Blood for transfusion

Credit: UAB Hospital

Long-term mortality is not affected by the amount of blood a patient receives following surgery, according to research published in The Lancet.

Investigators compared a liberal transfusion strategy, in which patients received blood to maintain a hemoglobin level at 100 g/L or higher, and a restrictive strategy, in which patients received blood when hemoglobin levels were lower than 80 g/L or if they had symptoms of anemia.

And, at about 3 years of follow-up, there was no difference in mortality between the two groups.

Jeffrey L. Carson, MD, of Robert Wood Johnson Medical School in New Jersey, and his colleagues conducted this research, analyzing data from the FOCUS trial, which included patients from 47 hospitals in the US and Canada.

The trial enrolled 2016 adults age 50 and older, with a history of or risk factors for cardiovascular disease, who had postoperative hemoglobin concentrations lower than 100 g/L within 3 days of surgery to repair a hip fracture.

Patients were randomized by a central telephone system to the liberal (n=1007) or restrictive (n=1009) transfusion groups. The investigators analyzed the long-term mortality of these patients, which was established by linking participants to national death registries in the US and Canada.

The results revealed no difference in mortality from cardiovascular disease, cancer, or severe infection due to the amount of the blood given after surgery.

This supports the initial results of the FOCUS trial, which Dr Carson and his colleagues published in NEJM in 2011 and which demonstrated the safety of fewer transfusions in the short-term.

For the current analysis, the median duration of follow-up was 3.1 years. Eight hundred and forty-one patients (42%) died during that time—432 in the liberal transfusion group and 409 in the restrictive transfusion group. This difference was not statistically significant, with a hazard ratio of 1.09 and a P value of 0.21.

“There has been a steady decline in the amount of blood in transfusions given to patients in the past 3 to 5 years,” Dr Carson noted. “I think it is very reassuring that we have found that using less blood is okay, not just from a short-term perspective, but also a long-term perspective.”

Medical experts had worried that larger amounts of transfused blood might suppress immune function—which could lead to death from infection or cancer—or that smaller transfusions might worsen a patient’s chronic heart disease by depriving the heart of oxygen and other nutrients that it might have absorbed by pumping more blood.

But in both instances, Dr Carson and his colleagues found no difference in long-term death rates, regardless of the number of transfusions.

Dr Carson noted that there are health conditions, such as heart attacks, where the effects of the two transfusion strategies are less certain. Preliminary evidence suggests heart attack patients need more blood, not less. But additional studies are needed to confirm that.

Blood for transfusion

Credit: UAB Hospital

Long-term mortality is not affected by the amount of blood a patient receives following surgery, according to research published in The Lancet.

Investigators compared a liberal transfusion strategy, in which patients received blood to maintain a hemoglobin level at 100 g/L or higher, and a restrictive strategy, in which patients received blood when hemoglobin levels were lower than 80 g/L or if they had symptoms of anemia.

And, at about 3 years of follow-up, there was no difference in mortality between the two groups.

Jeffrey L. Carson, MD, of Robert Wood Johnson Medical School in New Jersey, and his colleagues conducted this research, analyzing data from the FOCUS trial, which included patients from 47 hospitals in the US and Canada.

The trial enrolled 2016 adults age 50 and older, with a history of or risk factors for cardiovascular disease, who had postoperative hemoglobin concentrations lower than 100 g/L within 3 days of surgery to repair a hip fracture.

Patients were randomized by a central telephone system to the liberal (n=1007) or restrictive (n=1009) transfusion groups. The investigators analyzed the long-term mortality of these patients, which was established by linking participants to national death registries in the US and Canada.

The results revealed no difference in mortality from cardiovascular disease, cancer, or severe infection due to the amount of the blood given after surgery.

This supports the initial results of the FOCUS trial, which Dr Carson and his colleagues published in NEJM in 2011 and which demonstrated the safety of fewer transfusions in the short-term.

For the current analysis, the median duration of follow-up was 3.1 years. Eight hundred and forty-one patients (42%) died during that time—432 in the liberal transfusion group and 409 in the restrictive transfusion group. This difference was not statistically significant, with a hazard ratio of 1.09 and a P value of 0.21.

“There has been a steady decline in the amount of blood in transfusions given to patients in the past 3 to 5 years,” Dr Carson noted. “I think it is very reassuring that we have found that using less blood is okay, not just from a short-term perspective, but also a long-term perspective.”

Medical experts had worried that larger amounts of transfused blood might suppress immune function—which could lead to death from infection or cancer—or that smaller transfusions might worsen a patient’s chronic heart disease by depriving the heart of oxygen and other nutrients that it might have absorbed by pumping more blood.

But in both instances, Dr Carson and his colleagues found no difference in long-term death rates, regardless of the number of transfusions.

Dr Carson noted that there are health conditions, such as heart attacks, where the effects of the two transfusion strategies are less certain. Preliminary evidence suggests heart attack patients need more blood, not less. But additional studies are needed to confirm that.

Blood for transfusion

Credit: UAB Hospital

Long-term mortality is not affected by the amount of blood a patient receives following surgery, according to research published in The Lancet.

Investigators compared a liberal transfusion strategy, in which patients received blood to maintain a hemoglobin level at 100 g/L or higher, and a restrictive strategy, in which patients received blood when hemoglobin levels were lower than 80 g/L or if they had symptoms of anemia.

And, at about 3 years of follow-up, there was no difference in mortality between the two groups.

Jeffrey L. Carson, MD, of Robert Wood Johnson Medical School in New Jersey, and his colleagues conducted this research, analyzing data from the FOCUS trial, which included patients from 47 hospitals in the US and Canada.

The trial enrolled 2016 adults age 50 and older, with a history of or risk factors for cardiovascular disease, who had postoperative hemoglobin concentrations lower than 100 g/L within 3 days of surgery to repair a hip fracture.

Patients were randomized by a central telephone system to the liberal (n=1007) or restrictive (n=1009) transfusion groups. The investigators analyzed the long-term mortality of these patients, which was established by linking participants to national death registries in the US and Canada.

The results revealed no difference in mortality from cardiovascular disease, cancer, or severe infection due to the amount of the blood given after surgery.

This supports the initial results of the FOCUS trial, which Dr Carson and his colleagues published in NEJM in 2011 and which demonstrated the safety of fewer transfusions in the short-term.

For the current analysis, the median duration of follow-up was 3.1 years. Eight hundred and forty-one patients (42%) died during that time—432 in the liberal transfusion group and 409 in the restrictive transfusion group. This difference was not statistically significant, with a hazard ratio of 1.09 and a P value of 0.21.

“There has been a steady decline in the amount of blood in transfusions given to patients in the past 3 to 5 years,” Dr Carson noted. “I think it is very reassuring that we have found that using less blood is okay, not just from a short-term perspective, but also a long-term perspective.”

Medical experts had worried that larger amounts of transfused blood might suppress immune function—which could lead to death from infection or cancer—or that smaller transfusions might worsen a patient’s chronic heart disease by depriving the heart of oxygen and other nutrients that it might have absorbed by pumping more blood.

But in both instances, Dr Carson and his colleagues found no difference in long-term death rates, regardless of the number of transfusions.

Dr Carson noted that there are health conditions, such as heart attacks, where the effects of the two transfusion strategies are less certain. Preliminary evidence suggests heart attack patients need more blood, not less. But additional studies are needed to confirm that.

AML in the bone marrow

Researchers say they’ve identified novel prognostic markers for older patients with cytogenetically normal acute myeloid leukemia (CN-AML).

The team examined the expression of long noncoding RNAs (lncRNAs) in patients with CN-AML who were at least 60 years of age.

This revealed a pattern of 48 lncRNAs that predicted both response to standard chemotherapy and overall survival.

The researchers described this discovery in PNAS.

“[Our findings] strongly suggest that lncRNA expression profiles can predict which patients will respond to standard therapy,” said principal investigator Clara D. Bloomfield, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“That’s important because it would spare these patients from the toxic side effects of experimental therapies. Patients who are classified in the unfavorable group would receive different therapy: stem cell transplant or a clinical trial using new therapeutic approaches. Thus, this research will help to tailor leukemia therapy to each individual.”

In addition, she said, the study revealed novel targets for the development of new therapies.

Dr Bloomfield and her colleagues began this research by analyzing bone marrow samples from 148 older patients with CN-AML who were treated on Cancer and Leukemia Group B clinical trials. All had received similar chemotherapy regimens.

The researchers first identified the 48 lncRNAs that were most associated with survival. Using these 48 lncRNAs, the team divided patients into two groups: those with a favorable prognostic score and those with an unfavorable score.

The researchers then validated the scores in an independent matched set of 71 similarly treated CN-AML patients and compared patients with an unfavorable score to those with a favorable score.

Results showed that patients with an unfavorable score had a lower complete response (CR) rate—54%, compared to 89% for patients with a favorable score.

Three years after CR, only 7% of patients with an unfavorable score were disease-free, compared with 39% of patients with a favorable score.

Overall survival at 3 years for those with an unfavorable score was 10%, compared to 43% for patients with a favorable score.

Distinct lncRNA profiles were associated with mutations in 6 genes—FLT3, NPM1, CEBPA, IDH2, ASXL1, and RUNX1.

The researchers concluded that lncRNA expression profiles are associated with recurrent mutations, clinical features, and outcome in AML. A fraction of these lncRNAs may have a functional role in leukemogenesis. Furthermore, lncRNAs could be used as biomarkers for outcome in AML.

AML in the bone marrow

Researchers say they’ve identified novel prognostic markers for older patients with cytogenetically normal acute myeloid leukemia (CN-AML).

The team examined the expression of long noncoding RNAs (lncRNAs) in patients with CN-AML who were at least 60 years of age.

This revealed a pattern of 48 lncRNAs that predicted both response to standard chemotherapy and overall survival.

The researchers described this discovery in PNAS.

“[Our findings] strongly suggest that lncRNA expression profiles can predict which patients will respond to standard therapy,” said principal investigator Clara D. Bloomfield, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“That’s important because it would spare these patients from the toxic side effects of experimental therapies. Patients who are classified in the unfavorable group would receive different therapy: stem cell transplant or a clinical trial using new therapeutic approaches. Thus, this research will help to tailor leukemia therapy to each individual.”

In addition, she said, the study revealed novel targets for the development of new therapies.

Dr Bloomfield and her colleagues began this research by analyzing bone marrow samples from 148 older patients with CN-AML who were treated on Cancer and Leukemia Group B clinical trials. All had received similar chemotherapy regimens.

The researchers first identified the 48 lncRNAs that were most associated with survival. Using these 48 lncRNAs, the team divided patients into two groups: those with a favorable prognostic score and those with an unfavorable score.

The researchers then validated the scores in an independent matched set of 71 similarly treated CN-AML patients and compared patients with an unfavorable score to those with a favorable score.

Results showed that patients with an unfavorable score had a lower complete response (CR) rate—54%, compared to 89% for patients with a favorable score.

Three years after CR, only 7% of patients with an unfavorable score were disease-free, compared with 39% of patients with a favorable score.

Overall survival at 3 years for those with an unfavorable score was 10%, compared to 43% for patients with a favorable score.

Distinct lncRNA profiles were associated with mutations in 6 genes—FLT3, NPM1, CEBPA, IDH2, ASXL1, and RUNX1.

The researchers concluded that lncRNA expression profiles are associated with recurrent mutations, clinical features, and outcome in AML. A fraction of these lncRNAs may have a functional role in leukemogenesis. Furthermore, lncRNAs could be used as biomarkers for outcome in AML.

AML in the bone marrow

Researchers say they’ve identified novel prognostic markers for older patients with cytogenetically normal acute myeloid leukemia (CN-AML).

The team examined the expression of long noncoding RNAs (lncRNAs) in patients with CN-AML who were at least 60 years of age.

This revealed a pattern of 48 lncRNAs that predicted both response to standard chemotherapy and overall survival.

The researchers described this discovery in PNAS.

“[Our findings] strongly suggest that lncRNA expression profiles can predict which patients will respond to standard therapy,” said principal investigator Clara D. Bloomfield, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“That’s important because it would spare these patients from the toxic side effects of experimental therapies. Patients who are classified in the unfavorable group would receive different therapy: stem cell transplant or a clinical trial using new therapeutic approaches. Thus, this research will help to tailor leukemia therapy to each individual.”

In addition, she said, the study revealed novel targets for the development of new therapies.

Dr Bloomfield and her colleagues began this research by analyzing bone marrow samples from 148 older patients with CN-AML who were treated on Cancer and Leukemia Group B clinical trials. All had received similar chemotherapy regimens.

The researchers first identified the 48 lncRNAs that were most associated with survival. Using these 48 lncRNAs, the team divided patients into two groups: those with a favorable prognostic score and those with an unfavorable score.

The researchers then validated the scores in an independent matched set of 71 similarly treated CN-AML patients and compared patients with an unfavorable score to those with a favorable score.

Results showed that patients with an unfavorable score had a lower complete response (CR) rate—54%, compared to 89% for patients with a favorable score.

Three years after CR, only 7% of patients with an unfavorable score were disease-free, compared with 39% of patients with a favorable score.

Overall survival at 3 years for those with an unfavorable score was 10%, compared to 43% for patients with a favorable score.

Distinct lncRNA profiles were associated with mutations in 6 genes—FLT3, NPM1, CEBPA, IDH2, ASXL1, and RUNX1.

The researchers concluded that lncRNA expression profiles are associated with recurrent mutations, clinical features, and outcome in AML. A fraction of these lncRNAs may have a functional role in leukemogenesis. Furthermore, lncRNAs could be used as biomarkers for outcome in AML.

As detailed in Part 1 of this installment on uterine anomalies, a uterus that has developed abnormally can appear to be normal on 2D sonography and on unenhanced sonohysterography (Figure). Without the application of 3D coronal ultrasonography, accurate identification of the fundal contour, and ultimately the type and classification of the uterine anomaly, is not possible.^1-3 Fortunately, the lowered cost (compared with magnetic resonance imaging) and the noninvasive nature of this more detailed imaging modality makes its use convenient to both the physician and the patient.

In part 1 of this 2-part installment of our imaging series, we discussed the frequency with which uterine anomalies occur and their types and classifications, as well as offered an imaging library showing the normal endometrial cavity, arcuate uterus, incomplete (partial) uterine septum, and complete uterine septum. Here, we provide two cases demonstrating 3D sonography of the unicornuate, bicornuate, didelphic, and DES-exposed uterus.

A.	B.
C.	D.
E.	F.

 

G.

In sagittal view, a uterus with a congenital anomaly can appear normal. Sagittal views of a normal uterus (A) and didelphic uterus (B) and sonohysterogram of a unicornuate uterus (C). Transverse views of a normal (D) and didelphic uterus (E). 3D coronal views of a normal (F) and didelphic uterus (G).

Case 1: Unicornuate uterus

Transverse view of Mirena IUD in right horn and noncommunicating rudimentary left horn.

Case 2: Bicornuate uterus, with concave contour

A patient reporting pelvic pain is examined by 2D sonography, which reveals a bicornuate uterus (A). Note the concave fundal contour (arrow), indicating bicornuate uterus, both horns communicating. 3D imaging (B) revealing fundal “dimple” (concave contour, >1 cm), which is indicative of bicornuate uterus.  Complete separation of cavities (C).

A.

A patient presenting with primary infertility is found to have a didelphic uterus on 2D and 3D imaging. Note complete separation of uterine cavities on transverse, 2D views (A and B). The left horn sagittal, 2D view shows a normal appearing uterus (C). 3D imaging (D).

A.

B.

C.

D.

Additional images

As detailed in Part 1 of this installment on uterine anomalies, a uterus that has developed abnormally can appear to be normal on 2D sonography and on unenhanced sonohysterography (Figure). Without the application of 3D coronal ultrasonography, accurate identification of the fundal contour, and ultimately the type and classification of the uterine anomaly, is not possible.^1-3 Fortunately, the lowered cost (compared with magnetic resonance imaging) and the noninvasive nature of this more detailed imaging modality makes its use convenient to both the physician and the patient.

In part 1 of this 2-part installment of our imaging series, we discussed the frequency with which uterine anomalies occur and their types and classifications, as well as offered an imaging library showing the normal endometrial cavity, arcuate uterus, incomplete (partial) uterine septum, and complete uterine septum. Here, we provide two cases demonstrating 3D sonography of the unicornuate, bicornuate, didelphic, and DES-exposed uterus.

A.	B.
C.	D.
E.	F.

 

G.

In sagittal view, a uterus with a congenital anomaly can appear normal. Sagittal views of a normal uterus (A) and didelphic uterus (B) and sonohysterogram of a unicornuate uterus (C). Transverse views of a normal (D) and didelphic uterus (E). 3D coronal views of a normal (F) and didelphic uterus (G).

Case 1: Unicornuate uterus

Transverse view of Mirena IUD in right horn and noncommunicating rudimentary left horn.

Case 2: Bicornuate uterus, with concave contour

A patient reporting pelvic pain is examined by 2D sonography, which reveals a bicornuate uterus (A). Note the concave fundal contour (arrow), indicating bicornuate uterus, both horns communicating. 3D imaging (B) revealing fundal “dimple” (concave contour, >1 cm), which is indicative of bicornuate uterus.  Complete separation of cavities (C).

A.

A patient presenting with primary infertility is found to have a didelphic uterus on 2D and 3D imaging. Note complete separation of uterine cavities on transverse, 2D views (A and B). The left horn sagittal, 2D view shows a normal appearing uterus (C). 3D imaging (D).

A.

B.

C.

D.

Additional images

As detailed in Part 1 of this installment on uterine anomalies, a uterus that has developed abnormally can appear to be normal on 2D sonography and on unenhanced sonohysterography (Figure). Without the application of 3D coronal ultrasonography, accurate identification of the fundal contour, and ultimately the type and classification of the uterine anomaly, is not possible.^1-3 Fortunately, the lowered cost (compared with magnetic resonance imaging) and the noninvasive nature of this more detailed imaging modality makes its use convenient to both the physician and the patient.

In part 1 of this 2-part installment of our imaging series, we discussed the frequency with which uterine anomalies occur and their types and classifications, as well as offered an imaging library showing the normal endometrial cavity, arcuate uterus, incomplete (partial) uterine septum, and complete uterine septum. Here, we provide two cases demonstrating 3D sonography of the unicornuate, bicornuate, didelphic, and DES-exposed uterus.

A.	B.
C.	D.
E.	F.

 

G.

In sagittal view, a uterus with a congenital anomaly can appear normal. Sagittal views of a normal uterus (A) and didelphic uterus (B) and sonohysterogram of a unicornuate uterus (C). Transverse views of a normal (D) and didelphic uterus (E). 3D coronal views of a normal (F) and didelphic uterus (G).

Case 1: Unicornuate uterus

Transverse view of Mirena IUD in right horn and noncommunicating rudimentary left horn.

Case 2: Bicornuate uterus, with concave contour

A patient reporting pelvic pain is examined by 2D sonography, which reveals a bicornuate uterus (A). Note the concave fundal contour (arrow), indicating bicornuate uterus, both horns communicating. 3D imaging (B) revealing fundal “dimple” (concave contour, >1 cm), which is indicative of bicornuate uterus.  Complete separation of cavities (C).

A.

A patient presenting with primary infertility is found to have a didelphic uterus on 2D and 3D imaging. Note complete separation of uterine cavities on transverse, 2D views (A and B). The left horn sagittal, 2D view shows a normal appearing uterus (C). 3D imaging (D).

A.

B.

C.

D.

Additional images

SAN FRANCISCO – CAR-T cell therapy drove relapsed, refractory acute lymphoblastic leukemia into complete remission in 92% or all but three of 39 children in a phase I/IIa study.

Complete responses were seen within 28 days of receiving a chimeric antigen receptor (CAR)-T cell infusion and have persisted in 15 patients for a year or more, Dr. Stephan A. Grupp reported at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

Ten relapses have occurred during follow-up of up to 31 months (median 6 months). Half were due to disappearance of the T cells, resulting in CD19-positive relapse, and half were related to antigen escape, resulting in CD19-negative relapse.

Five of the relapsed patients died. No events have been seen in patients who remain in remission after 12 months.

Importantly, CAR-T cell therapy was not used as a bridge to transplant, with only three patients subsequently going on to stem cell transplantation, Dr. Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia (CHOP) and professor of pediatrics at the University of Pennsylvania, said during a press briefing.

When asked whether CAR-T therapy could be a replacement for transplantation in the future, Dr. Grupp responded, “That would be my fondest hope. We’re not quite there yet, but we’re a lot closer than we used to be.”

The novel immunotherapy first hit the front pages in 2011 after researchers at CHOP and the University of Pennsylvania reported breakthrough results in a handful of children treated with CTL019 cells. T cells are collected from the patient and then genetically reengineered with a CAR directed against tumor B cells expressing the CD19 surface antigen.

More than 130 patients have now been treated by the Pennsylvania team with the CTL019 approach, which received breakthrough therapy status from the Food and Drug Administration in July 2014.

The updated results presented by Dr. Grupp build on those reported earlier this year (N. Engl. J. Med. 2014;371:1507-17) and involve 39 children and young adults. This includes the first 30 pediatric patients with relapsed, refractory ALL treated in the pilot trial. Their median age was 10 years and most were refractory to multiple prior therapies.

At 6 months, the duration of response was 76% and event-free survival was 70%.

The ability of patients to retain their T cells for 6 months or longer was observed in about two-thirds of patients and “is a key point in maintaining remission in these patients,” Dr. Grupp said.

Response rates were independent of disease burden at the time of infusion: 82% response in patients with more than 50% leukemia blast cells, 88% in those with more than 5% blasts, and 100% in those with 0.01%-5% blasts or less than 0.01% blasts.

Patients with higher baseline disease burden (more than 50% blasts), however, were significantly more likely to experience severe cytokine release syndrome (CRS), compared with those with lower disease burden (P < .002).

CRS has been seen across CAR-T cell studies, but there are insufficient data to determine whether this toxicity differs between adult and pediatric patients.

“The key to the cytokine release syndrome, and I believe this carries across platforms and actually may also apply to blinatumomab, is the amplification of the macrophage system through interleukin-6,” Dr. Grupp explained. “This is a classical feedback loop that is actually druggable” using the IL-6 receptor blocker tocilizumab (Actemra).

This strategy produced “remarkable control” of the CRS toxicity, with many of the severe CRS cases experiencing resolution within hours and all cases resolving within 2-3 days, he said.

B-cell aplasia was observed in all responding patients to date and was managed with intravenous immunoglobulin replacement therapy.

The two key questions for the future of CTL019 therapy are toxicity and the logistics of collecting a cell sample and sending it to a centralized manufacturing facility, Dr. Grupp said. This process has already been done on a small scale at CHOP because their cells are made at the University of Pennsylvania. Novartis, which licensed the technology, has built a cell-manufacturing facility and an ongoing phase II study is evaluating whether the technology can be safely rolled out to eight or nine pediatric centers across the country. An adult study will follow, he said.

[email protected]

SAN FRANCISCO – CAR-T cell therapy drove relapsed, refractory acute lymphoblastic leukemia into complete remission in 92% or all but three of 39 children in a phase I/IIa study.

Complete responses were seen within 28 days of receiving a chimeric antigen receptor (CAR)-T cell infusion and have persisted in 15 patients for a year or more, Dr. Stephan A. Grupp reported at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

Ten relapses have occurred during follow-up of up to 31 months (median 6 months). Half were due to disappearance of the T cells, resulting in CD19-positive relapse, and half were related to antigen escape, resulting in CD19-negative relapse.

Five of the relapsed patients died. No events have been seen in patients who remain in remission after 12 months.

Importantly, CAR-T cell therapy was not used as a bridge to transplant, with only three patients subsequently going on to stem cell transplantation, Dr. Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia (CHOP) and professor of pediatrics at the University of Pennsylvania, said during a press briefing.

When asked whether CAR-T therapy could be a replacement for transplantation in the future, Dr. Grupp responded, “That would be my fondest hope. We’re not quite there yet, but we’re a lot closer than we used to be.”

The novel immunotherapy first hit the front pages in 2011 after researchers at CHOP and the University of Pennsylvania reported breakthrough results in a handful of children treated with CTL019 cells. T cells are collected from the patient and then genetically reengineered with a CAR directed against tumor B cells expressing the CD19 surface antigen.

More than 130 patients have now been treated by the Pennsylvania team with the CTL019 approach, which received breakthrough therapy status from the Food and Drug Administration in July 2014.

The updated results presented by Dr. Grupp build on those reported earlier this year (N. Engl. J. Med. 2014;371:1507-17) and involve 39 children and young adults. This includes the first 30 pediatric patients with relapsed, refractory ALL treated in the pilot trial. Their median age was 10 years and most were refractory to multiple prior therapies.

At 6 months, the duration of response was 76% and event-free survival was 70%.

The ability of patients to retain their T cells for 6 months or longer was observed in about two-thirds of patients and “is a key point in maintaining remission in these patients,” Dr. Grupp said.

Response rates were independent of disease burden at the time of infusion: 82% response in patients with more than 50% leukemia blast cells, 88% in those with more than 5% blasts, and 100% in those with 0.01%-5% blasts or less than 0.01% blasts.

Patients with higher baseline disease burden (more than 50% blasts), however, were significantly more likely to experience severe cytokine release syndrome (CRS), compared with those with lower disease burden (P < .002).

CRS has been seen across CAR-T cell studies, but there are insufficient data to determine whether this toxicity differs between adult and pediatric patients.

“The key to the cytokine release syndrome, and I believe this carries across platforms and actually may also apply to blinatumomab, is the amplification of the macrophage system through interleukin-6,” Dr. Grupp explained. “This is a classical feedback loop that is actually druggable” using the IL-6 receptor blocker tocilizumab (Actemra).

This strategy produced “remarkable control” of the CRS toxicity, with many of the severe CRS cases experiencing resolution within hours and all cases resolving within 2-3 days, he said.

B-cell aplasia was observed in all responding patients to date and was managed with intravenous immunoglobulin replacement therapy.

The two key questions for the future of CTL019 therapy are toxicity and the logistics of collecting a cell sample and sending it to a centralized manufacturing facility, Dr. Grupp said. This process has already been done on a small scale at CHOP because their cells are made at the University of Pennsylvania. Novartis, which licensed the technology, has built a cell-manufacturing facility and an ongoing phase II study is evaluating whether the technology can be safely rolled out to eight or nine pediatric centers across the country. An adult study will follow, he said.

[email protected]

SAN FRANCISCO – CAR-T cell therapy drove relapsed, refractory acute lymphoblastic leukemia into complete remission in 92% or all but three of 39 children in a phase I/IIa study.

Complete responses were seen within 28 days of receiving a chimeric antigen receptor (CAR)-T cell infusion and have persisted in 15 patients for a year or more, Dr. Stephan A. Grupp reported at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

Ten relapses have occurred during follow-up of up to 31 months (median 6 months). Half were due to disappearance of the T cells, resulting in CD19-positive relapse, and half were related to antigen escape, resulting in CD19-negative relapse.

Five of the relapsed patients died. No events have been seen in patients who remain in remission after 12 months.

Importantly, CAR-T cell therapy was not used as a bridge to transplant, with only three patients subsequently going on to stem cell transplantation, Dr. Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia (CHOP) and professor of pediatrics at the University of Pennsylvania, said during a press briefing.

When asked whether CAR-T therapy could be a replacement for transplantation in the future, Dr. Grupp responded, “That would be my fondest hope. We’re not quite there yet, but we’re a lot closer than we used to be.”

The novel immunotherapy first hit the front pages in 2011 after researchers at CHOP and the University of Pennsylvania reported breakthrough results in a handful of children treated with CTL019 cells. T cells are collected from the patient and then genetically reengineered with a CAR directed against tumor B cells expressing the CD19 surface antigen.

More than 130 patients have now been treated by the Pennsylvania team with the CTL019 approach, which received breakthrough therapy status from the Food and Drug Administration in July 2014.

The updated results presented by Dr. Grupp build on those reported earlier this year (N. Engl. J. Med. 2014;371:1507-17) and involve 39 children and young adults. This includes the first 30 pediatric patients with relapsed, refractory ALL treated in the pilot trial. Their median age was 10 years and most were refractory to multiple prior therapies.

At 6 months, the duration of response was 76% and event-free survival was 70%.

The ability of patients to retain their T cells for 6 months or longer was observed in about two-thirds of patients and “is a key point in maintaining remission in these patients,” Dr. Grupp said.

Response rates were independent of disease burden at the time of infusion: 82% response in patients with more than 50% leukemia blast cells, 88% in those with more than 5% blasts, and 100% in those with 0.01%-5% blasts or less than 0.01% blasts.

Patients with higher baseline disease burden (more than 50% blasts), however, were significantly more likely to experience severe cytokine release syndrome (CRS), compared with those with lower disease burden (P < .002).

CRS has been seen across CAR-T cell studies, but there are insufficient data to determine whether this toxicity differs between adult and pediatric patients.

“The key to the cytokine release syndrome, and I believe this carries across platforms and actually may also apply to blinatumomab, is the amplification of the macrophage system through interleukin-6,” Dr. Grupp explained. “This is a classical feedback loop that is actually druggable” using the IL-6 receptor blocker tocilizumab (Actemra).

This strategy produced “remarkable control” of the CRS toxicity, with many of the severe CRS cases experiencing resolution within hours and all cases resolving within 2-3 days, he said.

B-cell aplasia was observed in all responding patients to date and was managed with intravenous immunoglobulin replacement therapy.

The two key questions for the future of CTL019 therapy are toxicity and the logistics of collecting a cell sample and sending it to a centralized manufacturing facility, Dr. Grupp said. This process has already been done on a small scale at CHOP because their cells are made at the University of Pennsylvania. Novartis, which licensed the technology, has built a cell-manufacturing facility and an ongoing phase II study is evaluating whether the technology can be safely rolled out to eight or nine pediatric centers across the country. An adult study will follow, he said.

[email protected]

A new guideline update on radiotherapy treatments for head and neck cancer strengthened the previous guideline’s findings but did not find any new significant evidence on the effectiveness of other procedures.

The guideline, prepared by the Blue Cross and Blue Shield Association and published by the Agency for Healthcare Research and Quality, updates Comparative Effectiveness Review (CER) No. 20, published in 2010. The update includes three-dimensional conformal radiotherapy (3DCRT), intensity-modulated RT (IMRT), and proton-beam RT (PBT), which were in the previous guideline, but also includes stereotactic body RT (SBRT) and excludes two-dimensional RT (2DRT). The search included studies published from September 2009 to April 2013, except for SBRT, where studies from January 1, 1990, through April 2013 were included. Fourteen studies and one randomized controlled trial met inclusion criteria.

The update found new evidence that IMRT reduced xerostomia more than did 3DCRT or 2DRT, but no new evidence was found on how quality of life domains were improved, which were the primary findings of the CER No. 20. Evidence toward other radiotherapy comparisons was limited and insufficient to draw any new conclusions, and no evidence was found for PBT.

[email protected]

A new guideline update on radiotherapy treatments for head and neck cancer strengthened the previous guideline’s findings but did not find any new significant evidence on the effectiveness of other procedures.

The guideline, prepared by the Blue Cross and Blue Shield Association and published by the Agency for Healthcare Research and Quality, updates Comparative Effectiveness Review (CER) No. 20, published in 2010. The update includes three-dimensional conformal radiotherapy (3DCRT), intensity-modulated RT (IMRT), and proton-beam RT (PBT), which were in the previous guideline, but also includes stereotactic body RT (SBRT) and excludes two-dimensional RT (2DRT). The search included studies published from September 2009 to April 2013, except for SBRT, where studies from January 1, 1990, through April 2013 were included. Fourteen studies and one randomized controlled trial met inclusion criteria.

The update found new evidence that IMRT reduced xerostomia more than did 3DCRT or 2DRT, but no new evidence was found on how quality of life domains were improved, which were the primary findings of the CER No. 20. Evidence toward other radiotherapy comparisons was limited and insufficient to draw any new conclusions, and no evidence was found for PBT.

[email protected]

A new guideline update on radiotherapy treatments for head and neck cancer strengthened the previous guideline’s findings but did not find any new significant evidence on the effectiveness of other procedures.

The guideline, prepared by the Blue Cross and Blue Shield Association and published by the Agency for Healthcare Research and Quality, updates Comparative Effectiveness Review (CER) No. 20, published in 2010. The update includes three-dimensional conformal radiotherapy (3DCRT), intensity-modulated RT (IMRT), and proton-beam RT (PBT), which were in the previous guideline, but also includes stereotactic body RT (SBRT) and excludes two-dimensional RT (2DRT). The search included studies published from September 2009 to April 2013, except for SBRT, where studies from January 1, 1990, through April 2013 were included. Fourteen studies and one randomized controlled trial met inclusion criteria.

The update found new evidence that IMRT reduced xerostomia more than did 3DCRT or 2DRT, but no new evidence was found on how quality of life domains were improved, which were the primary findings of the CER No. 20. Evidence toward other radiotherapy comparisons was limited and insufficient to draw any new conclusions, and no evidence was found for PBT.

[email protected]

SAN DIEGO – Patients treated with ionizing radiation were 2.65 to 3.78 times more likely to develop basal cell carcinoma than were controls, and exposure at younger ages or relatively high doses further increased that risk, according to a pooled analysis presented at the annual meeting of the American Society for Dermatologic Surgery.

“Concomitant exposure to ultraviolet radiation may potentiate this effect,” said Dr. Min Deng, a dermatology resident at the University of Chicago. “With newer treatment protocols and improved shielding, it would be interesting to see if the effect of ionizing radiation has changed, or whether we as dermatologists should more actively screen this at-risk population.”

Basal cell carcinoma (BCC) is the most common skin cancer worldwide, but relatively few dermatology papers have assessed the effects of ionizing radiation on the incidence of BCC, said Dr. Deng and coauthor Dr. Diana Bolotin, also of the University of Chicago.

©Kelly Nelson/National Cancer Institute

To better understand the link, the researchers searched PubMed for controlled studies on the topic by using the terms “radiation,” “risk,” and “basal cell carcinoma.” They excluded case reports, animal studies, studies published in languages other than English, and trials of radiation as a treatment of BCC, they said. They also excluded studies of atomic bomb survivors, because exposure was uncontrolled and methods to estimate exposure in this group have changed over time, they noted.

In all, six studies published between 1991 and 2012 met the inclusion criteria, and all six showed a statistically significant relative risk or odds of BCC with ionizing radiation exposure, the investigators reported. Three analyses calculated the relative risk of BCC in patients who received radiation for tinea capitis or who underwent total-body irradiation before hematopoietic cell transplantation, they said. Two studies evaluated the odds of BCC in patients with a past history of radiation exposure, and one study assessed time to subsequent BCCs in patients with a history of BCC.

For the three studies that calculated relative risk, the researchers calculated a pooled RR of BCC after ionizing radiation treatment of 2.65 (95% confidence interval, 1.22-5.72) compared with controls. The study of total-body irradiation (TBI) did not report or control for the primary disease for which patients were treated, “which may have confounded the results,” they said. When they excluded that study from their calculation, the overall RR rose to 3.78 (95% CI, 2.62 to 5.44).

Notably, in the two studies of patients with tinea capitis, the relative risk of BCC fell by 12% to 16% for every additional year of age at which patients received radiation treatment, the researchers said. Similarly, risk of BCC dropped by 10.9% for every 1-year increase in age at total-body irradiation prior to cell transplantation.

The combined odds ratio for the next two studies was 4.28 (1.45-12.63). “Likewise, both studies found an elevated odds ratio with younger age at radiation exposure,” the researchers added. One study that stratified patients by type of medical condition detected a “markedly elevated” 8.7 odds of BCC after radiation treatment for acne (2.0 to 38.0), they noted.

The sixth study was a nested case-control analysis that found a statistically significant increase in the odds of BCC starting at a 1-Gy dose of ionizing radiation, and rising linearly up to doses of 35-63.3 Gy. “The risk for developing multiple BCCs also appears to be elevated in patients with a history of radiation therapy,” the researchers said. Patients who had been exposed to ionizing ratio were 2.3 times more likely to develop new BCCs compared with unexposed patients (1.7 to 3.1), they said.

The investigators reported no funding sources or conflicts of interest.

SAN DIEGO – Patients treated with ionizing radiation were 2.65 to 3.78 times more likely to develop basal cell carcinoma than were controls, and exposure at younger ages or relatively high doses further increased that risk, according to a pooled analysis presented at the annual meeting of the American Society for Dermatologic Surgery.

“Concomitant exposure to ultraviolet radiation may potentiate this effect,” said Dr. Min Deng, a dermatology resident at the University of Chicago. “With newer treatment protocols and improved shielding, it would be interesting to see if the effect of ionizing radiation has changed, or whether we as dermatologists should more actively screen this at-risk population.”

Basal cell carcinoma (BCC) is the most common skin cancer worldwide, but relatively few dermatology papers have assessed the effects of ionizing radiation on the incidence of BCC, said Dr. Deng and coauthor Dr. Diana Bolotin, also of the University of Chicago.

©Kelly Nelson/National Cancer Institute

To better understand the link, the researchers searched PubMed for controlled studies on the topic by using the terms “radiation,” “risk,” and “basal cell carcinoma.” They excluded case reports, animal studies, studies published in languages other than English, and trials of radiation as a treatment of BCC, they said. They also excluded studies of atomic bomb survivors, because exposure was uncontrolled and methods to estimate exposure in this group have changed over time, they noted.

In all, six studies published between 1991 and 2012 met the inclusion criteria, and all six showed a statistically significant relative risk or odds of BCC with ionizing radiation exposure, the investigators reported. Three analyses calculated the relative risk of BCC in patients who received radiation for tinea capitis or who underwent total-body irradiation before hematopoietic cell transplantation, they said. Two studies evaluated the odds of BCC in patients with a past history of radiation exposure, and one study assessed time to subsequent BCCs in patients with a history of BCC.

For the three studies that calculated relative risk, the researchers calculated a pooled RR of BCC after ionizing radiation treatment of 2.65 (95% confidence interval, 1.22-5.72) compared with controls. The study of total-body irradiation (TBI) did not report or control for the primary disease for which patients were treated, “which may have confounded the results,” they said. When they excluded that study from their calculation, the overall RR rose to 3.78 (95% CI, 2.62 to 5.44).

Notably, in the two studies of patients with tinea capitis, the relative risk of BCC fell by 12% to 16% for every additional year of age at which patients received radiation treatment, the researchers said. Similarly, risk of BCC dropped by 10.9% for every 1-year increase in age at total-body irradiation prior to cell transplantation.

The combined odds ratio for the next two studies was 4.28 (1.45-12.63). “Likewise, both studies found an elevated odds ratio with younger age at radiation exposure,” the researchers added. One study that stratified patients by type of medical condition detected a “markedly elevated” 8.7 odds of BCC after radiation treatment for acne (2.0 to 38.0), they noted.

The sixth study was a nested case-control analysis that found a statistically significant increase in the odds of BCC starting at a 1-Gy dose of ionizing radiation, and rising linearly up to doses of 35-63.3 Gy. “The risk for developing multiple BCCs also appears to be elevated in patients with a history of radiation therapy,” the researchers said. Patients who had been exposed to ionizing ratio were 2.3 times more likely to develop new BCCs compared with unexposed patients (1.7 to 3.1), they said.

The investigators reported no funding sources or conflicts of interest.

SAN DIEGO – Patients treated with ionizing radiation were 2.65 to 3.78 times more likely to develop basal cell carcinoma than were controls, and exposure at younger ages or relatively high doses further increased that risk, according to a pooled analysis presented at the annual meeting of the American Society for Dermatologic Surgery.

“Concomitant exposure to ultraviolet radiation may potentiate this effect,” said Dr. Min Deng, a dermatology resident at the University of Chicago. “With newer treatment protocols and improved shielding, it would be interesting to see if the effect of ionizing radiation has changed, or whether we as dermatologists should more actively screen this at-risk population.”

Basal cell carcinoma (BCC) is the most common skin cancer worldwide, but relatively few dermatology papers have assessed the effects of ionizing radiation on the incidence of BCC, said Dr. Deng and coauthor Dr. Diana Bolotin, also of the University of Chicago.

©Kelly Nelson/National Cancer Institute

To better understand the link, the researchers searched PubMed for controlled studies on the topic by using the terms “radiation,” “risk,” and “basal cell carcinoma.” They excluded case reports, animal studies, studies published in languages other than English, and trials of radiation as a treatment of BCC, they said. They also excluded studies of atomic bomb survivors, because exposure was uncontrolled and methods to estimate exposure in this group have changed over time, they noted.

In all, six studies published between 1991 and 2012 met the inclusion criteria, and all six showed a statistically significant relative risk or odds of BCC with ionizing radiation exposure, the investigators reported. Three analyses calculated the relative risk of BCC in patients who received radiation for tinea capitis or who underwent total-body irradiation before hematopoietic cell transplantation, they said. Two studies evaluated the odds of BCC in patients with a past history of radiation exposure, and one study assessed time to subsequent BCCs in patients with a history of BCC.

For the three studies that calculated relative risk, the researchers calculated a pooled RR of BCC after ionizing radiation treatment of 2.65 (95% confidence interval, 1.22-5.72) compared with controls. The study of total-body irradiation (TBI) did not report or control for the primary disease for which patients were treated, “which may have confounded the results,” they said. When they excluded that study from their calculation, the overall RR rose to 3.78 (95% CI, 2.62 to 5.44).

Notably, in the two studies of patients with tinea capitis, the relative risk of BCC fell by 12% to 16% for every additional year of age at which patients received radiation treatment, the researchers said. Similarly, risk of BCC dropped by 10.9% for every 1-year increase in age at total-body irradiation prior to cell transplantation.

The combined odds ratio for the next two studies was 4.28 (1.45-12.63). “Likewise, both studies found an elevated odds ratio with younger age at radiation exposure,” the researchers added. One study that stratified patients by type of medical condition detected a “markedly elevated” 8.7 odds of BCC after radiation treatment for acne (2.0 to 38.0), they noted.

The sixth study was a nested case-control analysis that found a statistically significant increase in the odds of BCC starting at a 1-Gy dose of ionizing radiation, and rising linearly up to doses of 35-63.3 Gy. “The risk for developing multiple BCCs also appears to be elevated in patients with a history of radiation therapy,” the researchers said. Patients who had been exposed to ionizing ratio were 2.3 times more likely to develop new BCCs compared with unexposed patients (1.7 to 3.1), they said.

The investigators reported no funding sources or conflicts of interest.

Nicola Gökbuget, MD, PhD

SAN FRANCISCO—The first international, multicenter trial in acute lymphoblastic leukemia (ALL) using minimal residual disease (MRD) as a criterion for inclusion has confirmed clinical benefit for patients using a non-chemotherapeutic approach.

In the BLAST trial, blinatumomab, a bispecific T-cell engager antibody that directs cytotoxic T cells to CD19-positive cells, produced a complete MRD response in 80% of patients who were in complete hematologic remission but had quantifiable MRD at the time of treatment.

This echoes results of an earlier phase 2 study, in which blinatumomab produced an 80% MRD response rate in 20 patients with B-precursor ALL and persistent or relapsed MRD.

Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy, according to Nicola Gökbuget, MD, PhD, of Goethe University Hospital in Frankfurt, Germany.

“The question,” she said, “is how to treat these patients.”

She presented one effective method, as shown by the BLAST trial, at the 2014 ASH Annual Meeting (abstract 379).

The trial enrolled 116 patients aged 18 or older with B-precursor ALL in complete hematologic remission but with MRD ≥ 10^-3.

Patients could be in second or later remission, but they were excluded if they had a prior allogeneic stem cell transplant, circulating blasts or extra medullary ALL involvement, CNS pathology, prior chemotherapy within 2 weeks, or radiotherapy within 4 weeks.

Enrolled patients were a median age of 45 years (range, 18-76), and 34% were 65 or older. Most patients had high baseline MRD levels: 39% were ≥ 10^-2 to < 10^-1, and 45% were ≥ 10^-3 to < 10^-2.

Investigators evaluated MRD levels after each cycle. Analysis was performed in a central lab in Kiel, Germany, and was based on amplification of immunoglobulin and/or T-cell receptor gene rearrangements by PCR.

The primary endpoint was the proportion of patients achieving a complete MRD response after 1 cycle of blinatumomab.

Patients received 15 μg/m² of blinatumomab per day by continuous intravenous infusion for 4 weeks, followed by a treatment-free period of 2 weeks. Responders could receive up to 4 cycles of therapy or receive a transplant any time after the first cycle.

Results

In the efficacy-evaluable population, 80% of 103 patients achieved a complete MRD response after 1 cycle, defined as MRD negative with no amplification in PCR with a minimum sensitivity of 10^-4. And 85% achieved an incomplete MRD response of <10^-4 with a minimum sensitivity of 10^-4.

Results were similar in the full analysis set of 113 patients: 78% achieved complete MRD response after 1 cycle, and 85% achieved an incomplete MRD response.

Dr Gökbuget noted that 2 patients who initially achieved an incomplete response achieved a complete response during continued treatment in cycle 2.

The investigators analyzed the clinical characteristics of the patients and found that no factor—age, treatment interruptions, neurologic events, relapse history, nor gender—correlated with MRD response.

“I think that the good news is that it means that the compound was active in all of the patients,” Dr Gökbuget commented.

Adverse events

All patients experienced at least one adverse event (AE), and 2 were fatal—subdural hemorrhage and treatment-related pneumonitis. Serious treatment-related AEs that occurred in 3% or more of the

patients included tremor (7%), aphasia (5%), and encephalopathy (5%).

Thirty-one percent of patients interrupted their treatment because of AEs, which were primarily due to cytokine-related symptoms like pyrexia and neurologic events, including tremor, aphasia, and dizziness. Seventeen percent of patients permanently discontinued treatment due to an AE.

However, Dr Gökbuget pointed out that most AEs were grade 1 or 2, and the treatment interruption did not correlate with response.

She said the next step for this trial is to investigate whether high MRD response translates into long-term clinical benefit such as continued molecular remission and long-term survival.

“For me personally, this trial is very important because it is an up-to-date trial where we used PCR-based methods to identify patients with a high risk of relapse and treat them before the relapse occurs,” Dr Gökbuget said. “[W]e used a new endpoint, which is also MRD based, and . . . we used a new, non-chemotherapy treatment to eradicate this highly resistant, persistent ALL subclone.”

Blinatumomab received US Food and Drug Administration approval a few days before the start of the ASH Annual Meeting.

The BLAST trial was funded by Amgen Inc., the company developing blinatumomab.

Nicola Gökbuget, MD, PhD

SAN FRANCISCO—The first international, multicenter trial in acute lymphoblastic leukemia (ALL) using minimal residual disease (MRD) as a criterion for inclusion has confirmed clinical benefit for patients using a non-chemotherapeutic approach.

In the BLAST trial, blinatumomab, a bispecific T-cell engager antibody that directs cytotoxic T cells to CD19-positive cells, produced a complete MRD response in 80% of patients who were in complete hematologic remission but had quantifiable MRD at the time of treatment.

This echoes results of an earlier phase 2 study, in which blinatumomab produced an 80% MRD response rate in 20 patients with B-precursor ALL and persistent or relapsed MRD.

Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy, according to Nicola Gökbuget, MD, PhD, of Goethe University Hospital in Frankfurt, Germany.

“The question,” she said, “is how to treat these patients.”

She presented one effective method, as shown by the BLAST trial, at the 2014 ASH Annual Meeting (abstract 379).

The trial enrolled 116 patients aged 18 or older with B-precursor ALL in complete hematologic remission but with MRD ≥ 10^-3.

Patients could be in second or later remission, but they were excluded if they had a prior allogeneic stem cell transplant, circulating blasts or extra medullary ALL involvement, CNS pathology, prior chemotherapy within 2 weeks, or radiotherapy within 4 weeks.

Enrolled patients were a median age of 45 years (range, 18-76), and 34% were 65 or older. Most patients had high baseline MRD levels: 39% were ≥ 10^-2 to < 10^-1, and 45% were ≥ 10^-3 to < 10^-2.

Investigators evaluated MRD levels after each cycle. Analysis was performed in a central lab in Kiel, Germany, and was based on amplification of immunoglobulin and/or T-cell receptor gene rearrangements by PCR.

The primary endpoint was the proportion of patients achieving a complete MRD response after 1 cycle of blinatumomab.

Patients received 15 μg/m² of blinatumomab per day by continuous intravenous infusion for 4 weeks, followed by a treatment-free period of 2 weeks. Responders could receive up to 4 cycles of therapy or receive a transplant any time after the first cycle.

Results

In the efficacy-evaluable population, 80% of 103 patients achieved a complete MRD response after 1 cycle, defined as MRD negative with no amplification in PCR with a minimum sensitivity of 10^-4. And 85% achieved an incomplete MRD response of <10^-4 with a minimum sensitivity of 10^-4.

Results were similar in the full analysis set of 113 patients: 78% achieved complete MRD response after 1 cycle, and 85% achieved an incomplete MRD response.

Dr Gökbuget noted that 2 patients who initially achieved an incomplete response achieved a complete response during continued treatment in cycle 2.

The investigators analyzed the clinical characteristics of the patients and found that no factor—age, treatment interruptions, neurologic events, relapse history, nor gender—correlated with MRD response.

“I think that the good news is that it means that the compound was active in all of the patients,” Dr Gökbuget commented.

Adverse events

All patients experienced at least one adverse event (AE), and 2 were fatal—subdural hemorrhage and treatment-related pneumonitis. Serious treatment-related AEs that occurred in 3% or more of the

patients included tremor (7%), aphasia (5%), and encephalopathy (5%).

Thirty-one percent of patients interrupted their treatment because of AEs, which were primarily due to cytokine-related symptoms like pyrexia and neurologic events, including tremor, aphasia, and dizziness. Seventeen percent of patients permanently discontinued treatment due to an AE.

However, Dr Gökbuget pointed out that most AEs were grade 1 or 2, and the treatment interruption did not correlate with response.

She said the next step for this trial is to investigate whether high MRD response translates into long-term clinical benefit such as continued molecular remission and long-term survival.

“For me personally, this trial is very important because it is an up-to-date trial where we used PCR-based methods to identify patients with a high risk of relapse and treat them before the relapse occurs,” Dr Gökbuget said. “[W]e used a new endpoint, which is also MRD based, and . . . we used a new, non-chemotherapy treatment to eradicate this highly resistant, persistent ALL subclone.”

Blinatumomab received US Food and Drug Administration approval a few days before the start of the ASH Annual Meeting.

The BLAST trial was funded by Amgen Inc., the company developing blinatumomab.

Nicola Gökbuget, MD, PhD

SAN FRANCISCO—The first international, multicenter trial in acute lymphoblastic leukemia (ALL) using minimal residual disease (MRD) as a criterion for inclusion has confirmed clinical benefit for patients using a non-chemotherapeutic approach.

In the BLAST trial, blinatumomab, a bispecific T-cell engager antibody that directs cytotoxic T cells to CD19-positive cells, produced a complete MRD response in 80% of patients who were in complete hematologic remission but had quantifiable MRD at the time of treatment.

This echoes results of an earlier phase 2 study, in which blinatumomab produced an 80% MRD response rate in 20 patients with B-precursor ALL and persistent or relapsed MRD.

Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy, according to Nicola Gökbuget, MD, PhD, of Goethe University Hospital in Frankfurt, Germany.

“The question,” she said, “is how to treat these patients.”

She presented one effective method, as shown by the BLAST trial, at the 2014 ASH Annual Meeting (abstract 379).

The trial enrolled 116 patients aged 18 or older with B-precursor ALL in complete hematologic remission but with MRD ≥ 10^-3.

Patients could be in second or later remission, but they were excluded if they had a prior allogeneic stem cell transplant, circulating blasts or extra medullary ALL involvement, CNS pathology, prior chemotherapy within 2 weeks, or radiotherapy within 4 weeks.

Enrolled patients were a median age of 45 years (range, 18-76), and 34% were 65 or older. Most patients had high baseline MRD levels: 39% were ≥ 10^-2 to < 10^-1, and 45% were ≥ 10^-3 to < 10^-2.

Investigators evaluated MRD levels after each cycle. Analysis was performed in a central lab in Kiel, Germany, and was based on amplification of immunoglobulin and/or T-cell receptor gene rearrangements by PCR.

The primary endpoint was the proportion of patients achieving a complete MRD response after 1 cycle of blinatumomab.

Patients received 15 μg/m² of blinatumomab per day by continuous intravenous infusion for 4 weeks, followed by a treatment-free period of 2 weeks. Responders could receive up to 4 cycles of therapy or receive a transplant any time after the first cycle.

Results

In the efficacy-evaluable population, 80% of 103 patients achieved a complete MRD response after 1 cycle, defined as MRD negative with no amplification in PCR with a minimum sensitivity of 10^-4. And 85% achieved an incomplete MRD response of <10^-4 with a minimum sensitivity of 10^-4.

Results were similar in the full analysis set of 113 patients: 78% achieved complete MRD response after 1 cycle, and 85% achieved an incomplete MRD response.

Dr Gökbuget noted that 2 patients who initially achieved an incomplete response achieved a complete response during continued treatment in cycle 2.

The investigators analyzed the clinical characteristics of the patients and found that no factor—age, treatment interruptions, neurologic events, relapse history, nor gender—correlated with MRD response.

“I think that the good news is that it means that the compound was active in all of the patients,” Dr Gökbuget commented.

Adverse events

All patients experienced at least one adverse event (AE), and 2 were fatal—subdural hemorrhage and treatment-related pneumonitis. Serious treatment-related AEs that occurred in 3% or more of the

patients included tremor (7%), aphasia (5%), and encephalopathy (5%).

Thirty-one percent of patients interrupted their treatment because of AEs, which were primarily due to cytokine-related symptoms like pyrexia and neurologic events, including tremor, aphasia, and dizziness. Seventeen percent of patients permanently discontinued treatment due to an AE.

However, Dr Gökbuget pointed out that most AEs were grade 1 or 2, and the treatment interruption did not correlate with response.

She said the next step for this trial is to investigate whether high MRD response translates into long-term clinical benefit such as continued molecular remission and long-term survival.

“For me personally, this trial is very important because it is an up-to-date trial where we used PCR-based methods to identify patients with a high risk of relapse and treat them before the relapse occurs,” Dr Gökbuget said. “[W]e used a new endpoint, which is also MRD based, and . . . we used a new, non-chemotherapy treatment to eradicate this highly resistant, persistent ALL subclone.”

Blinatumomab received US Food and Drug Administration approval a few days before the start of the ASH Annual Meeting.

The BLAST trial was funded by Amgen Inc., the company developing blinatumomab.