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Therapy may improve haplo-HSCT in leukemia patients
Photo by Bill Branson
VALENCIA, SPAIN—The adjunct T-cell therapy BPX-501 can make haploidentical hematopoietic stem cell transplant (haplo-HSCT) an “attractive option” for pediatric patients with acute leukemia, according to a presentation at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT).
Acute leukemia patients who received BPX-501 after haplo-HSCT in a phase 1/2 trial tended to have favorable outcomes.
At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free.
There were several cases of graft-versus-host disease (GVHD), but nearly all of these resolved.
Franco Locatelli, MD, PhD, of Bambino Gesù Children’s Hospital in Rome, Italy, presented these results at the EBMT meeting as abstract WP16.*
The trial, known as BP-004, was sponsored by Bellicum Pharmaceuticals, the company developing BPX-501.
About BPX-501
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate cells in the event of toxicity.
The goal is to allow physicians to more safely perform haplo-HSCTs by giving patients BPX-501 to speed immune reconstitution and provide control over viral infections. But the technology is designed to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs.
The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. The idea is that, if a patient develops severe GVHD, he can receive an infusion with the small molecule rimiducid. And this will trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.
About BP-004
In late 2014, Bellicum initiated BP-004, a phase 1/2 trial in children with leukemias, lymphomas, or orphan inherited blood disorders. The trial is being conducted in European and US pediatric transplant centers and is set to enroll up to 90 patients.
At the EBMT meeting, researchers reported results in 41 patients treated on this trial.
Dr Locatelli presented data on 17 patients with acute leukemias—13 with acute lymphoblastic leukemia and 4 with acute myeloid leukemia. Their median age at HSCT was 6.5 years (range, 0.9-16.1)
All of these patients received a T-cell-depleted haplo-HSCT without post-transplant GVHD prophylaxis. All were in complete remission at the time of transplant.
The patients received BPX-501 within 14 ± 4 days after haplo-HSCT. The phase 1 portion of the trial consisted of a classical 3+3 design, with 3 cohorts receiving escalating doses of BPX-501 cells—2.5 x 105, 5 x 105, and 1 x 106 cells/kg.
In the phase 2 portion, patients received 1 X 106 BPX-501 cells/kg. Rimiducid was only used in the event of uncontrollable GVHD.
Results
The median follow-up was 7 months (range, 1-15.6). The median time to platelet recovery was 11 days (range, 9-13), and the median time to neutrophil recovery was 17 days (range, 10-22).
Three patients developed skin-only acute GVHD, were treated with topical steroids, and the GVHD resolved. Two patients developed acute grade 3 GVHD, were treated with systemic steroids, and the GVHD resolved.
Two patients developed mild chronic GVHD, received systemic steroids, and the GVHD resolved. And 1 patient developed severe chronic GVHD, received systemic steroids and rimiducid, and the GVHD improved.
One patient relapsed. The estimated 1-year disease-free survival was 92.9%. Dr Locatelli noted that, although the follow-up is still limited, these results compare favorably to results in historical controls.
“These interim results continue to be very encouraging and indicate that a haploidentical transplant, with the addition of BPX-501-modified donor T cells, can be an attractive option for children in need of a transplant,” he said.
“Future studies will address the role of repeated infusions or higher numbers of BPX-501 cells in malignant patients with resistant disease.”
The BP-004 trial also included 24 patients with nonmalignant disorders. Results in these patients were presented at the EBMT meeting as abstract O007. 
*Information in the abstract differs from that presented at the meeting.
Photo by Bill Branson
VALENCIA, SPAIN—The adjunct T-cell therapy BPX-501 can make haploidentical hematopoietic stem cell transplant (haplo-HSCT) an “attractive option” for pediatric patients with acute leukemia, according to a presentation at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT).
Acute leukemia patients who received BPX-501 after haplo-HSCT in a phase 1/2 trial tended to have favorable outcomes.
At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free.
There were several cases of graft-versus-host disease (GVHD), but nearly all of these resolved.
Franco Locatelli, MD, PhD, of Bambino Gesù Children’s Hospital in Rome, Italy, presented these results at the EBMT meeting as abstract WP16.*
The trial, known as BP-004, was sponsored by Bellicum Pharmaceuticals, the company developing BPX-501.
About BPX-501
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate cells in the event of toxicity.
The goal is to allow physicians to more safely perform haplo-HSCTs by giving patients BPX-501 to speed immune reconstitution and provide control over viral infections. But the technology is designed to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs.
The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. The idea is that, if a patient develops severe GVHD, he can receive an infusion with the small molecule rimiducid. And this will trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.
About BP-004
In late 2014, Bellicum initiated BP-004, a phase 1/2 trial in children with leukemias, lymphomas, or orphan inherited blood disorders. The trial is being conducted in European and US pediatric transplant centers and is set to enroll up to 90 patients.
At the EBMT meeting, researchers reported results in 41 patients treated on this trial.
Dr Locatelli presented data on 17 patients with acute leukemias—13 with acute lymphoblastic leukemia and 4 with acute myeloid leukemia. Their median age at HSCT was 6.5 years (range, 0.9-16.1)
All of these patients received a T-cell-depleted haplo-HSCT without post-transplant GVHD prophylaxis. All were in complete remission at the time of transplant.
The patients received BPX-501 within 14 ± 4 days after haplo-HSCT. The phase 1 portion of the trial consisted of a classical 3+3 design, with 3 cohorts receiving escalating doses of BPX-501 cells—2.5 x 105, 5 x 105, and 1 x 106 cells/kg.
In the phase 2 portion, patients received 1 X 106 BPX-501 cells/kg. Rimiducid was only used in the event of uncontrollable GVHD.
Results
The median follow-up was 7 months (range, 1-15.6). The median time to platelet recovery was 11 days (range, 9-13), and the median time to neutrophil recovery was 17 days (range, 10-22).
Three patients developed skin-only acute GVHD, were treated with topical steroids, and the GVHD resolved. Two patients developed acute grade 3 GVHD, were treated with systemic steroids, and the GVHD resolved.
Two patients developed mild chronic GVHD, received systemic steroids, and the GVHD resolved. And 1 patient developed severe chronic GVHD, received systemic steroids and rimiducid, and the GVHD improved.
One patient relapsed. The estimated 1-year disease-free survival was 92.9%. Dr Locatelli noted that, although the follow-up is still limited, these results compare favorably to results in historical controls.
“These interim results continue to be very encouraging and indicate that a haploidentical transplant, with the addition of BPX-501-modified donor T cells, can be an attractive option for children in need of a transplant,” he said.
“Future studies will address the role of repeated infusions or higher numbers of BPX-501 cells in malignant patients with resistant disease.”
The BP-004 trial also included 24 patients with nonmalignant disorders. Results in these patients were presented at the EBMT meeting as abstract O007.
*Information in the abstract differs from that presented at the meeting.
Photo by Bill Branson
VALENCIA, SPAIN—The adjunct T-cell therapy BPX-501 can make haploidentical hematopoietic stem cell transplant (haplo-HSCT) an “attractive option” for pediatric patients with acute leukemia, according to a presentation at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT).
Acute leukemia patients who received BPX-501 after haplo-HSCT in a phase 1/2 trial tended to have favorable outcomes.
At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free.
There were several cases of graft-versus-host disease (GVHD), but nearly all of these resolved.
Franco Locatelli, MD, PhD, of Bambino Gesù Children’s Hospital in Rome, Italy, presented these results at the EBMT meeting as abstract WP16.*
The trial, known as BP-004, was sponsored by Bellicum Pharmaceuticals, the company developing BPX-501.
About BPX-501
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate cells in the event of toxicity.
The goal is to allow physicians to more safely perform haplo-HSCTs by giving patients BPX-501 to speed immune reconstitution and provide control over viral infections. But the technology is designed to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs.
The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. The idea is that, if a patient develops severe GVHD, he can receive an infusion with the small molecule rimiducid. And this will trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.
About BP-004
In late 2014, Bellicum initiated BP-004, a phase 1/2 trial in children with leukemias, lymphomas, or orphan inherited blood disorders. The trial is being conducted in European and US pediatric transplant centers and is set to enroll up to 90 patients.
At the EBMT meeting, researchers reported results in 41 patients treated on this trial.
Dr Locatelli presented data on 17 patients with acute leukemias—13 with acute lymphoblastic leukemia and 4 with acute myeloid leukemia. Their median age at HSCT was 6.5 years (range, 0.9-16.1)
All of these patients received a T-cell-depleted haplo-HSCT without post-transplant GVHD prophylaxis. All were in complete remission at the time of transplant.
The patients received BPX-501 within 14 ± 4 days after haplo-HSCT. The phase 1 portion of the trial consisted of a classical 3+3 design, with 3 cohorts receiving escalating doses of BPX-501 cells—2.5 x 105, 5 x 105, and 1 x 106 cells/kg.
In the phase 2 portion, patients received 1 X 106 BPX-501 cells/kg. Rimiducid was only used in the event of uncontrollable GVHD.
Results
The median follow-up was 7 months (range, 1-15.6). The median time to platelet recovery was 11 days (range, 9-13), and the median time to neutrophil recovery was 17 days (range, 10-22).
Three patients developed skin-only acute GVHD, were treated with topical steroids, and the GVHD resolved. Two patients developed acute grade 3 GVHD, were treated with systemic steroids, and the GVHD resolved.
Two patients developed mild chronic GVHD, received systemic steroids, and the GVHD resolved. And 1 patient developed severe chronic GVHD, received systemic steroids and rimiducid, and the GVHD improved.
One patient relapsed. The estimated 1-year disease-free survival was 92.9%. Dr Locatelli noted that, although the follow-up is still limited, these results compare favorably to results in historical controls.
“These interim results continue to be very encouraging and indicate that a haploidentical transplant, with the addition of BPX-501-modified donor T cells, can be an attractive option for children in need of a transplant,” he said.
“Future studies will address the role of repeated infusions or higher numbers of BPX-501 cells in malignant patients with resistant disease.”
The BP-004 trial also included 24 patients with nonmalignant disorders. Results in these patients were presented at the EBMT meeting as abstract O007.
*Information in the abstract differs from that presented at the meeting.
Immunotherapy may improve HSCT outcomes
VALENCIA, SPAIN—Results of a phase 2 trial suggest a personalized T-cell immunotherapy may improve outcomes in patients undergoing T-cell-depleted haploidentical hematopoietic stem cell transplant (HSCT).
Patients who received the therapy, ATIR101, after HSCT had significant improvements in transplant-related mortality (TRM) and overall survival (OS) when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.
None of the patients who received ATIR101 developed grade 3-4 graft-versus-host disease (GVHD), despite the fact that they had not received any prophylactic immunosuppressants. Still, there were a few cases of grade 2 GVHD reported.
Denis-Claude Roy, MD, of the University of Montreal in Québec, Canada, presented the results of this trial at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation (abstract O042*). The trial was sponsored by Kiadis Pharma, the company developing ATIR101.
Patients and treatment
The trial included 23 leukemia patients with a median age of 41 (range, 21-64). They were eligible for an allogeneic HSCT but could not find a matching donor in time. Sixteen patients had acute myeloid leukemia, and 7 had acute lymphoblastic leukemia.
All patients were in complete remission (CR) at the time of the HSCT. Fifteen were in CR1, and 8 were in CR2/3. The majority of patients (57%) had a poor prognosis based on their disease risk index and cytogenetic profile.
A myeloablative conditioning regimen was used, which consisted of total body irradiation (1200 cGy; n=11) or melphalan (120 mg/m2; n=12), along with thiotepa (10 mg/kg), fludarabine (30 mg/m2 x 5d), and anti-thymocyte globulin (2.5 mg/kg x 4d).
Patients then received a CD34+ selected graft from a haploidentical donor, containing 11 x 106 CD34+ cells/kg (range, 4.7-24.4) and 0.29 x 104 CD3+ cells/kg (range, 0-1.8).
The patients achieved neutrophil and platelet engraftment at a median of 12 days post-HSCT (range, 8-34 and 9-35, respectively). They did not receive any post-transplant GVHD prophylaxis.
At a median of 28 days post-transplant (range, 28-73), ATIR101 was infused, at a fixed dose of 2 x 106 CD3+ cells/kg.
ATIR101 is a personalized T-cell immunotherapy based on a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.
Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with a compound known as TH9402, which is selectively retained in activated T cells. Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.
Primary endpoint: TRM
The median follow-up, on March 24, 2016, was 414 days (range, 110-742) post-HSCT. At that point, all patients were beyond 6 months post-HSCT. This allowed for assessment of the primary endpoint, which is TRM at 6 months.
Three cases of TRM were reported, for a rate of 13%. In all cases, the cause of death was an infection.
The researchers compared these results to those in a historic control group. It consisted of 35 patients who matched the inclusion and exclusion criteria of this trial and underwent a similar HSCT procedure from haploidentical family members but without the addition of ATIR101.
TRM was significantly lower (P=0.005) in patients who received ATIR101 after a T-cell-depleted haploidentical transplant than in the historical controls. The 6-month TRM for HSCT + ATIR101 was 13%, compared to 37% for HSCT only.
Relapse and survival
Two patients experienced disease relapse within the first 12 months after HSCT—at days 61 and 90. And 1 patient died from disease relapse within the first 6 months.
The researchers said the low rates of relapse and TRM translated into significantly improved OS for patients undergoing HSCT + ATIR101 compared to the historical controls.
Based on Kaplan-Meier estimates, the 1-year OS was 64% in the HSCT + ATIR101 group and 20% in the historical control group (P=0.0026).
GVHD
None of the patients in this trial (0/23) developed grade 3-4 GVHD upon infusion of ATIR101.
However, 3 cases of grade 2 acute GVHD were reported. One case occurred before ATIR101 infusion, and the other 2 cases had a delayed onset, at day 173 and day 247 post-HSCT (145 and 219 days post-ATIR101 infusion).
In the patient who developed GVHD before ATIR101 infusion, GVHD resolved quickly. The patient then received ATIR101 and did not experience any further GVHD.
“With this latest data, we can confirm the safety of ATIR101, without any incidents of grade 3-4 GVHD, significant reduction in transplant-related mortality, low relapse rates, and very good event-free survival, which we believe confirms the efficiency of photodepletion-based elimination of allo-reactive T cells,” Dr Roy said.
“Indeed, the data of patients receiving transplants with a haploidentical donor and an ATIR101 infusion are very similar to those from patients with a matched donor. As a doctor, I am very excited about this development and its potential to change patient fates.”
Dr Roy and his colleagues will continue to follow patients in this trial to collect further long-term outcome data.
Kiadis Pharma is planning to proceed with the development of ATIR101 as an adjunctive immuno-therapeutic treatment to a haploidentical HSCT for patients with acute leukemia, initiating a randomized phase 3 trial in the second half of 2016. 
*Information in the abstract differs from that presented at the meeting.
VALENCIA, SPAIN—Results of a phase 2 trial suggest a personalized T-cell immunotherapy may improve outcomes in patients undergoing T-cell-depleted haploidentical hematopoietic stem cell transplant (HSCT).
Patients who received the therapy, ATIR101, after HSCT had significant improvements in transplant-related mortality (TRM) and overall survival (OS) when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.
None of the patients who received ATIR101 developed grade 3-4 graft-versus-host disease (GVHD), despite the fact that they had not received any prophylactic immunosuppressants. Still, there were a few cases of grade 2 GVHD reported.
Denis-Claude Roy, MD, of the University of Montreal in Québec, Canada, presented the results of this trial at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation (abstract O042*). The trial was sponsored by Kiadis Pharma, the company developing ATIR101.
Patients and treatment
The trial included 23 leukemia patients with a median age of 41 (range, 21-64). They were eligible for an allogeneic HSCT but could not find a matching donor in time. Sixteen patients had acute myeloid leukemia, and 7 had acute lymphoblastic leukemia.
All patients were in complete remission (CR) at the time of the HSCT. Fifteen were in CR1, and 8 were in CR2/3. The majority of patients (57%) had a poor prognosis based on their disease risk index and cytogenetic profile.
A myeloablative conditioning regimen was used, which consisted of total body irradiation (1200 cGy; n=11) or melphalan (120 mg/m2; n=12), along with thiotepa (10 mg/kg), fludarabine (30 mg/m2 x 5d), and anti-thymocyte globulin (2.5 mg/kg x 4d).
Patients then received a CD34+ selected graft from a haploidentical donor, containing 11 x 106 CD34+ cells/kg (range, 4.7-24.4) and 0.29 x 104 CD3+ cells/kg (range, 0-1.8).
The patients achieved neutrophil and platelet engraftment at a median of 12 days post-HSCT (range, 8-34 and 9-35, respectively). They did not receive any post-transplant GVHD prophylaxis.
At a median of 28 days post-transplant (range, 28-73), ATIR101 was infused, at a fixed dose of 2 x 106 CD3+ cells/kg.
ATIR101 is a personalized T-cell immunotherapy based on a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.
Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with a compound known as TH9402, which is selectively retained in activated T cells. Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.
Primary endpoint: TRM
The median follow-up, on March 24, 2016, was 414 days (range, 110-742) post-HSCT. At that point, all patients were beyond 6 months post-HSCT. This allowed for assessment of the primary endpoint, which is TRM at 6 months.
Three cases of TRM were reported, for a rate of 13%. In all cases, the cause of death was an infection.
The researchers compared these results to those in a historic control group. It consisted of 35 patients who matched the inclusion and exclusion criteria of this trial and underwent a similar HSCT procedure from haploidentical family members but without the addition of ATIR101.
TRM was significantly lower (P=0.005) in patients who received ATIR101 after a T-cell-depleted haploidentical transplant than in the historical controls. The 6-month TRM for HSCT + ATIR101 was 13%, compared to 37% for HSCT only.
Relapse and survival
Two patients experienced disease relapse within the first 12 months after HSCT—at days 61 and 90. And 1 patient died from disease relapse within the first 6 months.
The researchers said the low rates of relapse and TRM translated into significantly improved OS for patients undergoing HSCT + ATIR101 compared to the historical controls.
Based on Kaplan-Meier estimates, the 1-year OS was 64% in the HSCT + ATIR101 group and 20% in the historical control group (P=0.0026).
GVHD
None of the patients in this trial (0/23) developed grade 3-4 GVHD upon infusion of ATIR101.
However, 3 cases of grade 2 acute GVHD were reported. One case occurred before ATIR101 infusion, and the other 2 cases had a delayed onset, at day 173 and day 247 post-HSCT (145 and 219 days post-ATIR101 infusion).
In the patient who developed GVHD before ATIR101 infusion, GVHD resolved quickly. The patient then received ATIR101 and did not experience any further GVHD.
“With this latest data, we can confirm the safety of ATIR101, without any incidents of grade 3-4 GVHD, significant reduction in transplant-related mortality, low relapse rates, and very good event-free survival, which we believe confirms the efficiency of photodepletion-based elimination of allo-reactive T cells,” Dr Roy said.
“Indeed, the data of patients receiving transplants with a haploidentical donor and an ATIR101 infusion are very similar to those from patients with a matched donor. As a doctor, I am very excited about this development and its potential to change patient fates.”
Dr Roy and his colleagues will continue to follow patients in this trial to collect further long-term outcome data.
Kiadis Pharma is planning to proceed with the development of ATIR101 as an adjunctive immuno-therapeutic treatment to a haploidentical HSCT for patients with acute leukemia, initiating a randomized phase 3 trial in the second half of 2016.
*Information in the abstract differs from that presented at the meeting.
VALENCIA, SPAIN—Results of a phase 2 trial suggest a personalized T-cell immunotherapy may improve outcomes in patients undergoing T-cell-depleted haploidentical hematopoietic stem cell transplant (HSCT).
Patients who received the therapy, ATIR101, after HSCT had significant improvements in transplant-related mortality (TRM) and overall survival (OS) when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.
None of the patients who received ATIR101 developed grade 3-4 graft-versus-host disease (GVHD), despite the fact that they had not received any prophylactic immunosuppressants. Still, there were a few cases of grade 2 GVHD reported.
Denis-Claude Roy, MD, of the University of Montreal in Québec, Canada, presented the results of this trial at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation (abstract O042*). The trial was sponsored by Kiadis Pharma, the company developing ATIR101.
Patients and treatment
The trial included 23 leukemia patients with a median age of 41 (range, 21-64). They were eligible for an allogeneic HSCT but could not find a matching donor in time. Sixteen patients had acute myeloid leukemia, and 7 had acute lymphoblastic leukemia.
All patients were in complete remission (CR) at the time of the HSCT. Fifteen were in CR1, and 8 were in CR2/3. The majority of patients (57%) had a poor prognosis based on their disease risk index and cytogenetic profile.
A myeloablative conditioning regimen was used, which consisted of total body irradiation (1200 cGy; n=11) or melphalan (120 mg/m2; n=12), along with thiotepa (10 mg/kg), fludarabine (30 mg/m2 x 5d), and anti-thymocyte globulin (2.5 mg/kg x 4d).
Patients then received a CD34+ selected graft from a haploidentical donor, containing 11 x 106 CD34+ cells/kg (range, 4.7-24.4) and 0.29 x 104 CD3+ cells/kg (range, 0-1.8).
The patients achieved neutrophil and platelet engraftment at a median of 12 days post-HSCT (range, 8-34 and 9-35, respectively). They did not receive any post-transplant GVHD prophylaxis.
At a median of 28 days post-transplant (range, 28-73), ATIR101 was infused, at a fixed dose of 2 x 106 CD3+ cells/kg.
ATIR101 is a personalized T-cell immunotherapy based on a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.
Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with a compound known as TH9402, which is selectively retained in activated T cells. Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.
Primary endpoint: TRM
The median follow-up, on March 24, 2016, was 414 days (range, 110-742) post-HSCT. At that point, all patients were beyond 6 months post-HSCT. This allowed for assessment of the primary endpoint, which is TRM at 6 months.
Three cases of TRM were reported, for a rate of 13%. In all cases, the cause of death was an infection.
The researchers compared these results to those in a historic control group. It consisted of 35 patients who matched the inclusion and exclusion criteria of this trial and underwent a similar HSCT procedure from haploidentical family members but without the addition of ATIR101.
TRM was significantly lower (P=0.005) in patients who received ATIR101 after a T-cell-depleted haploidentical transplant than in the historical controls. The 6-month TRM for HSCT + ATIR101 was 13%, compared to 37% for HSCT only.
Relapse and survival
Two patients experienced disease relapse within the first 12 months after HSCT—at days 61 and 90. And 1 patient died from disease relapse within the first 6 months.
The researchers said the low rates of relapse and TRM translated into significantly improved OS for patients undergoing HSCT + ATIR101 compared to the historical controls.
Based on Kaplan-Meier estimates, the 1-year OS was 64% in the HSCT + ATIR101 group and 20% in the historical control group (P=0.0026).
GVHD
None of the patients in this trial (0/23) developed grade 3-4 GVHD upon infusion of ATIR101.
However, 3 cases of grade 2 acute GVHD were reported. One case occurred before ATIR101 infusion, and the other 2 cases had a delayed onset, at day 173 and day 247 post-HSCT (145 and 219 days post-ATIR101 infusion).
In the patient who developed GVHD before ATIR101 infusion, GVHD resolved quickly. The patient then received ATIR101 and did not experience any further GVHD.
“With this latest data, we can confirm the safety of ATIR101, without any incidents of grade 3-4 GVHD, significant reduction in transplant-related mortality, low relapse rates, and very good event-free survival, which we believe confirms the efficiency of photodepletion-based elimination of allo-reactive T cells,” Dr Roy said.
“Indeed, the data of patients receiving transplants with a haploidentical donor and an ATIR101 infusion are very similar to those from patients with a matched donor. As a doctor, I am very excited about this development and its potential to change patient fates.”
Dr Roy and his colleagues will continue to follow patients in this trial to collect further long-term outcome data.
Kiadis Pharma is planning to proceed with the development of ATIR101 as an adjunctive immuno-therapeutic treatment to a haploidentical HSCT for patients with acute leukemia, initiating a randomized phase 3 trial in the second half of 2016.
*Information in the abstract differs from that presented at the meeting.
Cancer drugs could treat vascular disorder
Photo by Aaron Logan
Two research teams have found evidence to suggest that mutations in PIK3CA, a gene linked to cancer, may drive venous malformations (VMs) in some patients.
Both groups of researchers showed that PIK3CA mutations give rise to VMs in mice, and PIK3CA mutations are present in humans with VMs.
Subsequent experiments with the mice suggested that PIK3CA inhibitors could be used to treat VMs.
Both groups reported their findings in Science Translational Medicine.
Pau Castel, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues were originally studying the role of PIK3CA in uterine cancer when they noticed that mice harboring PIK3CA mutations developed defective blood vessels that closely resembled VMs.
Sandra Castillo, PhD, of University College London in the UK, and her colleagues generated mice with PIK3CA-activating mutations that also mimicked the human disease, including during mouse embryonic development.
Both teams found the mutations spurred uncontrolled growth of endothelial cells, which formed abnormal clusters and faulty blood vessels.
To verify their mouse models, the researchers analyzed samples from patients with VMs. Dr Castillo and her colleagues looked at samples from 13 children, while Castel and his colleagues evaluated samples from 32 patients (both adults and children).
Dr Castillo and her colleagues found PIK3CA mutations in 25% of patients, and Castel and his colleagues found mutations in PIK3CA and related genes of the PI3K/AKT pathway in about 30% of patients.
Both groups of researchers then tested PI3K inhibitors in their mouse models and found these drugs could stunt blood vessel overgrowth.
“Rapamycin is a drug that blocks a signaling process that happens downstream of PIK3CA, so it stops one of PIK3CA’s effects but does not block it at the source,” Dr Castillo said. “When we gave rapamycin to the mice, it showed clinical benefit, but, in patients, it can have serious side effects and compromise the immune system.”
“Our colleagues at MSK [Memorial Sloan Kettering] then tested drugs on the mice that directly inhibit PIK3CA, developed to treat cancer. These drugs worked well and significantly reduced the size of the malformations, not only when given through the bloodstream but also when applied directly to the skin as a cream.”
Photo by Aaron Logan
Two research teams have found evidence to suggest that mutations in PIK3CA, a gene linked to cancer, may drive venous malformations (VMs) in some patients.
Both groups of researchers showed that PIK3CA mutations give rise to VMs in mice, and PIK3CA mutations are present in humans with VMs.
Subsequent experiments with the mice suggested that PIK3CA inhibitors could be used to treat VMs.
Both groups reported their findings in Science Translational Medicine.
Pau Castel, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues were originally studying the role of PIK3CA in uterine cancer when they noticed that mice harboring PIK3CA mutations developed defective blood vessels that closely resembled VMs.
Sandra Castillo, PhD, of University College London in the UK, and her colleagues generated mice with PIK3CA-activating mutations that also mimicked the human disease, including during mouse embryonic development.
Both teams found the mutations spurred uncontrolled growth of endothelial cells, which formed abnormal clusters and faulty blood vessels.
To verify their mouse models, the researchers analyzed samples from patients with VMs. Dr Castillo and her colleagues looked at samples from 13 children, while Castel and his colleagues evaluated samples from 32 patients (both adults and children).
Dr Castillo and her colleagues found PIK3CA mutations in 25% of patients, and Castel and his colleagues found mutations in PIK3CA and related genes of the PI3K/AKT pathway in about 30% of patients.
Both groups of researchers then tested PI3K inhibitors in their mouse models and found these drugs could stunt blood vessel overgrowth.
“Rapamycin is a drug that blocks a signaling process that happens downstream of PIK3CA, so it stops one of PIK3CA’s effects but does not block it at the source,” Dr Castillo said. “When we gave rapamycin to the mice, it showed clinical benefit, but, in patients, it can have serious side effects and compromise the immune system.”
“Our colleagues at MSK [Memorial Sloan Kettering] then tested drugs on the mice that directly inhibit PIK3CA, developed to treat cancer. These drugs worked well and significantly reduced the size of the malformations, not only when given through the bloodstream but also when applied directly to the skin as a cream.”
Photo by Aaron Logan
Two research teams have found evidence to suggest that mutations in PIK3CA, a gene linked to cancer, may drive venous malformations (VMs) in some patients.
Both groups of researchers showed that PIK3CA mutations give rise to VMs in mice, and PIK3CA mutations are present in humans with VMs.
Subsequent experiments with the mice suggested that PIK3CA inhibitors could be used to treat VMs.
Both groups reported their findings in Science Translational Medicine.
Pau Castel, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues were originally studying the role of PIK3CA in uterine cancer when they noticed that mice harboring PIK3CA mutations developed defective blood vessels that closely resembled VMs.
Sandra Castillo, PhD, of University College London in the UK, and her colleagues generated mice with PIK3CA-activating mutations that also mimicked the human disease, including during mouse embryonic development.
Both teams found the mutations spurred uncontrolled growth of endothelial cells, which formed abnormal clusters and faulty blood vessels.
To verify their mouse models, the researchers analyzed samples from patients with VMs. Dr Castillo and her colleagues looked at samples from 13 children, while Castel and his colleagues evaluated samples from 32 patients (both adults and children).
Dr Castillo and her colleagues found PIK3CA mutations in 25% of patients, and Castel and his colleagues found mutations in PIK3CA and related genes of the PI3K/AKT pathway in about 30% of patients.
Both groups of researchers then tested PI3K inhibitors in their mouse models and found these drugs could stunt blood vessel overgrowth.
“Rapamycin is a drug that blocks a signaling process that happens downstream of PIK3CA, so it stops one of PIK3CA’s effects but does not block it at the source,” Dr Castillo said. “When we gave rapamycin to the mice, it showed clinical benefit, but, in patients, it can have serious side effects and compromise the immune system.”
“Our colleagues at MSK [Memorial Sloan Kettering] then tested drugs on the mice that directly inhibit PIK3CA, developed to treat cancer. These drugs worked well and significantly reduced the size of the malformations, not only when given through the bloodstream but also when applied directly to the skin as a cream.”
Dual inhibitor shows early promise for DLBCL
The small-molecule inhibitor CUDC-907 can provide disease control in patients with relapsed or refractory lymphoma and multiple myeloma (MM), according to researchers.
In a phase 1 trial, CUDC-907 produced responses in a small number of patients with diffuse large B-cell lymphoma (DLBCL).
And more than half of patients had stable disease while on CUDC-907, including those with MM, DLBCL, Hodgkin lymphoma (HL), and other lymphomas.
However, a majority of patients in this trial—84%—discontinued treatment due to confirmed progressive disease or signs of progression.
These results were published in The Lancet. The trial was sponsored by Curis, Inc., the company developing CUDC-907, and the Leukemia and Lymphoma Society.
“The data from the phase 1 monotherapy trial for CUDC-907, especially in heavily pretreated patients with relapsed/refractory DLBCL are very encouraging, and we look forward to data emerging from the current phase 2 trial in patients with MYC-altered DLBCL,” said study author Anas Younes, MD, of the Memorial Sloan Kettering Cancer Center in New York, New York.
CUDC-907 is an oral, dual inhibitor of class I and II histone deacetylases (HDACs), as well as class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6, and 10 and PI3K-alpha, delta, and beta isoforms.
Between Jan 23, 2013, and July 27, 2015, the phase 1 trial of CUDC-907 enrolled 44 patients who were refractory to or had relapsed after 2 or more previous regimens. The patients’ median age was 63 (range, 22-83), and they had received a median of 5 prior treatments (range, 2-10).
Four patients had MM, 12 had HL, and 12 had DLBCL. The remaining 16 patients had other types of lymphoma, including lymphoplasmacytic lymphoma (n=3), small lymphocytic lymphoma (n=3), mantle cell lymphoma (n=3), follicular lymphoma (n=2), T-cell lymphoma (n=2), marginal zone lymphoma (n=1), Burkitt lymphoma (n=1), and gray zone lymphoma (n=1).
Treatment
CUDC-907 was given in a standard 3 + 3 dose-escalation design at 4 different dosing schedules—once daily, twice weekly, 3 times weekly, and daily for 5 days followed by a 2-day break (5/2)—in 21-day cycles.
Patients continued to receive CUDC-907 until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose.
Ten patients were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to 3-times-weekly (MTD 150 mg), and 7 to the 5/2 dosing schedule (MTD 60 mg).
Safety
Four dose-limiting toxicities (DLTs) occurred in 3 of 40 DLT-evaluable patients. The DLTs were diarrhea and hyperglycemia in 1 patient on 60 mg once daily, hyperglycemia in 1 patient on 150 mg twice weekly, and diarrhea in 1 patient on 150 mg 3 times weekly. There were no DLTs in patients on the 5/2 schedule.
The incidence of grade 3 or higher adverse events (AEs) was 43% (19/44). The most common of these AEs were thrombocytopenia (20%, n=9), neutropenia (7%, n=3), and hyperglycemia (7%, n=3).
Twenty-five percent of patients (11/44) had serious AEs. Three of these events were considered treatment-related. They were epistaxis and the DLTs of diarrhea and hyperglycemia.
AEs led to dose reductions in 6 patients (14%) and treatment discontinuation in 7 patients (16%).
Efficacy
Thirty-seven patients were evaluable for response, and 5 of these patients responded (14%). All responses—2 complete and 3 partial responses—occurred in patients with DLBCL.
Twenty-one of the response-evaluable patients (57%) had stable disease. This included 1 patient with DLBCL, 2 with MM, 8 with HL, and 10 with the “other” types of lymphoma.
The remaining 11 patients progressed (30%)—3 with DLBCL, 2 with MM, 2 with HL, and 4 with other lymphomas.
Thirty-seven patients (84%) discontinued CUDC-907 because of progressive disease or clinical signs of progressive disease at the data cutoff.
Based on the clinical activity of CUDC-907 in patients with relapsed/refractory DLBCL, particularly those with MYC alterations, Curis has initiated a phase 2 trial of the drug in these patients. The recommended phase 2 dose is 60 mg on the 5/2 dosing schedule.
The small-molecule inhibitor CUDC-907 can provide disease control in patients with relapsed or refractory lymphoma and multiple myeloma (MM), according to researchers.
In a phase 1 trial, CUDC-907 produced responses in a small number of patients with diffuse large B-cell lymphoma (DLBCL).
And more than half of patients had stable disease while on CUDC-907, including those with MM, DLBCL, Hodgkin lymphoma (HL), and other lymphomas.
However, a majority of patients in this trial—84%—discontinued treatment due to confirmed progressive disease or signs of progression.
These results were published in The Lancet. The trial was sponsored by Curis, Inc., the company developing CUDC-907, and the Leukemia and Lymphoma Society.
“The data from the phase 1 monotherapy trial for CUDC-907, especially in heavily pretreated patients with relapsed/refractory DLBCL are very encouraging, and we look forward to data emerging from the current phase 2 trial in patients with MYC-altered DLBCL,” said study author Anas Younes, MD, of the Memorial Sloan Kettering Cancer Center in New York, New York.
CUDC-907 is an oral, dual inhibitor of class I and II histone deacetylases (HDACs), as well as class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6, and 10 and PI3K-alpha, delta, and beta isoforms.
Between Jan 23, 2013, and July 27, 2015, the phase 1 trial of CUDC-907 enrolled 44 patients who were refractory to or had relapsed after 2 or more previous regimens. The patients’ median age was 63 (range, 22-83), and they had received a median of 5 prior treatments (range, 2-10).
Four patients had MM, 12 had HL, and 12 had DLBCL. The remaining 16 patients had other types of lymphoma, including lymphoplasmacytic lymphoma (n=3), small lymphocytic lymphoma (n=3), mantle cell lymphoma (n=3), follicular lymphoma (n=2), T-cell lymphoma (n=2), marginal zone lymphoma (n=1), Burkitt lymphoma (n=1), and gray zone lymphoma (n=1).
Treatment
CUDC-907 was given in a standard 3 + 3 dose-escalation design at 4 different dosing schedules—once daily, twice weekly, 3 times weekly, and daily for 5 days followed by a 2-day break (5/2)—in 21-day cycles.
Patients continued to receive CUDC-907 until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose.
Ten patients were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to 3-times-weekly (MTD 150 mg), and 7 to the 5/2 dosing schedule (MTD 60 mg).
Safety
Four dose-limiting toxicities (DLTs) occurred in 3 of 40 DLT-evaluable patients. The DLTs were diarrhea and hyperglycemia in 1 patient on 60 mg once daily, hyperglycemia in 1 patient on 150 mg twice weekly, and diarrhea in 1 patient on 150 mg 3 times weekly. There were no DLTs in patients on the 5/2 schedule.
The incidence of grade 3 or higher adverse events (AEs) was 43% (19/44). The most common of these AEs were thrombocytopenia (20%, n=9), neutropenia (7%, n=3), and hyperglycemia (7%, n=3).
Twenty-five percent of patients (11/44) had serious AEs. Three of these events were considered treatment-related. They were epistaxis and the DLTs of diarrhea and hyperglycemia.
AEs led to dose reductions in 6 patients (14%) and treatment discontinuation in 7 patients (16%).
Efficacy
Thirty-seven patients were evaluable for response, and 5 of these patients responded (14%). All responses—2 complete and 3 partial responses—occurred in patients with DLBCL.
Twenty-one of the response-evaluable patients (57%) had stable disease. This included 1 patient with DLBCL, 2 with MM, 8 with HL, and 10 with the “other” types of lymphoma.
The remaining 11 patients progressed (30%)—3 with DLBCL, 2 with MM, 2 with HL, and 4 with other lymphomas.
Thirty-seven patients (84%) discontinued CUDC-907 because of progressive disease or clinical signs of progressive disease at the data cutoff.
Based on the clinical activity of CUDC-907 in patients with relapsed/refractory DLBCL, particularly those with MYC alterations, Curis has initiated a phase 2 trial of the drug in these patients. The recommended phase 2 dose is 60 mg on the 5/2 dosing schedule.
The small-molecule inhibitor CUDC-907 can provide disease control in patients with relapsed or refractory lymphoma and multiple myeloma (MM), according to researchers.
In a phase 1 trial, CUDC-907 produced responses in a small number of patients with diffuse large B-cell lymphoma (DLBCL).
And more than half of patients had stable disease while on CUDC-907, including those with MM, DLBCL, Hodgkin lymphoma (HL), and other lymphomas.
However, a majority of patients in this trial—84%—discontinued treatment due to confirmed progressive disease or signs of progression.
These results were published in The Lancet. The trial was sponsored by Curis, Inc., the company developing CUDC-907, and the Leukemia and Lymphoma Society.
“The data from the phase 1 monotherapy trial for CUDC-907, especially in heavily pretreated patients with relapsed/refractory DLBCL are very encouraging, and we look forward to data emerging from the current phase 2 trial in patients with MYC-altered DLBCL,” said study author Anas Younes, MD, of the Memorial Sloan Kettering Cancer Center in New York, New York.
CUDC-907 is an oral, dual inhibitor of class I and II histone deacetylases (HDACs), as well as class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6, and 10 and PI3K-alpha, delta, and beta isoforms.
Between Jan 23, 2013, and July 27, 2015, the phase 1 trial of CUDC-907 enrolled 44 patients who were refractory to or had relapsed after 2 or more previous regimens. The patients’ median age was 63 (range, 22-83), and they had received a median of 5 prior treatments (range, 2-10).
Four patients had MM, 12 had HL, and 12 had DLBCL. The remaining 16 patients had other types of lymphoma, including lymphoplasmacytic lymphoma (n=3), small lymphocytic lymphoma (n=3), mantle cell lymphoma (n=3), follicular lymphoma (n=2), T-cell lymphoma (n=2), marginal zone lymphoma (n=1), Burkitt lymphoma (n=1), and gray zone lymphoma (n=1).
Treatment
CUDC-907 was given in a standard 3 + 3 dose-escalation design at 4 different dosing schedules—once daily, twice weekly, 3 times weekly, and daily for 5 days followed by a 2-day break (5/2)—in 21-day cycles.
Patients continued to receive CUDC-907 until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose.
Ten patients were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to 3-times-weekly (MTD 150 mg), and 7 to the 5/2 dosing schedule (MTD 60 mg).
Safety
Four dose-limiting toxicities (DLTs) occurred in 3 of 40 DLT-evaluable patients. The DLTs were diarrhea and hyperglycemia in 1 patient on 60 mg once daily, hyperglycemia in 1 patient on 150 mg twice weekly, and diarrhea in 1 patient on 150 mg 3 times weekly. There were no DLTs in patients on the 5/2 schedule.
The incidence of grade 3 or higher adverse events (AEs) was 43% (19/44). The most common of these AEs were thrombocytopenia (20%, n=9), neutropenia (7%, n=3), and hyperglycemia (7%, n=3).
Twenty-five percent of patients (11/44) had serious AEs. Three of these events were considered treatment-related. They were epistaxis and the DLTs of diarrhea and hyperglycemia.
AEs led to dose reductions in 6 patients (14%) and treatment discontinuation in 7 patients (16%).
Efficacy
Thirty-seven patients were evaluable for response, and 5 of these patients responded (14%). All responses—2 complete and 3 partial responses—occurred in patients with DLBCL.
Twenty-one of the response-evaluable patients (57%) had stable disease. This included 1 patient with DLBCL, 2 with MM, 8 with HL, and 10 with the “other” types of lymphoma.
The remaining 11 patients progressed (30%)—3 with DLBCL, 2 with MM, 2 with HL, and 4 with other lymphomas.
Thirty-seven patients (84%) discontinued CUDC-907 because of progressive disease or clinical signs of progressive disease at the data cutoff.
Based on the clinical activity of CUDC-907 in patients with relapsed/refractory DLBCL, particularly those with MYC alterations, Curis has initiated a phase 2 trial of the drug in these patients. The recommended phase 2 dose is 60 mg on the 5/2 dosing schedule.
Macaque-to-human transmission of malaria
Photo by Sakurai Midori
The parasite responsible for a form of malaria now spreading from macaques to humans in South Asia could evolve to infect humans more efficiently, according to a study published in Nature Communications.
Researchers identified a sugar variant on the surface of human red blood cells (RBCs) that currently limits the ability of the parasite Plasmodium knowlesi to invade.
But the team also found the parasite can evolve to get around this barrier and pass into the human population in a more virulent form.
“With increasing concern about the spread of P knowlesi into human populations, it is great to be able to gain insight into what the molecular stumbling blocks are for P knowlesi infection of humans and how the parasite can potentially overcome them,” said study author Selasi Dankwa, PhD, of Harvard T.H. Chan School of Public Health in Boston, Massachusetts.
The macaque malaria parasite P knowlesi has emerged as a major source of human infections in Southeast Asia. While most human infections are mild, increasing numbers of severe infections are being reported, leading to concerns that the parasite is adapting to infect humans more efficiently.
With this in mind, Dr Dankwa and her colleagues decided to explore the parasite’s ability to invade and adapt.
The team introduced the macaque sugar variant onto the human RBC surface and demonstrated that the parasite normally dependent on the macaque variant for invasion was unable to use the human version.
Specifically, macaques synthesize the sialic acid variant N-glycolylneuraminic acid (Neu5Gc), but humans lack Neu5Gc because of an Alu-mediated exon deletion in the gene encoding CMAH, which converts N-acetylneuraminic acid (Neu5Ac) to Neu5Gc.
So the absence of Neu5Gc on human RBCs limits P knowlesi invasion, but the researchers found that parasites can evolve to invade human RBCs via sialic acid-independent pathways.
Following prolonged adaptation to growth on human RBCs, P knowlesi invaded human RBCs independently of Neu5Gc. This occurred via duplication of the region containing the sialic acid-independent gene PkDBPα and complete deletion of the sialic acid-dependent gene PkDBPγ.
Based on these findings, the researchers are calling for continued monitoring of the P knowlesi parasite to ensure that it has not switched to using a sialic acid-independent pathway to invade human RBCs.
Photo by Sakurai Midori
The parasite responsible for a form of malaria now spreading from macaques to humans in South Asia could evolve to infect humans more efficiently, according to a study published in Nature Communications.
Researchers identified a sugar variant on the surface of human red blood cells (RBCs) that currently limits the ability of the parasite Plasmodium knowlesi to invade.
But the team also found the parasite can evolve to get around this barrier and pass into the human population in a more virulent form.
“With increasing concern about the spread of P knowlesi into human populations, it is great to be able to gain insight into what the molecular stumbling blocks are for P knowlesi infection of humans and how the parasite can potentially overcome them,” said study author Selasi Dankwa, PhD, of Harvard T.H. Chan School of Public Health in Boston, Massachusetts.
The macaque malaria parasite P knowlesi has emerged as a major source of human infections in Southeast Asia. While most human infections are mild, increasing numbers of severe infections are being reported, leading to concerns that the parasite is adapting to infect humans more efficiently.
With this in mind, Dr Dankwa and her colleagues decided to explore the parasite’s ability to invade and adapt.
The team introduced the macaque sugar variant onto the human RBC surface and demonstrated that the parasite normally dependent on the macaque variant for invasion was unable to use the human version.
Specifically, macaques synthesize the sialic acid variant N-glycolylneuraminic acid (Neu5Gc), but humans lack Neu5Gc because of an Alu-mediated exon deletion in the gene encoding CMAH, which converts N-acetylneuraminic acid (Neu5Ac) to Neu5Gc.
So the absence of Neu5Gc on human RBCs limits P knowlesi invasion, but the researchers found that parasites can evolve to invade human RBCs via sialic acid-independent pathways.
Following prolonged adaptation to growth on human RBCs, P knowlesi invaded human RBCs independently of Neu5Gc. This occurred via duplication of the region containing the sialic acid-independent gene PkDBPα and complete deletion of the sialic acid-dependent gene PkDBPγ.
Based on these findings, the researchers are calling for continued monitoring of the P knowlesi parasite to ensure that it has not switched to using a sialic acid-independent pathway to invade human RBCs.
Photo by Sakurai Midori
The parasite responsible for a form of malaria now spreading from macaques to humans in South Asia could evolve to infect humans more efficiently, according to a study published in Nature Communications.
Researchers identified a sugar variant on the surface of human red blood cells (RBCs) that currently limits the ability of the parasite Plasmodium knowlesi to invade.
But the team also found the parasite can evolve to get around this barrier and pass into the human population in a more virulent form.
“With increasing concern about the spread of P knowlesi into human populations, it is great to be able to gain insight into what the molecular stumbling blocks are for P knowlesi infection of humans and how the parasite can potentially overcome them,” said study author Selasi Dankwa, PhD, of Harvard T.H. Chan School of Public Health in Boston, Massachusetts.
The macaque malaria parasite P knowlesi has emerged as a major source of human infections in Southeast Asia. While most human infections are mild, increasing numbers of severe infections are being reported, leading to concerns that the parasite is adapting to infect humans more efficiently.
With this in mind, Dr Dankwa and her colleagues decided to explore the parasite’s ability to invade and adapt.
The team introduced the macaque sugar variant onto the human RBC surface and demonstrated that the parasite normally dependent on the macaque variant for invasion was unable to use the human version.
Specifically, macaques synthesize the sialic acid variant N-glycolylneuraminic acid (Neu5Gc), but humans lack Neu5Gc because of an Alu-mediated exon deletion in the gene encoding CMAH, which converts N-acetylneuraminic acid (Neu5Ac) to Neu5Gc.
So the absence of Neu5Gc on human RBCs limits P knowlesi invasion, but the researchers found that parasites can evolve to invade human RBCs via sialic acid-independent pathways.
Following prolonged adaptation to growth on human RBCs, P knowlesi invaded human RBCs independently of Neu5Gc. This occurred via duplication of the region containing the sialic acid-independent gene PkDBPα and complete deletion of the sialic acid-dependent gene PkDBPγ.
Based on these findings, the researchers are calling for continued monitoring of the P knowlesi parasite to ensure that it has not switched to using a sialic acid-independent pathway to invade human RBCs.
MicroRNA could be used to treat DLBCL, team says
A microRNA known as miR-181a dampens signals from the NF-κB pathway and affects the pathogenesis of diffuse large B-cell lymphoma (DLBCL), according to research published in Blood.
The study showed that, by reducing NF-κB signaling, miR-181a hinders tumor cell proliferation and survival.
And the effect is more pronounced in activated B-cell-like (ABC) DLBCL than in germinal center B-cell-like (GCB) DLBCL.
The researchers therefore believe miR-181a could be used to treat ABC DLBCL.
“The miR-181a microRNA is one of the first examples of a pathway that deactivates NF-κB at multiple levels, functioning as a master regulator,” said study author Izidore S. Lossos, MD, of the University of Miami Miller School of Medicine in Florida.
“In certain tumors, there is no expression of this microRNA, which allows cells to propagate. We believe miR-181a could eventually be used
therapeutically.”
To understand the role of miR-181a in the different types of DLBCL, Dr Lossos and his colleaguese studied both cell lines and mouse models.
The team found that miR-181a levels were significantly lower in ABC DLBCL than in GCB DLBCL.
When they increased miR-181a expression in DLBCL cell lines, the researchers observed a reduction in NF-κB activity and a decrease in cell proliferation and survival. These effects were more potent in ABC DLBCL than in GCB DLBCL.
When the researchers increased miR-181a expression in the mouse models, they observed a significant reduction in tumor growth and a significant increase in animal survival, but only in ABC DLBCL. In GCB DLBCL, there were no significant changes compared to controls.
The researchers said the ability of miR-181a to reduce NF-κB levels may be why the presence of miR-181a has been linked to better outcomes for certain DLBCL patients. Previous studies by Dr Lossos’s group have shown that DLBCL patients whose tumors contain more miR-181a have better prognoses.
With the current study, the team found that miR-181a is a master regulator, turning off a number of genes in the NF-κB pathway, including CARD11, a known DLBCL oncogene, and a number of transcription factors that drive NF-κB signaling.
“We knew that miR181a was biomarker for survival,” Dr Lossos said. “This explains the mechanisms behind it.”
In addition to providing a better understanding of the NF-κB pathway, these results provide hope that miR-181a could be used to improve treatment for patients with ABC DLBCL.
“We are trying to develop miR-181a as a potential therapy,” Dr Lossos said. “But we are only at the beginning. Much more work needs to be done. It will not be a simple journey, but we are sure it can be done and tested in humans eventually to see that it indeed will improve patients’ outcomes.”
A microRNA known as miR-181a dampens signals from the NF-κB pathway and affects the pathogenesis of diffuse large B-cell lymphoma (DLBCL), according to research published in Blood.
The study showed that, by reducing NF-κB signaling, miR-181a hinders tumor cell proliferation and survival.
And the effect is more pronounced in activated B-cell-like (ABC) DLBCL than in germinal center B-cell-like (GCB) DLBCL.
The researchers therefore believe miR-181a could be used to treat ABC DLBCL.
“The miR-181a microRNA is one of the first examples of a pathway that deactivates NF-κB at multiple levels, functioning as a master regulator,” said study author Izidore S. Lossos, MD, of the University of Miami Miller School of Medicine in Florida.
“In certain tumors, there is no expression of this microRNA, which allows cells to propagate. We believe miR-181a could eventually be used
therapeutically.”
To understand the role of miR-181a in the different types of DLBCL, Dr Lossos and his colleaguese studied both cell lines and mouse models.
The team found that miR-181a levels were significantly lower in ABC DLBCL than in GCB DLBCL.
When they increased miR-181a expression in DLBCL cell lines, the researchers observed a reduction in NF-κB activity and a decrease in cell proliferation and survival. These effects were more potent in ABC DLBCL than in GCB DLBCL.
When the researchers increased miR-181a expression in the mouse models, they observed a significant reduction in tumor growth and a significant increase in animal survival, but only in ABC DLBCL. In GCB DLBCL, there were no significant changes compared to controls.
The researchers said the ability of miR-181a to reduce NF-κB levels may be why the presence of miR-181a has been linked to better outcomes for certain DLBCL patients. Previous studies by Dr Lossos’s group have shown that DLBCL patients whose tumors contain more miR-181a have better prognoses.
With the current study, the team found that miR-181a is a master regulator, turning off a number of genes in the NF-κB pathway, including CARD11, a known DLBCL oncogene, and a number of transcription factors that drive NF-κB signaling.
“We knew that miR181a was biomarker for survival,” Dr Lossos said. “This explains the mechanisms behind it.”
In addition to providing a better understanding of the NF-κB pathway, these results provide hope that miR-181a could be used to improve treatment for patients with ABC DLBCL.
“We are trying to develop miR-181a as a potential therapy,” Dr Lossos said. “But we are only at the beginning. Much more work needs to be done. It will not be a simple journey, but we are sure it can be done and tested in humans eventually to see that it indeed will improve patients’ outcomes.”
A microRNA known as miR-181a dampens signals from the NF-κB pathway and affects the pathogenesis of diffuse large B-cell lymphoma (DLBCL), according to research published in Blood.
The study showed that, by reducing NF-κB signaling, miR-181a hinders tumor cell proliferation and survival.
And the effect is more pronounced in activated B-cell-like (ABC) DLBCL than in germinal center B-cell-like (GCB) DLBCL.
The researchers therefore believe miR-181a could be used to treat ABC DLBCL.
“The miR-181a microRNA is one of the first examples of a pathway that deactivates NF-κB at multiple levels, functioning as a master regulator,” said study author Izidore S. Lossos, MD, of the University of Miami Miller School of Medicine in Florida.
“In certain tumors, there is no expression of this microRNA, which allows cells to propagate. We believe miR-181a could eventually be used
therapeutically.”
To understand the role of miR-181a in the different types of DLBCL, Dr Lossos and his colleaguese studied both cell lines and mouse models.
The team found that miR-181a levels were significantly lower in ABC DLBCL than in GCB DLBCL.
When they increased miR-181a expression in DLBCL cell lines, the researchers observed a reduction in NF-κB activity and a decrease in cell proliferation and survival. These effects were more potent in ABC DLBCL than in GCB DLBCL.
When the researchers increased miR-181a expression in the mouse models, they observed a significant reduction in tumor growth and a significant increase in animal survival, but only in ABC DLBCL. In GCB DLBCL, there were no significant changes compared to controls.
The researchers said the ability of miR-181a to reduce NF-κB levels may be why the presence of miR-181a has been linked to better outcomes for certain DLBCL patients. Previous studies by Dr Lossos’s group have shown that DLBCL patients whose tumors contain more miR-181a have better prognoses.
With the current study, the team found that miR-181a is a master regulator, turning off a number of genes in the NF-κB pathway, including CARD11, a known DLBCL oncogene, and a number of transcription factors that drive NF-κB signaling.
“We knew that miR181a was biomarker for survival,” Dr Lossos said. “This explains the mechanisms behind it.”
In addition to providing a better understanding of the NF-κB pathway, these results provide hope that miR-181a could be used to improve treatment for patients with ABC DLBCL.
“We are trying to develop miR-181a as a potential therapy,” Dr Lossos said. “But we are only at the beginning. Much more work needs to be done. It will not be a simple journey, but we are sure it can be done and tested in humans eventually to see that it indeed will improve patients’ outcomes.”
Study provides new insight into blood vessel formation
A study published in Nature Cell Biology helps explain how hemodynamic forces contribute to the formation of new vascular lumens during blood vessel morphogenesis.
Investigators found that blood flow drives lumen expansion during sprouting angiogenesis in vivo by inducing spherical deformations of the apical
membrane of endothelial cells, in a process dubbed “inverse blebbing.”
“This work, combined with previous studies, highlights the importance of balanced endothelial cell contractility in allowing the expansion and maintenance of endothelial lumens during blood vessel development,” said study author Holger Gerhardt, PhD, of the Max Delbrück Center for Molecular Medicine in Berlin, Germany.
These results challenge the previous idea that sprouting cells expand lumens independently of blood flow during angiogenesis through the generation and fusion of intracellular vacuoles.
The investigators showed that hemodynamic forces dynamically shape the apical membrane of single or groups of endothelial cells during angiogenesis to form and expand new lumenized vascular tubes.
“We find that this process relies on a tight balance between the forces applied on the membrane and the local contractile responses from the endothelial cells, as impairing this balance either way leads to lumen defects,” Dr Gerhardt said.
These findings suggest the process of blebbing does not require a specific polarity but is likely to be generally applicable to situations in which external versus internal pressure differences challenge the stability and elasticity of the actin cortex.
It more generally raises the question of the role of apical membrane contractility in the adaptation to varying hemodynamic environments, both during blood vessel morphogenesis, as connections form or remodel, and in pathological settings.
“Understanding whether and how this plasticity of the apical membrane and its underlying cortex is challenged in pathological conditions, where vessels exhibit altered perfusion and lack organized structure, has the potential to provide deeper insight into mechanisms of vascular adaptation and maladaptation,” Dr Gerhardt said. “We will definitely further investigate this.”
A study published in Nature Cell Biology helps explain how hemodynamic forces contribute to the formation of new vascular lumens during blood vessel morphogenesis.
Investigators found that blood flow drives lumen expansion during sprouting angiogenesis in vivo by inducing spherical deformations of the apical
membrane of endothelial cells, in a process dubbed “inverse blebbing.”
“This work, combined with previous studies, highlights the importance of balanced endothelial cell contractility in allowing the expansion and maintenance of endothelial lumens during blood vessel development,” said study author Holger Gerhardt, PhD, of the Max Delbrück Center for Molecular Medicine in Berlin, Germany.
These results challenge the previous idea that sprouting cells expand lumens independently of blood flow during angiogenesis through the generation and fusion of intracellular vacuoles.
The investigators showed that hemodynamic forces dynamically shape the apical membrane of single or groups of endothelial cells during angiogenesis to form and expand new lumenized vascular tubes.
“We find that this process relies on a tight balance between the forces applied on the membrane and the local contractile responses from the endothelial cells, as impairing this balance either way leads to lumen defects,” Dr Gerhardt said.
These findings suggest the process of blebbing does not require a specific polarity but is likely to be generally applicable to situations in which external versus internal pressure differences challenge the stability and elasticity of the actin cortex.
It more generally raises the question of the role of apical membrane contractility in the adaptation to varying hemodynamic environments, both during blood vessel morphogenesis, as connections form or remodel, and in pathological settings.
“Understanding whether and how this plasticity of the apical membrane and its underlying cortex is challenged in pathological conditions, where vessels exhibit altered perfusion and lack organized structure, has the potential to provide deeper insight into mechanisms of vascular adaptation and maladaptation,” Dr Gerhardt said. “We will definitely further investigate this.”
A study published in Nature Cell Biology helps explain how hemodynamic forces contribute to the formation of new vascular lumens during blood vessel morphogenesis.
Investigators found that blood flow drives lumen expansion during sprouting angiogenesis in vivo by inducing spherical deformations of the apical
membrane of endothelial cells, in a process dubbed “inverse blebbing.”
“This work, combined with previous studies, highlights the importance of balanced endothelial cell contractility in allowing the expansion and maintenance of endothelial lumens during blood vessel development,” said study author Holger Gerhardt, PhD, of the Max Delbrück Center for Molecular Medicine in Berlin, Germany.
These results challenge the previous idea that sprouting cells expand lumens independently of blood flow during angiogenesis through the generation and fusion of intracellular vacuoles.
The investigators showed that hemodynamic forces dynamically shape the apical membrane of single or groups of endothelial cells during angiogenesis to form and expand new lumenized vascular tubes.
“We find that this process relies on a tight balance between the forces applied on the membrane and the local contractile responses from the endothelial cells, as impairing this balance either way leads to lumen defects,” Dr Gerhardt said.
These findings suggest the process of blebbing does not require a specific polarity but is likely to be generally applicable to situations in which external versus internal pressure differences challenge the stability and elasticity of the actin cortex.
It more generally raises the question of the role of apical membrane contractility in the adaptation to varying hemodynamic environments, both during blood vessel morphogenesis, as connections form or remodel, and in pathological settings.
“Understanding whether and how this plasticity of the apical membrane and its underlying cortex is challenged in pathological conditions, where vessels exhibit altered perfusion and lack organized structure, has the potential to provide deeper insight into mechanisms of vascular adaptation and maladaptation,” Dr Gerhardt said. “We will definitely further investigate this.”
Gene discovery could help fight malaria
Photo by James Gathany
Researchers believe they may have discovered a male-determining gene in the malaria-carrying mosquito species Anopheles gambiae.
The discovery of this gene provides scientists with a foundation for studying male mosquito biology.
And this is significant because male mosquitoes offer the potential to develop novel vector control strategies to combat malaria because males do not feed on blood or transmit disease.
One vector control method under development involves genetic modification of the mosquito to bias the population sex ratio toward males.
Modeling has shown the most efficient means for genetic modification of mosquitoes is engineering a driving Y chromosome.
A molecular-level understanding of the Y chromosome of the malaria-carrying mosquito is important to inform and optimize this type of a strategy.
So Omar Akbari, PhD, of the University of California, Riverside, and his colleagues set out to gain such an understanding.
The team used multiple genome sequencing techniques to identify an extensive dataset of Y chromosome sequences and explore their organization and evolution in the Anopheles gambiae complex, a group of at least 7 morphologically indistinguishable species of mosquitoes in the genus Anopheles.
This revealed that only 1 gene, YG2, is exclusive to the Y chromosome across the species complex and may therefore be a male-determining gene.
Dr Akbari and his colleagues described this discovery in PNAS.
Photo by James Gathany
Researchers believe they may have discovered a male-determining gene in the malaria-carrying mosquito species Anopheles gambiae.
The discovery of this gene provides scientists with a foundation for studying male mosquito biology.
And this is significant because male mosquitoes offer the potential to develop novel vector control strategies to combat malaria because males do not feed on blood or transmit disease.
One vector control method under development involves genetic modification of the mosquito to bias the population sex ratio toward males.
Modeling has shown the most efficient means for genetic modification of mosquitoes is engineering a driving Y chromosome.
A molecular-level understanding of the Y chromosome of the malaria-carrying mosquito is important to inform and optimize this type of a strategy.
So Omar Akbari, PhD, of the University of California, Riverside, and his colleagues set out to gain such an understanding.
The team used multiple genome sequencing techniques to identify an extensive dataset of Y chromosome sequences and explore their organization and evolution in the Anopheles gambiae complex, a group of at least 7 morphologically indistinguishable species of mosquitoes in the genus Anopheles.
This revealed that only 1 gene, YG2, is exclusive to the Y chromosome across the species complex and may therefore be a male-determining gene.
Dr Akbari and his colleagues described this discovery in PNAS.
Photo by James Gathany
Researchers believe they may have discovered a male-determining gene in the malaria-carrying mosquito species Anopheles gambiae.
The discovery of this gene provides scientists with a foundation for studying male mosquito biology.
And this is significant because male mosquitoes offer the potential to develop novel vector control strategies to combat malaria because males do not feed on blood or transmit disease.
One vector control method under development involves genetic modification of the mosquito to bias the population sex ratio toward males.
Modeling has shown the most efficient means for genetic modification of mosquitoes is engineering a driving Y chromosome.
A molecular-level understanding of the Y chromosome of the malaria-carrying mosquito is important to inform and optimize this type of a strategy.
So Omar Akbari, PhD, of the University of California, Riverside, and his colleagues set out to gain such an understanding.
The team used multiple genome sequencing techniques to identify an extensive dataset of Y chromosome sequences and explore their organization and evolution in the Anopheles gambiae complex, a group of at least 7 morphologically indistinguishable species of mosquitoes in the genus Anopheles.
This revealed that only 1 gene, YG2, is exclusive to the Y chromosome across the species complex and may therefore be a male-determining gene.
Dr Akbari and his colleagues described this discovery in PNAS.
CHMP recommends daratumumab for MM
Photo courtesy of Janssen
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended conditional marketing authorization for daratumumab (Darzalex), a first-in-class monoclonal antibody targeting CD38.
The recommended indication for daratumumab is as monotherapy for adults with relapsed and refractory multiple myeloma (MM).
The patients must have progressed on their last therapy and have received treatment with both a proteasome inhibitor and an immunomodulatory agent.
The CHMP’s positive opinion will now be reviewed by the European Commission, which has the authority to grant marketing authorization for medicines in the European Economic Area.
The European Commission’s final decision on daratumumab is anticipated in the coming months.
About conditional authorization
A product may receive conditional marketing authorization if the CHMP finds that, although comprehensive clinical data on the safety and efficacy of the product are not available, all of the following requirements are met:
- The risk-benefit balance of the product is positive
- The company developing the product will likely be in a position to provide comprehensive clinical data in the future
- Unmet medical needs will be fulfilled
- The benefit to public health of the immediate availability of the product outweighs the risk inherent in the fact that additional data are still required.
Conditional marketing authorizations are valid for 1 year, on a renewable basis. The holder will be required to complete ongoing studies or to conduct new studies with a view to confirming that the benefit-risk balance of a product is positive. In addition, specific obligations may be imposed in relation to the collection of pharmacovigilance data.
About daratumumab
Daratumumab is the first CD38-directed monoclonal antibody recommended for approval in Europe. It works by binding to CD38, a signaling molecule highly expressed on the surface of MM cells regardless of stage of disease.
In binding to CD38, daratumumab triggers the patient’s own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple, immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death via apoptosis.
The CHMP’s positive opinion of daratumumab was based on a review of data from the phase 2 SIRIUS study, the phase 1/2 GEN501 study, and 3 additional supportive studies.
The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.
The results suggested daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%. Most adverse events in this study were grade 1 or 2, although serious events did occur.
The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 patients received the drug at 16 mg/kg.
Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.
Findings from a combined efficacy analysis of the GEN501 and SIRIUS trials demonstrated that, after a mean follow-up of 14.8 months, the estimated median overall survival for patients who received single-agent daratumumab at 16 mg/kg was 20 months.
Five phase 3 clinical studies with daratumumab in MM patients—in relapsed and frontline settings—are ongoing. Additional studies are ongoing or planned to assess the drug’s potential in other malignant and pre-malignant diseases in which CD38 is expressed.
Janssen has exclusive worldwide rights to the development, manufacturing, and commercialization of daratumumab for all potential indications. Janssen licensed daratumumab from Genmab A/S in August 2012.
Photo courtesy of Janssen
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended conditional marketing authorization for daratumumab (Darzalex), a first-in-class monoclonal antibody targeting CD38.
The recommended indication for daratumumab is as monotherapy for adults with relapsed and refractory multiple myeloma (MM).
The patients must have progressed on their last therapy and have received treatment with both a proteasome inhibitor and an immunomodulatory agent.
The CHMP’s positive opinion will now be reviewed by the European Commission, which has the authority to grant marketing authorization for medicines in the European Economic Area.
The European Commission’s final decision on daratumumab is anticipated in the coming months.
About conditional authorization
A product may receive conditional marketing authorization if the CHMP finds that, although comprehensive clinical data on the safety and efficacy of the product are not available, all of the following requirements are met:
- The risk-benefit balance of the product is positive
- The company developing the product will likely be in a position to provide comprehensive clinical data in the future
- Unmet medical needs will be fulfilled
- The benefit to public health of the immediate availability of the product outweighs the risk inherent in the fact that additional data are still required.
Conditional marketing authorizations are valid for 1 year, on a renewable basis. The holder will be required to complete ongoing studies or to conduct new studies with a view to confirming that the benefit-risk balance of a product is positive. In addition, specific obligations may be imposed in relation to the collection of pharmacovigilance data.
About daratumumab
Daratumumab is the first CD38-directed monoclonal antibody recommended for approval in Europe. It works by binding to CD38, a signaling molecule highly expressed on the surface of MM cells regardless of stage of disease.
In binding to CD38, daratumumab triggers the patient’s own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple, immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death via apoptosis.
The CHMP’s positive opinion of daratumumab was based on a review of data from the phase 2 SIRIUS study, the phase 1/2 GEN501 study, and 3 additional supportive studies.
The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.
The results suggested daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%. Most adverse events in this study were grade 1 or 2, although serious events did occur.
The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 patients received the drug at 16 mg/kg.
Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.
Findings from a combined efficacy analysis of the GEN501 and SIRIUS trials demonstrated that, after a mean follow-up of 14.8 months, the estimated median overall survival for patients who received single-agent daratumumab at 16 mg/kg was 20 months.
Five phase 3 clinical studies with daratumumab in MM patients—in relapsed and frontline settings—are ongoing. Additional studies are ongoing or planned to assess the drug’s potential in other malignant and pre-malignant diseases in which CD38 is expressed.
Janssen has exclusive worldwide rights to the development, manufacturing, and commercialization of daratumumab for all potential indications. Janssen licensed daratumumab from Genmab A/S in August 2012.
Photo courtesy of Janssen
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended conditional marketing authorization for daratumumab (Darzalex), a first-in-class monoclonal antibody targeting CD38.
The recommended indication for daratumumab is as monotherapy for adults with relapsed and refractory multiple myeloma (MM).
The patients must have progressed on their last therapy and have received treatment with both a proteasome inhibitor and an immunomodulatory agent.
The CHMP’s positive opinion will now be reviewed by the European Commission, which has the authority to grant marketing authorization for medicines in the European Economic Area.
The European Commission’s final decision on daratumumab is anticipated in the coming months.
About conditional authorization
A product may receive conditional marketing authorization if the CHMP finds that, although comprehensive clinical data on the safety and efficacy of the product are not available, all of the following requirements are met:
- The risk-benefit balance of the product is positive
- The company developing the product will likely be in a position to provide comprehensive clinical data in the future
- Unmet medical needs will be fulfilled
- The benefit to public health of the immediate availability of the product outweighs the risk inherent in the fact that additional data are still required.
Conditional marketing authorizations are valid for 1 year, on a renewable basis. The holder will be required to complete ongoing studies or to conduct new studies with a view to confirming that the benefit-risk balance of a product is positive. In addition, specific obligations may be imposed in relation to the collection of pharmacovigilance data.
About daratumumab
Daratumumab is the first CD38-directed monoclonal antibody recommended for approval in Europe. It works by binding to CD38, a signaling molecule highly expressed on the surface of MM cells regardless of stage of disease.
In binding to CD38, daratumumab triggers the patient’s own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple, immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death via apoptosis.
The CHMP’s positive opinion of daratumumab was based on a review of data from the phase 2 SIRIUS study, the phase 1/2 GEN501 study, and 3 additional supportive studies.
The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.
The results suggested daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%. Most adverse events in this study were grade 1 or 2, although serious events did occur.
The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 patients received the drug at 16 mg/kg.
Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.
Findings from a combined efficacy analysis of the GEN501 and SIRIUS trials demonstrated that, after a mean follow-up of 14.8 months, the estimated median overall survival for patients who received single-agent daratumumab at 16 mg/kg was 20 months.
Five phase 3 clinical studies with daratumumab in MM patients—in relapsed and frontline settings—are ongoing. Additional studies are ongoing or planned to assess the drug’s potential in other malignant and pre-malignant diseases in which CD38 is expressed.
Janssen has exclusive worldwide rights to the development, manufacturing, and commercialization of daratumumab for all potential indications. Janssen licensed daratumumab from Genmab A/S in August 2012.
VTE risk varies with hormone therapy
Image by Andre E.X. Brown
Results of a case-control study indicate that estrogen-only hormone therapy carries a lower risk of venous thromboembolism (VTE) than combined estrogen-progestogen therapy.
The study also suggests the type of progestogen a patient receives does not significantly impact the risk of VTE, but the route of administration for estrogen does.
Annica Bergendal, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, and her colleagues reported these findings in Menopause.
The study was conducted in Sweden between 2003 and 2009. It included 838 women with VTE and 891 age-matched control subjects.
Analyses suggested the risk of VTE was almost 2-fold higher in women currently on hormone therapy than in those not taking hormones. The odds ratio (OR)—which was adjusted for smoking, body mass index, and immobilization—was 1.72 (95% CI 1.34-2.20).
Women who took combined estrogen-progestogen therapy had nearly 3 times the VTE risk of those who took no hormones (OR 2.85, 95% CI 2.08-3.90), but the risk was much lower for women who took estrogen alone (OR 1.31, 95% CI 0.78-2.21).
The risk of VTE with combined estrogen-progestogen treatment was about double that of estrogen alone (OR 2.18, 95% CI 1.21-3.92).
Researchers have wondered whether the type of progestogen used makes a difference in the risk of VTE, but this study didn’t show any significant difference in risk between 2 commonly used progestogens.
When oral estrogen was combined with progestogen, the risk of VTE was somewhat, but not significantly, higher among users of medroxyprogesterone acetate (OR 2.94, 95% CI 1.67-5.36) than among users of norethisterone acetate (OR 2.29, 95% CI 1.50-3.40).
On the other hand, the way estrogen was delivered appeared to impact the risk of VTE, with oral estrogen conferring the highest risk.
When the researchers used transdermal estrogen—given alone—as reference, they observed an increased risk of VTE associated with oral estrogen alone (OR 1.84, 95% CI 0.62-5.52).
And when the researchers used locally (vaginally) administered estrogen alone as reference, they saw an increased risk of VTE associated with oral estrogen alone (OR 2.64, 95% CI 1.30-5.38).
Among women using combined estrogen-progestogen treatment, with transdermal estrogen as a reference, there was an increase in VTE risk associated with oral estrogen (OR 2.21, 95% CI 0.88-5.60).
“This study adds to our knowledge that transdermal estrogen therapies are safer than oral, and that different estrogen or progestogen combinations may have different risks,” said JoAnn V. Pinkerton, MD, executive director of the North American Menopause Society, who was not involved in this study.
“The lack of blood clots with transdermal estrogen and with vaginal estrogen is very reassuring for women who need to continue taking hormones as they age, when risk of blood clots increases.”
Image by Andre E.X. Brown
Results of a case-control study indicate that estrogen-only hormone therapy carries a lower risk of venous thromboembolism (VTE) than combined estrogen-progestogen therapy.
The study also suggests the type of progestogen a patient receives does not significantly impact the risk of VTE, but the route of administration for estrogen does.
Annica Bergendal, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, and her colleagues reported these findings in Menopause.
The study was conducted in Sweden between 2003 and 2009. It included 838 women with VTE and 891 age-matched control subjects.
Analyses suggested the risk of VTE was almost 2-fold higher in women currently on hormone therapy than in those not taking hormones. The odds ratio (OR)—which was adjusted for smoking, body mass index, and immobilization—was 1.72 (95% CI 1.34-2.20).
Women who took combined estrogen-progestogen therapy had nearly 3 times the VTE risk of those who took no hormones (OR 2.85, 95% CI 2.08-3.90), but the risk was much lower for women who took estrogen alone (OR 1.31, 95% CI 0.78-2.21).
The risk of VTE with combined estrogen-progestogen treatment was about double that of estrogen alone (OR 2.18, 95% CI 1.21-3.92).
Researchers have wondered whether the type of progestogen used makes a difference in the risk of VTE, but this study didn’t show any significant difference in risk between 2 commonly used progestogens.
When oral estrogen was combined with progestogen, the risk of VTE was somewhat, but not significantly, higher among users of medroxyprogesterone acetate (OR 2.94, 95% CI 1.67-5.36) than among users of norethisterone acetate (OR 2.29, 95% CI 1.50-3.40).
On the other hand, the way estrogen was delivered appeared to impact the risk of VTE, with oral estrogen conferring the highest risk.
When the researchers used transdermal estrogen—given alone—as reference, they observed an increased risk of VTE associated with oral estrogen alone (OR 1.84, 95% CI 0.62-5.52).
And when the researchers used locally (vaginally) administered estrogen alone as reference, they saw an increased risk of VTE associated with oral estrogen alone (OR 2.64, 95% CI 1.30-5.38).
Among women using combined estrogen-progestogen treatment, with transdermal estrogen as a reference, there was an increase in VTE risk associated with oral estrogen (OR 2.21, 95% CI 0.88-5.60).
“This study adds to our knowledge that transdermal estrogen therapies are safer than oral, and that different estrogen or progestogen combinations may have different risks,” said JoAnn V. Pinkerton, MD, executive director of the North American Menopause Society, who was not involved in this study.
“The lack of blood clots with transdermal estrogen and with vaginal estrogen is very reassuring for women who need to continue taking hormones as they age, when risk of blood clots increases.”
Image by Andre E.X. Brown
Results of a case-control study indicate that estrogen-only hormone therapy carries a lower risk of venous thromboembolism (VTE) than combined estrogen-progestogen therapy.
The study also suggests the type of progestogen a patient receives does not significantly impact the risk of VTE, but the route of administration for estrogen does.
Annica Bergendal, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, and her colleagues reported these findings in Menopause.
The study was conducted in Sweden between 2003 and 2009. It included 838 women with VTE and 891 age-matched control subjects.
Analyses suggested the risk of VTE was almost 2-fold higher in women currently on hormone therapy than in those not taking hormones. The odds ratio (OR)—which was adjusted for smoking, body mass index, and immobilization—was 1.72 (95% CI 1.34-2.20).
Women who took combined estrogen-progestogen therapy had nearly 3 times the VTE risk of those who took no hormones (OR 2.85, 95% CI 2.08-3.90), but the risk was much lower for women who took estrogen alone (OR 1.31, 95% CI 0.78-2.21).
The risk of VTE with combined estrogen-progestogen treatment was about double that of estrogen alone (OR 2.18, 95% CI 1.21-3.92).
Researchers have wondered whether the type of progestogen used makes a difference in the risk of VTE, but this study didn’t show any significant difference in risk between 2 commonly used progestogens.
When oral estrogen was combined with progestogen, the risk of VTE was somewhat, but not significantly, higher among users of medroxyprogesterone acetate (OR 2.94, 95% CI 1.67-5.36) than among users of norethisterone acetate (OR 2.29, 95% CI 1.50-3.40).
On the other hand, the way estrogen was delivered appeared to impact the risk of VTE, with oral estrogen conferring the highest risk.
When the researchers used transdermal estrogen—given alone—as reference, they observed an increased risk of VTE associated with oral estrogen alone (OR 1.84, 95% CI 0.62-5.52).
And when the researchers used locally (vaginally) administered estrogen alone as reference, they saw an increased risk of VTE associated with oral estrogen alone (OR 2.64, 95% CI 1.30-5.38).
Among women using combined estrogen-progestogen treatment, with transdermal estrogen as a reference, there was an increase in VTE risk associated with oral estrogen (OR 2.21, 95% CI 0.88-5.60).
“This study adds to our knowledge that transdermal estrogen therapies are safer than oral, and that different estrogen or progestogen combinations may have different risks,” said JoAnn V. Pinkerton, MD, executive director of the North American Menopause Society, who was not involved in this study.
“The lack of blood clots with transdermal estrogen and with vaginal estrogen is very reassuring for women who need to continue taking hormones as they age, when risk of blood clots increases.”