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FDA grants drug breakthrough designation for AML
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to venetoclax (Venclexta®).
The designation is for venetoclax in combination with low-dose cytarabine to treat elderly patients with previously untreated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
About venetoclax
Venetoclax is a small molecule designed to selectively bind and inhibit the BCL-2 protein. The drug is being developed by AbbVie and Roche.
Last year, the FDA granted venetoclax accelerated approval to treat patients with chronic lymphocytic leukemia who have 17p deletion and have received at least one prior therapy. Continued approval of venetoclax for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
The FDA granted venetoclax breakthrough therapy designation for the AML indication based on data from an ongoing phase 1/2 study. Preliminary data from the study were presented at the 22nd European Hematology Association (EHA) Annual Congress.
The presentation included data on 61 elderly patients (older than 65) with previously untreated AML who were ineligible for intensive chemotherapy.
They received venetoclax in combination with low-dose cytarabine (as well as prophylaxis for tumor lysis syndrome). The patients’ median time on treatment was 6 months (range, <1 to 19 months), and 72% of patients discontinued treatment.
The overall response rate was 65%. Twenty-five percent of patients achieved a complete response, 38% had a complete response with incomplete blood count recovery, and 2% had a partial response.
The 30-day death rate was 3%, the 60-day death rate was 15%, and the median overall survival was approximately 12 months.
The most common adverse events of any grade (occurring in at least 30% of patients) were nausea (74%), hypokalemia (46%), diarrhea (46%), fatigue (44%), decreased appetite (41%), constipation (34%), hypomagnesemia (34%), vomiting (31%), thrombocytopenia (44%), febrile neutropenia (38%), and neutropenia (33%).
Grade 3/4 adverse events (occurring in at least 10% of patients) included thrombocytopenia (44%), febrile neutropenia (36%), neutropenia (33%), anemia (28%), hypokalemia (16%), hypophosphatemia (13%), and hypertension (12%). 
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to venetoclax (Venclexta®).
The designation is for venetoclax in combination with low-dose cytarabine to treat elderly patients with previously untreated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
About venetoclax
Venetoclax is a small molecule designed to selectively bind and inhibit the BCL-2 protein. The drug is being developed by AbbVie and Roche.
Last year, the FDA granted venetoclax accelerated approval to treat patients with chronic lymphocytic leukemia who have 17p deletion and have received at least one prior therapy. Continued approval of venetoclax for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
The FDA granted venetoclax breakthrough therapy designation for the AML indication based on data from an ongoing phase 1/2 study. Preliminary data from the study were presented at the 22nd European Hematology Association (EHA) Annual Congress.
The presentation included data on 61 elderly patients (older than 65) with previously untreated AML who were ineligible for intensive chemotherapy.
They received venetoclax in combination with low-dose cytarabine (as well as prophylaxis for tumor lysis syndrome). The patients’ median time on treatment was 6 months (range, <1 to 19 months), and 72% of patients discontinued treatment.
The overall response rate was 65%. Twenty-five percent of patients achieved a complete response, 38% had a complete response with incomplete blood count recovery, and 2% had a partial response.
The 30-day death rate was 3%, the 60-day death rate was 15%, and the median overall survival was approximately 12 months.
The most common adverse events of any grade (occurring in at least 30% of patients) were nausea (74%), hypokalemia (46%), diarrhea (46%), fatigue (44%), decreased appetite (41%), constipation (34%), hypomagnesemia (34%), vomiting (31%), thrombocytopenia (44%), febrile neutropenia (38%), and neutropenia (33%).
Grade 3/4 adverse events (occurring in at least 10% of patients) included thrombocytopenia (44%), febrile neutropenia (36%), neutropenia (33%), anemia (28%), hypokalemia (16%), hypophosphatemia (13%), and hypertension (12%).
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to venetoclax (Venclexta®).
The designation is for venetoclax in combination with low-dose cytarabine to treat elderly patients with previously untreated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
About venetoclax
Venetoclax is a small molecule designed to selectively bind and inhibit the BCL-2 protein. The drug is being developed by AbbVie and Roche.
Last year, the FDA granted venetoclax accelerated approval to treat patients with chronic lymphocytic leukemia who have 17p deletion and have received at least one prior therapy. Continued approval of venetoclax for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
The FDA granted venetoclax breakthrough therapy designation for the AML indication based on data from an ongoing phase 1/2 study. Preliminary data from the study were presented at the 22nd European Hematology Association (EHA) Annual Congress.
The presentation included data on 61 elderly patients (older than 65) with previously untreated AML who were ineligible for intensive chemotherapy.
They received venetoclax in combination with low-dose cytarabine (as well as prophylaxis for tumor lysis syndrome). The patients’ median time on treatment was 6 months (range, <1 to 19 months), and 72% of patients discontinued treatment.
The overall response rate was 65%. Twenty-five percent of patients achieved a complete response, 38% had a complete response with incomplete blood count recovery, and 2% had a partial response.
The 30-day death rate was 3%, the 60-day death rate was 15%, and the median overall survival was approximately 12 months.
The most common adverse events of any grade (occurring in at least 30% of patients) were nausea (74%), hypokalemia (46%), diarrhea (46%), fatigue (44%), decreased appetite (41%), constipation (34%), hypomagnesemia (34%), vomiting (31%), thrombocytopenia (44%), febrile neutropenia (38%), and neutropenia (33%).
Grade 3/4 adverse events (occurring in at least 10% of patients) included thrombocytopenia (44%), febrile neutropenia (36%), neutropenia (33%), anemia (28%), hypokalemia (16%), hypophosphatemia (13%), and hypertension (12%).
Developing better mouse models
Researchers say they have developed a new approach to model human immune variation that overcomes the limitations of traditional mouse models.
With this approach, the team identified genetic markers that directly correlate with the outcome of inflammatory and malignant diseases in humans, including chronic lymphocytic leukemia and Burkitt lymphoma.
The findings suggest that accounting for immune diversity is critical to the success of predicting disease outcomes based on immune cell measurements.
The team reported these findings in Nature Communications.
Traditionally, researchers have relied on inbred mouse strains to gain insight into human diseases while reducing experimental noise.
“If you take a black, a brown, or a white mouse, each one will give you a different answer in the same assay,” said Klaus Ley, MD, of La Jolla Institute for Allergy and Immunology in California.
“For example, if you vaccinate them, their responses will be different, which creates a lot of experimental noise. However, when you think about patients, or even healthy people, we are all different.”
To mine those differences for information, the researchers embraced the experimental noise. Instead of analyzing a single inbred mouse strain, they turned to the hybrid mouse diversity panel (HDMP).
The HDMP is a panel of about 100 different inbred mouse strains that mirror the breadth of genetic and immunological diversity found in the human population.
The researchers studied the natural variation in the activation pattern of abdominal macrophages. Macrophages isolated from 83 different mouse strains from the HDMP were exposed to lipopolysaccharide (LPS), a major component of the outer wall of gram-negative bacteria.
“Fundamentally, when the immune system is confronted with gram-negative bacteria, it can deal with the situation in 2 ways—either it gets very angry and tries to kill the bacteria or it can wall them off in an attempt to live with it,” explained Dr Ley. “Both strategies carry a certain risk, but a long evolutionary history has ensured that mice and people can survive with either strategy.”
The LPS-induced reactions of the macrophages covered the whole spectrum—from very aggressive (LPS+) to very tolerant (LPS-), depending on the mouse strain.
Next, the researchers asked which genes were active during each type of response to identify gene signatures that correlated with LPS responsiveness.
The team then ran these gene signatures across various human gene expression data sets and discovered they strongly correlated with human disease outcomes.
For example, macrophages isolated from healthy joints were enriched in LPS-tolerant genes, whereas macrophages from rheumatoid arthritis patients were strongly skewed toward LPS-aggressive.
Since it was known that mice and people with the aggressive phenotype are better at fighting cancer, the researchers specifically asked whether the level of LPS responsiveness could predict tumor survival.
After analyzing data from 18,000 biopsies across 39 different tumor types, the team found the LPS+ gene signature strongly correlated with survival, while the LPS- signature correlated with cancer death.
The pattern was significant across many types of cancer, including chronic lymphocytic leukemia, Burkitt lymphoma, osteosarcoma, melanoma, and large-cell lung carcinoma.
Researchers say they have developed a new approach to model human immune variation that overcomes the limitations of traditional mouse models.
With this approach, the team identified genetic markers that directly correlate with the outcome of inflammatory and malignant diseases in humans, including chronic lymphocytic leukemia and Burkitt lymphoma.
The findings suggest that accounting for immune diversity is critical to the success of predicting disease outcomes based on immune cell measurements.
The team reported these findings in Nature Communications.
Traditionally, researchers have relied on inbred mouse strains to gain insight into human diseases while reducing experimental noise.
“If you take a black, a brown, or a white mouse, each one will give you a different answer in the same assay,” said Klaus Ley, MD, of La Jolla Institute for Allergy and Immunology in California.
“For example, if you vaccinate them, their responses will be different, which creates a lot of experimental noise. However, when you think about patients, or even healthy people, we are all different.”
To mine those differences for information, the researchers embraced the experimental noise. Instead of analyzing a single inbred mouse strain, they turned to the hybrid mouse diversity panel (HDMP).
The HDMP is a panel of about 100 different inbred mouse strains that mirror the breadth of genetic and immunological diversity found in the human population.
The researchers studied the natural variation in the activation pattern of abdominal macrophages. Macrophages isolated from 83 different mouse strains from the HDMP were exposed to lipopolysaccharide (LPS), a major component of the outer wall of gram-negative bacteria.
“Fundamentally, when the immune system is confronted with gram-negative bacteria, it can deal with the situation in 2 ways—either it gets very angry and tries to kill the bacteria or it can wall them off in an attempt to live with it,” explained Dr Ley. “Both strategies carry a certain risk, but a long evolutionary history has ensured that mice and people can survive with either strategy.”
The LPS-induced reactions of the macrophages covered the whole spectrum—from very aggressive (LPS+) to very tolerant (LPS-), depending on the mouse strain.
Next, the researchers asked which genes were active during each type of response to identify gene signatures that correlated with LPS responsiveness.
The team then ran these gene signatures across various human gene expression data sets and discovered they strongly correlated with human disease outcomes.
For example, macrophages isolated from healthy joints were enriched in LPS-tolerant genes, whereas macrophages from rheumatoid arthritis patients were strongly skewed toward LPS-aggressive.
Since it was known that mice and people with the aggressive phenotype are better at fighting cancer, the researchers specifically asked whether the level of LPS responsiveness could predict tumor survival.
After analyzing data from 18,000 biopsies across 39 different tumor types, the team found the LPS+ gene signature strongly correlated with survival, while the LPS- signature correlated with cancer death.
The pattern was significant across many types of cancer, including chronic lymphocytic leukemia, Burkitt lymphoma, osteosarcoma, melanoma, and large-cell lung carcinoma.
Researchers say they have developed a new approach to model human immune variation that overcomes the limitations of traditional mouse models.
With this approach, the team identified genetic markers that directly correlate with the outcome of inflammatory and malignant diseases in humans, including chronic lymphocytic leukemia and Burkitt lymphoma.
The findings suggest that accounting for immune diversity is critical to the success of predicting disease outcomes based on immune cell measurements.
The team reported these findings in Nature Communications.
Traditionally, researchers have relied on inbred mouse strains to gain insight into human diseases while reducing experimental noise.
“If you take a black, a brown, or a white mouse, each one will give you a different answer in the same assay,” said Klaus Ley, MD, of La Jolla Institute for Allergy and Immunology in California.
“For example, if you vaccinate them, their responses will be different, which creates a lot of experimental noise. However, when you think about patients, or even healthy people, we are all different.”
To mine those differences for information, the researchers embraced the experimental noise. Instead of analyzing a single inbred mouse strain, they turned to the hybrid mouse diversity panel (HDMP).
The HDMP is a panel of about 100 different inbred mouse strains that mirror the breadth of genetic and immunological diversity found in the human population.
The researchers studied the natural variation in the activation pattern of abdominal macrophages. Macrophages isolated from 83 different mouse strains from the HDMP were exposed to lipopolysaccharide (LPS), a major component of the outer wall of gram-negative bacteria.
“Fundamentally, when the immune system is confronted with gram-negative bacteria, it can deal with the situation in 2 ways—either it gets very angry and tries to kill the bacteria or it can wall them off in an attempt to live with it,” explained Dr Ley. “Both strategies carry a certain risk, but a long evolutionary history has ensured that mice and people can survive with either strategy.”
The LPS-induced reactions of the macrophages covered the whole spectrum—from very aggressive (LPS+) to very tolerant (LPS-), depending on the mouse strain.
Next, the researchers asked which genes were active during each type of response to identify gene signatures that correlated with LPS responsiveness.
The team then ran these gene signatures across various human gene expression data sets and discovered they strongly correlated with human disease outcomes.
For example, macrophages isolated from healthy joints were enriched in LPS-tolerant genes, whereas macrophages from rheumatoid arthritis patients were strongly skewed toward LPS-aggressive.
Since it was known that mice and people with the aggressive phenotype are better at fighting cancer, the researchers specifically asked whether the level of LPS responsiveness could predict tumor survival.
After analyzing data from 18,000 biopsies across 39 different tumor types, the team found the LPS+ gene signature strongly correlated with survival, while the LPS- signature correlated with cancer death.
The pattern was significant across many types of cancer, including chronic lymphocytic leukemia, Burkitt lymphoma, osteosarcoma, melanoma, and large-cell lung carcinoma.
Team makes ‘fundamental’ AML discovery
A newly identified pathway plays a “fundamental” role in acute myeloid leukemia (AML), according to researchers.
The team discovered that AML cells have a secretory pathway that leads to the production and release of the immune receptor Tim-3 and its ligand galectin-9, both of which prevent natural killer (NK) and other cytotoxic cells from killing the AML cells.
Vadim Sumbayev, PhD, of the University of Kent in the UK, and his colleagues recounted these findings in EBioMedicine.
The researchers found that AML cells—but not healthy blood cells—express a receptor called latrophilin 1 (LPHN1). LPHN1 induces activation of PKCα, which triggers the translation and secretion of Tim-3 and galectin-9.
Soluble Tim-3 prevents the secretion of interleukin 2, which is required for the activation of NK cells and cytotoxic T cells. Galectin-9 impairs the AML-cell-killing ability of NK cells and other cytotoxic lymphocytes.
The researchers said their work revealed both biomarkers for AML diagnostics and potential targets for AML treatment.
“Targeting this pathway will crucially enhance patients’ own immune defenses, helping them to eliminate leukemia cells,” Dr Sumbayev said.
He added that his group’s discovery might be applied to the treatment of other cancers as well.
A newly identified pathway plays a “fundamental” role in acute myeloid leukemia (AML), according to researchers.
The team discovered that AML cells have a secretory pathway that leads to the production and release of the immune receptor Tim-3 and its ligand galectin-9, both of which prevent natural killer (NK) and other cytotoxic cells from killing the AML cells.
Vadim Sumbayev, PhD, of the University of Kent in the UK, and his colleagues recounted these findings in EBioMedicine.
The researchers found that AML cells—but not healthy blood cells—express a receptor called latrophilin 1 (LPHN1). LPHN1 induces activation of PKCα, which triggers the translation and secretion of Tim-3 and galectin-9.
Soluble Tim-3 prevents the secretion of interleukin 2, which is required for the activation of NK cells and cytotoxic T cells. Galectin-9 impairs the AML-cell-killing ability of NK cells and other cytotoxic lymphocytes.
The researchers said their work revealed both biomarkers for AML diagnostics and potential targets for AML treatment.
“Targeting this pathway will crucially enhance patients’ own immune defenses, helping them to eliminate leukemia cells,” Dr Sumbayev said.
He added that his group’s discovery might be applied to the treatment of other cancers as well.
A newly identified pathway plays a “fundamental” role in acute myeloid leukemia (AML), according to researchers.
The team discovered that AML cells have a secretory pathway that leads to the production and release of the immune receptor Tim-3 and its ligand galectin-9, both of which prevent natural killer (NK) and other cytotoxic cells from killing the AML cells.
Vadim Sumbayev, PhD, of the University of Kent in the UK, and his colleagues recounted these findings in EBioMedicine.
The researchers found that AML cells—but not healthy blood cells—express a receptor called latrophilin 1 (LPHN1). LPHN1 induces activation of PKCα, which triggers the translation and secretion of Tim-3 and galectin-9.
Soluble Tim-3 prevents the secretion of interleukin 2, which is required for the activation of NK cells and cytotoxic T cells. Galectin-9 impairs the AML-cell-killing ability of NK cells and other cytotoxic lymphocytes.
The researchers said their work revealed both biomarkers for AML diagnostics and potential targets for AML treatment.
“Targeting this pathway will crucially enhance patients’ own immune defenses, helping them to eliminate leukemia cells,” Dr Sumbayev said.
He added that his group’s discovery might be applied to the treatment of other cancers as well.
M13-982 trial in del(17p) CLL: High, durable response rates to venetoclax
New York – Venetoclax monotherapy is associated with high and durable objective response rates in patients with del(17p) chronic lymphocytic leukemia (CLL), according to efficacy findings from the open-label M13-982 trial.
Additionally, a safety expansion of the pivotal phase 2 study showed that treatment was well tolerated, and assessment of minimal residual disease (MRD) status in the peripheral blood and bone marrow of study participants correlated with the 24-month progression-free survival estimate of 100% for patients with complete remission/complete remission with incomplete blood count recovery (CR/CRi), Stephan Stilgenbauer, MD, of the University of Ulm, Germany, and his colleagues reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
That response was maintained at 1 year in 85% of participants.
The current findings, which represent data through April 2017 for those 107 patients from the main cohort, as well as for 51 patients in the safety expansion study, show an overall response rate of 77%, with 20% CR/CRi.
The median time to first response was 1 month, and time to CR/CRi was 9.8 months, they said.
Estimates at 24 months for duration of response, progression-free survival, and overall survival were 66%, 54%, and 73%, respectively.
Additionally, objective responses were seen in four of five previously untreated patients who were enrolled in the safety expansion, and two of them had complete remissions. One patient with best response of stable disease decided to discontinue treatment but remained in follow-up with stable disease.
“All patients were alive at the time of analysis and remain progression free,” the investigators wrote.
In 18 patients who received prior B-cell receptor pathway inhibitor (BCRi) therapy, the objective response rate was 61% and the complete remission rate was 11%, with 12-month, progression-free and overall survival estimates of 50% and 54%, respectively.
Treatment-emergent adverse events of any grade occurred in 98% of patients, and led to dosing interruption in 40% and dosing adjustment in 17%. The most common adverse event was neutropenia; grade 3/4 neutropenia occurred in 40% of patients.
Neutropenia lead to a dose reduction in 8% of patients and to treatment interruption in 6% of patients; no discontinuations were reported.
Infections occurred in 81% of 158 patients, and grade 3/4 infections occurred in 23%; these infections were consistent with the underlying disease, the investigators said.
Laboratory tumor lysis syndrome (TLS) occurred in 5% of patients, but there were no episodes of clinical TLS, they said, noting that five TLS patients required dose interruptions. TLS occurred in four patients with medium risk at screening and in four with high risk. All episodes of TLS occurred during initial dosing or ramp-up, and all resolved. Affected patients were able to resume venetoclax with dose escalation to 400 mg/day.
The rate of minimal residual disease negativity was 30% in the intention-to-treat population as demonstrated by flow cytometry and confirmed by next generation sequencing (NGS) in 21 of 29 patients with an evaluable matched time point specimen. Bone marrow MRD negativity was observed in 20 patients by flow cytometry, and in 9 patients by NGS.
When looking at flow cytometry and NGS data combined, the MRD negativity rate in peripheral blood was 25% overall and 40% in evaluable patients, and the MRD negativity rate in bone marrow was 11% overall and 24% in evaluable patients.
Of those who achieved CR/CRi, 69% were MRD negative in peripheral blood by flow cytometry, with a 24-month, progression-free survival estimate of 100%, and 13 of those had confirmed MRD-negative blood by NGS, 2 had MRD-positive blood by NGS at a matched flow cytometry assessment, and 7 were not evaluated by NGS. For the remaining CR/CRi patients, who were MRD-positive by flow cytometry, the 24-month progression-free survival estimate was 86%.
Study participants in the main cohort were adults with a median age of 67 years who had relapsed/refractory CLL with an indication for treatment by iwCLL criteria, del(17p), good performance status, adequate bone marrow function, and creatinine clearance of at least 50 mg/min. They received a single test dose of 20 mg on day 1, with gradual ramp up to 400 mg over 4-5 weeks based on laboratory assessments. All were hospitalized for the first 20 mg and 50 mg venetoclax doses during ramp up.
Those in the safety expansion were treated with once-daily oral venetoclax starting at a dose of 20 mg/day for 1 week and ramped up to 400 mg by week 5. To mitigate TLS risk, uric acid–lowering agents and hydration were started at least 72 hours prior to administering the first dose. Those with high TLS risk – and some with medium risk – were hospitalized for the first 20-mg and 50-mg doses. Those with low TLS risk – and most with medium risk – received initial venetoclax dosing in an outpatient setting.
“Continued follow-up of patients in this trial will provide additional data on the durability of response with venetoclax in patients with del(17p) CLL,” the investigators wrote.
This study was supported by AbbVie and Genentech. Dr. Stilgenbauer received research funding, honoraria, and travel support from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi.
New York – Venetoclax monotherapy is associated with high and durable objective response rates in patients with del(17p) chronic lymphocytic leukemia (CLL), according to efficacy findings from the open-label M13-982 trial.
Additionally, a safety expansion of the pivotal phase 2 study showed that treatment was well tolerated, and assessment of minimal residual disease (MRD) status in the peripheral blood and bone marrow of study participants correlated with the 24-month progression-free survival estimate of 100% for patients with complete remission/complete remission with incomplete blood count recovery (CR/CRi), Stephan Stilgenbauer, MD, of the University of Ulm, Germany, and his colleagues reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
That response was maintained at 1 year in 85% of participants.
The current findings, which represent data through April 2017 for those 107 patients from the main cohort, as well as for 51 patients in the safety expansion study, show an overall response rate of 77%, with 20% CR/CRi.
The median time to first response was 1 month, and time to CR/CRi was 9.8 months, they said.
Estimates at 24 months for duration of response, progression-free survival, and overall survival were 66%, 54%, and 73%, respectively.
Additionally, objective responses were seen in four of five previously untreated patients who were enrolled in the safety expansion, and two of them had complete remissions. One patient with best response of stable disease decided to discontinue treatment but remained in follow-up with stable disease.
“All patients were alive at the time of analysis and remain progression free,” the investigators wrote.
In 18 patients who received prior B-cell receptor pathway inhibitor (BCRi) therapy, the objective response rate was 61% and the complete remission rate was 11%, with 12-month, progression-free and overall survival estimates of 50% and 54%, respectively.
Treatment-emergent adverse events of any grade occurred in 98% of patients, and led to dosing interruption in 40% and dosing adjustment in 17%. The most common adverse event was neutropenia; grade 3/4 neutropenia occurred in 40% of patients.
Neutropenia lead to a dose reduction in 8% of patients and to treatment interruption in 6% of patients; no discontinuations were reported.
Infections occurred in 81% of 158 patients, and grade 3/4 infections occurred in 23%; these infections were consistent with the underlying disease, the investigators said.
Laboratory tumor lysis syndrome (TLS) occurred in 5% of patients, but there were no episodes of clinical TLS, they said, noting that five TLS patients required dose interruptions. TLS occurred in four patients with medium risk at screening and in four with high risk. All episodes of TLS occurred during initial dosing or ramp-up, and all resolved. Affected patients were able to resume venetoclax with dose escalation to 400 mg/day.
The rate of minimal residual disease negativity was 30% in the intention-to-treat population as demonstrated by flow cytometry and confirmed by next generation sequencing (NGS) in 21 of 29 patients with an evaluable matched time point specimen. Bone marrow MRD negativity was observed in 20 patients by flow cytometry, and in 9 patients by NGS.
When looking at flow cytometry and NGS data combined, the MRD negativity rate in peripheral blood was 25% overall and 40% in evaluable patients, and the MRD negativity rate in bone marrow was 11% overall and 24% in evaluable patients.
Of those who achieved CR/CRi, 69% were MRD negative in peripheral blood by flow cytometry, with a 24-month, progression-free survival estimate of 100%, and 13 of those had confirmed MRD-negative blood by NGS, 2 had MRD-positive blood by NGS at a matched flow cytometry assessment, and 7 were not evaluated by NGS. For the remaining CR/CRi patients, who were MRD-positive by flow cytometry, the 24-month progression-free survival estimate was 86%.
Study participants in the main cohort were adults with a median age of 67 years who had relapsed/refractory CLL with an indication for treatment by iwCLL criteria, del(17p), good performance status, adequate bone marrow function, and creatinine clearance of at least 50 mg/min. They received a single test dose of 20 mg on day 1, with gradual ramp up to 400 mg over 4-5 weeks based on laboratory assessments. All were hospitalized for the first 20 mg and 50 mg venetoclax doses during ramp up.
Those in the safety expansion were treated with once-daily oral venetoclax starting at a dose of 20 mg/day for 1 week and ramped up to 400 mg by week 5. To mitigate TLS risk, uric acid–lowering agents and hydration were started at least 72 hours prior to administering the first dose. Those with high TLS risk – and some with medium risk – were hospitalized for the first 20-mg and 50-mg doses. Those with low TLS risk – and most with medium risk – received initial venetoclax dosing in an outpatient setting.
“Continued follow-up of patients in this trial will provide additional data on the durability of response with venetoclax in patients with del(17p) CLL,” the investigators wrote.
This study was supported by AbbVie and Genentech. Dr. Stilgenbauer received research funding, honoraria, and travel support from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi.
New York – Venetoclax monotherapy is associated with high and durable objective response rates in patients with del(17p) chronic lymphocytic leukemia (CLL), according to efficacy findings from the open-label M13-982 trial.
Additionally, a safety expansion of the pivotal phase 2 study showed that treatment was well tolerated, and assessment of minimal residual disease (MRD) status in the peripheral blood and bone marrow of study participants correlated with the 24-month progression-free survival estimate of 100% for patients with complete remission/complete remission with incomplete blood count recovery (CR/CRi), Stephan Stilgenbauer, MD, of the University of Ulm, Germany, and his colleagues reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
That response was maintained at 1 year in 85% of participants.
The current findings, which represent data through April 2017 for those 107 patients from the main cohort, as well as for 51 patients in the safety expansion study, show an overall response rate of 77%, with 20% CR/CRi.
The median time to first response was 1 month, and time to CR/CRi was 9.8 months, they said.
Estimates at 24 months for duration of response, progression-free survival, and overall survival were 66%, 54%, and 73%, respectively.
Additionally, objective responses were seen in four of five previously untreated patients who were enrolled in the safety expansion, and two of them had complete remissions. One patient with best response of stable disease decided to discontinue treatment but remained in follow-up with stable disease.
“All patients were alive at the time of analysis and remain progression free,” the investigators wrote.
In 18 patients who received prior B-cell receptor pathway inhibitor (BCRi) therapy, the objective response rate was 61% and the complete remission rate was 11%, with 12-month, progression-free and overall survival estimates of 50% and 54%, respectively.
Treatment-emergent adverse events of any grade occurred in 98% of patients, and led to dosing interruption in 40% and dosing adjustment in 17%. The most common adverse event was neutropenia; grade 3/4 neutropenia occurred in 40% of patients.
Neutropenia lead to a dose reduction in 8% of patients and to treatment interruption in 6% of patients; no discontinuations were reported.
Infections occurred in 81% of 158 patients, and grade 3/4 infections occurred in 23%; these infections were consistent with the underlying disease, the investigators said.
Laboratory tumor lysis syndrome (TLS) occurred in 5% of patients, but there were no episodes of clinical TLS, they said, noting that five TLS patients required dose interruptions. TLS occurred in four patients with medium risk at screening and in four with high risk. All episodes of TLS occurred during initial dosing or ramp-up, and all resolved. Affected patients were able to resume venetoclax with dose escalation to 400 mg/day.
The rate of minimal residual disease negativity was 30% in the intention-to-treat population as demonstrated by flow cytometry and confirmed by next generation sequencing (NGS) in 21 of 29 patients with an evaluable matched time point specimen. Bone marrow MRD negativity was observed in 20 patients by flow cytometry, and in 9 patients by NGS.
When looking at flow cytometry and NGS data combined, the MRD negativity rate in peripheral blood was 25% overall and 40% in evaluable patients, and the MRD negativity rate in bone marrow was 11% overall and 24% in evaluable patients.
Of those who achieved CR/CRi, 69% were MRD negative in peripheral blood by flow cytometry, with a 24-month, progression-free survival estimate of 100%, and 13 of those had confirmed MRD-negative blood by NGS, 2 had MRD-positive blood by NGS at a matched flow cytometry assessment, and 7 were not evaluated by NGS. For the remaining CR/CRi patients, who were MRD-positive by flow cytometry, the 24-month progression-free survival estimate was 86%.
Study participants in the main cohort were adults with a median age of 67 years who had relapsed/refractory CLL with an indication for treatment by iwCLL criteria, del(17p), good performance status, adequate bone marrow function, and creatinine clearance of at least 50 mg/min. They received a single test dose of 20 mg on day 1, with gradual ramp up to 400 mg over 4-5 weeks based on laboratory assessments. All were hospitalized for the first 20 mg and 50 mg venetoclax doses during ramp up.
Those in the safety expansion were treated with once-daily oral venetoclax starting at a dose of 20 mg/day for 1 week and ramped up to 400 mg by week 5. To mitigate TLS risk, uric acid–lowering agents and hydration were started at least 72 hours prior to administering the first dose. Those with high TLS risk – and some with medium risk – were hospitalized for the first 20-mg and 50-mg doses. Those with low TLS risk – and most with medium risk – received initial venetoclax dosing in an outpatient setting.
“Continued follow-up of patients in this trial will provide additional data on the durability of response with venetoclax in patients with del(17p) CLL,” the investigators wrote.
This study was supported by AbbVie and Genentech. Dr. Stilgenbauer received research funding, honoraria, and travel support from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi.
AT THE iwCLL MEETING
Key clinical point:
Major finding: At April 2017 data analysis, the overall response rate was 77% with 20% CR/CRi.
Data source: The phase 2 open-label M13-982 Trial and safety expansion cohort of 158 total patients.
Disclosures: This study was supported by AbbVie and Genentech. Dr. Stilgenbauer received research funding, honoraria, and travel support from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi.
Predicting response to treatment in AML, MDS
Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.
The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.
The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.
And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.
Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.
In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.
The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.
The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.
The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.
Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.
The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.
DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.
In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.
Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.
The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.
The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.
And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.
Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.
In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.
The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.
The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.
The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.
Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.
The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.
DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.
In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.
Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.
The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.
The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.
And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.
Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.
In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.
The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.
The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.
The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.
Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.
The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.
DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.
In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.
High ORR with sequential regimen in CLL
LUGANO, SWITZERLAND—A sequential treatment regimen can produce a high overall response rate (ORR) in patients with treatment-naïve (TN) or relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), results of the CLL2-BAG study suggest.
Patients who received bendamustine followed by obinutuzumab and venetoclax achieved an ORR of 95%, and 87% of them were negative for minimal residual disease (MRD) in the peripheral blood.
In addition, this regimen did not lead to cumulative or unexpected toxicity, according to study investigator Paula Cramer, MD, of University Hospital of Cologne in Germany.
Dr Cramer presented results from CLL2-BAG at the 14th International Conference on Malignant Lymphoma (ICML). The trial was sponsored by the German CLL Study Group.
CLL2-BAG included 63 patients—34 with TN and 29 with RR CLL. The median age was 58 (range, 43-76) and 61 (range, 28-77), respectively.
Thirty-five percent of TN patients had bulky disease (>5 cm), as did 45% of RR patients. Twelve percent and 10%, respectively, had massive splenomegaly (>20 cm)
Twenty-one percent of TN patients and 35% of RR patients were Binet stage A. Thirty-two percent and 21%, respectively, were stage B, and 47% and 45%, respectively, were stage C.
Treatment
Patients first underwent debulking with bendamustine, given at 70 mg/m2 on days 1 and 2 for two 28-day cycles. They then received induction with obinutuzumab and venetoclax for six 28-day cycles.
In cycle 1, patients received obinutuzumab at 100 mg or 900 mg on day 1 or 2 and 1000 mg on days 8 and 15. For cycles 2-6, patients received 1000 mg of obinutuzumab on day 1.
In cycle 2, patients received venetoclax at 20 mg on days 1-7, 50 mg on days 8-14, 100 mg on days 15-21, and 200 mg on days 22-28. For cycles 3-6, they received venetoclax at 400 mg on days 1-28.
Patients also received maintenance with obinutuzumab and venetoclax for 2 to 8 cycles with a duration of 84 days. Obinutuzumab was given at 1000 mg on day 1 of each cycle, and venetoclax was given at 400 mg on days 1-84.
Maintenance was continued until patients completed 24 months of maintenance therapy, until 3 months after patients achieved a complete response (CR) or CR with incomplete count recovery (CRi) and MRD negativity, until progression of CLL or start of new CLL treatment, or until unacceptable toxicity.
ORR, MRD, and survival
At the end of induction, the ORR was 95% in the entire population—100% among TN patients and 90% among RR patients.
The rate of CR was 8%, 9%, and 7%, respectively. The rate of unconfirmed/clinical CR/CRi was 32%, 41%, and 21%, respectively.
Five percent of patients progressed, all of them in the RR group.
Eighty-seven percent of evaluable patients were MRD negative (<10-4) in the peripheral blood, including 91% of TN patients and 83% of RR patients. Two patients (3%) were missing data on MRD status in peripheral blood.
Thirteen percent of all evaluable patients were MRD negative in the bone marrow, including 12% of TN patients and 14% of RR patients. The remaining patients (87%, 88%, and 86%, respectively) were missing data on MRD status in the bone marrow.
The progression-free survival at 15 months was 100% in the TN patients and 83% in the RR patients.
Adverse events
After debulking, 28.1% of TN patients and 46.7% of RR patients had experienced adverse events (AEs).
These included (in TN and RR patients, respectively) neutropenia (9.4% and 13.3%), anemia (6.3% and 20.0%), thrombocytopenia (6.3% and 6.7%), infections (6.3% and 6.7%), coronary artery disorders (1 TN patient, 3.1%), rash (1 TN patient, 3.1%), tumor lysis syndrome (1 TN patient, 3.1%), vomiting (1 TN patient, 3.1%), and pyrexia (1 RR patient, 6.7%).
After induction, 54.3% of TN patients and 80.6% of RR patients had experienced AEs.
These included (in TN and RR patients, respectively) neutropenia (34.3% and 54.8%), infections (8.6% and 29.0%), thrombocytopenia (2.9% and 22.6%), infusion-related reactions (5 RR patients, 16.1%), neoplasms (2.9% and 9.7%), hypertension (2.9% and 6.5%), coronary artery disorders (2.9% and 6.5%), anemia (3 RR patients, 9.7%), and tumor lysis syndrome (2 RR patients, 6.5%).
LUGANO, SWITZERLAND—A sequential treatment regimen can produce a high overall response rate (ORR) in patients with treatment-naïve (TN) or relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), results of the CLL2-BAG study suggest.
Patients who received bendamustine followed by obinutuzumab and venetoclax achieved an ORR of 95%, and 87% of them were negative for minimal residual disease (MRD) in the peripheral blood.
In addition, this regimen did not lead to cumulative or unexpected toxicity, according to study investigator Paula Cramer, MD, of University Hospital of Cologne in Germany.
Dr Cramer presented results from CLL2-BAG at the 14th International Conference on Malignant Lymphoma (ICML). The trial was sponsored by the German CLL Study Group.
CLL2-BAG included 63 patients—34 with TN and 29 with RR CLL. The median age was 58 (range, 43-76) and 61 (range, 28-77), respectively.
Thirty-five percent of TN patients had bulky disease (>5 cm), as did 45% of RR patients. Twelve percent and 10%, respectively, had massive splenomegaly (>20 cm)
Twenty-one percent of TN patients and 35% of RR patients were Binet stage A. Thirty-two percent and 21%, respectively, were stage B, and 47% and 45%, respectively, were stage C.
Treatment
Patients first underwent debulking with bendamustine, given at 70 mg/m2 on days 1 and 2 for two 28-day cycles. They then received induction with obinutuzumab and venetoclax for six 28-day cycles.
In cycle 1, patients received obinutuzumab at 100 mg or 900 mg on day 1 or 2 and 1000 mg on days 8 and 15. For cycles 2-6, patients received 1000 mg of obinutuzumab on day 1.
In cycle 2, patients received venetoclax at 20 mg on days 1-7, 50 mg on days 8-14, 100 mg on days 15-21, and 200 mg on days 22-28. For cycles 3-6, they received venetoclax at 400 mg on days 1-28.
Patients also received maintenance with obinutuzumab and venetoclax for 2 to 8 cycles with a duration of 84 days. Obinutuzumab was given at 1000 mg on day 1 of each cycle, and venetoclax was given at 400 mg on days 1-84.
Maintenance was continued until patients completed 24 months of maintenance therapy, until 3 months after patients achieved a complete response (CR) or CR with incomplete count recovery (CRi) and MRD negativity, until progression of CLL or start of new CLL treatment, or until unacceptable toxicity.
ORR, MRD, and survival
At the end of induction, the ORR was 95% in the entire population—100% among TN patients and 90% among RR patients.
The rate of CR was 8%, 9%, and 7%, respectively. The rate of unconfirmed/clinical CR/CRi was 32%, 41%, and 21%, respectively.
Five percent of patients progressed, all of them in the RR group.
Eighty-seven percent of evaluable patients were MRD negative (<10-4) in the peripheral blood, including 91% of TN patients and 83% of RR patients. Two patients (3%) were missing data on MRD status in peripheral blood.
Thirteen percent of all evaluable patients were MRD negative in the bone marrow, including 12% of TN patients and 14% of RR patients. The remaining patients (87%, 88%, and 86%, respectively) were missing data on MRD status in the bone marrow.
The progression-free survival at 15 months was 100% in the TN patients and 83% in the RR patients.
Adverse events
After debulking, 28.1% of TN patients and 46.7% of RR patients had experienced adverse events (AEs).
These included (in TN and RR patients, respectively) neutropenia (9.4% and 13.3%), anemia (6.3% and 20.0%), thrombocytopenia (6.3% and 6.7%), infections (6.3% and 6.7%), coronary artery disorders (1 TN patient, 3.1%), rash (1 TN patient, 3.1%), tumor lysis syndrome (1 TN patient, 3.1%), vomiting (1 TN patient, 3.1%), and pyrexia (1 RR patient, 6.7%).
After induction, 54.3% of TN patients and 80.6% of RR patients had experienced AEs.
These included (in TN and RR patients, respectively) neutropenia (34.3% and 54.8%), infections (8.6% and 29.0%), thrombocytopenia (2.9% and 22.6%), infusion-related reactions (5 RR patients, 16.1%), neoplasms (2.9% and 9.7%), hypertension (2.9% and 6.5%), coronary artery disorders (2.9% and 6.5%), anemia (3 RR patients, 9.7%), and tumor lysis syndrome (2 RR patients, 6.5%).
LUGANO, SWITZERLAND—A sequential treatment regimen can produce a high overall response rate (ORR) in patients with treatment-naïve (TN) or relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), results of the CLL2-BAG study suggest.
Patients who received bendamustine followed by obinutuzumab and venetoclax achieved an ORR of 95%, and 87% of them were negative for minimal residual disease (MRD) in the peripheral blood.
In addition, this regimen did not lead to cumulative or unexpected toxicity, according to study investigator Paula Cramer, MD, of University Hospital of Cologne in Germany.
Dr Cramer presented results from CLL2-BAG at the 14th International Conference on Malignant Lymphoma (ICML). The trial was sponsored by the German CLL Study Group.
CLL2-BAG included 63 patients—34 with TN and 29 with RR CLL. The median age was 58 (range, 43-76) and 61 (range, 28-77), respectively.
Thirty-five percent of TN patients had bulky disease (>5 cm), as did 45% of RR patients. Twelve percent and 10%, respectively, had massive splenomegaly (>20 cm)
Twenty-one percent of TN patients and 35% of RR patients were Binet stage A. Thirty-two percent and 21%, respectively, were stage B, and 47% and 45%, respectively, were stage C.
Treatment
Patients first underwent debulking with bendamustine, given at 70 mg/m2 on days 1 and 2 for two 28-day cycles. They then received induction with obinutuzumab and venetoclax for six 28-day cycles.
In cycle 1, patients received obinutuzumab at 100 mg or 900 mg on day 1 or 2 and 1000 mg on days 8 and 15. For cycles 2-6, patients received 1000 mg of obinutuzumab on day 1.
In cycle 2, patients received venetoclax at 20 mg on days 1-7, 50 mg on days 8-14, 100 mg on days 15-21, and 200 mg on days 22-28. For cycles 3-6, they received venetoclax at 400 mg on days 1-28.
Patients also received maintenance with obinutuzumab and venetoclax for 2 to 8 cycles with a duration of 84 days. Obinutuzumab was given at 1000 mg on day 1 of each cycle, and venetoclax was given at 400 mg on days 1-84.
Maintenance was continued until patients completed 24 months of maintenance therapy, until 3 months after patients achieved a complete response (CR) or CR with incomplete count recovery (CRi) and MRD negativity, until progression of CLL or start of new CLL treatment, or until unacceptable toxicity.
ORR, MRD, and survival
At the end of induction, the ORR was 95% in the entire population—100% among TN patients and 90% among RR patients.
The rate of CR was 8%, 9%, and 7%, respectively. The rate of unconfirmed/clinical CR/CRi was 32%, 41%, and 21%, respectively.
Five percent of patients progressed, all of them in the RR group.
Eighty-seven percent of evaluable patients were MRD negative (<10-4) in the peripheral blood, including 91% of TN patients and 83% of RR patients. Two patients (3%) were missing data on MRD status in peripheral blood.
Thirteen percent of all evaluable patients were MRD negative in the bone marrow, including 12% of TN patients and 14% of RR patients. The remaining patients (87%, 88%, and 86%, respectively) were missing data on MRD status in the bone marrow.
The progression-free survival at 15 months was 100% in the TN patients and 83% in the RR patients.
Adverse events
After debulking, 28.1% of TN patients and 46.7% of RR patients had experienced adverse events (AEs).
These included (in TN and RR patients, respectively) neutropenia (9.4% and 13.3%), anemia (6.3% and 20.0%), thrombocytopenia (6.3% and 6.7%), infections (6.3% and 6.7%), coronary artery disorders (1 TN patient, 3.1%), rash (1 TN patient, 3.1%), tumor lysis syndrome (1 TN patient, 3.1%), vomiting (1 TN patient, 3.1%), and pyrexia (1 RR patient, 6.7%).
After induction, 54.3% of TN patients and 80.6% of RR patients had experienced AEs.
These included (in TN and RR patients, respectively) neutropenia (34.3% and 54.8%), infections (8.6% and 29.0%), thrombocytopenia (2.9% and 22.6%), infusion-related reactions (5 RR patients, 16.1%), neoplasms (2.9% and 9.7%), hypertension (2.9% and 6.5%), coronary artery disorders (2.9% and 6.5%), anemia (3 RR patients, 9.7%), and tumor lysis syndrome (2 RR patients, 6.5%).
CHMP recommends midostaurin for FLT3+ AML, SM
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) is recommending approval for midostaurin (Rydapt®) as a treatment for acute myeloid leukemia (AML) and systemic mastocytosis (SM).
If approved by the European Commission, midostaurin would be used in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation—followed by midostaurin maintenance for patients in complete response—in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3-mutation-positive.
Midostaurin would also be approved to treat adults with aggressive SM, SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).
If approved, midostaurin would be the first targeted treatment available in the European Union for newly diagnosed FLT3+ AML patients and advanced SM patients.
The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation. The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.
Midostaurin in AML
The CHMP’s recommendation for midostaurin in AML is based on results from the phase 3 RATIFY trial, which were recently published in NEJM.
In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.
The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).
And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).
The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infections.
The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.
Midostaurin in advanced SM
The CHMP’s recommendation for midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.
Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.
Study 2 included 116 patients, 115 of whom were evaluable for response.
The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.
Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.
Among the 17 patients with SM-AHN, there were 10 responses (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.
In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.
The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.
The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.
Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) is recommending approval for midostaurin (Rydapt®) as a treatment for acute myeloid leukemia (AML) and systemic mastocytosis (SM).
If approved by the European Commission, midostaurin would be used in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation—followed by midostaurin maintenance for patients in complete response—in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3-mutation-positive.
Midostaurin would also be approved to treat adults with aggressive SM, SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).
If approved, midostaurin would be the first targeted treatment available in the European Union for newly diagnosed FLT3+ AML patients and advanced SM patients.
The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation. The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.
Midostaurin in AML
The CHMP’s recommendation for midostaurin in AML is based on results from the phase 3 RATIFY trial, which were recently published in NEJM.
In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.
The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).
And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).
The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infections.
The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.
Midostaurin in advanced SM
The CHMP’s recommendation for midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.
Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.
Study 2 included 116 patients, 115 of whom were evaluable for response.
The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.
Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.
Among the 17 patients with SM-AHN, there were 10 responses (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.
In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.
The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.
The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.
Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) is recommending approval for midostaurin (Rydapt®) as a treatment for acute myeloid leukemia (AML) and systemic mastocytosis (SM).
If approved by the European Commission, midostaurin would be used in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation—followed by midostaurin maintenance for patients in complete response—in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3-mutation-positive.
Midostaurin would also be approved to treat adults with aggressive SM, SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).
If approved, midostaurin would be the first targeted treatment available in the European Union for newly diagnosed FLT3+ AML patients and advanced SM patients.
The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation. The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.
Midostaurin in AML
The CHMP’s recommendation for midostaurin in AML is based on results from the phase 3 RATIFY trial, which were recently published in NEJM.
In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.
The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).
And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).
The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infections.
The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.
Midostaurin in advanced SM
The CHMP’s recommendation for midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.
Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.
Study 2 included 116 patients, 115 of whom were evaluable for response.
The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.
Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.
Among the 17 patients with SM-AHN, there were 10 responses (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.
In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.
The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.
The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.
Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.
Modified, CB-derived NK cells target CLL and BL
Natural killer (NK) cells derived from cord blood (CB) can be modified to fight chronic lymphocytic leukemia (CLL) and Burkitt lymphoma (BL), according to research published in Leukemia.
Using a viral vector, researchers transduced CB-derived NK cells with a chimeric antigen receptor (CAR), interleukin-15 (IL-15), and an inducible caspase-9-based suicide gene.
The CAR directed the NK cells to kill CD19-expressing cells, IL-15 prolonged the NK cells’ survival and enhanced their antitumor activity, and the suicide gene allowed researchers to kill off the NK cells in the event of a severe inflammatory response.
“Natural killer cells are the immune system’s most potent killers, but they are short-lived, and cancers manage to evade a patient’s own NK cells to progress,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer—potentially for months instead of 2 or 3 weeks—are designed to address these challenges.”
Dr Rezvani and her colleagues tested their CB-derived CAR NK cells in primary CLL cells and a mouse model of BL. Compared to unmodified NK cells, the CAR NK cells killed malignant cells more efficiently and extended the survival of mice.
Another experiment showed the CB-derived CAR NK cells killed CLL cells more efficiently than NK cells that were taken from CLL patients and modified in the same way. The researchers said this highlights the need to transplant CAR-engineered NK cells derived from healthy CB rather than using a patient’s own cells.
Additional experiments in the mouse model of BL showed that a single infusion of low-dose CAR NK cells resulted in prolonged survival.
When CAR NK cells were given at a higher dose, none of the mice died of BL. Half of them survived 100 days and beyond. However, all mice treated with other types of NK cells died by day 41.
Some mice treated with the higher dose of CAR NK cells died of cytokine release syndrome (CRS).
To counteract this toxicity, the researchers activated the suicide gene (iC9) via treatment with a small-molecule dimerizer, AP1903.
The team found that adding as little as 10 nM of AP1903 to cell cultures induced apoptosis/necrosis of the CAR NK cells within 4 hours but had no effect on non-CAR CB-derived NK cells. Similar results were observed in the mouse model.
Next steps
A phase 1/2 trial of these CB-derived CAR NK cells opened at MD Anderson in June for patients with relapsed or refractory CLL, acute lymphocytic leukemia, or non-Hodgkin lymphoma.
Dr Rezvani, the principal investigator of the trial, said the protocol calls for vigilance for signs of CRS, treatment with steroids and tocilizumab for low-grade CRS, and AP1903 added to activate the suicide gene for grade 3 or 4 CRS.
She and her colleagues noted that CB-derived NK cells do not cause graft-vs-host disease. Therefore, they can be an off-the-shelf product, prepared in advance with the necessary receptor and given to patients promptly.
The researchers are developing CB-derived CAR NK cells for other targets in hematologic and solid tumor malignancies.
MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.
Funding for this research was provided by MD Anderson’s Moon Shots Program, the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (CA016672) to MD Anderson, and grants from the Leukemia and Lymphoma Society and the American Cancer Society.
Natural killer (NK) cells derived from cord blood (CB) can be modified to fight chronic lymphocytic leukemia (CLL) and Burkitt lymphoma (BL), according to research published in Leukemia.
Using a viral vector, researchers transduced CB-derived NK cells with a chimeric antigen receptor (CAR), interleukin-15 (IL-15), and an inducible caspase-9-based suicide gene.
The CAR directed the NK cells to kill CD19-expressing cells, IL-15 prolonged the NK cells’ survival and enhanced their antitumor activity, and the suicide gene allowed researchers to kill off the NK cells in the event of a severe inflammatory response.
“Natural killer cells are the immune system’s most potent killers, but they are short-lived, and cancers manage to evade a patient’s own NK cells to progress,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer—potentially for months instead of 2 or 3 weeks—are designed to address these challenges.”
Dr Rezvani and her colleagues tested their CB-derived CAR NK cells in primary CLL cells and a mouse model of BL. Compared to unmodified NK cells, the CAR NK cells killed malignant cells more efficiently and extended the survival of mice.
Another experiment showed the CB-derived CAR NK cells killed CLL cells more efficiently than NK cells that were taken from CLL patients and modified in the same way. The researchers said this highlights the need to transplant CAR-engineered NK cells derived from healthy CB rather than using a patient’s own cells.
Additional experiments in the mouse model of BL showed that a single infusion of low-dose CAR NK cells resulted in prolonged survival.
When CAR NK cells were given at a higher dose, none of the mice died of BL. Half of them survived 100 days and beyond. However, all mice treated with other types of NK cells died by day 41.
Some mice treated with the higher dose of CAR NK cells died of cytokine release syndrome (CRS).
To counteract this toxicity, the researchers activated the suicide gene (iC9) via treatment with a small-molecule dimerizer, AP1903.
The team found that adding as little as 10 nM of AP1903 to cell cultures induced apoptosis/necrosis of the CAR NK cells within 4 hours but had no effect on non-CAR CB-derived NK cells. Similar results were observed in the mouse model.
Next steps
A phase 1/2 trial of these CB-derived CAR NK cells opened at MD Anderson in June for patients with relapsed or refractory CLL, acute lymphocytic leukemia, or non-Hodgkin lymphoma.
Dr Rezvani, the principal investigator of the trial, said the protocol calls for vigilance for signs of CRS, treatment with steroids and tocilizumab for low-grade CRS, and AP1903 added to activate the suicide gene for grade 3 or 4 CRS.
She and her colleagues noted that CB-derived NK cells do not cause graft-vs-host disease. Therefore, they can be an off-the-shelf product, prepared in advance with the necessary receptor and given to patients promptly.
The researchers are developing CB-derived CAR NK cells for other targets in hematologic and solid tumor malignancies.
MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.
Funding for this research was provided by MD Anderson’s Moon Shots Program, the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (CA016672) to MD Anderson, and grants from the Leukemia and Lymphoma Society and the American Cancer Society.
Natural killer (NK) cells derived from cord blood (CB) can be modified to fight chronic lymphocytic leukemia (CLL) and Burkitt lymphoma (BL), according to research published in Leukemia.
Using a viral vector, researchers transduced CB-derived NK cells with a chimeric antigen receptor (CAR), interleukin-15 (IL-15), and an inducible caspase-9-based suicide gene.
The CAR directed the NK cells to kill CD19-expressing cells, IL-15 prolonged the NK cells’ survival and enhanced their antitumor activity, and the suicide gene allowed researchers to kill off the NK cells in the event of a severe inflammatory response.
“Natural killer cells are the immune system’s most potent killers, but they are short-lived, and cancers manage to evade a patient’s own NK cells to progress,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer—potentially for months instead of 2 or 3 weeks—are designed to address these challenges.”
Dr Rezvani and her colleagues tested their CB-derived CAR NK cells in primary CLL cells and a mouse model of BL. Compared to unmodified NK cells, the CAR NK cells killed malignant cells more efficiently and extended the survival of mice.
Another experiment showed the CB-derived CAR NK cells killed CLL cells more efficiently than NK cells that were taken from CLL patients and modified in the same way. The researchers said this highlights the need to transplant CAR-engineered NK cells derived from healthy CB rather than using a patient’s own cells.
Additional experiments in the mouse model of BL showed that a single infusion of low-dose CAR NK cells resulted in prolonged survival.
When CAR NK cells were given at a higher dose, none of the mice died of BL. Half of them survived 100 days and beyond. However, all mice treated with other types of NK cells died by day 41.
Some mice treated with the higher dose of CAR NK cells died of cytokine release syndrome (CRS).
To counteract this toxicity, the researchers activated the suicide gene (iC9) via treatment with a small-molecule dimerizer, AP1903.
The team found that adding as little as 10 nM of AP1903 to cell cultures induced apoptosis/necrosis of the CAR NK cells within 4 hours but had no effect on non-CAR CB-derived NK cells. Similar results were observed in the mouse model.
Next steps
A phase 1/2 trial of these CB-derived CAR NK cells opened at MD Anderson in June for patients with relapsed or refractory CLL, acute lymphocytic leukemia, or non-Hodgkin lymphoma.
Dr Rezvani, the principal investigator of the trial, said the protocol calls for vigilance for signs of CRS, treatment with steroids and tocilizumab for low-grade CRS, and AP1903 added to activate the suicide gene for grade 3 or 4 CRS.
She and her colleagues noted that CB-derived NK cells do not cause graft-vs-host disease. Therefore, they can be an off-the-shelf product, prepared in advance with the necessary receptor and given to patients promptly.
The researchers are developing CB-derived CAR NK cells for other targets in hematologic and solid tumor malignancies.
MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.
Funding for this research was provided by MD Anderson’s Moon Shots Program, the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (CA016672) to MD Anderson, and grants from the Leukemia and Lymphoma Society and the American Cancer Society.
AYA cancer survivors struggle with social functioning
New research suggests young cancer survivors struggle to get their social lives “back to normal” within the first 2 years of their diagnosis.
The study showed that adolescents and young adults (AYAs) with cancer had significantly worse social functioning than the general population around the time of cancer diagnosis as well as 1 year and 2 years later.
These findings were published in Cancer.
“The research is important to help these young survivors better reintegrate into society,” said study author Brad Zebrack, PhD, of the University of Michigan in Ann Arbor.
He and his colleagues collected data from 141 AYA cancer patients (ages 14 to 39) who visited 1 of 5 US medical facilities between March 2008 and April 2010.
The patients completed a self-report measure of social functioning within the first 4 months of diagnosis, then again at 12 months and 24 months.
Compared to the general population, the AYA cancer patients had significantly worse social functioning scores at all time points:
- Around the time of diagnosis—52.0 vs 85.1 (P<0.001)
- At 12 months—73.1 vs 85.1 (P<0.001)
- At 24 months—69.2 vs 85.1 (P<0.001).
Overall, the patients did experience improvements in social functioning from baseline to the 12-month time point, but their scores remained stable after that.
The researchers noted that 9% of patients had consistently high/normal social functioning, 47% had improvements in social functioning over time, 13% had worsening social functioning over time, and 32% had consistently low social functioning.
“This finding highlights the need to screen, identify, and respond to the needs of high-risk young adult-adolescent patients at the time of diagnosis and then monitor them over time,” Dr Zebrack said.
“They are likely the ones most in need of help in managing work, school, and potentially problematic relationships with family members and friends.”
New research suggests young cancer survivors struggle to get their social lives “back to normal” within the first 2 years of their diagnosis.
The study showed that adolescents and young adults (AYAs) with cancer had significantly worse social functioning than the general population around the time of cancer diagnosis as well as 1 year and 2 years later.
These findings were published in Cancer.
“The research is important to help these young survivors better reintegrate into society,” said study author Brad Zebrack, PhD, of the University of Michigan in Ann Arbor.
He and his colleagues collected data from 141 AYA cancer patients (ages 14 to 39) who visited 1 of 5 US medical facilities between March 2008 and April 2010.
The patients completed a self-report measure of social functioning within the first 4 months of diagnosis, then again at 12 months and 24 months.
Compared to the general population, the AYA cancer patients had significantly worse social functioning scores at all time points:
- Around the time of diagnosis—52.0 vs 85.1 (P<0.001)
- At 12 months—73.1 vs 85.1 (P<0.001)
- At 24 months—69.2 vs 85.1 (P<0.001).
Overall, the patients did experience improvements in social functioning from baseline to the 12-month time point, but their scores remained stable after that.
The researchers noted that 9% of patients had consistently high/normal social functioning, 47% had improvements in social functioning over time, 13% had worsening social functioning over time, and 32% had consistently low social functioning.
“This finding highlights the need to screen, identify, and respond to the needs of high-risk young adult-adolescent patients at the time of diagnosis and then monitor them over time,” Dr Zebrack said.
“They are likely the ones most in need of help in managing work, school, and potentially problematic relationships with family members and friends.”
New research suggests young cancer survivors struggle to get their social lives “back to normal” within the first 2 years of their diagnosis.
The study showed that adolescents and young adults (AYAs) with cancer had significantly worse social functioning than the general population around the time of cancer diagnosis as well as 1 year and 2 years later.
These findings were published in Cancer.
“The research is important to help these young survivors better reintegrate into society,” said study author Brad Zebrack, PhD, of the University of Michigan in Ann Arbor.
He and his colleagues collected data from 141 AYA cancer patients (ages 14 to 39) who visited 1 of 5 US medical facilities between March 2008 and April 2010.
The patients completed a self-report measure of social functioning within the first 4 months of diagnosis, then again at 12 months and 24 months.
Compared to the general population, the AYA cancer patients had significantly worse social functioning scores at all time points:
- Around the time of diagnosis—52.0 vs 85.1 (P<0.001)
- At 12 months—73.1 vs 85.1 (P<0.001)
- At 24 months—69.2 vs 85.1 (P<0.001).
Overall, the patients did experience improvements in social functioning from baseline to the 12-month time point, but their scores remained stable after that.
The researchers noted that 9% of patients had consistently high/normal social functioning, 47% had improvements in social functioning over time, 13% had worsening social functioning over time, and 32% had consistently low social functioning.
“This finding highlights the need to screen, identify, and respond to the needs of high-risk young adult-adolescent patients at the time of diagnosis and then monitor them over time,” Dr Zebrack said.
“They are likely the ones most in need of help in managing work, school, and potentially problematic relationships with family members and friends.”
FDA grants orphan designation to gilteritinib in AML
The US Food and Drug Administration (FDA) has granted orphan drug designation to gilteritinib for the treatment of patients with acute myeloid leukemia (AML).
Gilteritinib, an inhibitor of FLT3 and AXL, has demonstrated activity against FLT3 internal tandem duplication (ITD) as well as tyrosine kinase domain, 2 mutations that are seen in up to a third of patients with AML.
Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.
Results from a phase 1/2 study of gilteritinib in AML were presented at the 2017 ASCO Annual Meeting.
The goal of the study was to determine the tolerability and antileukemic activity of once-daily gilteritinib in a FLT3-ITD-enriched, relapsed/refractory AML population.
The drug exhibited “potent” FLT3 inhibition at doses greater than 80 mg/day. In patients who received such doses, the greatest overall response rate was 52%, and the longest median overall survival was 31 weeks.
The maximum tolerated dose of gilteritinib was 300 mg/day. Dose-limiting toxicities included diarrhea and liver function abnormalities.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to gilteritinib for the treatment of patients with acute myeloid leukemia (AML).
Gilteritinib, an inhibitor of FLT3 and AXL, has demonstrated activity against FLT3 internal tandem duplication (ITD) as well as tyrosine kinase domain, 2 mutations that are seen in up to a third of patients with AML.
Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.
Results from a phase 1/2 study of gilteritinib in AML were presented at the 2017 ASCO Annual Meeting.
The goal of the study was to determine the tolerability and antileukemic activity of once-daily gilteritinib in a FLT3-ITD-enriched, relapsed/refractory AML population.
The drug exhibited “potent” FLT3 inhibition at doses greater than 80 mg/day. In patients who received such doses, the greatest overall response rate was 52%, and the longest median overall survival was 31 weeks.
The maximum tolerated dose of gilteritinib was 300 mg/day. Dose-limiting toxicities included diarrhea and liver function abnormalities.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to gilteritinib for the treatment of patients with acute myeloid leukemia (AML).
Gilteritinib, an inhibitor of FLT3 and AXL, has demonstrated activity against FLT3 internal tandem duplication (ITD) as well as tyrosine kinase domain, 2 mutations that are seen in up to a third of patients with AML.
Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.
Results from a phase 1/2 study of gilteritinib in AML were presented at the 2017 ASCO Annual Meeting.
The goal of the study was to determine the tolerability and antileukemic activity of once-daily gilteritinib in a FLT3-ITD-enriched, relapsed/refractory AML population.
The drug exhibited “potent” FLT3 inhibition at doses greater than 80 mg/day. In patients who received such doses, the greatest overall response rate was 52%, and the longest median overall survival was 31 weeks.
The maximum tolerated dose of gilteritinib was 300 mg/day. Dose-limiting toxicities included diarrhea and liver function abnormalities.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.