses in treatment-naive and relapsed refractory patients. You saw that, in the treatment-naive group, there is, in fact, only one patient who has progressed so far,” Dr. O’Brien said.

In a separate study, investigators from the phase III RESONATE-2 trial reported updated safety and efficacy data showing that in first-line therapy for patients aged 65 years and older with CLL/SLL with active disease, ibrutinib was associated with significantly better PFS at 24 months, compared with chlorambucil.

In this study by Dr. O’Brien and colleagues, 31 patients with previously untreated CLL/SLL and 101 patients with relapsed/refractory disease (progression or no objective response within 24 months of starting on chemoimmunotherapy) were treated with oral ibrutinib once daily at doses of 420 mg or 840 mg until disease progression or unacceptable toxicity.

After 5 years of follow-up, 20 of the 31 treatment-naive patients (65%) and 30 of the 101 relapsed/refractory patients (30%) remained on ibrutinib therapy. The primary reasons for discontinuation among relapsed/refractory patients included progressive disease in 33%, adverse events in 21%, and investigator decision in 11%.

Best response rates in treatment-naive patients were 87% (29% complete response, 55% partial response, 3% partial response-L) and 89% in relapsed/refractory patients (10%, 76%, and 3%, respectively).

An analysis of survival by IGHV (immunoglobulin heavy chain variable) mutational status in patients with relapsed/refractory disease showed a 53% 5-year PFS rate among patients with mutated IGHV and a median PFS of 63 months, compared with 38% and 43 months for patients with unmutated IGHV. Respective 5-year overall survival rates were 66% (median OS, 63 months) and 55% (median not reached).

In an analysis of survival outcomes by chromosomal abnormalities detected by FISH (fluorescent in situ hybridization) among patients with relapsed/refractory disease, median PFS and OS rates were highest among patients with the 13q deletion, at 91% for both PFS and OS, compared with 80% for each in patients with trisomy 12, 33% and 61% for patients with deletion 11q, and 19% and 32% for patients with deletion 17p. In patients with no chromosomal abnormalities, the 5-year PFS rate was 66% (median not reached), and the 5-year OS rate was 83% (median not reached).

Among patients with complex karyotype, 90% of whom had relapsed refractory disease, the 5-year PFS rate was 36% (median 33 months), and the OS rate was 46% (median 57 months). In contrast, respective PFS and OS rates for patients without complex karyotype were 69% and 84%, with the median not reached in either survival category.

In multivariate analysis, only deletion 17p was identified as a significant predictor of PFS and OS.

Grade 3 or greater treatment-emergent adverse events occurred mostly frequently in the first year of therapy and declined thereafter. The most common grade 3 or greater events were hypertension, (26% of all patients), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%).

Paul M. Barr, MD, of the University of Rochester presented updated data from RESONATE-2, comparing ibrutinib with chlorambucil in patients 65 and older with newly diagnosed, active CLL/SLL.

At a median follow-up of 29 months, the rates of 2-year PFS were 89% for patients treated with ibrutinib (median PFS not reached) vs. 34% for chlorambucil (median PFS 15 months). This translated into a hazard ratio for ibrutinib of 0.121 (P less than .0001). The benefit of ibrutinib occurred without regard to IGHV status, and ibrutinib continues to demonstrate an OS benefit over chlorambucil with longer follow-up and crossover. Overall survival at 24 months was 95% for patients treated with ibrutinib (included 55 patients who were crossed over from chlorambucil) vs. 84% for patients treated with chlorambucil only.

“The depth of the responses has improved over time, now with 18% of patients achieving a CR with ibrutinib, and lastly, ibrutinib remains tolerable in this elderly population, with 79% of patients that are continuing on therapy,” Dr. Barr said.

Both studies were funded by Pharmacyclics. Dr. Barr and Dr. O’Brien disclosed serving as consultants to the company, and Dr. O’Brien further disclosed honoraria and research funding from Pharmacyclics.

Lab mouse

Investigators may have discovered a new way to treat mixed-lineage leukemia (MLL)-rearranged leukemia, according to research published in Cell.

The team found they could disrupt the balance between wild-type MLL proteins and MLL chimeras.
 
This impeded MLL leukemia cell proliferation in vitro, delayed disease progression in a mouse model of MLL-AF9 leukemia, and prolonged survival in the mice.

The investigators are now attempting to translate these findings to the clinic.

“We’ve spent the last 20 years in my laboratory trying to molecularly understand how MLL translocations cause this rare and devastating form of leukemia in children so that we can use this information to develop an effective therapy for this cancer,” said lead investigator Ali Shilatifard, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“Now, we’ve made a fundamentally important breakthrough.”

The investigators found that wild-type MLL protein is less stable than the MLL chimeras in MLL leukemia cells. They therefore theorized that stabilizing the wild-type copy of the protein would displace the mutated version that drives MLL-rearranged leukemia.

The team set out to identify factors regulating MLL protein degradation and found the ubiquitin-conjugating enzyme E2O (UBE2O).

The investigators said UBE2O regulates the stability of wild-type MLL in response to interleukin-1 signaling. And inhibiting interleukin-1 receptor-associated kinases (IRAKs) increases the stability and chromatin occupancy of wild-type MLL.

The team also found that IRAK inhibition displaces the MLL chimera and subunits of the super elongation complex at a subset of target genes (LGALS1, LMO2, and GNA15).

To determine the implications of these findings for treatment, the investigators tested an IRAK4 inhibitor in patient-derived cell lines, including MLL leukemia and non-MLL leukemia/lymphoma cells. The inhibitor preferentially impeded the growth of MLL-rearranged leukemia cells.

The team also tested IRAK inhibitors in a murine MLL-AF9 leukemia transplantation model. They injected the animals with IRAK inhibitors on day 19 after transplant, which is just before the mice succumb to leukemia.

The mice received injections with an IRAK1/4 inhibitor (8 mg/kg), an IRAK4 inhibitor (75 mg/kg), or vehicle control every other day for 10 days.

The investigators said both IRAK inhibitors significantly extended survival beyond the 27-day mark, when all of the vehicle-treated mice had succumbed to the disease. Two mice treated with an IRAK inhibitor (1 mouse for each drug) were still alive at day 55.

The team also treated mice with the IRAK inhibitors or vehicle control at 10 days after transplant.

Eight of the 10 mice that received the IRAK1/4 inhibitor had not developed MLL-AF9 leukemia as of day 55. And the same was true for 4 of the 9 mice that received the IRAK4 inhibitor.

However, all of the vehicle-treated mice had succumbed to the disease by the 31-day mark.

The investigators said they are now synthesizing better compounds and hope to eventually launch a phase 1 trial to test these compounds in Chicago.

Lab mouse

Investigators may have discovered a new way to treat mixed-lineage leukemia (MLL)-rearranged leukemia, according to research published in Cell.

The team found they could disrupt the balance between wild-type MLL proteins and MLL chimeras.
 
This impeded MLL leukemia cell proliferation in vitro, delayed disease progression in a mouse model of MLL-AF9 leukemia, and prolonged survival in the mice.

The investigators are now attempting to translate these findings to the clinic.

“We’ve spent the last 20 years in my laboratory trying to molecularly understand how MLL translocations cause this rare and devastating form of leukemia in children so that we can use this information to develop an effective therapy for this cancer,” said lead investigator Ali Shilatifard, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“Now, we’ve made a fundamentally important breakthrough.”

The investigators found that wild-type MLL protein is less stable than the MLL chimeras in MLL leukemia cells. They therefore theorized that stabilizing the wild-type copy of the protein would displace the mutated version that drives MLL-rearranged leukemia.

The team set out to identify factors regulating MLL protein degradation and found the ubiquitin-conjugating enzyme E2O (UBE2O).

The investigators said UBE2O regulates the stability of wild-type MLL in response to interleukin-1 signaling. And inhibiting interleukin-1 receptor-associated kinases (IRAKs) increases the stability and chromatin occupancy of wild-type MLL.

The team also found that IRAK inhibition displaces the MLL chimera and subunits of the super elongation complex at a subset of target genes (LGALS1, LMO2, and GNA15).

To determine the implications of these findings for treatment, the investigators tested an IRAK4 inhibitor in patient-derived cell lines, including MLL leukemia and non-MLL leukemia/lymphoma cells. The inhibitor preferentially impeded the growth of MLL-rearranged leukemia cells.

The team also tested IRAK inhibitors in a murine MLL-AF9 leukemia transplantation model. They injected the animals with IRAK inhibitors on day 19 after transplant, which is just before the mice succumb to leukemia.

The mice received injections with an IRAK1/4 inhibitor (8 mg/kg), an IRAK4 inhibitor (75 mg/kg), or vehicle control every other day for 10 days.

The investigators said both IRAK inhibitors significantly extended survival beyond the 27-day mark, when all of the vehicle-treated mice had succumbed to the disease. Two mice treated with an IRAK inhibitor (1 mouse for each drug) were still alive at day 55.

The team also treated mice with the IRAK inhibitors or vehicle control at 10 days after transplant.

Eight of the 10 mice that received the IRAK1/4 inhibitor had not developed MLL-AF9 leukemia as of day 55. And the same was true for 4 of the 9 mice that received the IRAK4 inhibitor.

However, all of the vehicle-treated mice had succumbed to the disease by the 31-day mark.

The investigators said they are now synthesizing better compounds and hope to eventually launch a phase 1 trial to test these compounds in Chicago.

Lab mouse

Investigators may have discovered a new way to treat mixed-lineage leukemia (MLL)-rearranged leukemia, according to research published in Cell.

The team found they could disrupt the balance between wild-type MLL proteins and MLL chimeras.
 
This impeded MLL leukemia cell proliferation in vitro, delayed disease progression in a mouse model of MLL-AF9 leukemia, and prolonged survival in the mice.

The investigators are now attempting to translate these findings to the clinic.

“We’ve spent the last 20 years in my laboratory trying to molecularly understand how MLL translocations cause this rare and devastating form of leukemia in children so that we can use this information to develop an effective therapy for this cancer,” said lead investigator Ali Shilatifard, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“Now, we’ve made a fundamentally important breakthrough.”

The investigators found that wild-type MLL protein is less stable than the MLL chimeras in MLL leukemia cells. They therefore theorized that stabilizing the wild-type copy of the protein would displace the mutated version that drives MLL-rearranged leukemia.

The team set out to identify factors regulating MLL protein degradation and found the ubiquitin-conjugating enzyme E2O (UBE2O).

The investigators said UBE2O regulates the stability of wild-type MLL in response to interleukin-1 signaling. And inhibiting interleukin-1 receptor-associated kinases (IRAKs) increases the stability and chromatin occupancy of wild-type MLL.

The team also found that IRAK inhibition displaces the MLL chimera and subunits of the super elongation complex at a subset of target genes (LGALS1, LMO2, and GNA15).

To determine the implications of these findings for treatment, the investigators tested an IRAK4 inhibitor in patient-derived cell lines, including MLL leukemia and non-MLL leukemia/lymphoma cells. The inhibitor preferentially impeded the growth of MLL-rearranged leukemia cells.

The team also tested IRAK inhibitors in a murine MLL-AF9 leukemia transplantation model. They injected the animals with IRAK inhibitors on day 19 after transplant, which is just before the mice succumb to leukemia.

The mice received injections with an IRAK1/4 inhibitor (8 mg/kg), an IRAK4 inhibitor (75 mg/kg), or vehicle control every other day for 10 days.

The investigators said both IRAK inhibitors significantly extended survival beyond the 27-day mark, when all of the vehicle-treated mice had succumbed to the disease. Two mice treated with an IRAK inhibitor (1 mouse for each drug) were still alive at day 55.

The team also treated mice with the IRAK inhibitors or vehicle control at 10 days after transplant.

Eight of the 10 mice that received the IRAK1/4 inhibitor had not developed MLL-AF9 leukemia as of day 55. And the same was true for 4 of the 9 mice that received the IRAK4 inhibitor.

However, all of the vehicle-treated mice had succumbed to the disease by the 31-day mark.

The investigators said they are now synthesizing better compounds and hope to eventually launch a phase 1 trial to test these compounds in Chicago.