User login
Dose-escalated blinatumomab plus dexamethasone induced responses in relapsed/refractory DLBCL
Blinatumomab, administered in a stepwise, dose-escalated regimen with prophylactic dexamethasone, induced responses in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a report published in Blood.
The phase II study included 25 patients who were refractory to their last treatment, had relapsed after autologous hematopoietic stem cell transplant (HSCT), or had relapsed disease and were ineligible for autologous HSCT.
In a previous phase I study that did not use a dose-escalated regimen, neurological adverse events were dose limiting at a maximum tolerated blinatumomab dose of 60 mcg/d. The current study used a 14-day stepwise dose escalation and corticosteroid premedication to minimize adverse events: blinatumomab was given at 9 mcg/d in the first week, 28 mcg/d in the second week, and 112 mcg/d thereafter.
Patients had received a median of three prior therapies. In total, 17 of 25 patients ended in cycle 1 (induction) because of disease progression, adverse events, or physician decision; 7 ended in cycle 2 (consolidation), and 1 ended in retreatment.
Among the 21 evaluable patients who received at least 1 week of blinatumomab at the target dose of 112 mcg/day or who discontinued treatment earlier because of progressive disease, the overall response rate was 43% (9/21) and the complete response rate was 19% (4/21). “At least 1 week of treatment at the target dose of 112 mcg/d appears to be required for efficacy,” wrote Dr. Andreas Viardot of the department of internal medicine III, University Hospital Ulm (Germany) and colleagues (Blood. 2016;127(11):1410-16).
The most common adverse events of grade 3 or higher were thrombocytopenia (17%) and leukopenia (17%). Grade 3 neurologic events included encephalopathy (9%) and aphasia (9%); no grade 4 or 5 neurologic events were reported. Cytokine release syndrome or cytokine storm were not reported.
Blinatumomab (Blincyto) is a bispecific T-cell engager antibody approved for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Blinatumomab transiently links CD3-positive T cells to CD19-positive B cells, which activates T cells and leads to T cell–mediated lysis of tumor cells and concomitant T-cell proliferation.
The study was supported by Amgen, the maker of Blincyto. Dr. Viardot reported having financial ties with Amgen and several other drug companies.
Blinatumomab, administered in a stepwise, dose-escalated regimen with prophylactic dexamethasone, induced responses in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a report published in Blood.
The phase II study included 25 patients who were refractory to their last treatment, had relapsed after autologous hematopoietic stem cell transplant (HSCT), or had relapsed disease and were ineligible for autologous HSCT.
In a previous phase I study that did not use a dose-escalated regimen, neurological adverse events were dose limiting at a maximum tolerated blinatumomab dose of 60 mcg/d. The current study used a 14-day stepwise dose escalation and corticosteroid premedication to minimize adverse events: blinatumomab was given at 9 mcg/d in the first week, 28 mcg/d in the second week, and 112 mcg/d thereafter.
Patients had received a median of three prior therapies. In total, 17 of 25 patients ended in cycle 1 (induction) because of disease progression, adverse events, or physician decision; 7 ended in cycle 2 (consolidation), and 1 ended in retreatment.
Among the 21 evaluable patients who received at least 1 week of blinatumomab at the target dose of 112 mcg/day or who discontinued treatment earlier because of progressive disease, the overall response rate was 43% (9/21) and the complete response rate was 19% (4/21). “At least 1 week of treatment at the target dose of 112 mcg/d appears to be required for efficacy,” wrote Dr. Andreas Viardot of the department of internal medicine III, University Hospital Ulm (Germany) and colleagues (Blood. 2016;127(11):1410-16).
The most common adverse events of grade 3 or higher were thrombocytopenia (17%) and leukopenia (17%). Grade 3 neurologic events included encephalopathy (9%) and aphasia (9%); no grade 4 or 5 neurologic events were reported. Cytokine release syndrome or cytokine storm were not reported.
Blinatumomab (Blincyto) is a bispecific T-cell engager antibody approved for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Blinatumomab transiently links CD3-positive T cells to CD19-positive B cells, which activates T cells and leads to T cell–mediated lysis of tumor cells and concomitant T-cell proliferation.
The study was supported by Amgen, the maker of Blincyto. Dr. Viardot reported having financial ties with Amgen and several other drug companies.
Blinatumomab, administered in a stepwise, dose-escalated regimen with prophylactic dexamethasone, induced responses in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a report published in Blood.
The phase II study included 25 patients who were refractory to their last treatment, had relapsed after autologous hematopoietic stem cell transplant (HSCT), or had relapsed disease and were ineligible for autologous HSCT.
In a previous phase I study that did not use a dose-escalated regimen, neurological adverse events were dose limiting at a maximum tolerated blinatumomab dose of 60 mcg/d. The current study used a 14-day stepwise dose escalation and corticosteroid premedication to minimize adverse events: blinatumomab was given at 9 mcg/d in the first week, 28 mcg/d in the second week, and 112 mcg/d thereafter.
Patients had received a median of three prior therapies. In total, 17 of 25 patients ended in cycle 1 (induction) because of disease progression, adverse events, or physician decision; 7 ended in cycle 2 (consolidation), and 1 ended in retreatment.
Among the 21 evaluable patients who received at least 1 week of blinatumomab at the target dose of 112 mcg/day or who discontinued treatment earlier because of progressive disease, the overall response rate was 43% (9/21) and the complete response rate was 19% (4/21). “At least 1 week of treatment at the target dose of 112 mcg/d appears to be required for efficacy,” wrote Dr. Andreas Viardot of the department of internal medicine III, University Hospital Ulm (Germany) and colleagues (Blood. 2016;127(11):1410-16).
The most common adverse events of grade 3 or higher were thrombocytopenia (17%) and leukopenia (17%). Grade 3 neurologic events included encephalopathy (9%) and aphasia (9%); no grade 4 or 5 neurologic events were reported. Cytokine release syndrome or cytokine storm were not reported.
Blinatumomab (Blincyto) is a bispecific T-cell engager antibody approved for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Blinatumomab transiently links CD3-positive T cells to CD19-positive B cells, which activates T cells and leads to T cell–mediated lysis of tumor cells and concomitant T-cell proliferation.
The study was supported by Amgen, the maker of Blincyto. Dr. Viardot reported having financial ties with Amgen and several other drug companies.
FROM BLOOD
Key clinical point: Stepwise dose-escalated administration of blinatumomab plus dexamethasone may be effective in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
Major finding: The overall response rate in 21 evaluable patients was 43% and the complete response rate was 19%.
Data sources: Phase II study of 25 patients who had received a median of three prior therapies.
Disclosures: The study was supported by Amgen, the maker of blinatumomab. Dr. Viardot reported having financial ties with Amgen and several other drug makers.
Chronic conditions decrease HRQOL in CCSs
Photo from Dana-Farber/
Boston Children’s Cancer
and Blood Disorders Center
Young adult survivors of childhood cancer tend to have inferior health-related quality of life (HRQOL) when compared to the general population, according to research published in the Journal of the National Cancer Institute.
Childhood cancer survivors (CCSs) ages 18 to 29 reported overall HRQOL similar to that of people from the general population who were in their 40s.
However, CCSs fared better if they did not have chronic health conditions.
“Our findings indicate survivors’ accelerated aging and also help us understand the health-related risks associated with having had cancer as a child,” said study author Lisa Diller, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School in Boston, Massachusetts.
“What’s encouraging is that the lower quality of life scores are associated with chronic disease after treatment, not with a history of pediatric cancer itself. If we can prevent treatment-related conditions by changes in the therapy we use for the cancer, then childhood cancer will become an acute, rather than a chronic, illness.”
Dr Diller and her colleagues used information from the Childhood Cancer Survivor Study to compare CCSs (n=7105) and their siblings (n=372) and information from the Medical Expenditures Panel Survey to make comparisons to the general population (n=12,803).
The researchers estimated health utility, a summary measure of quality of life, in these subjects using the Short Form-6D (SF-6D). A score of “1” indicated perfect health, and a score of “0” indicated death.
Results showed that CCSs had significantly lower SF-6D scores than the general population. The mean scores were 0.77 and 0.81, respectively (P<0.001).
But there were no clinically meaningful differences between the CCSs’ siblings and the general population. Their mean SF-6D scores were 0.80 and 0.81, respectively.
Young adult CCSs ages 18 to 29 had a mean score of 0.78, which was roughly equivalent to that reported for 40-to-49-year-old adults in the general population.
However, the presence or absence of chronic health conditions played a role in HRQOL. CCSs who reported no chronic conditions had SF-6D scores similar to the general population, with a mean score of 0.81.
But CCSs with chronic conditions had scores that matched the scores of chronically ill members of the general population. CCSs with 2 chronic conditions had a mean score of 0.77. Those with 3 or more disabling, severe, or life-threatening conditions had a mean score of 0.70.
“By enabling comparisons to the general population, our findings provide context to better understand how the cancer experience may influence the long-term well-being of survivors,” said study author Jennifer Yeh, PhD, of the Harvard T.H. Chan School of Public Health in Boston.
“This is another way to understand the health challenges survivors face and where to focus efforts to improve the long-term health and quality of life of survivors.” 
Photo from Dana-Farber/
Boston Children’s Cancer
and Blood Disorders Center
Young adult survivors of childhood cancer tend to have inferior health-related quality of life (HRQOL) when compared to the general population, according to research published in the Journal of the National Cancer Institute.
Childhood cancer survivors (CCSs) ages 18 to 29 reported overall HRQOL similar to that of people from the general population who were in their 40s.
However, CCSs fared better if they did not have chronic health conditions.
“Our findings indicate survivors’ accelerated aging and also help us understand the health-related risks associated with having had cancer as a child,” said study author Lisa Diller, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School in Boston, Massachusetts.
“What’s encouraging is that the lower quality of life scores are associated with chronic disease after treatment, not with a history of pediatric cancer itself. If we can prevent treatment-related conditions by changes in the therapy we use for the cancer, then childhood cancer will become an acute, rather than a chronic, illness.”
Dr Diller and her colleagues used information from the Childhood Cancer Survivor Study to compare CCSs (n=7105) and their siblings (n=372) and information from the Medical Expenditures Panel Survey to make comparisons to the general population (n=12,803).
The researchers estimated health utility, a summary measure of quality of life, in these subjects using the Short Form-6D (SF-6D). A score of “1” indicated perfect health, and a score of “0” indicated death.
Results showed that CCSs had significantly lower SF-6D scores than the general population. The mean scores were 0.77 and 0.81, respectively (P<0.001).
But there were no clinically meaningful differences between the CCSs’ siblings and the general population. Their mean SF-6D scores were 0.80 and 0.81, respectively.
Young adult CCSs ages 18 to 29 had a mean score of 0.78, which was roughly equivalent to that reported for 40-to-49-year-old adults in the general population.
However, the presence or absence of chronic health conditions played a role in HRQOL. CCSs who reported no chronic conditions had SF-6D scores similar to the general population, with a mean score of 0.81.
But CCSs with chronic conditions had scores that matched the scores of chronically ill members of the general population. CCSs with 2 chronic conditions had a mean score of 0.77. Those with 3 or more disabling, severe, or life-threatening conditions had a mean score of 0.70.
“By enabling comparisons to the general population, our findings provide context to better understand how the cancer experience may influence the long-term well-being of survivors,” said study author Jennifer Yeh, PhD, of the Harvard T.H. Chan School of Public Health in Boston.
“This is another way to understand the health challenges survivors face and where to focus efforts to improve the long-term health and quality of life of survivors.”
Photo from Dana-Farber/
Boston Children’s Cancer
and Blood Disorders Center
Young adult survivors of childhood cancer tend to have inferior health-related quality of life (HRQOL) when compared to the general population, according to research published in the Journal of the National Cancer Institute.
Childhood cancer survivors (CCSs) ages 18 to 29 reported overall HRQOL similar to that of people from the general population who were in their 40s.
However, CCSs fared better if they did not have chronic health conditions.
“Our findings indicate survivors’ accelerated aging and also help us understand the health-related risks associated with having had cancer as a child,” said study author Lisa Diller, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School in Boston, Massachusetts.
“What’s encouraging is that the lower quality of life scores are associated with chronic disease after treatment, not with a history of pediatric cancer itself. If we can prevent treatment-related conditions by changes in the therapy we use for the cancer, then childhood cancer will become an acute, rather than a chronic, illness.”
Dr Diller and her colleagues used information from the Childhood Cancer Survivor Study to compare CCSs (n=7105) and their siblings (n=372) and information from the Medical Expenditures Panel Survey to make comparisons to the general population (n=12,803).
The researchers estimated health utility, a summary measure of quality of life, in these subjects using the Short Form-6D (SF-6D). A score of “1” indicated perfect health, and a score of “0” indicated death.
Results showed that CCSs had significantly lower SF-6D scores than the general population. The mean scores were 0.77 and 0.81, respectively (P<0.001).
But there were no clinically meaningful differences between the CCSs’ siblings and the general population. Their mean SF-6D scores were 0.80 and 0.81, respectively.
Young adult CCSs ages 18 to 29 had a mean score of 0.78, which was roughly equivalent to that reported for 40-to-49-year-old adults in the general population.
However, the presence or absence of chronic health conditions played a role in HRQOL. CCSs who reported no chronic conditions had SF-6D scores similar to the general population, with a mean score of 0.81.
But CCSs with chronic conditions had scores that matched the scores of chronically ill members of the general population. CCSs with 2 chronic conditions had a mean score of 0.77. Those with 3 or more disabling, severe, or life-threatening conditions had a mean score of 0.70.
“By enabling comparisons to the general population, our findings provide context to better understand how the cancer experience may influence the long-term well-being of survivors,” said study author Jennifer Yeh, PhD, of the Harvard T.H. Chan School of Public Health in Boston.
“This is another way to understand the health challenges survivors face and where to focus efforts to improve the long-term health and quality of life of survivors.”
Treatment can produce durable responses in NHL
2016 AACR Annual Meeting
© AACR/Todd Buchanan
NEW ORLEANS—Administering an antibody-radionuclide conjugate after B-cell depletion with rituximab can produce lasting responses in patients with relapsed non-Hodgkin lymphoma (NHL), according to a phase 1/2 study.
The conjugate, 177Lu-DOTA-HH1 (Betalutin), consists of the tumor-specific antibody HH1, which targets the CD37 antigen on the surface of NHL cells, conjugated to the β-emitting isotope lutetium-177 (Lu-177) via the chemical linker DOTA.
In an ongoing phase 1/2 study, Betalutin given after rituximab produced an overall response rate of 63.2%.
The median duration of response has not yet been reached, and 1 patient has maintained a response for more than 36 months.
In addition, the researchers said Betalutin was well tolerated, with a predictable and manageable safety profile. Most adverse events were hematologic, and all have been transient and reversible.
These results were presented at the 2016 AACR Annual Meeting (abstract LB-252*). The study is sponsored by Nordic Nanovector ASA.
Patients and study design
The researchers presented data on 21 patients—19 with follicular lymphoma and 2 with mantle cell lymphoma. All tumors were positive for CD37.
The patients’ median age was 68 (range, 41-78). Sixty-seven percent were male, and they had received 1 to 8 prior treatment regimens.
In this dose-escalation study, patients received Betalutin at 3 different doses, but they were also divided into 2 arms according to predosing with cold HH1 antibody.
In Arm 1 (n=12), patients received rituximab (at 375 mg/m2) on day -28 and -21 to deplete circulating B cells. On day 0, predosing with 50 mg HH1 was given before Betalutin injection. Then, patients received Betalutin at 10 MBq/kg (n=3), 15 MBq/kg (n=6), or 20 MBq/kg (n=3).
In Arm 2 (n=4), patients received rituximab at the same dose and schedule as Arm 1, but Betalutin was administered without HH1 predosing on day 0 at either 10 MBq/kg (n=2) or 15 MBq/kg (n=2).
The first patient treated on this trial received 250 mg/m2 of rituximab on day -7 and day 0 prior to Betalutin administration and was included in the 10 MBq/kg group in Arm 2.
The 15 MBq/kg dose level of Arm 1 has been expanded into the phase 2 portion of the study, as dose-limiting toxicities occurred at the 20 MBq/kg dose. Five patients have been treated in the phase 2 portion.
Safety
Adverse events (AEs) from the phase 2 portion of the study were not reported, as the data are still being collected.
In the phase 1 portion, grade 3/4 AEs were hematologic in nature and included decreases in platelet counts (3 grade 3 and 6 grade 4) and neutrophil counts (5 grade 3 and 4 grade 4).
Serious AEs included decreases in platelet counts (n=2), atrial fibrillation (n=2), epistaxis (n=1), fractured sternum (n=1), decreased neutrophil count (n=1), pharyngitis (n=1), pneumonia (n=1), pulmonary embolism (n=1), and sepsis (n=1).
The pulmonary embolism was deemed unrelated to treatment, but the remaining events were considered possibly or probably related to Betalutin.
The researchers noted that 1 patient experienced pharyngitis, pneumonia, pulmonary embolism, epistaxis, sepsis, and a decrease in lymphocyte count.
All patients’ platelets and neutrophils recovered. Two patients required platelet transfusions—one patient in the 20 MBq/kg cohort of Arm 1 and one patient in the 15 MBq/kg cohort of Arm 2.
Efficacy
Nineteen patients were evaluable for response. The overall response rate was 63.2% (n=12) and included both complete (31.6%, n=6) and partial responses (31.6%, n=6). Progression occurred in 21.1% of patients (n=4), and 15.8% (n=3) had stable disease.
The researchers presented data on 9 patients treated at the recommended 15 MBq/kg dose level with 50 mg HH1 predosing. Five patients were treated in phase 1 and 4 in phase 2. One of these patients was excluded from the analysis due to transformed lymphoma.
Two patients in phase 1 responded—both complete responses—and 3 patients in phase 2 responded—2 complete and 1 partial response.
For the entire study cohort, the median duration of response has not yet been reached. Six responses are ongoing—2 for 3+ months, 1 for 6+ months, 1 for 18+ months, 1 for 24+ months, and 1 for 36+ months.
*Information in the abstract differs from that presented at the meeting.
2016 AACR Annual Meeting
© AACR/Todd Buchanan
NEW ORLEANS—Administering an antibody-radionuclide conjugate after B-cell depletion with rituximab can produce lasting responses in patients with relapsed non-Hodgkin lymphoma (NHL), according to a phase 1/2 study.
The conjugate, 177Lu-DOTA-HH1 (Betalutin), consists of the tumor-specific antibody HH1, which targets the CD37 antigen on the surface of NHL cells, conjugated to the β-emitting isotope lutetium-177 (Lu-177) via the chemical linker DOTA.
In an ongoing phase 1/2 study, Betalutin given after rituximab produced an overall response rate of 63.2%.
The median duration of response has not yet been reached, and 1 patient has maintained a response for more than 36 months.
In addition, the researchers said Betalutin was well tolerated, with a predictable and manageable safety profile. Most adverse events were hematologic, and all have been transient and reversible.
These results were presented at the 2016 AACR Annual Meeting (abstract LB-252*). The study is sponsored by Nordic Nanovector ASA.
Patients and study design
The researchers presented data on 21 patients—19 with follicular lymphoma and 2 with mantle cell lymphoma. All tumors were positive for CD37.
The patients’ median age was 68 (range, 41-78). Sixty-seven percent were male, and they had received 1 to 8 prior treatment regimens.
In this dose-escalation study, patients received Betalutin at 3 different doses, but they were also divided into 2 arms according to predosing with cold HH1 antibody.
In Arm 1 (n=12), patients received rituximab (at 375 mg/m2) on day -28 and -21 to deplete circulating B cells. On day 0, predosing with 50 mg HH1 was given before Betalutin injection. Then, patients received Betalutin at 10 MBq/kg (n=3), 15 MBq/kg (n=6), or 20 MBq/kg (n=3).
In Arm 2 (n=4), patients received rituximab at the same dose and schedule as Arm 1, but Betalutin was administered without HH1 predosing on day 0 at either 10 MBq/kg (n=2) or 15 MBq/kg (n=2).
The first patient treated on this trial received 250 mg/m2 of rituximab on day -7 and day 0 prior to Betalutin administration and was included in the 10 MBq/kg group in Arm 2.
The 15 MBq/kg dose level of Arm 1 has been expanded into the phase 2 portion of the study, as dose-limiting toxicities occurred at the 20 MBq/kg dose. Five patients have been treated in the phase 2 portion.
Safety
Adverse events (AEs) from the phase 2 portion of the study were not reported, as the data are still being collected.
In the phase 1 portion, grade 3/4 AEs were hematologic in nature and included decreases in platelet counts (3 grade 3 and 6 grade 4) and neutrophil counts (5 grade 3 and 4 grade 4).
Serious AEs included decreases in platelet counts (n=2), atrial fibrillation (n=2), epistaxis (n=1), fractured sternum (n=1), decreased neutrophil count (n=1), pharyngitis (n=1), pneumonia (n=1), pulmonary embolism (n=1), and sepsis (n=1).
The pulmonary embolism was deemed unrelated to treatment, but the remaining events were considered possibly or probably related to Betalutin.
The researchers noted that 1 patient experienced pharyngitis, pneumonia, pulmonary embolism, epistaxis, sepsis, and a decrease in lymphocyte count.
All patients’ platelets and neutrophils recovered. Two patients required platelet transfusions—one patient in the 20 MBq/kg cohort of Arm 1 and one patient in the 15 MBq/kg cohort of Arm 2.
Efficacy
Nineteen patients were evaluable for response. The overall response rate was 63.2% (n=12) and included both complete (31.6%, n=6) and partial responses (31.6%, n=6). Progression occurred in 21.1% of patients (n=4), and 15.8% (n=3) had stable disease.
The researchers presented data on 9 patients treated at the recommended 15 MBq/kg dose level with 50 mg HH1 predosing. Five patients were treated in phase 1 and 4 in phase 2. One of these patients was excluded from the analysis due to transformed lymphoma.
Two patients in phase 1 responded—both complete responses—and 3 patients in phase 2 responded—2 complete and 1 partial response.
For the entire study cohort, the median duration of response has not yet been reached. Six responses are ongoing—2 for 3+ months, 1 for 6+ months, 1 for 18+ months, 1 for 24+ months, and 1 for 36+ months.
*Information in the abstract differs from that presented at the meeting.
2016 AACR Annual Meeting
© AACR/Todd Buchanan
NEW ORLEANS—Administering an antibody-radionuclide conjugate after B-cell depletion with rituximab can produce lasting responses in patients with relapsed non-Hodgkin lymphoma (NHL), according to a phase 1/2 study.
The conjugate, 177Lu-DOTA-HH1 (Betalutin), consists of the tumor-specific antibody HH1, which targets the CD37 antigen on the surface of NHL cells, conjugated to the β-emitting isotope lutetium-177 (Lu-177) via the chemical linker DOTA.
In an ongoing phase 1/2 study, Betalutin given after rituximab produced an overall response rate of 63.2%.
The median duration of response has not yet been reached, and 1 patient has maintained a response for more than 36 months.
In addition, the researchers said Betalutin was well tolerated, with a predictable and manageable safety profile. Most adverse events were hematologic, and all have been transient and reversible.
These results were presented at the 2016 AACR Annual Meeting (abstract LB-252*). The study is sponsored by Nordic Nanovector ASA.
Patients and study design
The researchers presented data on 21 patients—19 with follicular lymphoma and 2 with mantle cell lymphoma. All tumors were positive for CD37.
The patients’ median age was 68 (range, 41-78). Sixty-seven percent were male, and they had received 1 to 8 prior treatment regimens.
In this dose-escalation study, patients received Betalutin at 3 different doses, but they were also divided into 2 arms according to predosing with cold HH1 antibody.
In Arm 1 (n=12), patients received rituximab (at 375 mg/m2) on day -28 and -21 to deplete circulating B cells. On day 0, predosing with 50 mg HH1 was given before Betalutin injection. Then, patients received Betalutin at 10 MBq/kg (n=3), 15 MBq/kg (n=6), or 20 MBq/kg (n=3).
In Arm 2 (n=4), patients received rituximab at the same dose and schedule as Arm 1, but Betalutin was administered without HH1 predosing on day 0 at either 10 MBq/kg (n=2) or 15 MBq/kg (n=2).
The first patient treated on this trial received 250 mg/m2 of rituximab on day -7 and day 0 prior to Betalutin administration and was included in the 10 MBq/kg group in Arm 2.
The 15 MBq/kg dose level of Arm 1 has been expanded into the phase 2 portion of the study, as dose-limiting toxicities occurred at the 20 MBq/kg dose. Five patients have been treated in the phase 2 portion.
Safety
Adverse events (AEs) from the phase 2 portion of the study were not reported, as the data are still being collected.
In the phase 1 portion, grade 3/4 AEs were hematologic in nature and included decreases in platelet counts (3 grade 3 and 6 grade 4) and neutrophil counts (5 grade 3 and 4 grade 4).
Serious AEs included decreases in platelet counts (n=2), atrial fibrillation (n=2), epistaxis (n=1), fractured sternum (n=1), decreased neutrophil count (n=1), pharyngitis (n=1), pneumonia (n=1), pulmonary embolism (n=1), and sepsis (n=1).
The pulmonary embolism was deemed unrelated to treatment, but the remaining events were considered possibly or probably related to Betalutin.
The researchers noted that 1 patient experienced pharyngitis, pneumonia, pulmonary embolism, epistaxis, sepsis, and a decrease in lymphocyte count.
All patients’ platelets and neutrophils recovered. Two patients required platelet transfusions—one patient in the 20 MBq/kg cohort of Arm 1 and one patient in the 15 MBq/kg cohort of Arm 2.
Efficacy
Nineteen patients were evaluable for response. The overall response rate was 63.2% (n=12) and included both complete (31.6%, n=6) and partial responses (31.6%, n=6). Progression occurred in 21.1% of patients (n=4), and 15.8% (n=3) had stable disease.
The researchers presented data on 9 patients treated at the recommended 15 MBq/kg dose level with 50 mg HH1 predosing. Five patients were treated in phase 1 and 4 in phase 2. One of these patients was excluded from the analysis due to transformed lymphoma.
Two patients in phase 1 responded—both complete responses—and 3 patients in phase 2 responded—2 complete and 1 partial response.
For the entire study cohort, the median duration of response has not yet been reached. Six responses are ongoing—2 for 3+ months, 1 for 6+ months, 1 for 18+ months, 1 for 24+ months, and 1 for 36+ months.
*Information in the abstract differs from that presented at the meeting.
Drug shows early promise for low-grade lymphoma
follicular lymphoma
NEW ORLEANS—The TLR9 agonist SD-101 has produced encouraging early results in patients with low-grade B-cell lymphoma, according to researchers.
In an ongoing phase 1/2 study, patients received low-dose radiation, followed by an injection of SD-101 into one of their tumors.
This prompted changes in the tumor microenvironment that potentially induced a systemic antitumor response and decreased the volume of both treated and untreated tumors.
In addition, SD-101 was considered well tolerated, with no dose-limiting toxicities or maximum-tolerated dose.
“We are pleased to have already demonstrated a safety profile, pharmacodynamics, and preliminary efficacy in this study,” said Ronald Levy, MD, of Stanford University in California.
Dr Levy and his colleagues presented these results at the 2016 AACR Annual Meeting (abstract CT047). The study is sponsored by Dynavax Technologies Corporation, the company developing SD-101.
The researchers reported data for 13 patients with untreated, low-grade B-cell lymphoma. They had a mean age of 63.2, and 53.8% were male.
Patients had follicular lymphoma (n=9), small lymphocytic lymphoma (n=2), chronic lymphocytic leukemia (n=1), and nodal marginal zone lymphoma (n=1).
At least 2 sites of measurable disease were required for participation in this study. One site was treated with low-dose radiation (2 Gy) and injected with SD-101 on days 1, 8, 15, 22, and 29. Other lesions received no treatment.
In Part 1—the dose-escalation portion of the study—patients received SD-101 at 1 mg (n=3), 2 mg (n=3), 4 mg (n=3), or 8 mg (n=4). The phase 2 expansion portion of the study is ongoing, with enrollment in 2 dose cohorts (1 mg and 8 mg).
“This clinical trial design is unique and takes advantage of the fact that lymphoma patients have easily injectable sites of disease,” Dr Levy said. “The local injections are conveniently added to low-dose radiotherapy, a standard treatment for low-grade lymphoma.”
Safety
All 13 patients experienced at least 1 adverse event (AEs), although nearly all were grade 1 or 2.
The most common treatment-related AEs were local injection-site reactions and flu-like symptoms, including fever, chills, and myalgia (n=11 for all 3). However, the researchers said these AEs were primarily short-lived and controlled by over-the-counter acetaminophen in most cases.
In the 8 mg dosing cohort, 1 patient had grade 3 neutropenia and 2 had grade 3 malaise, all of which were considered treatment-related. In addition, there was a case of grade 3 asymptomatic pulmonary embolism in the 4 mg dose cohort, which was deemed serious but unrelated to treatment.
Efficacy
The researchers observed induction of interferon-responsive genes at all dose levels 24 hours after the second dose of SD-101 was given (Day 9).
In addition, T-cell numbers increased at the treated site by Day 8. The total T cells increased in 7 of 10 evaluable patients by Day 8 (range, >300% to 18%).
CD4+ and CD8+ T cells increased simultaneously in 5 of 7 evaluable patients, regulatory T cells decreased in 8 of 10 evaluable patients by Day 8, and follicular T helper cells decreased in 9 of 9 evaluable patients by Day 8.
Furthermore, treated and untreated tumors decreased in volume across all dose groups.
At Day 90, 12 patients had a reduction of the product of diameters in treated tumors (median -45.3%; range, -87 to +100), and 11 patients had a reduction in untreated tumors (median -8.1%; range, -48 to +45).
In 9 patients, these abscopal effects were sustained for at least 180 to 360 days.
However, 6 patients discontinued from the study due to progression. Three had radiographic progression—1 at Day 92 (in the 4 mg cohort) and 2 at 1 year (1 in the 1 mg cohort and 1 in the 2 mg cohort).
Two patients had clinical progression—1 at Day 197 (4 mg) and 1 at Day 273 (2 mg). And 1 patient discontinued at Day 203 due to a combination of clinical and radiographic progression (8 mg).
The researchers pointed out that there was no evidence of a dose response with SD-101, but the study included a limited number of patients.
follicular lymphoma
NEW ORLEANS—The TLR9 agonist SD-101 has produced encouraging early results in patients with low-grade B-cell lymphoma, according to researchers.
In an ongoing phase 1/2 study, patients received low-dose radiation, followed by an injection of SD-101 into one of their tumors.
This prompted changes in the tumor microenvironment that potentially induced a systemic antitumor response and decreased the volume of both treated and untreated tumors.
In addition, SD-101 was considered well tolerated, with no dose-limiting toxicities or maximum-tolerated dose.
“We are pleased to have already demonstrated a safety profile, pharmacodynamics, and preliminary efficacy in this study,” said Ronald Levy, MD, of Stanford University in California.
Dr Levy and his colleagues presented these results at the 2016 AACR Annual Meeting (abstract CT047). The study is sponsored by Dynavax Technologies Corporation, the company developing SD-101.
The researchers reported data for 13 patients with untreated, low-grade B-cell lymphoma. They had a mean age of 63.2, and 53.8% were male.
Patients had follicular lymphoma (n=9), small lymphocytic lymphoma (n=2), chronic lymphocytic leukemia (n=1), and nodal marginal zone lymphoma (n=1).
At least 2 sites of measurable disease were required for participation in this study. One site was treated with low-dose radiation (2 Gy) and injected with SD-101 on days 1, 8, 15, 22, and 29. Other lesions received no treatment.
In Part 1—the dose-escalation portion of the study—patients received SD-101 at 1 mg (n=3), 2 mg (n=3), 4 mg (n=3), or 8 mg (n=4). The phase 2 expansion portion of the study is ongoing, with enrollment in 2 dose cohorts (1 mg and 8 mg).
“This clinical trial design is unique and takes advantage of the fact that lymphoma patients have easily injectable sites of disease,” Dr Levy said. “The local injections are conveniently added to low-dose radiotherapy, a standard treatment for low-grade lymphoma.”
Safety
All 13 patients experienced at least 1 adverse event (AEs), although nearly all were grade 1 or 2.
The most common treatment-related AEs were local injection-site reactions and flu-like symptoms, including fever, chills, and myalgia (n=11 for all 3). However, the researchers said these AEs were primarily short-lived and controlled by over-the-counter acetaminophen in most cases.
In the 8 mg dosing cohort, 1 patient had grade 3 neutropenia and 2 had grade 3 malaise, all of which were considered treatment-related. In addition, there was a case of grade 3 asymptomatic pulmonary embolism in the 4 mg dose cohort, which was deemed serious but unrelated to treatment.
Efficacy
The researchers observed induction of interferon-responsive genes at all dose levels 24 hours after the second dose of SD-101 was given (Day 9).
In addition, T-cell numbers increased at the treated site by Day 8. The total T cells increased in 7 of 10 evaluable patients by Day 8 (range, >300% to 18%).
CD4+ and CD8+ T cells increased simultaneously in 5 of 7 evaluable patients, regulatory T cells decreased in 8 of 10 evaluable patients by Day 8, and follicular T helper cells decreased in 9 of 9 evaluable patients by Day 8.
Furthermore, treated and untreated tumors decreased in volume across all dose groups.
At Day 90, 12 patients had a reduction of the product of diameters in treated tumors (median -45.3%; range, -87 to +100), and 11 patients had a reduction in untreated tumors (median -8.1%; range, -48 to +45).
In 9 patients, these abscopal effects were sustained for at least 180 to 360 days.
However, 6 patients discontinued from the study due to progression. Three had radiographic progression—1 at Day 92 (in the 4 mg cohort) and 2 at 1 year (1 in the 1 mg cohort and 1 in the 2 mg cohort).
Two patients had clinical progression—1 at Day 197 (4 mg) and 1 at Day 273 (2 mg). And 1 patient discontinued at Day 203 due to a combination of clinical and radiographic progression (8 mg).
The researchers pointed out that there was no evidence of a dose response with SD-101, but the study included a limited number of patients.
follicular lymphoma
NEW ORLEANS—The TLR9 agonist SD-101 has produced encouraging early results in patients with low-grade B-cell lymphoma, according to researchers.
In an ongoing phase 1/2 study, patients received low-dose radiation, followed by an injection of SD-101 into one of their tumors.
This prompted changes in the tumor microenvironment that potentially induced a systemic antitumor response and decreased the volume of both treated and untreated tumors.
In addition, SD-101 was considered well tolerated, with no dose-limiting toxicities or maximum-tolerated dose.
“We are pleased to have already demonstrated a safety profile, pharmacodynamics, and preliminary efficacy in this study,” said Ronald Levy, MD, of Stanford University in California.
Dr Levy and his colleagues presented these results at the 2016 AACR Annual Meeting (abstract CT047). The study is sponsored by Dynavax Technologies Corporation, the company developing SD-101.
The researchers reported data for 13 patients with untreated, low-grade B-cell lymphoma. They had a mean age of 63.2, and 53.8% were male.
Patients had follicular lymphoma (n=9), small lymphocytic lymphoma (n=2), chronic lymphocytic leukemia (n=1), and nodal marginal zone lymphoma (n=1).
At least 2 sites of measurable disease were required for participation in this study. One site was treated with low-dose radiation (2 Gy) and injected with SD-101 on days 1, 8, 15, 22, and 29. Other lesions received no treatment.
In Part 1—the dose-escalation portion of the study—patients received SD-101 at 1 mg (n=3), 2 mg (n=3), 4 mg (n=3), or 8 mg (n=4). The phase 2 expansion portion of the study is ongoing, with enrollment in 2 dose cohorts (1 mg and 8 mg).
“This clinical trial design is unique and takes advantage of the fact that lymphoma patients have easily injectable sites of disease,” Dr Levy said. “The local injections are conveniently added to low-dose radiotherapy, a standard treatment for low-grade lymphoma.”
Safety
All 13 patients experienced at least 1 adverse event (AEs), although nearly all were grade 1 or 2.
The most common treatment-related AEs were local injection-site reactions and flu-like symptoms, including fever, chills, and myalgia (n=11 for all 3). However, the researchers said these AEs were primarily short-lived and controlled by over-the-counter acetaminophen in most cases.
In the 8 mg dosing cohort, 1 patient had grade 3 neutropenia and 2 had grade 3 malaise, all of which were considered treatment-related. In addition, there was a case of grade 3 asymptomatic pulmonary embolism in the 4 mg dose cohort, which was deemed serious but unrelated to treatment.
Efficacy
The researchers observed induction of interferon-responsive genes at all dose levels 24 hours after the second dose of SD-101 was given (Day 9).
In addition, T-cell numbers increased at the treated site by Day 8. The total T cells increased in 7 of 10 evaluable patients by Day 8 (range, >300% to 18%).
CD4+ and CD8+ T cells increased simultaneously in 5 of 7 evaluable patients, regulatory T cells decreased in 8 of 10 evaluable patients by Day 8, and follicular T helper cells decreased in 9 of 9 evaluable patients by Day 8.
Furthermore, treated and untreated tumors decreased in volume across all dose groups.
At Day 90, 12 patients had a reduction of the product of diameters in treated tumors (median -45.3%; range, -87 to +100), and 11 patients had a reduction in untreated tumors (median -8.1%; range, -48 to +45).
In 9 patients, these abscopal effects were sustained for at least 180 to 360 days.
However, 6 patients discontinued from the study due to progression. Three had radiographic progression—1 at Day 92 (in the 4 mg cohort) and 2 at 1 year (1 in the 1 mg cohort and 1 in the 2 mg cohort).
Two patients had clinical progression—1 at Day 197 (4 mg) and 1 at Day 273 (2 mg). And 1 patient discontinued at Day 203 due to a combination of clinical and radiographic progression (8 mg).
The researchers pointed out that there was no evidence of a dose response with SD-101, but the study included a limited number of patients.
Antibody shows activity against ALL, CLL
Photo by Aaron Logan
NEW ORLEANS—Preclinical data suggest IMMU-114, a humanized anti-HLA-DR IgG4 antibody, is active against acute and chronic leukemias.
In a mouse model of chronic lymphocytic leukemia (CLL), IMMU-114 significantly prolonged survival when compared to rituximab.
IMMU-114 also produced a significant survival benefit in a mouse model of acute lymphoblastic leukemia (ALL) that is refractory to doxorubicin.
These results were presented at the 2016 AACR Annual Meeting (abstract 587). The research was carried out by employees of Immunomedics, Inc., the company developing IMMU-114.
The researchers generated a mouse model of human CLL by growing the cell line JVM-3 in SCID mice. The team noted that this model has similar HLA-DR and CD20 expression.
So they compared the efficacy of IMMU-114 and the anti-CD20 antibody rituximab in these mice and found that, at all doses tested, IMMU-114 significantly improved the median survival time (MST).
When both drugs were given at 50 µg, the MST was 42 days with IMMU-114 and 19 days with rituximab (P<0.0001).
When both drugs were given at 100 µg, the MSTs were 54 days and 18 days, respectively (P=0.017). And when both drugs were given at 200 µg, the MSTs were 46 days and 18 days, respectively (P<0.0001).
In control mice that received only saline, the MST was 14 days.
In in vitro experiments with the cell line JVM-3, IMMU-114 and the BTK inhibitor ibrutinib exhibited synergy fighting against the CLL cells. When given with the PI3K inhibitor idelalisib, IMMU-114 produced an additive effect.
In a doxorubicin-refractory mouse model of ALL (MN 60), IMMU-114 provided a significant survival benefit over doxorubicin and saline controls.
The MSTs were 21 days with saline, 23 days with doxorubicin, 39 days with IMMU-114 at 25 µg (P<0.0001), and 42.5 days with IMMU-114 at 50 µg (P<0.0001).
The researchers said IMMU-114 was well tolerated in these experiments, as evidenced by no significant weight loss in the mice.
Photo by Aaron Logan
NEW ORLEANS—Preclinical data suggest IMMU-114, a humanized anti-HLA-DR IgG4 antibody, is active against acute and chronic leukemias.
In a mouse model of chronic lymphocytic leukemia (CLL), IMMU-114 significantly prolonged survival when compared to rituximab.
IMMU-114 also produced a significant survival benefit in a mouse model of acute lymphoblastic leukemia (ALL) that is refractory to doxorubicin.
These results were presented at the 2016 AACR Annual Meeting (abstract 587). The research was carried out by employees of Immunomedics, Inc., the company developing IMMU-114.
The researchers generated a mouse model of human CLL by growing the cell line JVM-3 in SCID mice. The team noted that this model has similar HLA-DR and CD20 expression.
So they compared the efficacy of IMMU-114 and the anti-CD20 antibody rituximab in these mice and found that, at all doses tested, IMMU-114 significantly improved the median survival time (MST).
When both drugs were given at 50 µg, the MST was 42 days with IMMU-114 and 19 days with rituximab (P<0.0001).
When both drugs were given at 100 µg, the MSTs were 54 days and 18 days, respectively (P=0.017). And when both drugs were given at 200 µg, the MSTs were 46 days and 18 days, respectively (P<0.0001).
In control mice that received only saline, the MST was 14 days.
In in vitro experiments with the cell line JVM-3, IMMU-114 and the BTK inhibitor ibrutinib exhibited synergy fighting against the CLL cells. When given with the PI3K inhibitor idelalisib, IMMU-114 produced an additive effect.
In a doxorubicin-refractory mouse model of ALL (MN 60), IMMU-114 provided a significant survival benefit over doxorubicin and saline controls.
The MSTs were 21 days with saline, 23 days with doxorubicin, 39 days with IMMU-114 at 25 µg (P<0.0001), and 42.5 days with IMMU-114 at 50 µg (P<0.0001).
The researchers said IMMU-114 was well tolerated in these experiments, as evidenced by no significant weight loss in the mice.
Photo by Aaron Logan
NEW ORLEANS—Preclinical data suggest IMMU-114, a humanized anti-HLA-DR IgG4 antibody, is active against acute and chronic leukemias.
In a mouse model of chronic lymphocytic leukemia (CLL), IMMU-114 significantly prolonged survival when compared to rituximab.
IMMU-114 also produced a significant survival benefit in a mouse model of acute lymphoblastic leukemia (ALL) that is refractory to doxorubicin.
These results were presented at the 2016 AACR Annual Meeting (abstract 587). The research was carried out by employees of Immunomedics, Inc., the company developing IMMU-114.
The researchers generated a mouse model of human CLL by growing the cell line JVM-3 in SCID mice. The team noted that this model has similar HLA-DR and CD20 expression.
So they compared the efficacy of IMMU-114 and the anti-CD20 antibody rituximab in these mice and found that, at all doses tested, IMMU-114 significantly improved the median survival time (MST).
When both drugs were given at 50 µg, the MST was 42 days with IMMU-114 and 19 days with rituximab (P<0.0001).
When both drugs were given at 100 µg, the MSTs were 54 days and 18 days, respectively (P=0.017). And when both drugs were given at 200 µg, the MSTs were 46 days and 18 days, respectively (P<0.0001).
In control mice that received only saline, the MST was 14 days.
In in vitro experiments with the cell line JVM-3, IMMU-114 and the BTK inhibitor ibrutinib exhibited synergy fighting against the CLL cells. When given with the PI3K inhibitor idelalisib, IMMU-114 produced an additive effect.
In a doxorubicin-refractory mouse model of ALL (MN 60), IMMU-114 provided a significant survival benefit over doxorubicin and saline controls.
The MSTs were 21 days with saline, 23 days with doxorubicin, 39 days with IMMU-114 at 25 µg (P<0.0001), and 42.5 days with IMMU-114 at 50 µg (P<0.0001).
The researchers said IMMU-114 was well tolerated in these experiments, as evidenced by no significant weight loss in the mice.
Drug granted breakthrough designation for cHL
Photo courtesy of Merck
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for pembrolizumab (Keytruda) to treat patients with relapsed or refractory classical Hodgkin lymphoma (cHL).
Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response.
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.
The breakthrough designation for pembrolizumab in cHL is based on data from the phase 1b KEYNOTE-013 trial and the phase 2 KEYNOTE-087 trial.
Findings from the KEYNOTE-013 study were presented at ASH 2014 (in patients with cHL) and ASH 2015 (in primary mediastinal large B-cell lymphoma).
Data from KEYNOTE-087 will be presented at an upcoming medical meeting, according to Merck, the company developing pembrolizumab.
Pembrolizumab also has breakthrough designation from the FDA as a treatment for advanced melanoma, advanced non-small cell lung cancer, and advanced colorectal cancer.
The drug is already FDA-approved to treat melanoma and non-small cell lung cancer. Pembrolizumab is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every 3 weeks for the approved indications.
Photo courtesy of Merck
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for pembrolizumab (Keytruda) to treat patients with relapsed or refractory classical Hodgkin lymphoma (cHL).
Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response.
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.
The breakthrough designation for pembrolizumab in cHL is based on data from the phase 1b KEYNOTE-013 trial and the phase 2 KEYNOTE-087 trial.
Findings from the KEYNOTE-013 study were presented at ASH 2014 (in patients with cHL) and ASH 2015 (in primary mediastinal large B-cell lymphoma).
Data from KEYNOTE-087 will be presented at an upcoming medical meeting, according to Merck, the company developing pembrolizumab.
Pembrolizumab also has breakthrough designation from the FDA as a treatment for advanced melanoma, advanced non-small cell lung cancer, and advanced colorectal cancer.
The drug is already FDA-approved to treat melanoma and non-small cell lung cancer. Pembrolizumab is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every 3 weeks for the approved indications.
Photo courtesy of Merck
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for pembrolizumab (Keytruda) to treat patients with relapsed or refractory classical Hodgkin lymphoma (cHL).
Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response.
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.
The breakthrough designation for pembrolizumab in cHL is based on data from the phase 1b KEYNOTE-013 trial and the phase 2 KEYNOTE-087 trial.
Findings from the KEYNOTE-013 study were presented at ASH 2014 (in patients with cHL) and ASH 2015 (in primary mediastinal large B-cell lymphoma).
Data from KEYNOTE-087 will be presented at an upcoming medical meeting, according to Merck, the company developing pembrolizumab.
Pembrolizumab also has breakthrough designation from the FDA as a treatment for advanced melanoma, advanced non-small cell lung cancer, and advanced colorectal cancer.
The drug is already FDA-approved to treat melanoma and non-small cell lung cancer. Pembrolizumab is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every 3 weeks for the approved indications.
Patients with ASD may have lower cancer risk
Photo by Darren Baker
New research suggests that patients diagnosed with an autism spectrum disorder (ASD) have a higher burden of mutations in oncogenes but lower rates of cancer than the rest of the population.
Investigators analyzed large, publicly available genomic databases of patients with ASD and found that, compared to a set of control subjects, ASD patients had significantly higher rates of DNA variation in oncogenes.
The team followed up this result with an analysis of the University of Iowa Hospitals and Clinics’ electronic medical record and discovered that ASD patients were also significantly less likely to have a co-occurring diagnosis of cancer.
“It’s a very provocative result that makes sense on one level and is extremely perplexing on another,” said Benjamin Darbro, MD, PhD, of the University of Iowa Carver College of Medicine in Iowa City.
Dr Darbro and his colleagues discussed the result, and the research that led to it, in a paper published in PLOS ONE.
The investigators used exome sequencing data from the ARRA Autism Sequencing Collaboration and compared that data to a control cohort from the Exome Variant Server database.
This revealed that rare, coding variants within oncogenes were greatly enriched in the ARRA ASD cohort. By comparison, variants were not significantly enriched in tumor suppressor genes.
To ensure the genetic differences were not technical artifacts but actually bona fide differences in genetic architecture in ASD, the investigators ran numerous controls.
As expected, they found that individuals with ASD had many more DNA variations in genes previously associated with autism, epilepsy, and intellectual disability compared to control individuals.
However, there was no difference between the ASD and control groups when it came to genes involved in other, unrelated conditions such as skeletal dysplasia, retinitis pigmentosa, dilated cardiomyopathy, and non-syndromic hearing loss.
The investigators then turned their attention to the electronic medical record at the University of Iowa Hospitals and Clinics and conducted a retrospective case-control analysis comparing 1837 patients with ASD to 9336 patients with any other diagnosis, and determined what proportion of each group carried a cancer diagnosis.
The team found that, for children and adults with ASD, there appeared to be a protective effect against cancer. The cancer incidence was 1.3% for patients with ASD and 3.9% for controls.
The protective effect was evident in both males and females with ASD, but it was strongest for the youngest group of patients and decreased with age. For ASD patients who were under 14 years of age, the odds of having cancer were reduced by 94% compared to controls.
When the investigators determined the rates of other systemic diseases—such as high blood pressure and diabetes—in the ASD population, they found no relationship.
Furthermore, the team found no relationship with cancer when they examined the rates of other common conditions such as esophageal reflux, allergic rhinitis, atopic dermatitis, and short stature. They said this demonstrated that the inverse relationship observed between ASD and cancer is not due to a technical artifact.
Photo by Darren Baker
New research suggests that patients diagnosed with an autism spectrum disorder (ASD) have a higher burden of mutations in oncogenes but lower rates of cancer than the rest of the population.
Investigators analyzed large, publicly available genomic databases of patients with ASD and found that, compared to a set of control subjects, ASD patients had significantly higher rates of DNA variation in oncogenes.
The team followed up this result with an analysis of the University of Iowa Hospitals and Clinics’ electronic medical record and discovered that ASD patients were also significantly less likely to have a co-occurring diagnosis of cancer.
“It’s a very provocative result that makes sense on one level and is extremely perplexing on another,” said Benjamin Darbro, MD, PhD, of the University of Iowa Carver College of Medicine in Iowa City.
Dr Darbro and his colleagues discussed the result, and the research that led to it, in a paper published in PLOS ONE.
The investigators used exome sequencing data from the ARRA Autism Sequencing Collaboration and compared that data to a control cohort from the Exome Variant Server database.
This revealed that rare, coding variants within oncogenes were greatly enriched in the ARRA ASD cohort. By comparison, variants were not significantly enriched in tumor suppressor genes.
To ensure the genetic differences were not technical artifacts but actually bona fide differences in genetic architecture in ASD, the investigators ran numerous controls.
As expected, they found that individuals with ASD had many more DNA variations in genes previously associated with autism, epilepsy, and intellectual disability compared to control individuals.
However, there was no difference between the ASD and control groups when it came to genes involved in other, unrelated conditions such as skeletal dysplasia, retinitis pigmentosa, dilated cardiomyopathy, and non-syndromic hearing loss.
The investigators then turned their attention to the electronic medical record at the University of Iowa Hospitals and Clinics and conducted a retrospective case-control analysis comparing 1837 patients with ASD to 9336 patients with any other diagnosis, and determined what proportion of each group carried a cancer diagnosis.
The team found that, for children and adults with ASD, there appeared to be a protective effect against cancer. The cancer incidence was 1.3% for patients with ASD and 3.9% for controls.
The protective effect was evident in both males and females with ASD, but it was strongest for the youngest group of patients and decreased with age. For ASD patients who were under 14 years of age, the odds of having cancer were reduced by 94% compared to controls.
When the investigators determined the rates of other systemic diseases—such as high blood pressure and diabetes—in the ASD population, they found no relationship.
Furthermore, the team found no relationship with cancer when they examined the rates of other common conditions such as esophageal reflux, allergic rhinitis, atopic dermatitis, and short stature. They said this demonstrated that the inverse relationship observed between ASD and cancer is not due to a technical artifact.
Photo by Darren Baker
New research suggests that patients diagnosed with an autism spectrum disorder (ASD) have a higher burden of mutations in oncogenes but lower rates of cancer than the rest of the population.
Investigators analyzed large, publicly available genomic databases of patients with ASD and found that, compared to a set of control subjects, ASD patients had significantly higher rates of DNA variation in oncogenes.
The team followed up this result with an analysis of the University of Iowa Hospitals and Clinics’ electronic medical record and discovered that ASD patients were also significantly less likely to have a co-occurring diagnosis of cancer.
“It’s a very provocative result that makes sense on one level and is extremely perplexing on another,” said Benjamin Darbro, MD, PhD, of the University of Iowa Carver College of Medicine in Iowa City.
Dr Darbro and his colleagues discussed the result, and the research that led to it, in a paper published in PLOS ONE.
The investigators used exome sequencing data from the ARRA Autism Sequencing Collaboration and compared that data to a control cohort from the Exome Variant Server database.
This revealed that rare, coding variants within oncogenes were greatly enriched in the ARRA ASD cohort. By comparison, variants were not significantly enriched in tumor suppressor genes.
To ensure the genetic differences were not technical artifacts but actually bona fide differences in genetic architecture in ASD, the investigators ran numerous controls.
As expected, they found that individuals with ASD had many more DNA variations in genes previously associated with autism, epilepsy, and intellectual disability compared to control individuals.
However, there was no difference between the ASD and control groups when it came to genes involved in other, unrelated conditions such as skeletal dysplasia, retinitis pigmentosa, dilated cardiomyopathy, and non-syndromic hearing loss.
The investigators then turned their attention to the electronic medical record at the University of Iowa Hospitals and Clinics and conducted a retrospective case-control analysis comparing 1837 patients with ASD to 9336 patients with any other diagnosis, and determined what proportion of each group carried a cancer diagnosis.
The team found that, for children and adults with ASD, there appeared to be a protective effect against cancer. The cancer incidence was 1.3% for patients with ASD and 3.9% for controls.
The protective effect was evident in both males and females with ASD, but it was strongest for the youngest group of patients and decreased with age. For ASD patients who were under 14 years of age, the odds of having cancer were reduced by 94% compared to controls.
When the investigators determined the rates of other systemic diseases—such as high blood pressure and diabetes—in the ASD population, they found no relationship.
Furthermore, the team found no relationship with cancer when they examined the rates of other common conditions such as esophageal reflux, allergic rhinitis, atopic dermatitis, and short stature. They said this demonstrated that the inverse relationship observed between ASD and cancer is not due to a technical artifact.
Gut bacteria could help prevent lymphoma, other cancers
New research published in PLOS ONE suggests certain intestinal bacteria could potentially be used to reduce the risk of lymphomas and other cancers.
Researchers believe doctors might be able to reduce a person’s risk of these cancers by analyzing the levels and types of intestinal bacteria in the body and then prescribing probiotics to replace or bolster the amount of bacteria with anti-inflammatory properties.
“It is not invasive and rather easy to do,” said study author Robert Schiestl, PhD, of the University of California, Los Angeles.
Dr Schiestl and his colleagues isolated a bacterium called Lactobacillus johnsonii 456, which is the most abundant of the beneficial bacteria.
The team found this bacterium reduced gene damage and inflammation, which, as they pointed out, plays a key role in cancers and other diseases.
Previous research led by Dr Schiestl presented the first evidence of a relationship between intestinal microbiota and the onset of lymphoma.
The new study explains how this microbiota might delay the onset of cancer and suggests that probiotic supplements could help keep cancer from forming.
For both studies, Dr Schiestl and his team used mice that had mutations in the gene ATM, which made them susceptible to a neurologic disorder called ataxia telangiectasia. The disorder is associated with a high incidence of leukemias, lymphomas, and other cancers.
The mice were divided into two groups—one that was given only anti-inflammatory bacteria and another that received a mix of inflammatory and anti-inflammatory microbes that typically co-exist in the intestines.
With their previous study, Dr Schiestl and his team showed that, in the mice with more of the beneficial bacteria, the lymphoma took significantly longer to form.
For the new study, the researchers analyzed metabolites in the mice’s urine and feces and found the mice that were receiving only the beneficial microbiota produced metabolites that are known to prevent cancer.
Those mice also had more efficient fat and oxidative metabolism, which the researchers believe might also lower the risk for cancer.
Among the other results, in the mice receiving only the good bacteria, lymphoma formed only half as quickly as it did in the other mice. In addition, mice with the good bacteria lived 4 times longer and had less DNA damage and inflammation.
The researchers said these findings lend credence to the idea that manipulating microbial composition could be used to prevent or alleviate cancer susceptibility. They hope that, in the future, probiotic supplements could be chemopreventive for the average person and decrease tumor incidence in cancer-susceptible populations.
The University of California, Los Angeles has a patent pending on the use of Lactobacillus johnsonii 456 as an anti-inflammatory agent.
New research published in PLOS ONE suggests certain intestinal bacteria could potentially be used to reduce the risk of lymphomas and other cancers.
Researchers believe doctors might be able to reduce a person’s risk of these cancers by analyzing the levels and types of intestinal bacteria in the body and then prescribing probiotics to replace or bolster the amount of bacteria with anti-inflammatory properties.
“It is not invasive and rather easy to do,” said study author Robert Schiestl, PhD, of the University of California, Los Angeles.
Dr Schiestl and his colleagues isolated a bacterium called Lactobacillus johnsonii 456, which is the most abundant of the beneficial bacteria.
The team found this bacterium reduced gene damage and inflammation, which, as they pointed out, plays a key role in cancers and other diseases.
Previous research led by Dr Schiestl presented the first evidence of a relationship between intestinal microbiota and the onset of lymphoma.
The new study explains how this microbiota might delay the onset of cancer and suggests that probiotic supplements could help keep cancer from forming.
For both studies, Dr Schiestl and his team used mice that had mutations in the gene ATM, which made them susceptible to a neurologic disorder called ataxia telangiectasia. The disorder is associated with a high incidence of leukemias, lymphomas, and other cancers.
The mice were divided into two groups—one that was given only anti-inflammatory bacteria and another that received a mix of inflammatory and anti-inflammatory microbes that typically co-exist in the intestines.
With their previous study, Dr Schiestl and his team showed that, in the mice with more of the beneficial bacteria, the lymphoma took significantly longer to form.
For the new study, the researchers analyzed metabolites in the mice’s urine and feces and found the mice that were receiving only the beneficial microbiota produced metabolites that are known to prevent cancer.
Those mice also had more efficient fat and oxidative metabolism, which the researchers believe might also lower the risk for cancer.
Among the other results, in the mice receiving only the good bacteria, lymphoma formed only half as quickly as it did in the other mice. In addition, mice with the good bacteria lived 4 times longer and had less DNA damage and inflammation.
The researchers said these findings lend credence to the idea that manipulating microbial composition could be used to prevent or alleviate cancer susceptibility. They hope that, in the future, probiotic supplements could be chemopreventive for the average person and decrease tumor incidence in cancer-susceptible populations.
The University of California, Los Angeles has a patent pending on the use of Lactobacillus johnsonii 456 as an anti-inflammatory agent.
New research published in PLOS ONE suggests certain intestinal bacteria could potentially be used to reduce the risk of lymphomas and other cancers.
Researchers believe doctors might be able to reduce a person’s risk of these cancers by analyzing the levels and types of intestinal bacteria in the body and then prescribing probiotics to replace or bolster the amount of bacteria with anti-inflammatory properties.
“It is not invasive and rather easy to do,” said study author Robert Schiestl, PhD, of the University of California, Los Angeles.
Dr Schiestl and his colleagues isolated a bacterium called Lactobacillus johnsonii 456, which is the most abundant of the beneficial bacteria.
The team found this bacterium reduced gene damage and inflammation, which, as they pointed out, plays a key role in cancers and other diseases.
Previous research led by Dr Schiestl presented the first evidence of a relationship between intestinal microbiota and the onset of lymphoma.
The new study explains how this microbiota might delay the onset of cancer and suggests that probiotic supplements could help keep cancer from forming.
For both studies, Dr Schiestl and his team used mice that had mutations in the gene ATM, which made them susceptible to a neurologic disorder called ataxia telangiectasia. The disorder is associated with a high incidence of leukemias, lymphomas, and other cancers.
The mice were divided into two groups—one that was given only anti-inflammatory bacteria and another that received a mix of inflammatory and anti-inflammatory microbes that typically co-exist in the intestines.
With their previous study, Dr Schiestl and his team showed that, in the mice with more of the beneficial bacteria, the lymphoma took significantly longer to form.
For the new study, the researchers analyzed metabolites in the mice’s urine and feces and found the mice that were receiving only the beneficial microbiota produced metabolites that are known to prevent cancer.
Those mice also had more efficient fat and oxidative metabolism, which the researchers believe might also lower the risk for cancer.
Among the other results, in the mice receiving only the good bacteria, lymphoma formed only half as quickly as it did in the other mice. In addition, mice with the good bacteria lived 4 times longer and had less DNA damage and inflammation.
The researchers said these findings lend credence to the idea that manipulating microbial composition could be used to prevent or alleviate cancer susceptibility. They hope that, in the future, probiotic supplements could be chemopreventive for the average person and decrease tumor incidence in cancer-susceptible populations.
The University of California, Los Angeles has a patent pending on the use of Lactobacillus johnsonii 456 as an anti-inflammatory agent.
PD-1 inhibitor granted priority review for cHL
Photo courtesy of Business Wire
The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application seeking to expand use of the PD-1 inhibitor nivolumab (Opdivo) to patients with previously treated classical Hodgkin lymphoma (cHL).
A priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.
To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.
About nivolumab
Nivolumab is an inhibitor that binds to the checkpoint receptor PD-1, which is expressed on activated T cells. The drug prevents PD-L1 and PD-L2 from binding, thereby preventing the PD-1 pathway’s suppressive signaling on the immune system, including interference with an anti-tumor immune response.
Nivolumab is being developed by Bristol-Myers Squibb. The drug currently has regulatory approval in 48 countries.
In the US, nivolumab is approved—both as a single agent and in combination—to treat certain patients with melanoma, non-small-cell lung cancer, or advanced renal cell carcinoma.
According to Bristol-Myers Squibb, nivolumab has the potential to become first PD-1 inhibitor approved for a hematologic malignancy in the US.
The supplemental biologics license application for nivolumab included data from the phase 2 trial CheckMate 205. In this ongoing trial, researchers are evaluating nivolumab in patients with relapsed or refractory cHL who have received an autologous stem cell transplant and brentuximab vedotin.
Data from this trial are expected to be presented at a medical meeting later this year.
The FDA previously granted nivolumab breakthrough therapy designation for cHL. The FDA’s breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
Photo courtesy of Business Wire
The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application seeking to expand use of the PD-1 inhibitor nivolumab (Opdivo) to patients with previously treated classical Hodgkin lymphoma (cHL).
A priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.
To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.
About nivolumab
Nivolumab is an inhibitor that binds to the checkpoint receptor PD-1, which is expressed on activated T cells. The drug prevents PD-L1 and PD-L2 from binding, thereby preventing the PD-1 pathway’s suppressive signaling on the immune system, including interference with an anti-tumor immune response.
Nivolumab is being developed by Bristol-Myers Squibb. The drug currently has regulatory approval in 48 countries.
In the US, nivolumab is approved—both as a single agent and in combination—to treat certain patients with melanoma, non-small-cell lung cancer, or advanced renal cell carcinoma.
According to Bristol-Myers Squibb, nivolumab has the potential to become first PD-1 inhibitor approved for a hematologic malignancy in the US.
The supplemental biologics license application for nivolumab included data from the phase 2 trial CheckMate 205. In this ongoing trial, researchers are evaluating nivolumab in patients with relapsed or refractory cHL who have received an autologous stem cell transplant and brentuximab vedotin.
Data from this trial are expected to be presented at a medical meeting later this year.
The FDA previously granted nivolumab breakthrough therapy designation for cHL. The FDA’s breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
Photo courtesy of Business Wire
The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application seeking to expand use of the PD-1 inhibitor nivolumab (Opdivo) to patients with previously treated classical Hodgkin lymphoma (cHL).
A priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.
To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.
About nivolumab
Nivolumab is an inhibitor that binds to the checkpoint receptor PD-1, which is expressed on activated T cells. The drug prevents PD-L1 and PD-L2 from binding, thereby preventing the PD-1 pathway’s suppressive signaling on the immune system, including interference with an anti-tumor immune response.
Nivolumab is being developed by Bristol-Myers Squibb. The drug currently has regulatory approval in 48 countries.
In the US, nivolumab is approved—both as a single agent and in combination—to treat certain patients with melanoma, non-small-cell lung cancer, or advanced renal cell carcinoma.
According to Bristol-Myers Squibb, nivolumab has the potential to become first PD-1 inhibitor approved for a hematologic malignancy in the US.
The supplemental biologics license application for nivolumab included data from the phase 2 trial CheckMate 205. In this ongoing trial, researchers are evaluating nivolumab in patients with relapsed or refractory cHL who have received an autologous stem cell transplant and brentuximab vedotin.
Data from this trial are expected to be presented at a medical meeting later this year.
The FDA previously granted nivolumab breakthrough therapy designation for cHL. The FDA’s breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
Alternative splicing regulates activity of MALT1
Photo courtesy of
Helmholtz Zentrum München
Researchers say they have gained new insights into the workings of MALT1, a protein that controls the activation of lymphocytes.
The team found that, through alternative splicing, two variants of MALT1 may arise, and one has a stronger effect than the other.
The researchers say understanding this process is important because previous research has suggested MALT1 may be a therapeutic
target for lymphomas and other diseases.
Isabel Meininger, a doctoral student at Helmholtz Zentrum München in Neuherberg, Germany, and her colleagues described their MALT1-related findings in Nature Communications.
“To our surprise, we showed that MALT1 is regulated by post-transcriptional splicing,” Meininger said. “Depending on which MALT1 variant is expressed, the immune system is activated more or less.”
The researchers explained that most pre-messenger RNAs in mammals are prone to alternative splicing, which results in the generation of multiple transcripts and proteins with diverse functions.
In the case of MALT1, the variants MALT1A and MALT1B differ only through the presence of exon 7, a short sequence that encodes 11 amino acids.
If exon 7 is missing, as in the case of MALT1B, the protein’s ability to stimulate T cells is impaired. So MALT1A has a stronger effect on T cells than MALT1B.
The researchers also found that a molecule called hnRNP U (heterogeneous nuclear ribonucleoprotein U) regulates which of the two variants is preferably expressed.
If hnRNP U is present in small amounts, higher levels of MALT1A are expressed, resulting in stronger activation of T cells. With higher levels of hnRNP U, higher levels of MALT1B are expressed, and the response of the T cells is weaker.
“Our findings contribute to a better understanding of the function of MALT1 and enable us to better assess the potential impact of a pharmacological effect on this promising drug candidate,” said study author Daniel Krappmann, PhD, of Helmholtz Zentrum München.
In a previous study, Dr Krappmann and his team identified small molecules that can inhibit MALT1 to treat diffuse large B-cell lymphoma.
In future studies, the researchers want to confirm, in a preclinical model, the effects of MALT1 splicing on the immune system and disease development.
Photo courtesy of
Helmholtz Zentrum München
Researchers say they have gained new insights into the workings of MALT1, a protein that controls the activation of lymphocytes.
The team found that, through alternative splicing, two variants of MALT1 may arise, and one has a stronger effect than the other.
The researchers say understanding this process is important because previous research has suggested MALT1 may be a therapeutic
target for lymphomas and other diseases.
Isabel Meininger, a doctoral student at Helmholtz Zentrum München in Neuherberg, Germany, and her colleagues described their MALT1-related findings in Nature Communications.
“To our surprise, we showed that MALT1 is regulated by post-transcriptional splicing,” Meininger said. “Depending on which MALT1 variant is expressed, the immune system is activated more or less.”
The researchers explained that most pre-messenger RNAs in mammals are prone to alternative splicing, which results in the generation of multiple transcripts and proteins with diverse functions.
In the case of MALT1, the variants MALT1A and MALT1B differ only through the presence of exon 7, a short sequence that encodes 11 amino acids.
If exon 7 is missing, as in the case of MALT1B, the protein’s ability to stimulate T cells is impaired. So MALT1A has a stronger effect on T cells than MALT1B.
The researchers also found that a molecule called hnRNP U (heterogeneous nuclear ribonucleoprotein U) regulates which of the two variants is preferably expressed.
If hnRNP U is present in small amounts, higher levels of MALT1A are expressed, resulting in stronger activation of T cells. With higher levels of hnRNP U, higher levels of MALT1B are expressed, and the response of the T cells is weaker.
“Our findings contribute to a better understanding of the function of MALT1 and enable us to better assess the potential impact of a pharmacological effect on this promising drug candidate,” said study author Daniel Krappmann, PhD, of Helmholtz Zentrum München.
In a previous study, Dr Krappmann and his team identified small molecules that can inhibit MALT1 to treat diffuse large B-cell lymphoma.
In future studies, the researchers want to confirm, in a preclinical model, the effects of MALT1 splicing on the immune system and disease development.
Photo courtesy of
Helmholtz Zentrum München
Researchers say they have gained new insights into the workings of MALT1, a protein that controls the activation of lymphocytes.
The team found that, through alternative splicing, two variants of MALT1 may arise, and one has a stronger effect than the other.
The researchers say understanding this process is important because previous research has suggested MALT1 may be a therapeutic
target for lymphomas and other diseases.
Isabel Meininger, a doctoral student at Helmholtz Zentrum München in Neuherberg, Germany, and her colleagues described their MALT1-related findings in Nature Communications.
“To our surprise, we showed that MALT1 is regulated by post-transcriptional splicing,” Meininger said. “Depending on which MALT1 variant is expressed, the immune system is activated more or less.”
The researchers explained that most pre-messenger RNAs in mammals are prone to alternative splicing, which results in the generation of multiple transcripts and proteins with diverse functions.
In the case of MALT1, the variants MALT1A and MALT1B differ only through the presence of exon 7, a short sequence that encodes 11 amino acids.
If exon 7 is missing, as in the case of MALT1B, the protein’s ability to stimulate T cells is impaired. So MALT1A has a stronger effect on T cells than MALT1B.
The researchers also found that a molecule called hnRNP U (heterogeneous nuclear ribonucleoprotein U) regulates which of the two variants is preferably expressed.
If hnRNP U is present in small amounts, higher levels of MALT1A are expressed, resulting in stronger activation of T cells. With higher levels of hnRNP U, higher levels of MALT1B are expressed, and the response of the T cells is weaker.
“Our findings contribute to a better understanding of the function of MALT1 and enable us to better assess the potential impact of a pharmacological effect on this promising drug candidate,” said study author Daniel Krappmann, PhD, of Helmholtz Zentrum München.
In a previous study, Dr Krappmann and his team identified small molecules that can inhibit MALT1 to treat diffuse large B-cell lymphoma.
In future studies, the researchers want to confirm, in a preclinical model, the effects of MALT1 splicing on the immune system and disease development.