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Agent preferentially targets FLT3-ITD AML
PHILADELPHIA—Preclinical research suggests a novel agent has preferential activity in acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations.
The agent, VNLG-152, proved more cytotoxic in AML cell lines and patient samples with FLT3-ITD than in samples and cell lines with wild-type FLT3.
Exactly how and why this occurs remains somewhat of a mystery, however.
Sheetal Karne, MD, of the University of Maryland School of Medicine in Baltimore, and her colleagues detailed this mystery in a poster presentation at the AACR Annual Meeting 2015 (abstract 5408*).
Dr Karne noted that VNLG-152 targets translation by promoting the degradation of MAPK-interacting kinases (Mnks).
“[VNLG-152] has been previously published as functioning in Mnk degradation, which has been shown in triple-negative breast cancer and prostate cancer—in vivo and in vitro,” she said. “Our hypothesis was that, since [the drug] worked via decreasing translation, it would function in leukemia cells and, specifically, in leukemic cells with ITD mutations.”
So the investigators tested VNLG-152 in samples from AML patients, as well as both murine and human cell lines. They found that VNLG-152 was more cytotoxic in the presence of FLT3-ITD mutations, as evidenced by low micromolar IC50 concentrations.
The IC50 concentration was 3.4 μM in Ba/F3-ITD cells and 5.8 μM in Ba/F3-WT cells, which are murine cells transfected with human FLT3-ITD and wild-type FLT3, respectively. Similarly, the IC50 concentration was 1.8 μM in 32D-ITD cells and 18.2 μM in 32D-WT cells.
In the human FLT3-ITD AML cell lines MV4-11 and MOLM-14, IC50 concentrations were 2.3 μM and 4.2 μM, respectively. But concentrations were greater than 10 µM in the wild-type FLT3 human cell lines HL60 and U937.
In patient samples, the IC50 concentration was 1.0 μM in FLT3-ITD AML and 7.5 μM in AML with wild-type FLT3.
In additional tests with murine cell lines, the investigators found that VNLG-152 inhibits the growth of Ba/F3-ITD and Ba/F3-WT cells. But the drug induces apoptosis in these cell lines only when given in high concentrations.
Looking into the mechanism of VNLG-152, the investigators found that the drug decreased Mnk-1 expression in Ba/F3-ITD and Ba/F3-WT cell lines.
“We saw that VNLG-152 worked via degradation of Mnk, but it was the same in both wild-type and ITD, so we’re still looking for an explanation as to what caused this difference,” Dr Karne said.
She and her colleagues believe the Mnk degradation inhibits the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), a downstream target of FLT3-ITD. But they are still investigating that possibility.
The team is also hoping to test VNLG-152 in combination with other drugs, such as FLT3 inhibitors or chemotherapeutic agents. 
*Information in the abstract differs from that presented at the meeting.
PHILADELPHIA—Preclinical research suggests a novel agent has preferential activity in acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations.
The agent, VNLG-152, proved more cytotoxic in AML cell lines and patient samples with FLT3-ITD than in samples and cell lines with wild-type FLT3.
Exactly how and why this occurs remains somewhat of a mystery, however.
Sheetal Karne, MD, of the University of Maryland School of Medicine in Baltimore, and her colleagues detailed this mystery in a poster presentation at the AACR Annual Meeting 2015 (abstract 5408*).
Dr Karne noted that VNLG-152 targets translation by promoting the degradation of MAPK-interacting kinases (Mnks).
“[VNLG-152] has been previously published as functioning in Mnk degradation, which has been shown in triple-negative breast cancer and prostate cancer—in vivo and in vitro,” she said. “Our hypothesis was that, since [the drug] worked via decreasing translation, it would function in leukemia cells and, specifically, in leukemic cells with ITD mutations.”
So the investigators tested VNLG-152 in samples from AML patients, as well as both murine and human cell lines. They found that VNLG-152 was more cytotoxic in the presence of FLT3-ITD mutations, as evidenced by low micromolar IC50 concentrations.
The IC50 concentration was 3.4 μM in Ba/F3-ITD cells and 5.8 μM in Ba/F3-WT cells, which are murine cells transfected with human FLT3-ITD and wild-type FLT3, respectively. Similarly, the IC50 concentration was 1.8 μM in 32D-ITD cells and 18.2 μM in 32D-WT cells.
In the human FLT3-ITD AML cell lines MV4-11 and MOLM-14, IC50 concentrations were 2.3 μM and 4.2 μM, respectively. But concentrations were greater than 10 µM in the wild-type FLT3 human cell lines HL60 and U937.
In patient samples, the IC50 concentration was 1.0 μM in FLT3-ITD AML and 7.5 μM in AML with wild-type FLT3.
In additional tests with murine cell lines, the investigators found that VNLG-152 inhibits the growth of Ba/F3-ITD and Ba/F3-WT cells. But the drug induces apoptosis in these cell lines only when given in high concentrations.
Looking into the mechanism of VNLG-152, the investigators found that the drug decreased Mnk-1 expression in Ba/F3-ITD and Ba/F3-WT cell lines.
“We saw that VNLG-152 worked via degradation of Mnk, but it was the same in both wild-type and ITD, so we’re still looking for an explanation as to what caused this difference,” Dr Karne said.
She and her colleagues believe the Mnk degradation inhibits the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), a downstream target of FLT3-ITD. But they are still investigating that possibility.
The team is also hoping to test VNLG-152 in combination with other drugs, such as FLT3 inhibitors or chemotherapeutic agents.
*Information in the abstract differs from that presented at the meeting.
PHILADELPHIA—Preclinical research suggests a novel agent has preferential activity in acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations.
The agent, VNLG-152, proved more cytotoxic in AML cell lines and patient samples with FLT3-ITD than in samples and cell lines with wild-type FLT3.
Exactly how and why this occurs remains somewhat of a mystery, however.
Sheetal Karne, MD, of the University of Maryland School of Medicine in Baltimore, and her colleagues detailed this mystery in a poster presentation at the AACR Annual Meeting 2015 (abstract 5408*).
Dr Karne noted that VNLG-152 targets translation by promoting the degradation of MAPK-interacting kinases (Mnks).
“[VNLG-152] has been previously published as functioning in Mnk degradation, which has been shown in triple-negative breast cancer and prostate cancer—in vivo and in vitro,” she said. “Our hypothesis was that, since [the drug] worked via decreasing translation, it would function in leukemia cells and, specifically, in leukemic cells with ITD mutations.”
So the investigators tested VNLG-152 in samples from AML patients, as well as both murine and human cell lines. They found that VNLG-152 was more cytotoxic in the presence of FLT3-ITD mutations, as evidenced by low micromolar IC50 concentrations.
The IC50 concentration was 3.4 μM in Ba/F3-ITD cells and 5.8 μM in Ba/F3-WT cells, which are murine cells transfected with human FLT3-ITD and wild-type FLT3, respectively. Similarly, the IC50 concentration was 1.8 μM in 32D-ITD cells and 18.2 μM in 32D-WT cells.
In the human FLT3-ITD AML cell lines MV4-11 and MOLM-14, IC50 concentrations were 2.3 μM and 4.2 μM, respectively. But concentrations were greater than 10 µM in the wild-type FLT3 human cell lines HL60 and U937.
In patient samples, the IC50 concentration was 1.0 μM in FLT3-ITD AML and 7.5 μM in AML with wild-type FLT3.
In additional tests with murine cell lines, the investigators found that VNLG-152 inhibits the growth of Ba/F3-ITD and Ba/F3-WT cells. But the drug induces apoptosis in these cell lines only when given in high concentrations.
Looking into the mechanism of VNLG-152, the investigators found that the drug decreased Mnk-1 expression in Ba/F3-ITD and Ba/F3-WT cell lines.
“We saw that VNLG-152 worked via degradation of Mnk, but it was the same in both wild-type and ITD, so we’re still looking for an explanation as to what caused this difference,” Dr Karne said.
She and her colleagues believe the Mnk degradation inhibits the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), a downstream target of FLT3-ITD. But they are still investigating that possibility.
The team is also hoping to test VNLG-152 in combination with other drugs, such as FLT3 inhibitors or chemotherapeutic agents.
*Information in the abstract differs from that presented at the meeting.
Inhibitor gets breakthrough designation for CLL
Though a safety issue previously slowed development of the BCL-2 inhibitor venetoclax (ABT-199), the drug is now moving through the pipeline.
The US Food and Drug Administration (FDA) has granted venetoclax breakthrough therapy designation to treat patients with relapsed or refractory chronic lymphocytic leukemia (CLL), including those with 17p deletion.
The drug has proven active against CLL and other hematologic malignancies.
However, it is also known to induce tumor lysis syndrome (TLS). In fact, TLS-related deaths temporarily halted enrollment in trials of venetoclax. But researchers discovered ways to reduce the risk of TLS, and the trials continued.
Now, the FDA has granted the drug breakthrough designation, which is intended to expedite the development and review of drugs indicated for serious or life-threatening conditions.
The criteria for breakthrough designation include preliminary clinical evidence suggesting the drug may offer substantial improvement on at least one clinically significant endpoint compared to available therapy.
Venetoclax in CLL/SLL
Results presented at the 2014 EHA Congress suggested that venetoclax can be effective in patients with CLL/small lymphocytic lymphoma (SLL), and certain measures can reduce the risk of TLS.
Researchers reported that modifying the dosing schedule of venetoclax, administering TLS prophylaxis, and monitoring patients can decrease or eliminate the risk of TLS. And venetoclax can produce responses in patients with high-risk disease.
In a phase 1 trial, the researchers tested venetoclax monotherapy in 105 patients with high-risk CLL/SLL. Seventy-eight patients were evaluable for treatment response as of April 2014. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.
The response rate was 77% overall, 79% among patients with del (17p), 76% in patients who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23%, 26%, 22%, and 29%, respectively.
The median progression-free survival was about 18 months overall, but the median progression-free survival had not been reached for patients treated at or above 400 mg.
Seven patients developed TLS. One of these patients died, and 1 required dialysis. At the time of analysis, there were no cases of TLS among the 49 patients who received TLS prophylaxis and were given venetoclax according to the modified dosing schedule.
Common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.
Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).
Venetoclax is now being tested in phase 2 and 3 trials of CLL, as well as trials in other hematologic malignancies. Venetoclax is under development by AbbVie and Genentech/Roche.
Though a safety issue previously slowed development of the BCL-2 inhibitor venetoclax (ABT-199), the drug is now moving through the pipeline.
The US Food and Drug Administration (FDA) has granted venetoclax breakthrough therapy designation to treat patients with relapsed or refractory chronic lymphocytic leukemia (CLL), including those with 17p deletion.
The drug has proven active against CLL and other hematologic malignancies.
However, it is also known to induce tumor lysis syndrome (TLS). In fact, TLS-related deaths temporarily halted enrollment in trials of venetoclax. But researchers discovered ways to reduce the risk of TLS, and the trials continued.
Now, the FDA has granted the drug breakthrough designation, which is intended to expedite the development and review of drugs indicated for serious or life-threatening conditions.
The criteria for breakthrough designation include preliminary clinical evidence suggesting the drug may offer substantial improvement on at least one clinically significant endpoint compared to available therapy.
Venetoclax in CLL/SLL
Results presented at the 2014 EHA Congress suggested that venetoclax can be effective in patients with CLL/small lymphocytic lymphoma (SLL), and certain measures can reduce the risk of TLS.
Researchers reported that modifying the dosing schedule of venetoclax, administering TLS prophylaxis, and monitoring patients can decrease or eliminate the risk of TLS. And venetoclax can produce responses in patients with high-risk disease.
In a phase 1 trial, the researchers tested venetoclax monotherapy in 105 patients with high-risk CLL/SLL. Seventy-eight patients were evaluable for treatment response as of April 2014. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.
The response rate was 77% overall, 79% among patients with del (17p), 76% in patients who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23%, 26%, 22%, and 29%, respectively.
The median progression-free survival was about 18 months overall, but the median progression-free survival had not been reached for patients treated at or above 400 mg.
Seven patients developed TLS. One of these patients died, and 1 required dialysis. At the time of analysis, there were no cases of TLS among the 49 patients who received TLS prophylaxis and were given venetoclax according to the modified dosing schedule.
Common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.
Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).
Venetoclax is now being tested in phase 2 and 3 trials of CLL, as well as trials in other hematologic malignancies. Venetoclax is under development by AbbVie and Genentech/Roche.
Though a safety issue previously slowed development of the BCL-2 inhibitor venetoclax (ABT-199), the drug is now moving through the pipeline.
The US Food and Drug Administration (FDA) has granted venetoclax breakthrough therapy designation to treat patients with relapsed or refractory chronic lymphocytic leukemia (CLL), including those with 17p deletion.
The drug has proven active against CLL and other hematologic malignancies.
However, it is also known to induce tumor lysis syndrome (TLS). In fact, TLS-related deaths temporarily halted enrollment in trials of venetoclax. But researchers discovered ways to reduce the risk of TLS, and the trials continued.
Now, the FDA has granted the drug breakthrough designation, which is intended to expedite the development and review of drugs indicated for serious or life-threatening conditions.
The criteria for breakthrough designation include preliminary clinical evidence suggesting the drug may offer substantial improvement on at least one clinically significant endpoint compared to available therapy.
Venetoclax in CLL/SLL
Results presented at the 2014 EHA Congress suggested that venetoclax can be effective in patients with CLL/small lymphocytic lymphoma (SLL), and certain measures can reduce the risk of TLS.
Researchers reported that modifying the dosing schedule of venetoclax, administering TLS prophylaxis, and monitoring patients can decrease or eliminate the risk of TLS. And venetoclax can produce responses in patients with high-risk disease.
In a phase 1 trial, the researchers tested venetoclax monotherapy in 105 patients with high-risk CLL/SLL. Seventy-eight patients were evaluable for treatment response as of April 2014. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.
The response rate was 77% overall, 79% among patients with del (17p), 76% in patients who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23%, 26%, 22%, and 29%, respectively.
The median progression-free survival was about 18 months overall, but the median progression-free survival had not been reached for patients treated at or above 400 mg.
Seven patients developed TLS. One of these patients died, and 1 required dialysis. At the time of analysis, there were no cases of TLS among the 49 patients who received TLS prophylaxis and were given venetoclax according to the modified dosing schedule.
Common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.
Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).
Venetoclax is now being tested in phase 2 and 3 trials of CLL, as well as trials in other hematologic malignancies. Venetoclax is under development by AbbVie and Genentech/Roche.
Drug can alleviate transfusion dependence in non-del-5q MDS
Photo courtesy of Celgene
WASHINGTON, DC—Results of a phase 3 trial support the use of lenalidomide in patients with lower-risk myelodysplastic syndromes (MDS) without 5q deletion who are unresponsive or refractory to erythropoiesis-stimulating agents (ESAs), according to researchers.
About 27% of patients who received lenalidomide achieved transfusion independence for 8 weeks or more, and about 18% were transfusion-independent for 24 weeks or more.
Valeria Santini, MD, of AOU Careggi in Florence, Italy, and her colleagues presented these results at the 13th International Symposium on Myelodysplastic Syndromes (abstract 115). The trial, MDS-005, was supported by Celgene Corporation, the company developing lenalidomide.
The trial was a comparison of lenalidomide and placebo in 239 patients with non-del-5q MDS who had failed treatment with ESAs. The patients were transfusion-dependent and had low- or intermediate-1-risk disease according to the International Prognostic Scoring System.
Patients were randomized 2:1 to receive oral lenalidomide at 10 mg once daily on days 1 to 28 of 28-day cycles (5 mg for patients with creatinine clearance 40 to 60 mL/min) or placebo.
Significantly more patients in the lenalidomide arm than in the placebo arm achieved transfusion independence for 8 weeks or more—26.9% vs 2.5% (P<0.001).
Likewise, significantly more patients in the lenalidomide arm than in the placebo arm achieved transfusion independence for 24 weeks or more—17.5% vs 0% (P<0.001).
Ninety percent of the lenalidomide-treated patients who achieved transfusion independence for 8 weeks or more responded within 4 cycles of treatment. The median duration of response was 32.9 weeks.
The median follow-up was 1.6 years (range, 0-3.6) in the lenalidomide arm and 1.3 years (range, 0-4.0) in the placebo arm. Within these time periods, patients in the placebo arm were more likely than those who received lenalidomide to progress to acute myeloid leukemia (AML) or to develop second primary malignancies (SPMs).
The AML incidence rate per 100 person-years was 1.91 in the lenalidomide arm and 2.46 in the placebo arm. And the SPM incidence rate per 100 person-years was 2.19 in the lenalidomide arm and 2.27 in the placebo arm.
As expected, treatment-emergent adverse events (AEs) were more common in the lenalidomide arm than in the placebo arm. AEs included neutropenia (64.4% vs 12.7%), thrombocytopenia (39.4% vs 7.6%), diarrhea (42.5% vs 22.8%), constipation (22.5% vs 12.7%), infections (51.9% vs 43%), hemorrhage (20.6% vs 10.1%), hepatic disorders (14.4% vs 5.1%), cardiac arrhythmia (11.3% vs 8.9%), and cutaneous reactions (10% vs 1.3%).
Grade 3-4 AEs in the lenalidomide arm included neutropenia (61.9%), thrombocytopenia (35.6%), infections (14.4%), hepatic disorders (5%), diarrhea (2.5%), hemorrhage (1.9%), deep vein thrombosis (1.9%), cardiac arrhythmia (1.3%), and cutaneous reactions (1.3%).
Based on the results of this trial, Celgene plans to submit a regulatory filing with the US Food and Drug Administration in the second half of 2015. Lenalidomide is not approved in the US to treat patients with non-del-5q MDS.
Photo courtesy of Celgene
WASHINGTON, DC—Results of a phase 3 trial support the use of lenalidomide in patients with lower-risk myelodysplastic syndromes (MDS) without 5q deletion who are unresponsive or refractory to erythropoiesis-stimulating agents (ESAs), according to researchers.
About 27% of patients who received lenalidomide achieved transfusion independence for 8 weeks or more, and about 18% were transfusion-independent for 24 weeks or more.
Valeria Santini, MD, of AOU Careggi in Florence, Italy, and her colleagues presented these results at the 13th International Symposium on Myelodysplastic Syndromes (abstract 115). The trial, MDS-005, was supported by Celgene Corporation, the company developing lenalidomide.
The trial was a comparison of lenalidomide and placebo in 239 patients with non-del-5q MDS who had failed treatment with ESAs. The patients were transfusion-dependent and had low- or intermediate-1-risk disease according to the International Prognostic Scoring System.
Patients were randomized 2:1 to receive oral lenalidomide at 10 mg once daily on days 1 to 28 of 28-day cycles (5 mg for patients with creatinine clearance 40 to 60 mL/min) or placebo.
Significantly more patients in the lenalidomide arm than in the placebo arm achieved transfusion independence for 8 weeks or more—26.9% vs 2.5% (P<0.001).
Likewise, significantly more patients in the lenalidomide arm than in the placebo arm achieved transfusion independence for 24 weeks or more—17.5% vs 0% (P<0.001).
Ninety percent of the lenalidomide-treated patients who achieved transfusion independence for 8 weeks or more responded within 4 cycles of treatment. The median duration of response was 32.9 weeks.
The median follow-up was 1.6 years (range, 0-3.6) in the lenalidomide arm and 1.3 years (range, 0-4.0) in the placebo arm. Within these time periods, patients in the placebo arm were more likely than those who received lenalidomide to progress to acute myeloid leukemia (AML) or to develop second primary malignancies (SPMs).
The AML incidence rate per 100 person-years was 1.91 in the lenalidomide arm and 2.46 in the placebo arm. And the SPM incidence rate per 100 person-years was 2.19 in the lenalidomide arm and 2.27 in the placebo arm.
As expected, treatment-emergent adverse events (AEs) were more common in the lenalidomide arm than in the placebo arm. AEs included neutropenia (64.4% vs 12.7%), thrombocytopenia (39.4% vs 7.6%), diarrhea (42.5% vs 22.8%), constipation (22.5% vs 12.7%), infections (51.9% vs 43%), hemorrhage (20.6% vs 10.1%), hepatic disorders (14.4% vs 5.1%), cardiac arrhythmia (11.3% vs 8.9%), and cutaneous reactions (10% vs 1.3%).
Grade 3-4 AEs in the lenalidomide arm included neutropenia (61.9%), thrombocytopenia (35.6%), infections (14.4%), hepatic disorders (5%), diarrhea (2.5%), hemorrhage (1.9%), deep vein thrombosis (1.9%), cardiac arrhythmia (1.3%), and cutaneous reactions (1.3%).
Based on the results of this trial, Celgene plans to submit a regulatory filing with the US Food and Drug Administration in the second half of 2015. Lenalidomide is not approved in the US to treat patients with non-del-5q MDS.
Photo courtesy of Celgene
WASHINGTON, DC—Results of a phase 3 trial support the use of lenalidomide in patients with lower-risk myelodysplastic syndromes (MDS) without 5q deletion who are unresponsive or refractory to erythropoiesis-stimulating agents (ESAs), according to researchers.
About 27% of patients who received lenalidomide achieved transfusion independence for 8 weeks or more, and about 18% were transfusion-independent for 24 weeks or more.
Valeria Santini, MD, of AOU Careggi in Florence, Italy, and her colleagues presented these results at the 13th International Symposium on Myelodysplastic Syndromes (abstract 115). The trial, MDS-005, was supported by Celgene Corporation, the company developing lenalidomide.
The trial was a comparison of lenalidomide and placebo in 239 patients with non-del-5q MDS who had failed treatment with ESAs. The patients were transfusion-dependent and had low- or intermediate-1-risk disease according to the International Prognostic Scoring System.
Patients were randomized 2:1 to receive oral lenalidomide at 10 mg once daily on days 1 to 28 of 28-day cycles (5 mg for patients with creatinine clearance 40 to 60 mL/min) or placebo.
Significantly more patients in the lenalidomide arm than in the placebo arm achieved transfusion independence for 8 weeks or more—26.9% vs 2.5% (P<0.001).
Likewise, significantly more patients in the lenalidomide arm than in the placebo arm achieved transfusion independence for 24 weeks or more—17.5% vs 0% (P<0.001).
Ninety percent of the lenalidomide-treated patients who achieved transfusion independence for 8 weeks or more responded within 4 cycles of treatment. The median duration of response was 32.9 weeks.
The median follow-up was 1.6 years (range, 0-3.6) in the lenalidomide arm and 1.3 years (range, 0-4.0) in the placebo arm. Within these time periods, patients in the placebo arm were more likely than those who received lenalidomide to progress to acute myeloid leukemia (AML) or to develop second primary malignancies (SPMs).
The AML incidence rate per 100 person-years was 1.91 in the lenalidomide arm and 2.46 in the placebo arm. And the SPM incidence rate per 100 person-years was 2.19 in the lenalidomide arm and 2.27 in the placebo arm.
As expected, treatment-emergent adverse events (AEs) were more common in the lenalidomide arm than in the placebo arm. AEs included neutropenia (64.4% vs 12.7%), thrombocytopenia (39.4% vs 7.6%), diarrhea (42.5% vs 22.8%), constipation (22.5% vs 12.7%), infections (51.9% vs 43%), hemorrhage (20.6% vs 10.1%), hepatic disorders (14.4% vs 5.1%), cardiac arrhythmia (11.3% vs 8.9%), and cutaneous reactions (10% vs 1.3%).
Grade 3-4 AEs in the lenalidomide arm included neutropenia (61.9%), thrombocytopenia (35.6%), infections (14.4%), hepatic disorders (5%), diarrhea (2.5%), hemorrhage (1.9%), deep vein thrombosis (1.9%), cardiac arrhythmia (1.3%), and cutaneous reactions (1.3%).
Based on the results of this trial, Celgene plans to submit a regulatory filing with the US Food and Drug Administration in the second half of 2015. Lenalidomide is not approved in the US to treat patients with non-del-5q MDS.
Reversing glucocorticoid resistance in ALL
Photo courtesy of St. Jude
Researchers say they have identified a mechanism that helps leukemia cells resist glucocorticoids.
They believe the mechanism is responsible for about a third of steroid resistance in children and adolescents with acute lymphoblastic leukemia (ALL).
However, additional research is needed to determine if the process is at work in adults with ALL, where steroid resistance is more common and long-term survival lags.
The researchers described the mechanism in Nature Genetics.
“Based on these findings, research has already begun to identify small molecules with the potential to reverse glucocorticoid resistance, leading to more effective treatment and increased survival,” said study author William Evans, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
Dr Evans and his colleagues analyzed samples from 444 newly diagnosed ALL patients being treated at St. Jude or in clinical trials sponsored by the Dutch Childhood Oncology Group and the German Cooperative Study Group for Childhood ALL.
The team also analyzed samples collected at diagnosis and relapse from 49 pediatric ALL patients enrolled in clinical trials organized by the Children’s Oncology Group.
The researchers found differences in gene expression that correlated with sensitivity to steroids. CASP1 and NLRP3 were among the genes with increased activity in steroid-resistant leukemia cells.
The team also identified a reason for the increased gene activity. Leukemia cells overexpressing CASP1 and NLRP3 had lower levels of methylation compared to cells with normal expression.
Previous research showed that steroid resistance was more common in young ALL patients who relapsed than in newly diagnosed patients. Dr Evans and his colleagues found that expression of CASP1 and NLRP3 was significantly higher in ALL patients who relapsed.
The researchers also discovered that CASP1 blocks glucocorticoids by splitting the receptor where the drug binds and therefore blocks its access to the nucleus.
“Cells that overexpress CASP1 are chewing up their glucocorticoid receptor,” Dr Evans said. “That means when steroids enter the cell, there is no receptor for the drugs to bind to or fulfill its therapeutic function.”
To confirm that CASP1 cleavage of the steroid receptor is pivotal to ALL steroid resistance, the researchers engineered a receptor that lacked the CASP1 cleavage site. When they introduced the genetically engineered receptors into ALL cells that expressed high levels of CASP1, the cells remained sensitive to steroids.
Using a variety of techniques, the researchers showed that steroid resistance rose or fell in leukemia cells based on CASP1 levels. Overexpression of CASP1 rendered ALL cells 5 to 15 times more resistant to the glucocorticoids dexamethasone and prednisolone.
However, reducing CASP1 using genetic, pharmacologic, and other methods restored steroid sensitivity in leukemia cells.
Photo courtesy of St. Jude
Researchers say they have identified a mechanism that helps leukemia cells resist glucocorticoids.
They believe the mechanism is responsible for about a third of steroid resistance in children and adolescents with acute lymphoblastic leukemia (ALL).
However, additional research is needed to determine if the process is at work in adults with ALL, where steroid resistance is more common and long-term survival lags.
The researchers described the mechanism in Nature Genetics.
“Based on these findings, research has already begun to identify small molecules with the potential to reverse glucocorticoid resistance, leading to more effective treatment and increased survival,” said study author William Evans, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
Dr Evans and his colleagues analyzed samples from 444 newly diagnosed ALL patients being treated at St. Jude or in clinical trials sponsored by the Dutch Childhood Oncology Group and the German Cooperative Study Group for Childhood ALL.
The team also analyzed samples collected at diagnosis and relapse from 49 pediatric ALL patients enrolled in clinical trials organized by the Children’s Oncology Group.
The researchers found differences in gene expression that correlated with sensitivity to steroids. CASP1 and NLRP3 were among the genes with increased activity in steroid-resistant leukemia cells.
The team also identified a reason for the increased gene activity. Leukemia cells overexpressing CASP1 and NLRP3 had lower levels of methylation compared to cells with normal expression.
Previous research showed that steroid resistance was more common in young ALL patients who relapsed than in newly diagnosed patients. Dr Evans and his colleagues found that expression of CASP1 and NLRP3 was significantly higher in ALL patients who relapsed.
The researchers also discovered that CASP1 blocks glucocorticoids by splitting the receptor where the drug binds and therefore blocks its access to the nucleus.
“Cells that overexpress CASP1 are chewing up their glucocorticoid receptor,” Dr Evans said. “That means when steroids enter the cell, there is no receptor for the drugs to bind to or fulfill its therapeutic function.”
To confirm that CASP1 cleavage of the steroid receptor is pivotal to ALL steroid resistance, the researchers engineered a receptor that lacked the CASP1 cleavage site. When they introduced the genetically engineered receptors into ALL cells that expressed high levels of CASP1, the cells remained sensitive to steroids.
Using a variety of techniques, the researchers showed that steroid resistance rose or fell in leukemia cells based on CASP1 levels. Overexpression of CASP1 rendered ALL cells 5 to 15 times more resistant to the glucocorticoids dexamethasone and prednisolone.
However, reducing CASP1 using genetic, pharmacologic, and other methods restored steroid sensitivity in leukemia cells.
Photo courtesy of St. Jude
Researchers say they have identified a mechanism that helps leukemia cells resist glucocorticoids.
They believe the mechanism is responsible for about a third of steroid resistance in children and adolescents with acute lymphoblastic leukemia (ALL).
However, additional research is needed to determine if the process is at work in adults with ALL, where steroid resistance is more common and long-term survival lags.
The researchers described the mechanism in Nature Genetics.
“Based on these findings, research has already begun to identify small molecules with the potential to reverse glucocorticoid resistance, leading to more effective treatment and increased survival,” said study author William Evans, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
Dr Evans and his colleagues analyzed samples from 444 newly diagnosed ALL patients being treated at St. Jude or in clinical trials sponsored by the Dutch Childhood Oncology Group and the German Cooperative Study Group for Childhood ALL.
The team also analyzed samples collected at diagnosis and relapse from 49 pediatric ALL patients enrolled in clinical trials organized by the Children’s Oncology Group.
The researchers found differences in gene expression that correlated with sensitivity to steroids. CASP1 and NLRP3 were among the genes with increased activity in steroid-resistant leukemia cells.
The team also identified a reason for the increased gene activity. Leukemia cells overexpressing CASP1 and NLRP3 had lower levels of methylation compared to cells with normal expression.
Previous research showed that steroid resistance was more common in young ALL patients who relapsed than in newly diagnosed patients. Dr Evans and his colleagues found that expression of CASP1 and NLRP3 was significantly higher in ALL patients who relapsed.
The researchers also discovered that CASP1 blocks glucocorticoids by splitting the receptor where the drug binds and therefore blocks its access to the nucleus.
“Cells that overexpress CASP1 are chewing up their glucocorticoid receptor,” Dr Evans said. “That means when steroids enter the cell, there is no receptor for the drugs to bind to or fulfill its therapeutic function.”
To confirm that CASP1 cleavage of the steroid receptor is pivotal to ALL steroid resistance, the researchers engineered a receptor that lacked the CASP1 cleavage site. When they introduced the genetically engineered receptors into ALL cells that expressed high levels of CASP1, the cells remained sensitive to steroids.
Using a variety of techniques, the researchers showed that steroid resistance rose or fell in leukemia cells based on CASP1 levels. Overexpression of CASP1 rendered ALL cells 5 to 15 times more resistant to the glucocorticoids dexamethasone and prednisolone.
However, reducing CASP1 using genetic, pharmacologic, and other methods restored steroid sensitivity in leukemia cells.
Inhibitor improves OS in poor-prognosis MDS
WASHINGTON, DC—A small-molecule inhibitor can improve overall survival (OS) in certain patients with previously treated myelodysplastic syndromes (MDS), results of a phase 3 trial suggest.
Overall, patients who received the dual PI3K/PLK pathway inhibitor rigosertib along with best supportive care (BSC) did not see a significant improvement in OS compared to patients who received BSC alone.
However, rigosertib did improve OS in patients with poor prognosis.
Guillermo Garcia-Manero, MD, of the MD Anderson Cancer Center in Houston, Texas, and his colleagues presented these results at the 13th International Symposium on Myelodysplastic Syndromes (abstract 112).
The trial, known as ONTIME, was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.
The trial included 299 higher-risk MDS patients with excess blasts (5% to 30% bone marrow blasts) who had failed to respond to (25%), progressed on (37%), or relapsed after (38%) treatment with hypomethylating agents (HMAs).
Patients were randomized 2:1 to receive rigosertib plus BSC or BSC alone. Patients treated with rigosertib received 1800 mg every 24 hours for 72 hours as a continuous, intravenous, ambulatory infusion, every 2 weeks for the first 16 weeks, then every 4 weeks.
The treatment arms were generally balanced in terms of baseline characteristics. The majority of patients were male (66%) and white (82%). The median age was 74 years. Most patients (85%) had an Eastern Cooperative Oncology Group score of 0 or 1.
The median duration of the last HMA therapy was 8.8 months for patients in the rigosertib arm and 10.3 months for patients in the BSC arm.
The researchers found no significant difference in OS between the treatment arms. The median OS was 8.4 months in the rigosertib arm and 5.9 months in the BSC arm, and the 12-month OS was 35% and 25%, respectively (hazard ratio[HR]=0.87, P=0.31).
On the other hand, certain patients did see a significant improvement in OS with rigosertib. Among patients with primary HMA failure (those who failed to respond to or progressed during HMA therapy), the median OS was 8.6 months in the rigosertib arm and 5.3 months in the BSC arm (HR=0.69, P=0.040).
For patients who received HMAs for less than 9 months, the median OS was 7.7 months in the rigosertib arm and 4.5 months in the BSC arm (HR=0.55, P=0.003). Among patients younger than 75 years of age, the median OS was 9.7 months in the rigosertib arm and 4.1 months in the BSC arm (HR=0.52, P=0.0004).
And for patients with very high-risk disease according to the Revised International Prognostic Scoring System, the median OS was 7.6 months in the rigosertib arm and 3.2 months in the BSC arm (HR=0.56, P=0.005).
The researchers said there were no obvious differences between the treatment arms with regard to overall adverse events (AEs) or grade 3 or higher AEs.
Overall, 99% of patients in the rigosertib arm and 85% in the BSC arm experienced treatment-emergent AEs. The incidence of grade 3 or higher AEs was 79% and 68%, respectively.
Treatment-emergent AEs of all grades—occurring in the rigosertib and BSC arms, respectively—included nausea (35% vs 18%), diarrhea (33% vs 20%), constipation (31% vs 11%), fatigue (30% vs 18%), pyrexia (27% vs 21%), anemia (23% vs 9%), peripheral edema (21% vs 16%), and thrombocytopenia (21% vs 8%).
Considering the study results together, Dr Garcia-Manero and his colleagues concluded that rigosertib is likely most effective in high-risk MDS patients with the worst prognosis, and these patients can safely receive the drug.
WASHINGTON, DC—A small-molecule inhibitor can improve overall survival (OS) in certain patients with previously treated myelodysplastic syndromes (MDS), results of a phase 3 trial suggest.
Overall, patients who received the dual PI3K/PLK pathway inhibitor rigosertib along with best supportive care (BSC) did not see a significant improvement in OS compared to patients who received BSC alone.
However, rigosertib did improve OS in patients with poor prognosis.
Guillermo Garcia-Manero, MD, of the MD Anderson Cancer Center in Houston, Texas, and his colleagues presented these results at the 13th International Symposium on Myelodysplastic Syndromes (abstract 112).
The trial, known as ONTIME, was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.
The trial included 299 higher-risk MDS patients with excess blasts (5% to 30% bone marrow blasts) who had failed to respond to (25%), progressed on (37%), or relapsed after (38%) treatment with hypomethylating agents (HMAs).
Patients were randomized 2:1 to receive rigosertib plus BSC or BSC alone. Patients treated with rigosertib received 1800 mg every 24 hours for 72 hours as a continuous, intravenous, ambulatory infusion, every 2 weeks for the first 16 weeks, then every 4 weeks.
The treatment arms were generally balanced in terms of baseline characteristics. The majority of patients were male (66%) and white (82%). The median age was 74 years. Most patients (85%) had an Eastern Cooperative Oncology Group score of 0 or 1.
The median duration of the last HMA therapy was 8.8 months for patients in the rigosertib arm and 10.3 months for patients in the BSC arm.
The researchers found no significant difference in OS between the treatment arms. The median OS was 8.4 months in the rigosertib arm and 5.9 months in the BSC arm, and the 12-month OS was 35% and 25%, respectively (hazard ratio[HR]=0.87, P=0.31).
On the other hand, certain patients did see a significant improvement in OS with rigosertib. Among patients with primary HMA failure (those who failed to respond to or progressed during HMA therapy), the median OS was 8.6 months in the rigosertib arm and 5.3 months in the BSC arm (HR=0.69, P=0.040).
For patients who received HMAs for less than 9 months, the median OS was 7.7 months in the rigosertib arm and 4.5 months in the BSC arm (HR=0.55, P=0.003). Among patients younger than 75 years of age, the median OS was 9.7 months in the rigosertib arm and 4.1 months in the BSC arm (HR=0.52, P=0.0004).
And for patients with very high-risk disease according to the Revised International Prognostic Scoring System, the median OS was 7.6 months in the rigosertib arm and 3.2 months in the BSC arm (HR=0.56, P=0.005).
The researchers said there were no obvious differences between the treatment arms with regard to overall adverse events (AEs) or grade 3 or higher AEs.
Overall, 99% of patients in the rigosertib arm and 85% in the BSC arm experienced treatment-emergent AEs. The incidence of grade 3 or higher AEs was 79% and 68%, respectively.
Treatment-emergent AEs of all grades—occurring in the rigosertib and BSC arms, respectively—included nausea (35% vs 18%), diarrhea (33% vs 20%), constipation (31% vs 11%), fatigue (30% vs 18%), pyrexia (27% vs 21%), anemia (23% vs 9%), peripheral edema (21% vs 16%), and thrombocytopenia (21% vs 8%).
Considering the study results together, Dr Garcia-Manero and his colleagues concluded that rigosertib is likely most effective in high-risk MDS patients with the worst prognosis, and these patients can safely receive the drug.
WASHINGTON, DC—A small-molecule inhibitor can improve overall survival (OS) in certain patients with previously treated myelodysplastic syndromes (MDS), results of a phase 3 trial suggest.
Overall, patients who received the dual PI3K/PLK pathway inhibitor rigosertib along with best supportive care (BSC) did not see a significant improvement in OS compared to patients who received BSC alone.
However, rigosertib did improve OS in patients with poor prognosis.
Guillermo Garcia-Manero, MD, of the MD Anderson Cancer Center in Houston, Texas, and his colleagues presented these results at the 13th International Symposium on Myelodysplastic Syndromes (abstract 112).
The trial, known as ONTIME, was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.
The trial included 299 higher-risk MDS patients with excess blasts (5% to 30% bone marrow blasts) who had failed to respond to (25%), progressed on (37%), or relapsed after (38%) treatment with hypomethylating agents (HMAs).
Patients were randomized 2:1 to receive rigosertib plus BSC or BSC alone. Patients treated with rigosertib received 1800 mg every 24 hours for 72 hours as a continuous, intravenous, ambulatory infusion, every 2 weeks for the first 16 weeks, then every 4 weeks.
The treatment arms were generally balanced in terms of baseline characteristics. The majority of patients were male (66%) and white (82%). The median age was 74 years. Most patients (85%) had an Eastern Cooperative Oncology Group score of 0 or 1.
The median duration of the last HMA therapy was 8.8 months for patients in the rigosertib arm and 10.3 months for patients in the BSC arm.
The researchers found no significant difference in OS between the treatment arms. The median OS was 8.4 months in the rigosertib arm and 5.9 months in the BSC arm, and the 12-month OS was 35% and 25%, respectively (hazard ratio[HR]=0.87, P=0.31).
On the other hand, certain patients did see a significant improvement in OS with rigosertib. Among patients with primary HMA failure (those who failed to respond to or progressed during HMA therapy), the median OS was 8.6 months in the rigosertib arm and 5.3 months in the BSC arm (HR=0.69, P=0.040).
For patients who received HMAs for less than 9 months, the median OS was 7.7 months in the rigosertib arm and 4.5 months in the BSC arm (HR=0.55, P=0.003). Among patients younger than 75 years of age, the median OS was 9.7 months in the rigosertib arm and 4.1 months in the BSC arm (HR=0.52, P=0.0004).
And for patients with very high-risk disease according to the Revised International Prognostic Scoring System, the median OS was 7.6 months in the rigosertib arm and 3.2 months in the BSC arm (HR=0.56, P=0.005).
The researchers said there were no obvious differences between the treatment arms with regard to overall adverse events (AEs) or grade 3 or higher AEs.
Overall, 99% of patients in the rigosertib arm and 85% in the BSC arm experienced treatment-emergent AEs. The incidence of grade 3 or higher AEs was 79% and 68%, respectively.
Treatment-emergent AEs of all grades—occurring in the rigosertib and BSC arms, respectively—included nausea (35% vs 18%), diarrhea (33% vs 20%), constipation (31% vs 11%), fatigue (30% vs 18%), pyrexia (27% vs 21%), anemia (23% vs 9%), peripheral edema (21% vs 16%), and thrombocytopenia (21% vs 8%).
Considering the study results together, Dr Garcia-Manero and his colleagues concluded that rigosertib is likely most effective in high-risk MDS patients with the worst prognosis, and these patients can safely receive the drug.
Drug shows promise for lower-risk MDS
WASHINGTON, DC—An investigational drug can increase hemoglobin levels and eliminate transfusion dependence in patients with lower-risk myelodysplastic syndromes (MDS), results of a phase 2 trial suggest.
The drug, luspatercept, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the TGF-β superfamily involved in the late stages of erythropoiesis.
Luspatercept regulates late-stage erythrocyte precursor differentiation and maturation.
Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented results from an ongoing phase 2 study of luspatercept at the 13th International Symposium on Myelodysplastic Syndromes (abstract 53).
The trial is supported by Acceleron Pharma Inc. and Celgene Corporation, the companies developing luspatercept.
“We are excited by the results in lower-risk MDS patients, which confirm and extend our previous findings,” Dr Platzbecker said. “Luspatercept may be useful early in the treatment of lower-risk MDS patients, either as the initial treatment for anemia or in patients who do not respond or become refractory to treatment with erythropoiesis-stimulating agents.”
Patient and dosing details
The researchers enrolled 58 patients in this study. Twenty-seven have completed treatment as part of the dose-escalation cohort. These patients received luspatercept at 7 doses ranging from 0.125 mg/kg to 1.75 mg/kg.
Thirty-one patients are still receiving treatment in the expansion cohort. The starting dose in this cohort is 1.0 mg/kg, and patients are receiving individual dose titration up to 1.75 mg/kg. Seventeen patients from this cohort received at least 4 cycles of treatment or discontinued early and were included in the analysis presented at the meeting.
In all, Dr Platzbecker presented results in 44 patients. Their median age was 71 (range, 27-88), and 57% were male. The median time since diagnosis was 2.5 years (range, 0.2-13.6 years). Sixty-one percent of patients had received prior treatment with erythropoiesis-stimulating agents, and 21% had received lenalidomide.
Fifteen patients had a low transfusion burden (LTB), as they received less than 4 units of red blood cells (RBCs) over 8 weeks. For these patients, the median hemoglobin at baseline was 9.0 g/dL (range, 6.8-10.1), and the median number of RBCs transfused over 8 weeks was 2 (range, 2-2).
Twenty-nine patients had a high transfusion burden (HTB) and received 4 or more RBC units over 8 weeks. The median number of RBCs transfused in this group was 6 (range, 4-14).
Fifty percent of patients had low-risk MDS according to IPSS, 46% had intermediate-1-risk disease, and 4% had intermediate-2-risk MDS. Eighty-one percent of patients were positive for ring sideroblasts, and 58% had the SF3B1 splicing mutation.
Efficacy and safety
The study’s primary efficacy endpoint was an increase in hemoglobin and/or a reduction in transfusion use. For LTB patients, the endpoint was a hemoglobin increase of 1.5 g/dL or more for 2 weeks or longer. For HTB patients, it was decrease in transfusion of 4 or more RBC units or a 50% or greater reduction in transfusion over 8 weeks.
Among the 9 patients who received lower doses of luspatercept (0.125-0.5 mg/kg), 33% met the primary efficacy endpoint. And 63% of the 35 patients in the higher dose group (0.75-1.75 mg/kg) achieved the primary efficacy endpoint.
Twenty-two percent of patients in the lower dose group achieved the International Working Group (IWG) hematologic improvement-erythroid (HI-E) threshold of efficacy, as did 54% of patients in the higher dose group.
Fourteen percent of patients in the lower dose group achieved transfusion independence, as did 36% of patients in the higher dose group. In the higher dose group, this included 4 of 6 patients with LTB and 6 of 22 patients with HTB.
Among patients who were ring-sideroblast-positive and received higher doses of luspatercept, 39% achieved transfusion independence, and 63% achieved IWG HI-E.
The majority of adverse events (AEs) were mild to moderate (grade 1 or 2). AEs included nasopharyngitis (14%), diarrhea (14%), myalgia (11%), bone pain (9%), bronchitis (9%), headache (9%), and muscle spasms (9%).
There were 2 serious AEs—grade 3 muscle pain and grade 3 worsening of general condition—that were considered possibly related to treatment. One non-serious grade 3 AE of blast cell count increase was considered possibly treatment-related as well.
In closing, Dr Platzbecker said luspatercept was generally safe and well-tolerated, in addition to providing “robust hematologic improvement.” And these results support further study of the drug in patients with lower-risk MDS.
WASHINGTON, DC—An investigational drug can increase hemoglobin levels and eliminate transfusion dependence in patients with lower-risk myelodysplastic syndromes (MDS), results of a phase 2 trial suggest.
The drug, luspatercept, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the TGF-β superfamily involved in the late stages of erythropoiesis.
Luspatercept regulates late-stage erythrocyte precursor differentiation and maturation.
Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented results from an ongoing phase 2 study of luspatercept at the 13th International Symposium on Myelodysplastic Syndromes (abstract 53).
The trial is supported by Acceleron Pharma Inc. and Celgene Corporation, the companies developing luspatercept.
“We are excited by the results in lower-risk MDS patients, which confirm and extend our previous findings,” Dr Platzbecker said. “Luspatercept may be useful early in the treatment of lower-risk MDS patients, either as the initial treatment for anemia or in patients who do not respond or become refractory to treatment with erythropoiesis-stimulating agents.”
Patient and dosing details
The researchers enrolled 58 patients in this study. Twenty-seven have completed treatment as part of the dose-escalation cohort. These patients received luspatercept at 7 doses ranging from 0.125 mg/kg to 1.75 mg/kg.
Thirty-one patients are still receiving treatment in the expansion cohort. The starting dose in this cohort is 1.0 mg/kg, and patients are receiving individual dose titration up to 1.75 mg/kg. Seventeen patients from this cohort received at least 4 cycles of treatment or discontinued early and were included in the analysis presented at the meeting.
In all, Dr Platzbecker presented results in 44 patients. Their median age was 71 (range, 27-88), and 57% were male. The median time since diagnosis was 2.5 years (range, 0.2-13.6 years). Sixty-one percent of patients had received prior treatment with erythropoiesis-stimulating agents, and 21% had received lenalidomide.
Fifteen patients had a low transfusion burden (LTB), as they received less than 4 units of red blood cells (RBCs) over 8 weeks. For these patients, the median hemoglobin at baseline was 9.0 g/dL (range, 6.8-10.1), and the median number of RBCs transfused over 8 weeks was 2 (range, 2-2).
Twenty-nine patients had a high transfusion burden (HTB) and received 4 or more RBC units over 8 weeks. The median number of RBCs transfused in this group was 6 (range, 4-14).
Fifty percent of patients had low-risk MDS according to IPSS, 46% had intermediate-1-risk disease, and 4% had intermediate-2-risk MDS. Eighty-one percent of patients were positive for ring sideroblasts, and 58% had the SF3B1 splicing mutation.
Efficacy and safety
The study’s primary efficacy endpoint was an increase in hemoglobin and/or a reduction in transfusion use. For LTB patients, the endpoint was a hemoglobin increase of 1.5 g/dL or more for 2 weeks or longer. For HTB patients, it was decrease in transfusion of 4 or more RBC units or a 50% or greater reduction in transfusion over 8 weeks.
Among the 9 patients who received lower doses of luspatercept (0.125-0.5 mg/kg), 33% met the primary efficacy endpoint. And 63% of the 35 patients in the higher dose group (0.75-1.75 mg/kg) achieved the primary efficacy endpoint.
Twenty-two percent of patients in the lower dose group achieved the International Working Group (IWG) hematologic improvement-erythroid (HI-E) threshold of efficacy, as did 54% of patients in the higher dose group.
Fourteen percent of patients in the lower dose group achieved transfusion independence, as did 36% of patients in the higher dose group. In the higher dose group, this included 4 of 6 patients with LTB and 6 of 22 patients with HTB.
Among patients who were ring-sideroblast-positive and received higher doses of luspatercept, 39% achieved transfusion independence, and 63% achieved IWG HI-E.
The majority of adverse events (AEs) were mild to moderate (grade 1 or 2). AEs included nasopharyngitis (14%), diarrhea (14%), myalgia (11%), bone pain (9%), bronchitis (9%), headache (9%), and muscle spasms (9%).
There were 2 serious AEs—grade 3 muscle pain and grade 3 worsening of general condition—that were considered possibly related to treatment. One non-serious grade 3 AE of blast cell count increase was considered possibly treatment-related as well.
In closing, Dr Platzbecker said luspatercept was generally safe and well-tolerated, in addition to providing “robust hematologic improvement.” And these results support further study of the drug in patients with lower-risk MDS.
WASHINGTON, DC—An investigational drug can increase hemoglobin levels and eliminate transfusion dependence in patients with lower-risk myelodysplastic syndromes (MDS), results of a phase 2 trial suggest.
The drug, luspatercept, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the TGF-β superfamily involved in the late stages of erythropoiesis.
Luspatercept regulates late-stage erythrocyte precursor differentiation and maturation.
Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented results from an ongoing phase 2 study of luspatercept at the 13th International Symposium on Myelodysplastic Syndromes (abstract 53).
The trial is supported by Acceleron Pharma Inc. and Celgene Corporation, the companies developing luspatercept.
“We are excited by the results in lower-risk MDS patients, which confirm and extend our previous findings,” Dr Platzbecker said. “Luspatercept may be useful early in the treatment of lower-risk MDS patients, either as the initial treatment for anemia or in patients who do not respond or become refractory to treatment with erythropoiesis-stimulating agents.”
Patient and dosing details
The researchers enrolled 58 patients in this study. Twenty-seven have completed treatment as part of the dose-escalation cohort. These patients received luspatercept at 7 doses ranging from 0.125 mg/kg to 1.75 mg/kg.
Thirty-one patients are still receiving treatment in the expansion cohort. The starting dose in this cohort is 1.0 mg/kg, and patients are receiving individual dose titration up to 1.75 mg/kg. Seventeen patients from this cohort received at least 4 cycles of treatment or discontinued early and were included in the analysis presented at the meeting.
In all, Dr Platzbecker presented results in 44 patients. Their median age was 71 (range, 27-88), and 57% were male. The median time since diagnosis was 2.5 years (range, 0.2-13.6 years). Sixty-one percent of patients had received prior treatment with erythropoiesis-stimulating agents, and 21% had received lenalidomide.
Fifteen patients had a low transfusion burden (LTB), as they received less than 4 units of red blood cells (RBCs) over 8 weeks. For these patients, the median hemoglobin at baseline was 9.0 g/dL (range, 6.8-10.1), and the median number of RBCs transfused over 8 weeks was 2 (range, 2-2).
Twenty-nine patients had a high transfusion burden (HTB) and received 4 or more RBC units over 8 weeks. The median number of RBCs transfused in this group was 6 (range, 4-14).
Fifty percent of patients had low-risk MDS according to IPSS, 46% had intermediate-1-risk disease, and 4% had intermediate-2-risk MDS. Eighty-one percent of patients were positive for ring sideroblasts, and 58% had the SF3B1 splicing mutation.
Efficacy and safety
The study’s primary efficacy endpoint was an increase in hemoglobin and/or a reduction in transfusion use. For LTB patients, the endpoint was a hemoglobin increase of 1.5 g/dL or more for 2 weeks or longer. For HTB patients, it was decrease in transfusion of 4 or more RBC units or a 50% or greater reduction in transfusion over 8 weeks.
Among the 9 patients who received lower doses of luspatercept (0.125-0.5 mg/kg), 33% met the primary efficacy endpoint. And 63% of the 35 patients in the higher dose group (0.75-1.75 mg/kg) achieved the primary efficacy endpoint.
Twenty-two percent of patients in the lower dose group achieved the International Working Group (IWG) hematologic improvement-erythroid (HI-E) threshold of efficacy, as did 54% of patients in the higher dose group.
Fourteen percent of patients in the lower dose group achieved transfusion independence, as did 36% of patients in the higher dose group. In the higher dose group, this included 4 of 6 patients with LTB and 6 of 22 patients with HTB.
Among patients who were ring-sideroblast-positive and received higher doses of luspatercept, 39% achieved transfusion independence, and 63% achieved IWG HI-E.
The majority of adverse events (AEs) were mild to moderate (grade 1 or 2). AEs included nasopharyngitis (14%), diarrhea (14%), myalgia (11%), bone pain (9%), bronchitis (9%), headache (9%), and muscle spasms (9%).
There were 2 serious AEs—grade 3 muscle pain and grade 3 worsening of general condition—that were considered possibly related to treatment. One non-serious grade 3 AE of blast cell count increase was considered possibly treatment-related as well.
In closing, Dr Platzbecker said luspatercept was generally safe and well-tolerated, in addition to providing “robust hematologic improvement.” And these results support further study of the drug in patients with lower-risk MDS.
Targeting receptors to better treat AML
Photo courtesy of UT
Southwestern Medical Center
Preclinical research suggests that certain receptors containing the immunoreceptor tyrosine-based inhibition motif (ITIM) are important for the development of acute myeloid leukemia (AML).
“Although counterintuitive, this result is consistent with the generally immune-suppressive and, thus, tumor-promoting roles of inhibitory receptors in the immune system,” said Chengcheng Zhang, PhD, of UT Southwestern Medical Center in Dallas, Texas.
“These findings suggest that blocking ITIM-receptor signaling in combination with conventional therapies may represent a novel strategy for AML treatment.”
Dr Zhang and his colleagues reported their findings in Nature Cell Biology.
The team focused mainly on an ITIM-containing receptor called LAIR1. They found that deleting LAIR1 abolished leukemia in several different mouse models, without affecting normal hematopoiesis.
The investigators also identified a pathway that sustains the survival and self-renewal of AML cells, the mechanism by which LAIR1 supports AML development.
They said LAIR1 induces activation of SHP-1, which acts as a phosphatase-independent signaling adaptor to recruit CAMK1 for activation of downstream CREB in AML cells. And the LAIR1–SHP-1–CAMK1–CREB pathway sustains AML stem cells.
So the investigators believe that inhibiting the signaling initiated by LAIR1 and other ITIM-containing receptors could help us treat AML more effectively.
“Our study suggests that current treatment options, including chemotherapy, may not efficiently target cancer stem cells because these inhibitory receptors enable the leukemia stem cells to survive conventional therapies, eventually resulting in tumor relapse,” Dr Zhang said.
“The blockade of ITIM-receptor signaling may prove to be a novel, effective strategy for elimination of leukemia stem cells and lead to complete remission in patients.”
Photo courtesy of UT
Southwestern Medical Center
Preclinical research suggests that certain receptors containing the immunoreceptor tyrosine-based inhibition motif (ITIM) are important for the development of acute myeloid leukemia (AML).
“Although counterintuitive, this result is consistent with the generally immune-suppressive and, thus, tumor-promoting roles of inhibitory receptors in the immune system,” said Chengcheng Zhang, PhD, of UT Southwestern Medical Center in Dallas, Texas.
“These findings suggest that blocking ITIM-receptor signaling in combination with conventional therapies may represent a novel strategy for AML treatment.”
Dr Zhang and his colleagues reported their findings in Nature Cell Biology.
The team focused mainly on an ITIM-containing receptor called LAIR1. They found that deleting LAIR1 abolished leukemia in several different mouse models, without affecting normal hematopoiesis.
The investigators also identified a pathway that sustains the survival and self-renewal of AML cells, the mechanism by which LAIR1 supports AML development.
They said LAIR1 induces activation of SHP-1, which acts as a phosphatase-independent signaling adaptor to recruit CAMK1 for activation of downstream CREB in AML cells. And the LAIR1–SHP-1–CAMK1–CREB pathway sustains AML stem cells.
So the investigators believe that inhibiting the signaling initiated by LAIR1 and other ITIM-containing receptors could help us treat AML more effectively.
“Our study suggests that current treatment options, including chemotherapy, may not efficiently target cancer stem cells because these inhibitory receptors enable the leukemia stem cells to survive conventional therapies, eventually resulting in tumor relapse,” Dr Zhang said.
“The blockade of ITIM-receptor signaling may prove to be a novel, effective strategy for elimination of leukemia stem cells and lead to complete remission in patients.”
Photo courtesy of UT
Southwestern Medical Center
Preclinical research suggests that certain receptors containing the immunoreceptor tyrosine-based inhibition motif (ITIM) are important for the development of acute myeloid leukemia (AML).
“Although counterintuitive, this result is consistent with the generally immune-suppressive and, thus, tumor-promoting roles of inhibitory receptors in the immune system,” said Chengcheng Zhang, PhD, of UT Southwestern Medical Center in Dallas, Texas.
“These findings suggest that blocking ITIM-receptor signaling in combination with conventional therapies may represent a novel strategy for AML treatment.”
Dr Zhang and his colleagues reported their findings in Nature Cell Biology.
The team focused mainly on an ITIM-containing receptor called LAIR1. They found that deleting LAIR1 abolished leukemia in several different mouse models, without affecting normal hematopoiesis.
The investigators also identified a pathway that sustains the survival and self-renewal of AML cells, the mechanism by which LAIR1 supports AML development.
They said LAIR1 induces activation of SHP-1, which acts as a phosphatase-independent signaling adaptor to recruit CAMK1 for activation of downstream CREB in AML cells. And the LAIR1–SHP-1–CAMK1–CREB pathway sustains AML stem cells.
So the investigators believe that inhibiting the signaling initiated by LAIR1 and other ITIM-containing receptors could help us treat AML more effectively.
“Our study suggests that current treatment options, including chemotherapy, may not efficiently target cancer stem cells because these inhibitory receptors enable the leukemia stem cells to survive conventional therapies, eventually resulting in tumor relapse,” Dr Zhang said.
“The blockade of ITIM-receptor signaling may prove to be a novel, effective strategy for elimination of leukemia stem cells and lead to complete remission in patients.”
Susceptibility to 2nd cancers in WM/LPL survivors
PHILADELPHIA—A retrospective study has revealed factors that appear to influence a person’s susceptibility to Waldenström’s macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) and other malignancies.
Study investigators looked at patients diagnosed with WM or LPL over a 20-year period and found about a 50% excess of second primary cancers in this population.
The patients had a significantly increased risk of multiple hematologic and solid tumor malignancies, and a few of these malignancies had shared susceptibility factors with WM/LPL.
The investigators believe that identifying these factors may prove useful for determining genetic susceptibility to WM/LPL.
Mary L. McMaster, MD, of the National Cancer Institute in Bethesda, Maryland, and her colleagues presented these findings at the AACR Annual Meeting 2015 (abstract 3709).
The team used data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SSER) database to evaluate the risk of subsequent primary cancer in 3825 patients diagnosed with WM (n=2163) or LPL (n=1662) from 1992 to 2011. The patients’ median age was 70, most of them were male (n=2221), and most were white (n=3153).
Dr McMaster said she and her colleagues looked at both WM and LPL in this study because SEER does not include information about immunoglobulin subtype, which makes it difficult to identify all WM cases with absolute certainty.
“[D]epending on what information a pathologist has when they review a bone marrow biopsy, for example, they may or may not know whether there’s IgM present,” Dr McMaster said. “So you may have a diagnosis of LPL and not have the information required to make the diagnosis of WM. For that reason, we combined both entities for this study.”
Dr McMaster and her colleagues calculated the observed-to-expected standardized incidence ratios (SIRs) for invasive cancers. After adjusting for multiple comparisons, the team found that survivors of WM/LPL had a significantly increased risk of developing a second primary malignancy (SIR=1.49).
This increased risk was seen for males and females and persisted throughout follow-up. The risk was higher for patients younger than 65 years of age (SIR=1.95).
Hematologic malignancies
WM/LPL survivors had a significantly increased risk of several hematologic malignancies. The SIR was 4.09 for all hematologic malignancies, 4.29 for lymphomas, and 3.16 for leukemias.
Dr McMaster pointed out that several lymphoma subtypes can have lymphoplasmacytic differentiation, the most common being marginal zone lymphoma. And this could potentially result in misclassification.
“So we actually ran the study with and without marginal zone lymphoma and saw no difference in the results,” she said. “So we don’t think misclassification accounts for the majority of what we’re seeing.”
The investigators found that WM/LPL survivors had the highest risk of developing Burkitt lymphoma (SIR=13.45), followed by Hodgkin lymphoma (SIR=9.80), T-cell non-Hodgkin lymphoma (SIR=6.62), mantle cell lymphoma (SIR=5.37), diffuse large B-cell lymphoma (DLBCL, SIR=4.76), multiple myeloma (SIR=4.40), any non-Hodgkin lymphoma (SIR=4.08), and acute myeloid leukemia (AML, SIR=3.27).
“Waldenström’s is known to transform, on occasion, to DLBCL,” Dr McMaster said. “So that may well account for the excess of DLBCL that we see in this population.”
She also noted that, prior to the early 2000s, WM was typically treated with alkylating agents. And alkylating agents have been linked to an increased risk of AML.
In this population, the risk of AML peaked 5 to 10 years after WM/LPL diagnosis and was only present in patients treated prior to 2002. This suggests the AML observed in this study was likely treatment-related.
Dr McMaster and her colleagues also found that WM/LPL survivors did not have a significantly increased risk of developing acute lymphocytic leukemia (SIR=0), hairy cell leukemia (SIR=0), chronic lymphocytic leukemia/small lymphocytic lymphoma (SIR=0.97), or follicular lymphoma (SIR=2.25).
Solid tumors
WM/LPL survivors did have a significantly increased risk of certain solid tumor malignancies. The overall SIR for solid tumors was 1.21.
The risk was significant for non-epithelial skin cancers (SIR=5.15), thyroid cancers (SIR=3.13), melanoma (SIR=1.72), and cancers of the lung and bronchus (SIR=1.44) or respiratory system (SIR=1.42).
“Melanoma has an immunological basis, as does Waldenström’s, so we think there may be some shared etiology there,” Dr McMaster said.
She also noted that a strong risk factor for thyroid cancer, particularly papillary thyroid cancer, is a history of autoimmune thyroid disease.
“Autoimmune disease of any sort is a risk factor for Waldenström’s macroglobulinemia,” she said. “So again, we think there might be a basis for shared susceptibility there.”
Dr McMaster said this research suggests that multiple primary cancers may occur in a single individual because of shared genetic susceptibility, shared environmental exposures, treatment effects, or chance. She believes future research will show that both genetic and environmental factors contribute to WM.
Investigators are currently conducting whole-exome sequencing studies and genome-wide association studies in patients with familial and spontaneous WM, with the hopes of identifying genes that contribute to WM susceptibility.
PHILADELPHIA—A retrospective study has revealed factors that appear to influence a person’s susceptibility to Waldenström’s macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) and other malignancies.
Study investigators looked at patients diagnosed with WM or LPL over a 20-year period and found about a 50% excess of second primary cancers in this population.
The patients had a significantly increased risk of multiple hematologic and solid tumor malignancies, and a few of these malignancies had shared susceptibility factors with WM/LPL.
The investigators believe that identifying these factors may prove useful for determining genetic susceptibility to WM/LPL.
Mary L. McMaster, MD, of the National Cancer Institute in Bethesda, Maryland, and her colleagues presented these findings at the AACR Annual Meeting 2015 (abstract 3709).
The team used data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SSER) database to evaluate the risk of subsequent primary cancer in 3825 patients diagnosed with WM (n=2163) or LPL (n=1662) from 1992 to 2011. The patients’ median age was 70, most of them were male (n=2221), and most were white (n=3153).
Dr McMaster said she and her colleagues looked at both WM and LPL in this study because SEER does not include information about immunoglobulin subtype, which makes it difficult to identify all WM cases with absolute certainty.
“[D]epending on what information a pathologist has when they review a bone marrow biopsy, for example, they may or may not know whether there’s IgM present,” Dr McMaster said. “So you may have a diagnosis of LPL and not have the information required to make the diagnosis of WM. For that reason, we combined both entities for this study.”
Dr McMaster and her colleagues calculated the observed-to-expected standardized incidence ratios (SIRs) for invasive cancers. After adjusting for multiple comparisons, the team found that survivors of WM/LPL had a significantly increased risk of developing a second primary malignancy (SIR=1.49).
This increased risk was seen for males and females and persisted throughout follow-up. The risk was higher for patients younger than 65 years of age (SIR=1.95).
Hematologic malignancies
WM/LPL survivors had a significantly increased risk of several hematologic malignancies. The SIR was 4.09 for all hematologic malignancies, 4.29 for lymphomas, and 3.16 for leukemias.
Dr McMaster pointed out that several lymphoma subtypes can have lymphoplasmacytic differentiation, the most common being marginal zone lymphoma. And this could potentially result in misclassification.
“So we actually ran the study with and without marginal zone lymphoma and saw no difference in the results,” she said. “So we don’t think misclassification accounts for the majority of what we’re seeing.”
The investigators found that WM/LPL survivors had the highest risk of developing Burkitt lymphoma (SIR=13.45), followed by Hodgkin lymphoma (SIR=9.80), T-cell non-Hodgkin lymphoma (SIR=6.62), mantle cell lymphoma (SIR=5.37), diffuse large B-cell lymphoma (DLBCL, SIR=4.76), multiple myeloma (SIR=4.40), any non-Hodgkin lymphoma (SIR=4.08), and acute myeloid leukemia (AML, SIR=3.27).
“Waldenström’s is known to transform, on occasion, to DLBCL,” Dr McMaster said. “So that may well account for the excess of DLBCL that we see in this population.”
She also noted that, prior to the early 2000s, WM was typically treated with alkylating agents. And alkylating agents have been linked to an increased risk of AML.
In this population, the risk of AML peaked 5 to 10 years after WM/LPL diagnosis and was only present in patients treated prior to 2002. This suggests the AML observed in this study was likely treatment-related.
Dr McMaster and her colleagues also found that WM/LPL survivors did not have a significantly increased risk of developing acute lymphocytic leukemia (SIR=0), hairy cell leukemia (SIR=0), chronic lymphocytic leukemia/small lymphocytic lymphoma (SIR=0.97), or follicular lymphoma (SIR=2.25).
Solid tumors
WM/LPL survivors did have a significantly increased risk of certain solid tumor malignancies. The overall SIR for solid tumors was 1.21.
The risk was significant for non-epithelial skin cancers (SIR=5.15), thyroid cancers (SIR=3.13), melanoma (SIR=1.72), and cancers of the lung and bronchus (SIR=1.44) or respiratory system (SIR=1.42).
“Melanoma has an immunological basis, as does Waldenström’s, so we think there may be some shared etiology there,” Dr McMaster said.
She also noted that a strong risk factor for thyroid cancer, particularly papillary thyroid cancer, is a history of autoimmune thyroid disease.
“Autoimmune disease of any sort is a risk factor for Waldenström’s macroglobulinemia,” she said. “So again, we think there might be a basis for shared susceptibility there.”
Dr McMaster said this research suggests that multiple primary cancers may occur in a single individual because of shared genetic susceptibility, shared environmental exposures, treatment effects, or chance. She believes future research will show that both genetic and environmental factors contribute to WM.
Investigators are currently conducting whole-exome sequencing studies and genome-wide association studies in patients with familial and spontaneous WM, with the hopes of identifying genes that contribute to WM susceptibility.
PHILADELPHIA—A retrospective study has revealed factors that appear to influence a person’s susceptibility to Waldenström’s macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) and other malignancies.
Study investigators looked at patients diagnosed with WM or LPL over a 20-year period and found about a 50% excess of second primary cancers in this population.
The patients had a significantly increased risk of multiple hematologic and solid tumor malignancies, and a few of these malignancies had shared susceptibility factors with WM/LPL.
The investigators believe that identifying these factors may prove useful for determining genetic susceptibility to WM/LPL.
Mary L. McMaster, MD, of the National Cancer Institute in Bethesda, Maryland, and her colleagues presented these findings at the AACR Annual Meeting 2015 (abstract 3709).
The team used data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SSER) database to evaluate the risk of subsequent primary cancer in 3825 patients diagnosed with WM (n=2163) or LPL (n=1662) from 1992 to 2011. The patients’ median age was 70, most of them were male (n=2221), and most were white (n=3153).
Dr McMaster said she and her colleagues looked at both WM and LPL in this study because SEER does not include information about immunoglobulin subtype, which makes it difficult to identify all WM cases with absolute certainty.
“[D]epending on what information a pathologist has when they review a bone marrow biopsy, for example, they may or may not know whether there’s IgM present,” Dr McMaster said. “So you may have a diagnosis of LPL and not have the information required to make the diagnosis of WM. For that reason, we combined both entities for this study.”
Dr McMaster and her colleagues calculated the observed-to-expected standardized incidence ratios (SIRs) for invasive cancers. After adjusting for multiple comparisons, the team found that survivors of WM/LPL had a significantly increased risk of developing a second primary malignancy (SIR=1.49).
This increased risk was seen for males and females and persisted throughout follow-up. The risk was higher for patients younger than 65 years of age (SIR=1.95).
Hematologic malignancies
WM/LPL survivors had a significantly increased risk of several hematologic malignancies. The SIR was 4.09 for all hematologic malignancies, 4.29 for lymphomas, and 3.16 for leukemias.
Dr McMaster pointed out that several lymphoma subtypes can have lymphoplasmacytic differentiation, the most common being marginal zone lymphoma. And this could potentially result in misclassification.
“So we actually ran the study with and without marginal zone lymphoma and saw no difference in the results,” she said. “So we don’t think misclassification accounts for the majority of what we’re seeing.”
The investigators found that WM/LPL survivors had the highest risk of developing Burkitt lymphoma (SIR=13.45), followed by Hodgkin lymphoma (SIR=9.80), T-cell non-Hodgkin lymphoma (SIR=6.62), mantle cell lymphoma (SIR=5.37), diffuse large B-cell lymphoma (DLBCL, SIR=4.76), multiple myeloma (SIR=4.40), any non-Hodgkin lymphoma (SIR=4.08), and acute myeloid leukemia (AML, SIR=3.27).
“Waldenström’s is known to transform, on occasion, to DLBCL,” Dr McMaster said. “So that may well account for the excess of DLBCL that we see in this population.”
She also noted that, prior to the early 2000s, WM was typically treated with alkylating agents. And alkylating agents have been linked to an increased risk of AML.
In this population, the risk of AML peaked 5 to 10 years after WM/LPL diagnosis and was only present in patients treated prior to 2002. This suggests the AML observed in this study was likely treatment-related.
Dr McMaster and her colleagues also found that WM/LPL survivors did not have a significantly increased risk of developing acute lymphocytic leukemia (SIR=0), hairy cell leukemia (SIR=0), chronic lymphocytic leukemia/small lymphocytic lymphoma (SIR=0.97), or follicular lymphoma (SIR=2.25).
Solid tumors
WM/LPL survivors did have a significantly increased risk of certain solid tumor malignancies. The overall SIR for solid tumors was 1.21.
The risk was significant for non-epithelial skin cancers (SIR=5.15), thyroid cancers (SIR=3.13), melanoma (SIR=1.72), and cancers of the lung and bronchus (SIR=1.44) or respiratory system (SIR=1.42).
“Melanoma has an immunological basis, as does Waldenström’s, so we think there may be some shared etiology there,” Dr McMaster said.
She also noted that a strong risk factor for thyroid cancer, particularly papillary thyroid cancer, is a history of autoimmune thyroid disease.
“Autoimmune disease of any sort is a risk factor for Waldenström’s macroglobulinemia,” she said. “So again, we think there might be a basis for shared susceptibility there.”
Dr McMaster said this research suggests that multiple primary cancers may occur in a single individual because of shared genetic susceptibility, shared environmental exposures, treatment effects, or chance. She believes future research will show that both genetic and environmental factors contribute to WM.
Investigators are currently conducting whole-exome sequencing studies and genome-wide association studies in patients with familial and spontaneous WM, with the hopes of identifying genes that contribute to WM susceptibility.
MKIs can overcome resistance in CML
PHILADELPHIA—Two multikinase inhibitors (MKIs) can treat chronic myeloid leukemia (CML) that is resistant to other inhibitors, according to preclinical research.
A series of in vitro experiments showed that the MKIs, sorafenib and axitinib, can overcome treatment resistance mediated by hyperactivation of the Src kinase Lyn, overexpression of the docking protein Gab2, and the presence of the Bcr-Abl T315I mutation.
Sebastian Halbach, of the University of Freiburg in Germany, and his colleagues presented these findings in a poster at the AACR Annual Meeting 2015 (abstract 2708).
Mechanisms of resistance
Halbach noted that CML is driven by the hyperactive fusion kinase Bcr-Abl, which builds up its own signaling network with various proteins, such as Gab2 and Lyn.
Resistance to tyrosine kinase inhibitors (TKIs) and MKIs can be caused by mutations in the Bcr-Abl oncogene, such as T315I, or by aberrant activity of components of the Bcr-Abl signaling network.
“We have previously shown in our lab that overexpression of the docking protein Gab2 . . . confers resistance against imatinib and dasatinib,” Halbach said. “And another mechanism of resistance is hyperactivation of the Src kinase Lyn.”
For the current study, Halbach and his colleagues investigated the role of Lyn by introducing imatinib, dasatinib, or DMSO to K562 cells (blast-phase CML), Lyn-transformed K562 cells, and Lyn-Y508F-transformed K562 cells.
They also compared imatinib and DMSO in Ba/F3 cells (a murine pro-B cell line), Lyn-transformed Ba/F3 cells, and Lyn-Y508F-transformed Ba/F3 cells.
The results of these experiments showed that hyperactive Lyn confers resistance to imatinib but not dasatinib.
“That’s not that surprising because dasatinib is a multikinase inhibitor which targets Src kinases,” Halbach noted. “Therefore, the hyperactivity of Lyn is directly targeted.”
Identifying new drugs
Having established that TKI and MKI resistance in CML can be mediated by Lyn and Gab2, as well as T315I, Halbach and his colleagues wanted to find drugs that would overcome this problem. They screened a panel of inhibitors and identified sorafenib and axitinib.
The researchers first evaluated the effects of sorafenib and axitinib against the T315I mutation. They tested the 2 MKIs—as well as imatinib, dasatinib, nilotinib, ponatinib, and DMSO—in the KBM5 cell line (blast-phase CML) and the KBM5-T315I cell line (imatinib-resistant CML).
Sorafenib and axitinib killed KBM5-T315I cells more effectively than any of the other inhibitors. The 2 MKIs also decreased the metabolic activity of T315I-positive cells more effectively than imatinib, dasatinib, or nilotinib, but not ponatinib, which produced similar results.
Next, Halbach and his colleagues tested sorafenib, axitinib, and the aforementioned inhibitors in K562 cells overexpressing Gab2. Overexpression of Gab2 conferred resistance to imatinib, dasatinib, nilotinib, and ponatinib, but not sorafenib and axitinib.
Both sorafenib and axitinib decreased the metabolic activity of Gab2-overexpressing cells more effectively than any of the other inhibitors.
Lastly, the researchers tested all of the inhibitors in Lyn-transformed K562 cells, Lyn-Y508F-transformed K562 cells, and K562 cells. They found that sorafenib and axitinib both overcame Lyn-Y508F-mediated resistance.
Sorafenib and axitinib killed K562 cells and Lyn-transformed K562 cells more effectively than any of the other inhibitors. The 2 MKIs also killed Lyn-Y508F-transformed K562 cells more effectively than imatinib and nilotinib, but not ponatinib or dasatinib.
Sorafenib decreased the metabolic activity of Lyn-Y508F-transformed K562 cells more effectively than all of the other inhibitors. But axitinib only proved more effective than imatinib in this regard.
Halbach said he hopes sorafenib and axitinib can one day serve as alternatives to ponatinib for CML patients, especially those with T315I mutations or high Gab2 levels.
For now, his team’s next step is to further analyze the influence of axitinib and sorafenib on the Bcr-Abl—Gab2 signaling complex.
PHILADELPHIA—Two multikinase inhibitors (MKIs) can treat chronic myeloid leukemia (CML) that is resistant to other inhibitors, according to preclinical research.
A series of in vitro experiments showed that the MKIs, sorafenib and axitinib, can overcome treatment resistance mediated by hyperactivation of the Src kinase Lyn, overexpression of the docking protein Gab2, and the presence of the Bcr-Abl T315I mutation.
Sebastian Halbach, of the University of Freiburg in Germany, and his colleagues presented these findings in a poster at the AACR Annual Meeting 2015 (abstract 2708).
Mechanisms of resistance
Halbach noted that CML is driven by the hyperactive fusion kinase Bcr-Abl, which builds up its own signaling network with various proteins, such as Gab2 and Lyn.
Resistance to tyrosine kinase inhibitors (TKIs) and MKIs can be caused by mutations in the Bcr-Abl oncogene, such as T315I, or by aberrant activity of components of the Bcr-Abl signaling network.
“We have previously shown in our lab that overexpression of the docking protein Gab2 . . . confers resistance against imatinib and dasatinib,” Halbach said. “And another mechanism of resistance is hyperactivation of the Src kinase Lyn.”
For the current study, Halbach and his colleagues investigated the role of Lyn by introducing imatinib, dasatinib, or DMSO to K562 cells (blast-phase CML), Lyn-transformed K562 cells, and Lyn-Y508F-transformed K562 cells.
They also compared imatinib and DMSO in Ba/F3 cells (a murine pro-B cell line), Lyn-transformed Ba/F3 cells, and Lyn-Y508F-transformed Ba/F3 cells.
The results of these experiments showed that hyperactive Lyn confers resistance to imatinib but not dasatinib.
“That’s not that surprising because dasatinib is a multikinase inhibitor which targets Src kinases,” Halbach noted. “Therefore, the hyperactivity of Lyn is directly targeted.”
Identifying new drugs
Having established that TKI and MKI resistance in CML can be mediated by Lyn and Gab2, as well as T315I, Halbach and his colleagues wanted to find drugs that would overcome this problem. They screened a panel of inhibitors and identified sorafenib and axitinib.
The researchers first evaluated the effects of sorafenib and axitinib against the T315I mutation. They tested the 2 MKIs—as well as imatinib, dasatinib, nilotinib, ponatinib, and DMSO—in the KBM5 cell line (blast-phase CML) and the KBM5-T315I cell line (imatinib-resistant CML).
Sorafenib and axitinib killed KBM5-T315I cells more effectively than any of the other inhibitors. The 2 MKIs also decreased the metabolic activity of T315I-positive cells more effectively than imatinib, dasatinib, or nilotinib, but not ponatinib, which produced similar results.
Next, Halbach and his colleagues tested sorafenib, axitinib, and the aforementioned inhibitors in K562 cells overexpressing Gab2. Overexpression of Gab2 conferred resistance to imatinib, dasatinib, nilotinib, and ponatinib, but not sorafenib and axitinib.
Both sorafenib and axitinib decreased the metabolic activity of Gab2-overexpressing cells more effectively than any of the other inhibitors.
Lastly, the researchers tested all of the inhibitors in Lyn-transformed K562 cells, Lyn-Y508F-transformed K562 cells, and K562 cells. They found that sorafenib and axitinib both overcame Lyn-Y508F-mediated resistance.
Sorafenib and axitinib killed K562 cells and Lyn-transformed K562 cells more effectively than any of the other inhibitors. The 2 MKIs also killed Lyn-Y508F-transformed K562 cells more effectively than imatinib and nilotinib, but not ponatinib or dasatinib.
Sorafenib decreased the metabolic activity of Lyn-Y508F-transformed K562 cells more effectively than all of the other inhibitors. But axitinib only proved more effective than imatinib in this regard.
Halbach said he hopes sorafenib and axitinib can one day serve as alternatives to ponatinib for CML patients, especially those with T315I mutations or high Gab2 levels.
For now, his team’s next step is to further analyze the influence of axitinib and sorafenib on the Bcr-Abl—Gab2 signaling complex.
PHILADELPHIA—Two multikinase inhibitors (MKIs) can treat chronic myeloid leukemia (CML) that is resistant to other inhibitors, according to preclinical research.
A series of in vitro experiments showed that the MKIs, sorafenib and axitinib, can overcome treatment resistance mediated by hyperactivation of the Src kinase Lyn, overexpression of the docking protein Gab2, and the presence of the Bcr-Abl T315I mutation.
Sebastian Halbach, of the University of Freiburg in Germany, and his colleagues presented these findings in a poster at the AACR Annual Meeting 2015 (abstract 2708).
Mechanisms of resistance
Halbach noted that CML is driven by the hyperactive fusion kinase Bcr-Abl, which builds up its own signaling network with various proteins, such as Gab2 and Lyn.
Resistance to tyrosine kinase inhibitors (TKIs) and MKIs can be caused by mutations in the Bcr-Abl oncogene, such as T315I, or by aberrant activity of components of the Bcr-Abl signaling network.
“We have previously shown in our lab that overexpression of the docking protein Gab2 . . . confers resistance against imatinib and dasatinib,” Halbach said. “And another mechanism of resistance is hyperactivation of the Src kinase Lyn.”
For the current study, Halbach and his colleagues investigated the role of Lyn by introducing imatinib, dasatinib, or DMSO to K562 cells (blast-phase CML), Lyn-transformed K562 cells, and Lyn-Y508F-transformed K562 cells.
They also compared imatinib and DMSO in Ba/F3 cells (a murine pro-B cell line), Lyn-transformed Ba/F3 cells, and Lyn-Y508F-transformed Ba/F3 cells.
The results of these experiments showed that hyperactive Lyn confers resistance to imatinib but not dasatinib.
“That’s not that surprising because dasatinib is a multikinase inhibitor which targets Src kinases,” Halbach noted. “Therefore, the hyperactivity of Lyn is directly targeted.”
Identifying new drugs
Having established that TKI and MKI resistance in CML can be mediated by Lyn and Gab2, as well as T315I, Halbach and his colleagues wanted to find drugs that would overcome this problem. They screened a panel of inhibitors and identified sorafenib and axitinib.
The researchers first evaluated the effects of sorafenib and axitinib against the T315I mutation. They tested the 2 MKIs—as well as imatinib, dasatinib, nilotinib, ponatinib, and DMSO—in the KBM5 cell line (blast-phase CML) and the KBM5-T315I cell line (imatinib-resistant CML).
Sorafenib and axitinib killed KBM5-T315I cells more effectively than any of the other inhibitors. The 2 MKIs also decreased the metabolic activity of T315I-positive cells more effectively than imatinib, dasatinib, or nilotinib, but not ponatinib, which produced similar results.
Next, Halbach and his colleagues tested sorafenib, axitinib, and the aforementioned inhibitors in K562 cells overexpressing Gab2. Overexpression of Gab2 conferred resistance to imatinib, dasatinib, nilotinib, and ponatinib, but not sorafenib and axitinib.
Both sorafenib and axitinib decreased the metabolic activity of Gab2-overexpressing cells more effectively than any of the other inhibitors.
Lastly, the researchers tested all of the inhibitors in Lyn-transformed K562 cells, Lyn-Y508F-transformed K562 cells, and K562 cells. They found that sorafenib and axitinib both overcame Lyn-Y508F-mediated resistance.
Sorafenib and axitinib killed K562 cells and Lyn-transformed K562 cells more effectively than any of the other inhibitors. The 2 MKIs also killed Lyn-Y508F-transformed K562 cells more effectively than imatinib and nilotinib, but not ponatinib or dasatinib.
Sorafenib decreased the metabolic activity of Lyn-Y508F-transformed K562 cells more effectively than all of the other inhibitors. But axitinib only proved more effective than imatinib in this regard.
Halbach said he hopes sorafenib and axitinib can one day serve as alternatives to ponatinib for CML patients, especially those with T315I mutations or high Gab2 levels.
For now, his team’s next step is to further analyze the influence of axitinib and sorafenib on the Bcr-Abl—Gab2 signaling complex.
Inotuzumab ozogamicin study reaches primary endpoint for ALL
Pfizer has announced that its phase III study of inotuzumab ozogamicin, an investigational antibody-drug conjugate, met its primary endpoint of a higher complete hematologic remission rate than standard therapy in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL).
The INO-VATE ALL Study is an open-label, randomized study evaluating the safety and efficacy of inotuzumab ozogamicin, compared with standard chemotherapy in adult patients with ALL. The two primary endpoints are hematologic remission (as defined by a complete response with or without platelet and/or neutrophil recovery) and overall survival. Pfizer said that the study will continue in order to allow the data on overall survival to mature.
Inotuzumab ozogamicin was administered intravenously once weekly for 3 weeks for a 3- to 4-week cycle up to six cycles. There were 326 patients enrolled in the trial.
Pfizer has announced that its phase III study of inotuzumab ozogamicin, an investigational antibody-drug conjugate, met its primary endpoint of a higher complete hematologic remission rate than standard therapy in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL).
The INO-VATE ALL Study is an open-label, randomized study evaluating the safety and efficacy of inotuzumab ozogamicin, compared with standard chemotherapy in adult patients with ALL. The two primary endpoints are hematologic remission (as defined by a complete response with or without platelet and/or neutrophil recovery) and overall survival. Pfizer said that the study will continue in order to allow the data on overall survival to mature.
Inotuzumab ozogamicin was administered intravenously once weekly for 3 weeks for a 3- to 4-week cycle up to six cycles. There were 326 patients enrolled in the trial.
Pfizer has announced that its phase III study of inotuzumab ozogamicin, an investigational antibody-drug conjugate, met its primary endpoint of a higher complete hematologic remission rate than standard therapy in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL).
The INO-VATE ALL Study is an open-label, randomized study evaluating the safety and efficacy of inotuzumab ozogamicin, compared with standard chemotherapy in adult patients with ALL. The two primary endpoints are hematologic remission (as defined by a complete response with or without platelet and/or neutrophil recovery) and overall survival. Pfizer said that the study will continue in order to allow the data on overall survival to mature.
Inotuzumab ozogamicin was administered intravenously once weekly for 3 weeks for a 3- to 4-week cycle up to six cycles. There were 326 patients enrolled in the trial.