User login
Drug shows early promise for hematologic malignancies
A drug that targets mitochondrial function is largely safe and can be active in heavily pretreated patients with hematologic malignancies, a phase 1 trial indicates.
The drug, CPI-613, prompted responses in only 4 of 21 evaluable patients. However, 2 of those responses lasted more than 2 years.
CPI-613 was generally well-tolerated and did not induce bone marrow suppression. Four patients experienced renal failure, but it was reversed in 3 of them.
These results appear in Clinical Cancer Research.
“This drug is selectively taken up by cancer cells and then shuts down the production of energy in the mitochondria,” said study author Timothy Pardee, MD, PhD, of the Comprehensive Cancer Center of Wake Forest University in Winston-Salem, North Carolina.
“This is the first drug to inhibit mitochondria in this way, and, if it proves effective in further clinical trials, it will open up a whole new approach to fighting cancer.”
Dr Pardee and his colleagues evaluated CPI-613 in 26 patients with relapsed or refractory hematologic malignancies—11 with acute myeloid leukemia, 6 with non-Hodgkin lymphoma, 4 with multiple myeloma, 4 with myelodysplastic syndrome (MDS), and 1 with Hodgkin lymphoma.
The median patient age was 65 years (range, 19-81), and the median number of prior therapies was 3 (range, 1-9).
Treatment dosing and toxicity
Patients received CPI-613 as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days.
When the infusion time was shortened to 1 hour, renal failure occurred in 2 patients. At 3780 mg/m2, there were 2 dose-limiting toxicities. There were no such toxicities at a dose of 2940 mg/m2 over 2 hours, so this was considered the maximum-tolerated dose.
The following grade 2 or higher toxicities were probably or definitely related to treatment: nausea (1 grade 2), vomiting (1 grade 3), diarrhea (3 grade 2), proteinuria (1 grade 2), renal failure (4 grade 3), hypotension (1 grade 2), hypocalcemia (1 grade 2), hypoalbuminemia (1 grade 2), and hyperkalemia (1 grade 3).
Renal failure was resolved in 3 of the 4 patients. The remaining patient chose hospice care.
Response data
Five patients discontinued treatment—1 refused therapy, 1 acquired an infection, and 3 developed acute kidney failure.
Of the 21 patients evaluable for response, 4 had an objective response following CPI-613 treatment, and 2 had prolonged stable disease.
One patient with MDS achieved a complete response that has been maintained for more than 3 years. A patient with acute myeloid leukemia achieved a morphologically leukemia-free state, went on to transplant, and is still alive and leukemia-free.
A patient with Burkitt lymphoma achieved a partial response after 3 cycles of therapy that was maintained for 17 cycles. She discontinued CPI-613 to have her residual disease resected, and has not received any treatment since. She is now disease-free more than 12 months later.
A patient with cutaneous T-cell lymphoma achieved a partial response that has been sustained for more than 2 years. At her request, she started to receive continuous therapy (no 1-week rest period), and she remains on treatment without significant toxicities and no evidence of marrow suppression.
The 2 patients with prolonged stable disease had MDS. Their disease was stable for 8 and 12 cycles, respectively. Two patients with multiple myeloma also initially had stable disease, but they progressed after 2 and 4 cycles, respectively.
Two patients died from disease progression while on study.
The researchers said these results suggest that agents targeting mitochondrial metabolism can be safe and active in hematologic malignancies. A phase 2 trial of CPI-613 is now underway.
Support for the phase 1 trial was provided by National Cancer Institute grants P30CA012197 and 1K08CA169809, the Doug Coley Foundation for Leukemia Research, the Frances P. Tutwiler Fund, The MacKay Foundation for Cancer Research, and Cornerstone Pharmaceuticals, which manufactured and provided CPI-613. 
A drug that targets mitochondrial function is largely safe and can be active in heavily pretreated patients with hematologic malignancies, a phase 1 trial indicates.
The drug, CPI-613, prompted responses in only 4 of 21 evaluable patients. However, 2 of those responses lasted more than 2 years.
CPI-613 was generally well-tolerated and did not induce bone marrow suppression. Four patients experienced renal failure, but it was reversed in 3 of them.
These results appear in Clinical Cancer Research.
“This drug is selectively taken up by cancer cells and then shuts down the production of energy in the mitochondria,” said study author Timothy Pardee, MD, PhD, of the Comprehensive Cancer Center of Wake Forest University in Winston-Salem, North Carolina.
“This is the first drug to inhibit mitochondria in this way, and, if it proves effective in further clinical trials, it will open up a whole new approach to fighting cancer.”
Dr Pardee and his colleagues evaluated CPI-613 in 26 patients with relapsed or refractory hematologic malignancies—11 with acute myeloid leukemia, 6 with non-Hodgkin lymphoma, 4 with multiple myeloma, 4 with myelodysplastic syndrome (MDS), and 1 with Hodgkin lymphoma.
The median patient age was 65 years (range, 19-81), and the median number of prior therapies was 3 (range, 1-9).
Treatment dosing and toxicity
Patients received CPI-613 as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days.
When the infusion time was shortened to 1 hour, renal failure occurred in 2 patients. At 3780 mg/m2, there were 2 dose-limiting toxicities. There were no such toxicities at a dose of 2940 mg/m2 over 2 hours, so this was considered the maximum-tolerated dose.
The following grade 2 or higher toxicities were probably or definitely related to treatment: nausea (1 grade 2), vomiting (1 grade 3), diarrhea (3 grade 2), proteinuria (1 grade 2), renal failure (4 grade 3), hypotension (1 grade 2), hypocalcemia (1 grade 2), hypoalbuminemia (1 grade 2), and hyperkalemia (1 grade 3).
Renal failure was resolved in 3 of the 4 patients. The remaining patient chose hospice care.
Response data
Five patients discontinued treatment—1 refused therapy, 1 acquired an infection, and 3 developed acute kidney failure.
Of the 21 patients evaluable for response, 4 had an objective response following CPI-613 treatment, and 2 had prolonged stable disease.
One patient with MDS achieved a complete response that has been maintained for more than 3 years. A patient with acute myeloid leukemia achieved a morphologically leukemia-free state, went on to transplant, and is still alive and leukemia-free.
A patient with Burkitt lymphoma achieved a partial response after 3 cycles of therapy that was maintained for 17 cycles. She discontinued CPI-613 to have her residual disease resected, and has not received any treatment since. She is now disease-free more than 12 months later.
A patient with cutaneous T-cell lymphoma achieved a partial response that has been sustained for more than 2 years. At her request, she started to receive continuous therapy (no 1-week rest period), and she remains on treatment without significant toxicities and no evidence of marrow suppression.
The 2 patients with prolonged stable disease had MDS. Their disease was stable for 8 and 12 cycles, respectively. Two patients with multiple myeloma also initially had stable disease, but they progressed after 2 and 4 cycles, respectively.
Two patients died from disease progression while on study.
The researchers said these results suggest that agents targeting mitochondrial metabolism can be safe and active in hematologic malignancies. A phase 2 trial of CPI-613 is now underway.
Support for the phase 1 trial was provided by National Cancer Institute grants P30CA012197 and 1K08CA169809, the Doug Coley Foundation for Leukemia Research, the Frances P. Tutwiler Fund, The MacKay Foundation for Cancer Research, and Cornerstone Pharmaceuticals, which manufactured and provided CPI-613.
A drug that targets mitochondrial function is largely safe and can be active in heavily pretreated patients with hematologic malignancies, a phase 1 trial indicates.
The drug, CPI-613, prompted responses in only 4 of 21 evaluable patients. However, 2 of those responses lasted more than 2 years.
CPI-613 was generally well-tolerated and did not induce bone marrow suppression. Four patients experienced renal failure, but it was reversed in 3 of them.
These results appear in Clinical Cancer Research.
“This drug is selectively taken up by cancer cells and then shuts down the production of energy in the mitochondria,” said study author Timothy Pardee, MD, PhD, of the Comprehensive Cancer Center of Wake Forest University in Winston-Salem, North Carolina.
“This is the first drug to inhibit mitochondria in this way, and, if it proves effective in further clinical trials, it will open up a whole new approach to fighting cancer.”
Dr Pardee and his colleagues evaluated CPI-613 in 26 patients with relapsed or refractory hematologic malignancies—11 with acute myeloid leukemia, 6 with non-Hodgkin lymphoma, 4 with multiple myeloma, 4 with myelodysplastic syndrome (MDS), and 1 with Hodgkin lymphoma.
The median patient age was 65 years (range, 19-81), and the median number of prior therapies was 3 (range, 1-9).
Treatment dosing and toxicity
Patients received CPI-613 as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days.
When the infusion time was shortened to 1 hour, renal failure occurred in 2 patients. At 3780 mg/m2, there were 2 dose-limiting toxicities. There were no such toxicities at a dose of 2940 mg/m2 over 2 hours, so this was considered the maximum-tolerated dose.
The following grade 2 or higher toxicities were probably or definitely related to treatment: nausea (1 grade 2), vomiting (1 grade 3), diarrhea (3 grade 2), proteinuria (1 grade 2), renal failure (4 grade 3), hypotension (1 grade 2), hypocalcemia (1 grade 2), hypoalbuminemia (1 grade 2), and hyperkalemia (1 grade 3).
Renal failure was resolved in 3 of the 4 patients. The remaining patient chose hospice care.
Response data
Five patients discontinued treatment—1 refused therapy, 1 acquired an infection, and 3 developed acute kidney failure.
Of the 21 patients evaluable for response, 4 had an objective response following CPI-613 treatment, and 2 had prolonged stable disease.
One patient with MDS achieved a complete response that has been maintained for more than 3 years. A patient with acute myeloid leukemia achieved a morphologically leukemia-free state, went on to transplant, and is still alive and leukemia-free.
A patient with Burkitt lymphoma achieved a partial response after 3 cycles of therapy that was maintained for 17 cycles. She discontinued CPI-613 to have her residual disease resected, and has not received any treatment since. She is now disease-free more than 12 months later.
A patient with cutaneous T-cell lymphoma achieved a partial response that has been sustained for more than 2 years. At her request, she started to receive continuous therapy (no 1-week rest period), and she remains on treatment without significant toxicities and no evidence of marrow suppression.
The 2 patients with prolonged stable disease had MDS. Their disease was stable for 8 and 12 cycles, respectively. Two patients with multiple myeloma also initially had stable disease, but they progressed after 2 and 4 cycles, respectively.
Two patients died from disease progression while on study.
The researchers said these results suggest that agents targeting mitochondrial metabolism can be safe and active in hematologic malignancies. A phase 2 trial of CPI-613 is now underway.
Support for the phase 1 trial was provided by National Cancer Institute grants P30CA012197 and 1K08CA169809, the Doug Coley Foundation for Leukemia Research, the Frances P. Tutwiler Fund, The MacKay Foundation for Cancer Research, and Cornerstone Pharmaceuticals, which manufactured and provided CPI-613.
Deaths from childhood cancer on decline in UK
Credit: Logan Tuttle
The rate of children dying from cancer in the UK has dropped 22% in the last decade, according to new figures published by Cancer Research UK.
From 2001 to 2003, 328 children died from cancer each year. But from 2010 to 2012, the annual death toll from childhood cancers decreased to 258.
The steepest decline in mortality was among leukemia patients. Death rates across all forms of leukemia combined dropped by 47%, from 102 to 53 deaths each year.
For acute lymphoblastic leukemia, the annual mortality rate decreased by 52%, falling from 63 to 29 deaths per year. For acute myeloid leukemia, the death rate fell by 33%, from 30 to 20 deaths per year. And for chronic myeloid leukemia, the death rate decreased by 74%, from 2 deaths per year to 1.
Annual mortality rates decreased for lymphoma patients as well. For all lymphomas, the death rate decreased by 31%, falling from 15 to 11 deaths per year. And for non-Hodgkin lymphomas, the rate dropped 35%, from 14 to 10 deaths per year.
Much of this success is due to new combinations of chemotherapy drugs, but efforts to improve imaging and radiotherapy techniques has also played a part, according to Cancer Research UK.
“It’s very encouraging to see that fewer children are dying of cancer, but a lot more needs to be done,” said Pam Kearns, director of the Cancer Research UK Clinical Trials Unit in Birmingham.
“Many children who survive cancer will live with the long-term side effects of their treatment that can have an impact throughout their adult lives, so it’s vital that we find kinder and even more effective treatments for them.”
Around 1600 children are diagnosed with cancer every year in the UK. Overall survival for childhood cancer has tripled since the 1960s. The proportion of children surviving their cancer for at least 10 years increased from 24% in 1966-1970 to 76% in 2001-2005.
Note: The above figures are age-standardized mortality rates, which take the age and size of the population into account, providing a figure for the number of children who die from cancer per million individuals. Looking at the numbers of children dying from the disease does not adjust for the increasing size of the UK population over the last 10 years, so changes in the numbers of deaths will not match the changes in rates.
Credit: Logan Tuttle
The rate of children dying from cancer in the UK has dropped 22% in the last decade, according to new figures published by Cancer Research UK.
From 2001 to 2003, 328 children died from cancer each year. But from 2010 to 2012, the annual death toll from childhood cancers decreased to 258.
The steepest decline in mortality was among leukemia patients. Death rates across all forms of leukemia combined dropped by 47%, from 102 to 53 deaths each year.
For acute lymphoblastic leukemia, the annual mortality rate decreased by 52%, falling from 63 to 29 deaths per year. For acute myeloid leukemia, the death rate fell by 33%, from 30 to 20 deaths per year. And for chronic myeloid leukemia, the death rate decreased by 74%, from 2 deaths per year to 1.
Annual mortality rates decreased for lymphoma patients as well. For all lymphomas, the death rate decreased by 31%, falling from 15 to 11 deaths per year. And for non-Hodgkin lymphomas, the rate dropped 35%, from 14 to 10 deaths per year.
Much of this success is due to new combinations of chemotherapy drugs, but efforts to improve imaging and radiotherapy techniques has also played a part, according to Cancer Research UK.
“It’s very encouraging to see that fewer children are dying of cancer, but a lot more needs to be done,” said Pam Kearns, director of the Cancer Research UK Clinical Trials Unit in Birmingham.
“Many children who survive cancer will live with the long-term side effects of their treatment that can have an impact throughout their adult lives, so it’s vital that we find kinder and even more effective treatments for them.”
Around 1600 children are diagnosed with cancer every year in the UK. Overall survival for childhood cancer has tripled since the 1960s. The proportion of children surviving their cancer for at least 10 years increased from 24% in 1966-1970 to 76% in 2001-2005.
Note: The above figures are age-standardized mortality rates, which take the age and size of the population into account, providing a figure for the number of children who die from cancer per million individuals. Looking at the numbers of children dying from the disease does not adjust for the increasing size of the UK population over the last 10 years, so changes in the numbers of deaths will not match the changes in rates.
Credit: Logan Tuttle
The rate of children dying from cancer in the UK has dropped 22% in the last decade, according to new figures published by Cancer Research UK.
From 2001 to 2003, 328 children died from cancer each year. But from 2010 to 2012, the annual death toll from childhood cancers decreased to 258.
The steepest decline in mortality was among leukemia patients. Death rates across all forms of leukemia combined dropped by 47%, from 102 to 53 deaths each year.
For acute lymphoblastic leukemia, the annual mortality rate decreased by 52%, falling from 63 to 29 deaths per year. For acute myeloid leukemia, the death rate fell by 33%, from 30 to 20 deaths per year. And for chronic myeloid leukemia, the death rate decreased by 74%, from 2 deaths per year to 1.
Annual mortality rates decreased for lymphoma patients as well. For all lymphomas, the death rate decreased by 31%, falling from 15 to 11 deaths per year. And for non-Hodgkin lymphomas, the rate dropped 35%, from 14 to 10 deaths per year.
Much of this success is due to new combinations of chemotherapy drugs, but efforts to improve imaging and radiotherapy techniques has also played a part, according to Cancer Research UK.
“It’s very encouraging to see that fewer children are dying of cancer, but a lot more needs to be done,” said Pam Kearns, director of the Cancer Research UK Clinical Trials Unit in Birmingham.
“Many children who survive cancer will live with the long-term side effects of their treatment that can have an impact throughout their adult lives, so it’s vital that we find kinder and even more effective treatments for them.”
Around 1600 children are diagnosed with cancer every year in the UK. Overall survival for childhood cancer has tripled since the 1960s. The proportion of children surviving their cancer for at least 10 years increased from 24% in 1966-1970 to 76% in 2001-2005.
Note: The above figures are age-standardized mortality rates, which take the age and size of the population into account, providing a figure for the number of children who die from cancer per million individuals. Looking at the numbers of children dying from the disease does not adjust for the increasing size of the UK population over the last 10 years, so changes in the numbers of deaths will not match the changes in rates.
Treatment Failure Patterns in Patients With Chronic Lymphocytic Leukemia: Results of a Large U.S. Observational Study
Purpose: Treatment for patients with chronic lymphocytic leukemia (CLL) is often not curative. Therefore, patients with CLL eventually experience disease progression with limited therapeutic options, even if the duration of remission can be long. Median overall survival for patients with CLL is usually 8 to 12 years, but there is a large variation in survival among individual patients, ranging from several months to a normal life expectancy. This retrospective observational study describes course of treatment and occurrence of treatment failure in patients with CLL.
Methods: Adult patients with ≥ 1 diagnosis of CLL and ≥ 1 claim for a medication used to treat CLL were identified in the IMS PharMetrics Plus database (January 2008 to September 2013). Patients were excluded if they had evidence of a nonhematologic malignancy, used a non-CLL antineoplastic agent, or received a stem cell transplant during the 12-month baseline period. Initial therapy was defined as the single agent or the combination of medications used to treat CLL that was given to patients in the first 30 days following the first claim for a medication (index date) used to treat CLL. Treatment failure was identified based on earliest occurrence of one of the following events: initiation of a new treatment for CLL that was not part of the initial therapy, resumption of any CLL treatment following a minimum of 3-month break in treatment, radiotherapy, stem cell transplant, hospital mortality, or hospice care.
Results: A total of 6,015 patients with CLL were identified (mean patient aged 63 years; proportion female: 36%). Patients were observed for 22.7 months on average following treatment initiation. Median time between first CLL diagnosis and first claim for a medication used to treat CLL was 102 days. Mean Charlson comorbidity index was 3.2. More frequent comorbidities were hypertension (44%), anemias (37%), coagulation deficiency (21%), diabetes without chronic complications (18%), and chronic pulmonary disease (18%). Of the 6,015 patients with CLL, 2,734 (45%) experienced treatment failure. Main observed measures for treatment failure were initiation of a new CLL treatment that was not part of the initial therapy (41%; mean time to treatment failure [TTF]: 286 days), resumption of any CLL treatment (39%; TTF: 346 days), radiotherapy (14%; TTF: 199 days), and stem cell transplant (5%; TTF: 116 days). Very few patients experienced treatment failure observed through hospice care (0.4%; TTF: 387 days).
Conclusions: A notable number (45%) of patients with CLL experienced treatment failure, which was mainly observed through initiation of alternative therapies or the need for a holiday after initial therapy. These data help in our understanding of CLL treatment failure patterns, which is a first step toward reducing the burden of disease in patients with CLL. Further research evaluating the reasons and economic implications of treatment failure is warranted.
Purpose: Treatment for patients with chronic lymphocytic leukemia (CLL) is often not curative. Therefore, patients with CLL eventually experience disease progression with limited therapeutic options, even if the duration of remission can be long. Median overall survival for patients with CLL is usually 8 to 12 years, but there is a large variation in survival among individual patients, ranging from several months to a normal life expectancy. This retrospective observational study describes course of treatment and occurrence of treatment failure in patients with CLL.
Methods: Adult patients with ≥ 1 diagnosis of CLL and ≥ 1 claim for a medication used to treat CLL were identified in the IMS PharMetrics Plus database (January 2008 to September 2013). Patients were excluded if they had evidence of a nonhematologic malignancy, used a non-CLL antineoplastic agent, or received a stem cell transplant during the 12-month baseline period. Initial therapy was defined as the single agent or the combination of medications used to treat CLL that was given to patients in the first 30 days following the first claim for a medication (index date) used to treat CLL. Treatment failure was identified based on earliest occurrence of one of the following events: initiation of a new treatment for CLL that was not part of the initial therapy, resumption of any CLL treatment following a minimum of 3-month break in treatment, radiotherapy, stem cell transplant, hospital mortality, or hospice care.
Results: A total of 6,015 patients with CLL were identified (mean patient aged 63 years; proportion female: 36%). Patients were observed for 22.7 months on average following treatment initiation. Median time between first CLL diagnosis and first claim for a medication used to treat CLL was 102 days. Mean Charlson comorbidity index was 3.2. More frequent comorbidities were hypertension (44%), anemias (37%), coagulation deficiency (21%), diabetes without chronic complications (18%), and chronic pulmonary disease (18%). Of the 6,015 patients with CLL, 2,734 (45%) experienced treatment failure. Main observed measures for treatment failure were initiation of a new CLL treatment that was not part of the initial therapy (41%; mean time to treatment failure [TTF]: 286 days), resumption of any CLL treatment (39%; TTF: 346 days), radiotherapy (14%; TTF: 199 days), and stem cell transplant (5%; TTF: 116 days). Very few patients experienced treatment failure observed through hospice care (0.4%; TTF: 387 days).
Conclusions: A notable number (45%) of patients with CLL experienced treatment failure, which was mainly observed through initiation of alternative therapies or the need for a holiday after initial therapy. These data help in our understanding of CLL treatment failure patterns, which is a first step toward reducing the burden of disease in patients with CLL. Further research evaluating the reasons and economic implications of treatment failure is warranted.
Purpose: Treatment for patients with chronic lymphocytic leukemia (CLL) is often not curative. Therefore, patients with CLL eventually experience disease progression with limited therapeutic options, even if the duration of remission can be long. Median overall survival for patients with CLL is usually 8 to 12 years, but there is a large variation in survival among individual patients, ranging from several months to a normal life expectancy. This retrospective observational study describes course of treatment and occurrence of treatment failure in patients with CLL.
Methods: Adult patients with ≥ 1 diagnosis of CLL and ≥ 1 claim for a medication used to treat CLL were identified in the IMS PharMetrics Plus database (January 2008 to September 2013). Patients were excluded if they had evidence of a nonhematologic malignancy, used a non-CLL antineoplastic agent, or received a stem cell transplant during the 12-month baseline period. Initial therapy was defined as the single agent or the combination of medications used to treat CLL that was given to patients in the first 30 days following the first claim for a medication (index date) used to treat CLL. Treatment failure was identified based on earliest occurrence of one of the following events: initiation of a new treatment for CLL that was not part of the initial therapy, resumption of any CLL treatment following a minimum of 3-month break in treatment, radiotherapy, stem cell transplant, hospital mortality, or hospice care.
Results: A total of 6,015 patients with CLL were identified (mean patient aged 63 years; proportion female: 36%). Patients were observed for 22.7 months on average following treatment initiation. Median time between first CLL diagnosis and first claim for a medication used to treat CLL was 102 days. Mean Charlson comorbidity index was 3.2. More frequent comorbidities were hypertension (44%), anemias (37%), coagulation deficiency (21%), diabetes without chronic complications (18%), and chronic pulmonary disease (18%). Of the 6,015 patients with CLL, 2,734 (45%) experienced treatment failure. Main observed measures for treatment failure were initiation of a new CLL treatment that was not part of the initial therapy (41%; mean time to treatment failure [TTF]: 286 days), resumption of any CLL treatment (39%; TTF: 346 days), radiotherapy (14%; TTF: 199 days), and stem cell transplant (5%; TTF: 116 days). Very few patients experienced treatment failure observed through hospice care (0.4%; TTF: 387 days).
Conclusions: A notable number (45%) of patients with CLL experienced treatment failure, which was mainly observed through initiation of alternative therapies or the need for a holiday after initial therapy. These data help in our understanding of CLL treatment failure patterns, which is a first step toward reducing the burden of disease in patients with CLL. Further research evaluating the reasons and economic implications of treatment failure is warranted.
Association Between Rituximab Use and Progressive Multifocal Leukoencephalopathy Among Non-HIV Non-Hodgkin Lymphoma VA Patients
Purpose: Progressive multifocal leukoencephalopathy (PML) is a rare, fatal disease that results from activation of a highly prevalent, dormant John Cunningham (JC) virus—a variant of human polyomavirus—during immunosuppressed states. Rituximab, a CD20 monoclonal antibody immunomodulator, has been approved for non-Hodgkin lymphoma (NHL).
Methods: Using electronic medical records from the VA, ICD-9 codes were used to identify patients diagnosed with NHL, PML, and HIV within the VA from 2003 to 2011. Pharmacy records were used to identify patients receiving rituximab, cyclophosphamide, hydroxydaunorubicin, and vncristine. This project was conducted inside the Veterans Affairs Informatics and Computing Infrastructure after obtaining approvals from the VA IRB and other oversight groups.
Results: We identified 57,041 non-HIV NHL patients. A total of 14 out of 57,041 (0.025%) patients had developed PML; 7 out of 8,895 (7.8 per 10,000) were NHL patients who received rituximab subsequently developed PML; 7 out of 48,146 (1.5 per 10,000) were NHL patients who did not receive rituximab subsequently developed PML, which results in a statistically significant unadjusted relative risk of 5.4 (95% CI: 1.9 - 15.4) and an attributable risk of 6.3 per 10,000. Univariate analyses of other outcomes were not statistically significant between patients who received and those that did not receive rituximab.
Conclusions: These results show that among lymphoma patients, the use of rituximab is associated with a statistically significant relative risk for documented PML of 5.4. Measurement of JC virus prior to initiation of rituximab therapy as well as during rituximab therapy should be considered.
Purpose: Progressive multifocal leukoencephalopathy (PML) is a rare, fatal disease that results from activation of a highly prevalent, dormant John Cunningham (JC) virus—a variant of human polyomavirus—during immunosuppressed states. Rituximab, a CD20 monoclonal antibody immunomodulator, has been approved for non-Hodgkin lymphoma (NHL).
Methods: Using electronic medical records from the VA, ICD-9 codes were used to identify patients diagnosed with NHL, PML, and HIV within the VA from 2003 to 2011. Pharmacy records were used to identify patients receiving rituximab, cyclophosphamide, hydroxydaunorubicin, and vncristine. This project was conducted inside the Veterans Affairs Informatics and Computing Infrastructure after obtaining approvals from the VA IRB and other oversight groups.
Results: We identified 57,041 non-HIV NHL patients. A total of 14 out of 57,041 (0.025%) patients had developed PML; 7 out of 8,895 (7.8 per 10,000) were NHL patients who received rituximab subsequently developed PML; 7 out of 48,146 (1.5 per 10,000) were NHL patients who did not receive rituximab subsequently developed PML, which results in a statistically significant unadjusted relative risk of 5.4 (95% CI: 1.9 - 15.4) and an attributable risk of 6.3 per 10,000. Univariate analyses of other outcomes were not statistically significant between patients who received and those that did not receive rituximab.
Conclusions: These results show that among lymphoma patients, the use of rituximab is associated with a statistically significant relative risk for documented PML of 5.4. Measurement of JC virus prior to initiation of rituximab therapy as well as during rituximab therapy should be considered.
Purpose: Progressive multifocal leukoencephalopathy (PML) is a rare, fatal disease that results from activation of a highly prevalent, dormant John Cunningham (JC) virus—a variant of human polyomavirus—during immunosuppressed states. Rituximab, a CD20 monoclonal antibody immunomodulator, has been approved for non-Hodgkin lymphoma (NHL).
Methods: Using electronic medical records from the VA, ICD-9 codes were used to identify patients diagnosed with NHL, PML, and HIV within the VA from 2003 to 2011. Pharmacy records were used to identify patients receiving rituximab, cyclophosphamide, hydroxydaunorubicin, and vncristine. This project was conducted inside the Veterans Affairs Informatics and Computing Infrastructure after obtaining approvals from the VA IRB and other oversight groups.
Results: We identified 57,041 non-HIV NHL patients. A total of 14 out of 57,041 (0.025%) patients had developed PML; 7 out of 8,895 (7.8 per 10,000) were NHL patients who received rituximab subsequently developed PML; 7 out of 48,146 (1.5 per 10,000) were NHL patients who did not receive rituximab subsequently developed PML, which results in a statistically significant unadjusted relative risk of 5.4 (95% CI: 1.9 - 15.4) and an attributable risk of 6.3 per 10,000. Univariate analyses of other outcomes were not statistically significant between patients who received and those that did not receive rituximab.
Conclusions: These results show that among lymphoma patients, the use of rituximab is associated with a statistically significant relative risk for documented PML of 5.4. Measurement of JC virus prior to initiation of rituximab therapy as well as during rituximab therapy should be considered.
Case Report of Dasatinib-Induced Follicular Lymphoid Hyperplasia
Purpose: Dasatinib is a tyrosine kinase inhibitor indicated for the treatment of chronic myeloid leukemia (CML). In October 2013, reversible lymph node follicular hyperplasia associated with dasatinib was first reported. The purpose of this case report is to describe a reactive lymphoid process with follicular and interfollicular hyperplasia associated with dasatinib treatment.
Methods: This is a case report of a white male, aged 37 years, receiving oral dasatinib 100 mg once daily for chronic phase CML for 8 months following failure of imatinib and intolerance to nilotinib. A Pubmed literature review revealed only 1 other report of 9 cases developing cervical lymphadenopathy after a median of 20 months on dasatinib (range 9 to 35 months).
Results: Following 8 months of dasatinib therapy, the patient presented with facial swelling on his right jaw and right cheek bone. A CT scan revealed multiple mildly enlarged lymph nodes within the parotid gland and right level II nodal stations without any definite mucosal lesions seen. On physical exam, he was found to have a 1.5-cm right parotid nontender mass and a 3-cm right level II nontender nodular mass with no overlying erythema or edema. He failed a trial of antibiotics with amoxicillin 875 mg/clavulanate 125 mg for 10 days. Fine needle aspiration of both the right parotid mass and the right nodular mass revealed reactive lymphoid cells. An excisional biopsy of the right parotid mass with flow cytometry demonstrated fragmented benign lymphoid tissue with reactive follicles and expansion of the interfollicular region with no evidence of leukemic involvement. He then underwent right parotidectomy due to progressive swelling and discomfort. Pathology review was consistent with reactive lymphoid process with florid follicular and interfollicular hyperplasia. There was again no evidence of lymphoid or lymphomatous involvement. Dasatinib therapy was subsequently discontinued and resolution of follicular hyperplasia occurred within 1 month.
Conclusions: Follicular hyperplasia is a rare adverse effect associated with the use of dasatinib. Our patient presented much earlier (within 8 months of dasatinib therapy) than previously reported cases. Patients on dasatinib experiencing cervical or other lymph node enlargement should be evaluated for follicular hyperplasia. It is recommended that dasatinib be discontinued in the presence of follicular lymphoid hyperplasia; however, use of another tyrosine kinase inhibitor should be considered. Our patient was subsequently switched to bosutinib.
Purpose: Dasatinib is a tyrosine kinase inhibitor indicated for the treatment of chronic myeloid leukemia (CML). In October 2013, reversible lymph node follicular hyperplasia associated with dasatinib was first reported. The purpose of this case report is to describe a reactive lymphoid process with follicular and interfollicular hyperplasia associated with dasatinib treatment.
Methods: This is a case report of a white male, aged 37 years, receiving oral dasatinib 100 mg once daily for chronic phase CML for 8 months following failure of imatinib and intolerance to nilotinib. A Pubmed literature review revealed only 1 other report of 9 cases developing cervical lymphadenopathy after a median of 20 months on dasatinib (range 9 to 35 months).
Results: Following 8 months of dasatinib therapy, the patient presented with facial swelling on his right jaw and right cheek bone. A CT scan revealed multiple mildly enlarged lymph nodes within the parotid gland and right level II nodal stations without any definite mucosal lesions seen. On physical exam, he was found to have a 1.5-cm right parotid nontender mass and a 3-cm right level II nontender nodular mass with no overlying erythema or edema. He failed a trial of antibiotics with amoxicillin 875 mg/clavulanate 125 mg for 10 days. Fine needle aspiration of both the right parotid mass and the right nodular mass revealed reactive lymphoid cells. An excisional biopsy of the right parotid mass with flow cytometry demonstrated fragmented benign lymphoid tissue with reactive follicles and expansion of the interfollicular region with no evidence of leukemic involvement. He then underwent right parotidectomy due to progressive swelling and discomfort. Pathology review was consistent with reactive lymphoid process with florid follicular and interfollicular hyperplasia. There was again no evidence of lymphoid or lymphomatous involvement. Dasatinib therapy was subsequently discontinued and resolution of follicular hyperplasia occurred within 1 month.
Conclusions: Follicular hyperplasia is a rare adverse effect associated with the use of dasatinib. Our patient presented much earlier (within 8 months of dasatinib therapy) than previously reported cases. Patients on dasatinib experiencing cervical or other lymph node enlargement should be evaluated for follicular hyperplasia. It is recommended that dasatinib be discontinued in the presence of follicular lymphoid hyperplasia; however, use of another tyrosine kinase inhibitor should be considered. Our patient was subsequently switched to bosutinib.
Purpose: Dasatinib is a tyrosine kinase inhibitor indicated for the treatment of chronic myeloid leukemia (CML). In October 2013, reversible lymph node follicular hyperplasia associated with dasatinib was first reported. The purpose of this case report is to describe a reactive lymphoid process with follicular and interfollicular hyperplasia associated with dasatinib treatment.
Methods: This is a case report of a white male, aged 37 years, receiving oral dasatinib 100 mg once daily for chronic phase CML for 8 months following failure of imatinib and intolerance to nilotinib. A Pubmed literature review revealed only 1 other report of 9 cases developing cervical lymphadenopathy after a median of 20 months on dasatinib (range 9 to 35 months).
Results: Following 8 months of dasatinib therapy, the patient presented with facial swelling on his right jaw and right cheek bone. A CT scan revealed multiple mildly enlarged lymph nodes within the parotid gland and right level II nodal stations without any definite mucosal lesions seen. On physical exam, he was found to have a 1.5-cm right parotid nontender mass and a 3-cm right level II nontender nodular mass with no overlying erythema or edema. He failed a trial of antibiotics with amoxicillin 875 mg/clavulanate 125 mg for 10 days. Fine needle aspiration of both the right parotid mass and the right nodular mass revealed reactive lymphoid cells. An excisional biopsy of the right parotid mass with flow cytometry demonstrated fragmented benign lymphoid tissue with reactive follicles and expansion of the interfollicular region with no evidence of leukemic involvement. He then underwent right parotidectomy due to progressive swelling and discomfort. Pathology review was consistent with reactive lymphoid process with florid follicular and interfollicular hyperplasia. There was again no evidence of lymphoid or lymphomatous involvement. Dasatinib therapy was subsequently discontinued and resolution of follicular hyperplasia occurred within 1 month.
Conclusions: Follicular hyperplasia is a rare adverse effect associated with the use of dasatinib. Our patient presented much earlier (within 8 months of dasatinib therapy) than previously reported cases. Patients on dasatinib experiencing cervical or other lymph node enlargement should be evaluated for follicular hyperplasia. It is recommended that dasatinib be discontinued in the presence of follicular lymphoid hyperplasia; however, use of another tyrosine kinase inhibitor should be considered. Our patient was subsequently switched to bosutinib.
Antibody gets orphan status for CTCL in Europe
The European Commission has granted orphan drug designation to IPH4102 for the treatment of cutaneous T-cell lymphoma (CTCL).
IPH4102 is a cytotoxic anti-KIR3DL2 monoclonal antibody (mAb) that targets CTCL cells.
Orphan status provides Innate Pharma, the company developing IPH4102, with benefits such as tax incentives, market exclusivity for 10 years, possibilities for additional research funding, and additional guidance from the European Medicines Agency during clinical development.
Preclinical results with IPH4102 were presented in a poster at the 2014 T-cell Lymphoma Forum. The research was conducted by investigators from Innate Pharma and INSERM at Hôpital Saint Louis in Paris.
The researchers generated 3 mAbs that bind selectively to KIR3DL2 and evaluated their efficacy against KIR3DL2-expressing tumors and Sézary cell lines.
IPH4102 was among the 3 mAbs and emerged as the most promising drug candidate.
Experiments revealed that anti-KIR3DL2 mAbs can kill KIR3DL2+ cell lines through allo-antibody-dependent cell cytotoxicity, even at low tumor antigen density.
The mAbs also improved survival in KIR3DL2+ xenograft models. Survival in mAb-treated mice ranged from 30.5 days to 54.5 days, compared to 19 days in controls.
Finally, the mAbs mediated killing of primary Sézary cells with autologous natural killer cells nearly as efficiently as alemtuzumab.
The investigators said these results suggest anti-KIR3DL2 mAbs are a feasible treatment option for CTCL patients. They plan to prove this hypothesis with a phase 1 trial of IPH4102, which is expected to begin in 2015.
The European Commission has granted orphan drug designation to IPH4102 for the treatment of cutaneous T-cell lymphoma (CTCL).
IPH4102 is a cytotoxic anti-KIR3DL2 monoclonal antibody (mAb) that targets CTCL cells.
Orphan status provides Innate Pharma, the company developing IPH4102, with benefits such as tax incentives, market exclusivity for 10 years, possibilities for additional research funding, and additional guidance from the European Medicines Agency during clinical development.
Preclinical results with IPH4102 were presented in a poster at the 2014 T-cell Lymphoma Forum. The research was conducted by investigators from Innate Pharma and INSERM at Hôpital Saint Louis in Paris.
The researchers generated 3 mAbs that bind selectively to KIR3DL2 and evaluated their efficacy against KIR3DL2-expressing tumors and Sézary cell lines.
IPH4102 was among the 3 mAbs and emerged as the most promising drug candidate.
Experiments revealed that anti-KIR3DL2 mAbs can kill KIR3DL2+ cell lines through allo-antibody-dependent cell cytotoxicity, even at low tumor antigen density.
The mAbs also improved survival in KIR3DL2+ xenograft models. Survival in mAb-treated mice ranged from 30.5 days to 54.5 days, compared to 19 days in controls.
Finally, the mAbs mediated killing of primary Sézary cells with autologous natural killer cells nearly as efficiently as alemtuzumab.
The investigators said these results suggest anti-KIR3DL2 mAbs are a feasible treatment option for CTCL patients. They plan to prove this hypothesis with a phase 1 trial of IPH4102, which is expected to begin in 2015.
The European Commission has granted orphan drug designation to IPH4102 for the treatment of cutaneous T-cell lymphoma (CTCL).
IPH4102 is a cytotoxic anti-KIR3DL2 monoclonal antibody (mAb) that targets CTCL cells.
Orphan status provides Innate Pharma, the company developing IPH4102, with benefits such as tax incentives, market exclusivity for 10 years, possibilities for additional research funding, and additional guidance from the European Medicines Agency during clinical development.
Preclinical results with IPH4102 were presented in a poster at the 2014 T-cell Lymphoma Forum. The research was conducted by investigators from Innate Pharma and INSERM at Hôpital Saint Louis in Paris.
The researchers generated 3 mAbs that bind selectively to KIR3DL2 and evaluated their efficacy against KIR3DL2-expressing tumors and Sézary cell lines.
IPH4102 was among the 3 mAbs and emerged as the most promising drug candidate.
Experiments revealed that anti-KIR3DL2 mAbs can kill KIR3DL2+ cell lines through allo-antibody-dependent cell cytotoxicity, even at low tumor antigen density.
The mAbs also improved survival in KIR3DL2+ xenograft models. Survival in mAb-treated mice ranged from 30.5 days to 54.5 days, compared to 19 days in controls.
Finally, the mAbs mediated killing of primary Sézary cells with autologous natural killer cells nearly as efficiently as alemtuzumab.
The investigators said these results suggest anti-KIR3DL2 mAbs are a feasible treatment option for CTCL patients. They plan to prove this hypothesis with a phase 1 trial of IPH4102, which is expected to begin in 2015.
Program improves depression treatment in cancer
Credit: NIH
Results of a large study suggest major depression is common—but largely untreated—among cancer patients in Scotland.
And 2 additional studies of Scottish patients showed that a program specifically designed for individuals with cancer can treat depression and improve quality of life more effectively than current methods of care.
These studies appear in The Lancet, The Lancet Oncology, and The Lancet Psychiatry.
In The Lancet Psychiatry, researchers recounted their analysis of data from 21,151 patients treated at cancer clinics in Scotland. The team found that major depression was substantially more common in cancer patients than in the general population.
Major depression was most common in patients with lung cancer (13%) and lowest in those with genitourinary cancer (6%). Moreover, nearly three-quarters (73%) of depressed cancer patients were not receiving treatment.
To address the problem of inadequate treatment, researchers initiated the SMaRT Oncology-2 trial. They reported the results in The Lancet.
The team evaluated a new treatment program called “Depression Care for People with Cancer” (DCPC). DCPC is delivered by specially trained cancer nurses and psychiatrists, working in collaboration with the patient’s cancer team and general practitioner, and is given as part of cancer care. It is a systematic treatment program that includes both antidepressants and psychological therapy.
The trial included 500 adults with major depression and a cancer with a good prognosis (predicted survival of more than 12 months).
Patients were randomized to receive either DCPC or “usual care,” which was provided by a patient’s general practitioner and might have included prescribing antidepressants or referring the patient to mental health services for assessment or psychological treatment.
Results showed that DCPC was more effective than usual care in reducing depression. At 6 months, 62% of patients who received DCPC responded to treatment (experiencing at least a 50% reduction in the severity of their depression), compared with 17% of those who received the usual care (P<0.0001). This benefit was sustained at 12 months.
In addition, DCPC improved anxiety, pain, fatigue, functioning, and overall quality of life (all P<0.05). The researchers also noted that the cost of providing DCPC was modest (£613 per patient).
“The huge benefit that DCPC delivers for patients with cancer and depression shows what we can achieve for patients if we take as much care with the treatment of their depression as we do with the treatment of their cancer,” said study author Michael Sharpe, MD, of the University of Oxford in the UK.
To see if patients with a poor-prognosis cancer could also benefit from DCPC, researchers initiated the SMaRT Oncology-3 trial. They reported the results in The Lancet Oncology.
The team tested a version of DCPC adapted for cancer patients with a poor prognosis. The trial included 142 patients with lung cancer and major depression.
Patients who received the modified version of DCPC had a significantly greater improvement in depression than those who received the usual care during 32 weeks of follow-up (P=0.0003). DCPC also improved patients’ anxiety (P=0.046), functioning (P=0.0019), and quality of life (P=0.018).
“Patients with lung cancer often have a poor prognosis,” said study author Jane Walker, MBChB, PhD, of the University of Oxford and Sobell House Hospice in Oxford, UK.
“If they also have major depression, that can blight the time they have left to live. This trial shows that we can effectively treat depression in patients with poor-prognosis cancers, like lung cancer, and really improve patients’ lives.”
Credit: NIH
Results of a large study suggest major depression is common—but largely untreated—among cancer patients in Scotland.
And 2 additional studies of Scottish patients showed that a program specifically designed for individuals with cancer can treat depression and improve quality of life more effectively than current methods of care.
These studies appear in The Lancet, The Lancet Oncology, and The Lancet Psychiatry.
In The Lancet Psychiatry, researchers recounted their analysis of data from 21,151 patients treated at cancer clinics in Scotland. The team found that major depression was substantially more common in cancer patients than in the general population.
Major depression was most common in patients with lung cancer (13%) and lowest in those with genitourinary cancer (6%). Moreover, nearly three-quarters (73%) of depressed cancer patients were not receiving treatment.
To address the problem of inadequate treatment, researchers initiated the SMaRT Oncology-2 trial. They reported the results in The Lancet.
The team evaluated a new treatment program called “Depression Care for People with Cancer” (DCPC). DCPC is delivered by specially trained cancer nurses and psychiatrists, working in collaboration with the patient’s cancer team and general practitioner, and is given as part of cancer care. It is a systematic treatment program that includes both antidepressants and psychological therapy.
The trial included 500 adults with major depression and a cancer with a good prognosis (predicted survival of more than 12 months).
Patients were randomized to receive either DCPC or “usual care,” which was provided by a patient’s general practitioner and might have included prescribing antidepressants or referring the patient to mental health services for assessment or psychological treatment.
Results showed that DCPC was more effective than usual care in reducing depression. At 6 months, 62% of patients who received DCPC responded to treatment (experiencing at least a 50% reduction in the severity of their depression), compared with 17% of those who received the usual care (P<0.0001). This benefit was sustained at 12 months.
In addition, DCPC improved anxiety, pain, fatigue, functioning, and overall quality of life (all P<0.05). The researchers also noted that the cost of providing DCPC was modest (£613 per patient).
“The huge benefit that DCPC delivers for patients with cancer and depression shows what we can achieve for patients if we take as much care with the treatment of their depression as we do with the treatment of their cancer,” said study author Michael Sharpe, MD, of the University of Oxford in the UK.
To see if patients with a poor-prognosis cancer could also benefit from DCPC, researchers initiated the SMaRT Oncology-3 trial. They reported the results in The Lancet Oncology.
The team tested a version of DCPC adapted for cancer patients with a poor prognosis. The trial included 142 patients with lung cancer and major depression.
Patients who received the modified version of DCPC had a significantly greater improvement in depression than those who received the usual care during 32 weeks of follow-up (P=0.0003). DCPC also improved patients’ anxiety (P=0.046), functioning (P=0.0019), and quality of life (P=0.018).
“Patients with lung cancer often have a poor prognosis,” said study author Jane Walker, MBChB, PhD, of the University of Oxford and Sobell House Hospice in Oxford, UK.
“If they also have major depression, that can blight the time they have left to live. This trial shows that we can effectively treat depression in patients with poor-prognosis cancers, like lung cancer, and really improve patients’ lives.”
Credit: NIH
Results of a large study suggest major depression is common—but largely untreated—among cancer patients in Scotland.
And 2 additional studies of Scottish patients showed that a program specifically designed for individuals with cancer can treat depression and improve quality of life more effectively than current methods of care.
These studies appear in The Lancet, The Lancet Oncology, and The Lancet Psychiatry.
In The Lancet Psychiatry, researchers recounted their analysis of data from 21,151 patients treated at cancer clinics in Scotland. The team found that major depression was substantially more common in cancer patients than in the general population.
Major depression was most common in patients with lung cancer (13%) and lowest in those with genitourinary cancer (6%). Moreover, nearly three-quarters (73%) of depressed cancer patients were not receiving treatment.
To address the problem of inadequate treatment, researchers initiated the SMaRT Oncology-2 trial. They reported the results in The Lancet.
The team evaluated a new treatment program called “Depression Care for People with Cancer” (DCPC). DCPC is delivered by specially trained cancer nurses and psychiatrists, working in collaboration with the patient’s cancer team and general practitioner, and is given as part of cancer care. It is a systematic treatment program that includes both antidepressants and psychological therapy.
The trial included 500 adults with major depression and a cancer with a good prognosis (predicted survival of more than 12 months).
Patients were randomized to receive either DCPC or “usual care,” which was provided by a patient’s general practitioner and might have included prescribing antidepressants or referring the patient to mental health services for assessment or psychological treatment.
Results showed that DCPC was more effective than usual care in reducing depression. At 6 months, 62% of patients who received DCPC responded to treatment (experiencing at least a 50% reduction in the severity of their depression), compared with 17% of those who received the usual care (P<0.0001). This benefit was sustained at 12 months.
In addition, DCPC improved anxiety, pain, fatigue, functioning, and overall quality of life (all P<0.05). The researchers also noted that the cost of providing DCPC was modest (£613 per patient).
“The huge benefit that DCPC delivers for patients with cancer and depression shows what we can achieve for patients if we take as much care with the treatment of their depression as we do with the treatment of their cancer,” said study author Michael Sharpe, MD, of the University of Oxford in the UK.
To see if patients with a poor-prognosis cancer could also benefit from DCPC, researchers initiated the SMaRT Oncology-3 trial. They reported the results in The Lancet Oncology.
The team tested a version of DCPC adapted for cancer patients with a poor prognosis. The trial included 142 patients with lung cancer and major depression.
Patients who received the modified version of DCPC had a significantly greater improvement in depression than those who received the usual care during 32 weeks of follow-up (P=0.0003). DCPC also improved patients’ anxiety (P=0.046), functioning (P=0.0019), and quality of life (P=0.018).
“Patients with lung cancer often have a poor prognosis,” said study author Jane Walker, MBChB, PhD, of the University of Oxford and Sobell House Hospice in Oxford, UK.
“If they also have major depression, that can blight the time they have left to live. This trial shows that we can effectively treat depression in patients with poor-prognosis cancers, like lung cancer, and really improve patients’ lives.”
Nanoparticle may have multiple cancer applications
Credit: PNAS
A new type of nanoparticle (NP) could aid the diagnosis and treatment of cancers, according to research published in Nature Communications.
Built on an easy-to-make polymer, these particles can be used as contrast agents to light up tumors for MRI and PET scans or to deliver chemotherapy and other treatments to cancer cells.
Furthermore, in vivo experiments showed the particles are biocompatible and elicit minimal side effects.
“These are amazingly useful particles,” said study author Yuanpei Li, PhD, of the UC Davis Comprehensive Cancer Center in Sacramento, California.
“As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors, apply light to make the nanoparticles release singlet oxygen (photodynamic therapy), or use a laser to heat them (photothermal therapy)—all proven ways to destroy tumors.”
These NPs are built on a porphyrin/cholic acid polymer. Porphyrins are common organic compounds, and cholic acid is produced by the liver.
To further stabilize the particles, the researchers added the amino acid cysteine (creating CNPs), which prevents them from prematurely releasing their therapeutic payload when exposed to blood proteins and other barriers.
Therapeutic applications
The researchers tested the CNPs, both in vitro and in vivo, for a wide range of tasks. On the therapeutic side, the particles effectively transported anticancer drugs, such as doxorubicin.
CNPs carrying doxorubicin provided excellent cancer control in animals, with minimal side effects.
Even when kept in the blood for many hours, CNPs only released small amounts of the drug. However, when exposed to light or agents such as glutathione, they readily released their payloads.
The researchers showed that, when exposed to a single wavelength of light, the CNPs could generate heat or produce singlet oxygen to destroy tumor cells.
Imaging applications
CNPs offer a number of advantages to enhance imaging, according to the researchers. The particles readily chelate imaging agents and can remain in the body for long periods.
In animal studies, CNPs largely accumulated in tumors, rather than in normal tissue. So they dramatically enhanced tumor contrast for MRI and may also be promising for PET-MRI scans, the researchers said.
“These particles can combine imaging and therapeutics,” Dr Li noted. “We could potentially use them to simultaneously deliver treatment and monitor treatment efficacy.”
The researchers are now conducting additional preclinical studies with the CNPs. If all goes well, they will proceed to human trials. In the meantime, the team is excited about these capabilities.
“This is the first nanoparticle to perform so many different jobs,” Dr Li said. “From delivering chemo, photodynamic, and photothermal therapies, to enhancing diagnostic imaging, it’s the complete package.”
Credit: PNAS
A new type of nanoparticle (NP) could aid the diagnosis and treatment of cancers, according to research published in Nature Communications.
Built on an easy-to-make polymer, these particles can be used as contrast agents to light up tumors for MRI and PET scans or to deliver chemotherapy and other treatments to cancer cells.
Furthermore, in vivo experiments showed the particles are biocompatible and elicit minimal side effects.
“These are amazingly useful particles,” said study author Yuanpei Li, PhD, of the UC Davis Comprehensive Cancer Center in Sacramento, California.
“As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors, apply light to make the nanoparticles release singlet oxygen (photodynamic therapy), or use a laser to heat them (photothermal therapy)—all proven ways to destroy tumors.”
These NPs are built on a porphyrin/cholic acid polymer. Porphyrins are common organic compounds, and cholic acid is produced by the liver.
To further stabilize the particles, the researchers added the amino acid cysteine (creating CNPs), which prevents them from prematurely releasing their therapeutic payload when exposed to blood proteins and other barriers.
Therapeutic applications
The researchers tested the CNPs, both in vitro and in vivo, for a wide range of tasks. On the therapeutic side, the particles effectively transported anticancer drugs, such as doxorubicin.
CNPs carrying doxorubicin provided excellent cancer control in animals, with minimal side effects.
Even when kept in the blood for many hours, CNPs only released small amounts of the drug. However, when exposed to light or agents such as glutathione, they readily released their payloads.
The researchers showed that, when exposed to a single wavelength of light, the CNPs could generate heat or produce singlet oxygen to destroy tumor cells.
Imaging applications
CNPs offer a number of advantages to enhance imaging, according to the researchers. The particles readily chelate imaging agents and can remain in the body for long periods.
In animal studies, CNPs largely accumulated in tumors, rather than in normal tissue. So they dramatically enhanced tumor contrast for MRI and may also be promising for PET-MRI scans, the researchers said.
“These particles can combine imaging and therapeutics,” Dr Li noted. “We could potentially use them to simultaneously deliver treatment and monitor treatment efficacy.”
The researchers are now conducting additional preclinical studies with the CNPs. If all goes well, they will proceed to human trials. In the meantime, the team is excited about these capabilities.
“This is the first nanoparticle to perform so many different jobs,” Dr Li said. “From delivering chemo, photodynamic, and photothermal therapies, to enhancing diagnostic imaging, it’s the complete package.”
Credit: PNAS
A new type of nanoparticle (NP) could aid the diagnosis and treatment of cancers, according to research published in Nature Communications.
Built on an easy-to-make polymer, these particles can be used as contrast agents to light up tumors for MRI and PET scans or to deliver chemotherapy and other treatments to cancer cells.
Furthermore, in vivo experiments showed the particles are biocompatible and elicit minimal side effects.
“These are amazingly useful particles,” said study author Yuanpei Li, PhD, of the UC Davis Comprehensive Cancer Center in Sacramento, California.
“As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors, apply light to make the nanoparticles release singlet oxygen (photodynamic therapy), or use a laser to heat them (photothermal therapy)—all proven ways to destroy tumors.”
These NPs are built on a porphyrin/cholic acid polymer. Porphyrins are common organic compounds, and cholic acid is produced by the liver.
To further stabilize the particles, the researchers added the amino acid cysteine (creating CNPs), which prevents them from prematurely releasing their therapeutic payload when exposed to blood proteins and other barriers.
Therapeutic applications
The researchers tested the CNPs, both in vitro and in vivo, for a wide range of tasks. On the therapeutic side, the particles effectively transported anticancer drugs, such as doxorubicin.
CNPs carrying doxorubicin provided excellent cancer control in animals, with minimal side effects.
Even when kept in the blood for many hours, CNPs only released small amounts of the drug. However, when exposed to light or agents such as glutathione, they readily released their payloads.
The researchers showed that, when exposed to a single wavelength of light, the CNPs could generate heat or produce singlet oxygen to destroy tumor cells.
Imaging applications
CNPs offer a number of advantages to enhance imaging, according to the researchers. The particles readily chelate imaging agents and can remain in the body for long periods.
In animal studies, CNPs largely accumulated in tumors, rather than in normal tissue. So they dramatically enhanced tumor contrast for MRI and may also be promising for PET-MRI scans, the researchers said.
“These particles can combine imaging and therapeutics,” Dr Li noted. “We could potentially use them to simultaneously deliver treatment and monitor treatment efficacy.”
The researchers are now conducting additional preclinical studies with the CNPs. If all goes well, they will proceed to human trials. In the meantime, the team is excited about these capabilities.
“This is the first nanoparticle to perform so many different jobs,” Dr Li said. “From delivering chemo, photodynamic, and photothermal therapies, to enhancing diagnostic imaging, it’s the complete package.”
Mechlorethamine gel for early stage mycosis fungoides-type CTCL
Click on the PDF icon at the top of this introduction to read the full article.
Click on the PDF icon at the top of this introduction to read the full article.
Click on the PDF icon at the top of this introduction to read the full article.
Chemo and CAR T cells prompt responses in NHL
An infusion of chimeric antigen receptor (CAR) T-cell therapy following chemotherapy can elicit responses in patients with non-Hodgkin lymphoma, a small study suggests.
However, patients also experienced significant acute toxicities, including fever, low blood pressure, focal neurological deficits, and delirium.
James N. Kochenderfer, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues reported these results in the Journal of Clinical Oncology.
The trial was sponsored by the National Cancer Institute, but the CAR T-cell therapy being tested uses the same CAR construct as KTE-C19, which is being developed by Kite Pharma, Inc.
The study included 15 patients with advanced B-cell malignancies. The patients first received conditioning with cyclophosphamide and fludarabine.
A day later, they received a single infusion of the CAR T-cell therapy, which consists of T cells taken from each patient’s peripheral blood and modified to target CD19.
The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.
Response rates
Thirteen patients were evaluable for response. One patient was lost to follow-up because of noncompliance, and 1 died soon after treatment. The researchers said the cause of death was likely cardiac arrhythmia.
The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).
Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs are ongoing, with the duration ranging from 9 months to 22 months.
Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. All 3 CRs are ongoing, with the duration ranging from 14 months to 23 months.
Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the ongoing CR is 11 months.
Toxicity
As seen in other studies, the CAR T-cell therapy was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.
All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.
All patients had elevations in serum interferon gamma and/or IL-6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.
Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.
One of these patients developed aphasia on day 5 after CAR T-cell infusion. It occurred intermittently for 7 days before resolving. The patient also experienced right-sided facial paresis that lasted approximately 20 minutes on day 8 after infusion.
Another patient developed aphasia 5 days after CAR T-cell infusion, but this was followed by confusion and severe generalized myoclonus. All symptoms resolved by 11 days after the infusion, except for a mild tremor that resolved over the next month.
A third patient developed aphasia 5 days after CAR T-cell infusion. This was followed by confusion, hemifacial spasms, apraxia, and gait disturbances. These effects varied in severity but dramatically improved 20 days after the infusion, according to the researchers.
An infusion of chimeric antigen receptor (CAR) T-cell therapy following chemotherapy can elicit responses in patients with non-Hodgkin lymphoma, a small study suggests.
However, patients also experienced significant acute toxicities, including fever, low blood pressure, focal neurological deficits, and delirium.
James N. Kochenderfer, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues reported these results in the Journal of Clinical Oncology.
The trial was sponsored by the National Cancer Institute, but the CAR T-cell therapy being tested uses the same CAR construct as KTE-C19, which is being developed by Kite Pharma, Inc.
The study included 15 patients with advanced B-cell malignancies. The patients first received conditioning with cyclophosphamide and fludarabine.
A day later, they received a single infusion of the CAR T-cell therapy, which consists of T cells taken from each patient’s peripheral blood and modified to target CD19.
The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.
Response rates
Thirteen patients were evaluable for response. One patient was lost to follow-up because of noncompliance, and 1 died soon after treatment. The researchers said the cause of death was likely cardiac arrhythmia.
The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).
Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs are ongoing, with the duration ranging from 9 months to 22 months.
Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. All 3 CRs are ongoing, with the duration ranging from 14 months to 23 months.
Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the ongoing CR is 11 months.
Toxicity
As seen in other studies, the CAR T-cell therapy was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.
All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.
All patients had elevations in serum interferon gamma and/or IL-6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.
Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.
One of these patients developed aphasia on day 5 after CAR T-cell infusion. It occurred intermittently for 7 days before resolving. The patient also experienced right-sided facial paresis that lasted approximately 20 minutes on day 8 after infusion.
Another patient developed aphasia 5 days after CAR T-cell infusion, but this was followed by confusion and severe generalized myoclonus. All symptoms resolved by 11 days after the infusion, except for a mild tremor that resolved over the next month.
A third patient developed aphasia 5 days after CAR T-cell infusion. This was followed by confusion, hemifacial spasms, apraxia, and gait disturbances. These effects varied in severity but dramatically improved 20 days after the infusion, according to the researchers.
An infusion of chimeric antigen receptor (CAR) T-cell therapy following chemotherapy can elicit responses in patients with non-Hodgkin lymphoma, a small study suggests.
However, patients also experienced significant acute toxicities, including fever, low blood pressure, focal neurological deficits, and delirium.
James N. Kochenderfer, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues reported these results in the Journal of Clinical Oncology.
The trial was sponsored by the National Cancer Institute, but the CAR T-cell therapy being tested uses the same CAR construct as KTE-C19, which is being developed by Kite Pharma, Inc.
The study included 15 patients with advanced B-cell malignancies. The patients first received conditioning with cyclophosphamide and fludarabine.
A day later, they received a single infusion of the CAR T-cell therapy, which consists of T cells taken from each patient’s peripheral blood and modified to target CD19.
The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.
Response rates
Thirteen patients were evaluable for response. One patient was lost to follow-up because of noncompliance, and 1 died soon after treatment. The researchers said the cause of death was likely cardiac arrhythmia.
The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).
Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs are ongoing, with the duration ranging from 9 months to 22 months.
Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. All 3 CRs are ongoing, with the duration ranging from 14 months to 23 months.
Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the ongoing CR is 11 months.
Toxicity
As seen in other studies, the CAR T-cell therapy was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.
All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.
All patients had elevations in serum interferon gamma and/or IL-6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.
Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.
One of these patients developed aphasia on day 5 after CAR T-cell infusion. It occurred intermittently for 7 days before resolving. The patient also experienced right-sided facial paresis that lasted approximately 20 minutes on day 8 after infusion.
Another patient developed aphasia 5 days after CAR T-cell infusion, but this was followed by confusion and severe generalized myoclonus. All symptoms resolved by 11 days after the infusion, except for a mild tremor that resolved over the next month.
A third patient developed aphasia 5 days after CAR T-cell infusion. This was followed by confusion, hemifacial spasms, apraxia, and gait disturbances. These effects varied in severity but dramatically improved 20 days after the infusion, according to the researchers.