Lymphoma & Plasma Cell Disorders

Woman on a scale

A study of more than 400 women suggests that losing weight can reduce levels of cancer-promoting proteins in the blood.

Overweight or obese women who lost weight over a 12-month period—through diet alone or both diet and exercise—significantly lowered their levels of proteins that play a role in angiogenesis.

Researchers say this finding suggests that losing weight might help reduce the risk of developing certain cancers.

“We know that being overweight and having a sedentary lifestyle is associated with an increase in risk for developing certain types of cancer,” said Catherine Duggan, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“However, we don’t know exactly why. We wanted to investigate how levels of some biomarkers associated with angiogenesis were altered when overweight, sedentary, postmenopausal women enrolled in a research study lost weight and/or became physically active over the course of a year.”

Dr Duggan and her colleagues described this investigation in Cancer Research.

The team studied 439 women who were postmenopausal and overweight or obese but were otherwise healthy and ranged in age from 50 to 75.

The women were randomized to 1 of 4 study arms:

• A diet arm, in which women restricted their calorie intake to no more than 2000 kcal per day that included less than 30% of fat calories
• An aerobic exercise arm, in which women performed 45 minutes of moderate to vigorous exercise 5 days a week
• A combined diet and exercise arm
• A control arm.

The researchers collected blood samples at baseline and at 12 months, measuring levels of the angiogenesis-related proteins VEGF, PAI-1, and PEDF.

They also measured weight loss at 12 months and found that women in all 3 intervention arms had a significantly higher mean weight loss than women in the control arm.

The mean weight loss was 0.8% of body weight for women in the control arm, 2.4% for women in the exercise arm (P=0.03), 8.5% for women in the diet arm (P<0.001), and 10.8% for women in the diet and exercise arm (P<0.001).

Compared with women in the control arm, those in the diet-only arm and the diet and exercise arm had significantly lower levels of the angiogenesis-related proteins at 12 months. However, such effects were not apparent among women in the exercise-only arm.

Specifically, women in the diet and exercise arm had a significantly greater reduction in PAI-1 at 12 months than women in the control arm (-19.3% and +3.48%, respectively, P<0.0001).

Women in the diet-only arm and the diet and exercise arm had significantly greater reductions in PEDF than controls (-9.20%, -9.90%, and +0.18%, respectively, both P<0.0001).

And women in the diet-only arm (-8.25%, P=0.0005) and the diet and exercise arm (-9.98%, P<0.0001) had significantly greater reductions in VEGF than controls (-1.21%).

The researchers also observed a linear trend in the reductions. So the more weight loss the women experienced, the greater the reduction in angiogenesis-related protein levels.

“Our study shows that weight loss is a safe and effective method of improving the angiogenic profile in healthy individuals,” Dr Duggan said. “We were surprised by the magnitude of change in these biomarkers with weight loss.”

“While we can’t say for certain that reducing the circulating levels of angiogenic factors through weight loss would impact the growth of tumors, it is possible that they might be associated with a less favorable milieu for tumor growth and proliferation.”

Dr Duggan and her colleagues said limitations of this study include the fact that the researchers only measured 3 angiogenic factors and did not measure them in adipose or other tissues.

Woman on a scale

A study of more than 400 women suggests that losing weight can reduce levels of cancer-promoting proteins in the blood.

Overweight or obese women who lost weight over a 12-month period—through diet alone or both diet and exercise—significantly lowered their levels of proteins that play a role in angiogenesis.

Researchers say this finding suggests that losing weight might help reduce the risk of developing certain cancers.

“We know that being overweight and having a sedentary lifestyle is associated with an increase in risk for developing certain types of cancer,” said Catherine Duggan, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“However, we don’t know exactly why. We wanted to investigate how levels of some biomarkers associated with angiogenesis were altered when overweight, sedentary, postmenopausal women enrolled in a research study lost weight and/or became physically active over the course of a year.”

Dr Duggan and her colleagues described this investigation in Cancer Research.

The team studied 439 women who were postmenopausal and overweight or obese but were otherwise healthy and ranged in age from 50 to 75.

The women were randomized to 1 of 4 study arms:

• A diet arm, in which women restricted their calorie intake to no more than 2000 kcal per day that included less than 30% of fat calories
• An aerobic exercise arm, in which women performed 45 minutes of moderate to vigorous exercise 5 days a week
• A combined diet and exercise arm
• A control arm.

The researchers collected blood samples at baseline and at 12 months, measuring levels of the angiogenesis-related proteins VEGF, PAI-1, and PEDF.

They also measured weight loss at 12 months and found that women in all 3 intervention arms had a significantly higher mean weight loss than women in the control arm.

The mean weight loss was 0.8% of body weight for women in the control arm, 2.4% for women in the exercise arm (P=0.03), 8.5% for women in the diet arm (P<0.001), and 10.8% for women in the diet and exercise arm (P<0.001).

Compared with women in the control arm, those in the diet-only arm and the diet and exercise arm had significantly lower levels of the angiogenesis-related proteins at 12 months. However, such effects were not apparent among women in the exercise-only arm.

Specifically, women in the diet and exercise arm had a significantly greater reduction in PAI-1 at 12 months than women in the control arm (-19.3% and +3.48%, respectively, P<0.0001).

Women in the diet-only arm and the diet and exercise arm had significantly greater reductions in PEDF than controls (-9.20%, -9.90%, and +0.18%, respectively, both P<0.0001).

And women in the diet-only arm (-8.25%, P=0.0005) and the diet and exercise arm (-9.98%, P<0.0001) had significantly greater reductions in VEGF than controls (-1.21%).

The researchers also observed a linear trend in the reductions. So the more weight loss the women experienced, the greater the reduction in angiogenesis-related protein levels.

“Our study shows that weight loss is a safe and effective method of improving the angiogenic profile in healthy individuals,” Dr Duggan said. “We were surprised by the magnitude of change in these biomarkers with weight loss.”

“While we can’t say for certain that reducing the circulating levels of angiogenic factors through weight loss would impact the growth of tumors, it is possible that they might be associated with a less favorable milieu for tumor growth and proliferation.”

Dr Duggan and her colleagues said limitations of this study include the fact that the researchers only measured 3 angiogenic factors and did not measure them in adipose or other tissues.

Woman on a scale

A study of more than 400 women suggests that losing weight can reduce levels of cancer-promoting proteins in the blood.

Overweight or obese women who lost weight over a 12-month period—through diet alone or both diet and exercise—significantly lowered their levels of proteins that play a role in angiogenesis.

Researchers say this finding suggests that losing weight might help reduce the risk of developing certain cancers.

“We know that being overweight and having a sedentary lifestyle is associated with an increase in risk for developing certain types of cancer,” said Catherine Duggan, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“However, we don’t know exactly why. We wanted to investigate how levels of some biomarkers associated with angiogenesis were altered when overweight, sedentary, postmenopausal women enrolled in a research study lost weight and/or became physically active over the course of a year.”

Dr Duggan and her colleagues described this investigation in Cancer Research.

The team studied 439 women who were postmenopausal and overweight or obese but were otherwise healthy and ranged in age from 50 to 75.

The women were randomized to 1 of 4 study arms:

• A diet arm, in which women restricted their calorie intake to no more than 2000 kcal per day that included less than 30% of fat calories
• An aerobic exercise arm, in which women performed 45 minutes of moderate to vigorous exercise 5 days a week
• A combined diet and exercise arm
• A control arm.

The researchers collected blood samples at baseline and at 12 months, measuring levels of the angiogenesis-related proteins VEGF, PAI-1, and PEDF.

They also measured weight loss at 12 months and found that women in all 3 intervention arms had a significantly higher mean weight loss than women in the control arm.

The mean weight loss was 0.8% of body weight for women in the control arm, 2.4% for women in the exercise arm (P=0.03), 8.5% for women in the diet arm (P<0.001), and 10.8% for women in the diet and exercise arm (P<0.001).

Compared with women in the control arm, those in the diet-only arm and the diet and exercise arm had significantly lower levels of the angiogenesis-related proteins at 12 months. However, such effects were not apparent among women in the exercise-only arm.

Specifically, women in the diet and exercise arm had a significantly greater reduction in PAI-1 at 12 months than women in the control arm (-19.3% and +3.48%, respectively, P<0.0001).

Women in the diet-only arm and the diet and exercise arm had significantly greater reductions in PEDF than controls (-9.20%, -9.90%, and +0.18%, respectively, both P<0.0001).

And women in the diet-only arm (-8.25%, P=0.0005) and the diet and exercise arm (-9.98%, P<0.0001) had significantly greater reductions in VEGF than controls (-1.21%).

The researchers also observed a linear trend in the reductions. So the more weight loss the women experienced, the greater the reduction in angiogenesis-related protein levels.

“Our study shows that weight loss is a safe and effective method of improving the angiogenic profile in healthy individuals,” Dr Duggan said. “We were surprised by the magnitude of change in these biomarkers with weight loss.”

“While we can’t say for certain that reducing the circulating levels of angiogenic factors through weight loss would impact the growth of tumors, it is possible that they might be associated with a less favorable milieu for tumor growth and proliferation.”

Dr Duggan and her colleagues said limitations of this study include the fact that the researchers only measured 3 angiogenic factors and did not measure them in adipose or other tissues.

Vials of ipilimumab

Photo from Business Wire

Results of a phase 1 study suggest that repeated doses of the immunotherapy drug ipilimumab is a feasible treatment option for patients with hematologic diseases who relapse after allogeneic hematopoietic stem cell transplant (HSCT).

Seven of the 28 patients studied responded to the treatment, but immune-mediated toxic effects and graft-vs-host disease (GVHD) occurred as well.

These results were published in NEJM.

Ipilimumab, which is already approved to treat unresectable or metastatic melanoma, works by blocking the immune checkpoint CTLA-4. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.

“We believe [,in the case of relapse after HSCT,] the donor immune cells are present but can’t recognize the tumor cells because of inhibitory signals that disguise them,” said study author Matthew Davids, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“By blocking the checkpoint, you allow the donor cells to see the cancer cells.”

Dr Davids and his colleagues tested this theory in 28 patients who had relapsed after allogeneic HSCT. The patients had acute myeloid leukemia (AML, n=12), Hodgkin lymphoma (n=7), non-Hodgkin lymphoma (n=4), myelodysplastic syndromes (MDS, n=2), multiple myeloma (n=1), myeloproliferative neoplasm (n=1), or acute lymphoblastic leukemia (n=1).

Patients had received a median of 3 prior treatment regimens, excluding HSCT (range, 1 to 14), and 20 patients (71%) had received treatment for relapse after transplant. Eight patients (29%) previously had grade 1/2 acute GVHD, and 16 (57%) previously had chronic GVHD.

The median time from transplant to initial treatment with ipilimumab was 675 days (range, 198 to 1830), and the median time from relapse to initial treatment with ipilimumab was 97 days (range, 0 to

1415).

Patients received induction therapy with ipilimumab at a dose of 3 mg/kg or 10 mg/kg every 3 weeks for a total of 4 doses. Those who had a clinical benefit received additional doses every 12 weeks for up to 60 weeks.

Safety

Five patients discontinued ipilimumab due to dose-limiting toxic effects. Four of these patients had GVHD, and 1 had severe immune-related adverse events.

Dose-limiting GVHD presented as chronic GVHD of the liver in 3 patients and acute GVHD of the gut in 1 patient.

Immune-related adverse events included death (n=1), pneumonitis (2 grade 2 events, 1 grade 4 event), colitis (1 grade 3 event), immune thrombocytopenia (1 grade 2 event), and diarrhea (1 grade 2 event).

Efficacy

There were no responses in patients who received ipilimumab at 3 mg/kg. Among the 22 patients who received ipilimumab at 10 mg/kg, 5 had a complete response, and 2 had a partial response.

Six other patients did not qualify as having responses but had a decrease in their tumor burden. Altogether, ipilimumab reduced tumor burden in 59% of patients.

The complete responses occurred in 4 patients with extramedullary AML and 1 patient with MDS developing into AML. Two of the AML patients remained in complete response at 12 and 15 months, and the patient with MDS remained in complete response at 16 months.

At a median follow-up of 15 months (range, 8 to 27), the median duration of response had not been reached. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells.

The 1-year overall survival rate was 49%.

The investigators said these encouraging results have set the stage for larger trials of checkpoint blockade in this patient population. Further research is planned to determine whether immunotherapy drugs could be given to high-risk patients to prevent relapse.

Vials of ipilimumab

Photo from Business Wire

Results of a phase 1 study suggest that repeated doses of the immunotherapy drug ipilimumab is a feasible treatment option for patients with hematologic diseases who relapse after allogeneic hematopoietic stem cell transplant (HSCT).

Seven of the 28 patients studied responded to the treatment, but immune-mediated toxic effects and graft-vs-host disease (GVHD) occurred as well.

These results were published in NEJM.

Ipilimumab, which is already approved to treat unresectable or metastatic melanoma, works by blocking the immune checkpoint CTLA-4. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.

“We believe [,in the case of relapse after HSCT,] the donor immune cells are present but can’t recognize the tumor cells because of inhibitory signals that disguise them,” said study author Matthew Davids, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“By blocking the checkpoint, you allow the donor cells to see the cancer cells.”

Dr Davids and his colleagues tested this theory in 28 patients who had relapsed after allogeneic HSCT. The patients had acute myeloid leukemia (AML, n=12), Hodgkin lymphoma (n=7), non-Hodgkin lymphoma (n=4), myelodysplastic syndromes (MDS, n=2), multiple myeloma (n=1), myeloproliferative neoplasm (n=1), or acute lymphoblastic leukemia (n=1).

Patients had received a median of 3 prior treatment regimens, excluding HSCT (range, 1 to 14), and 20 patients (71%) had received treatment for relapse after transplant. Eight patients (29%) previously had grade 1/2 acute GVHD, and 16 (57%) previously had chronic GVHD.

The median time from transplant to initial treatment with ipilimumab was 675 days (range, 198 to 1830), and the median time from relapse to initial treatment with ipilimumab was 97 days (range, 0 to

1415).

Patients received induction therapy with ipilimumab at a dose of 3 mg/kg or 10 mg/kg every 3 weeks for a total of 4 doses. Those who had a clinical benefit received additional doses every 12 weeks for up to 60 weeks.

Safety

Five patients discontinued ipilimumab due to dose-limiting toxic effects. Four of these patients had GVHD, and 1 had severe immune-related adverse events.

Dose-limiting GVHD presented as chronic GVHD of the liver in 3 patients and acute GVHD of the gut in 1 patient.

Immune-related adverse events included death (n=1), pneumonitis (2 grade 2 events, 1 grade 4 event), colitis (1 grade 3 event), immune thrombocytopenia (1 grade 2 event), and diarrhea (1 grade 2 event).

Efficacy

There were no responses in patients who received ipilimumab at 3 mg/kg. Among the 22 patients who received ipilimumab at 10 mg/kg, 5 had a complete response, and 2 had a partial response.

Six other patients did not qualify as having responses but had a decrease in their tumor burden. Altogether, ipilimumab reduced tumor burden in 59% of patients.

The complete responses occurred in 4 patients with extramedullary AML and 1 patient with MDS developing into AML. Two of the AML patients remained in complete response at 12 and 15 months, and the patient with MDS remained in complete response at 16 months.

At a median follow-up of 15 months (range, 8 to 27), the median duration of response had not been reached. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells.

The 1-year overall survival rate was 49%.

The investigators said these encouraging results have set the stage for larger trials of checkpoint blockade in this patient population. Further research is planned to determine whether immunotherapy drugs could be given to high-risk patients to prevent relapse.

Vials of ipilimumab

Photo from Business Wire

Results of a phase 1 study suggest that repeated doses of the immunotherapy drug ipilimumab is a feasible treatment option for patients with hematologic diseases who relapse after allogeneic hematopoietic stem cell transplant (HSCT).

Seven of the 28 patients studied responded to the treatment, but immune-mediated toxic effects and graft-vs-host disease (GVHD) occurred as well.

These results were published in NEJM.

Ipilimumab, which is already approved to treat unresectable or metastatic melanoma, works by blocking the immune checkpoint CTLA-4. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.

“We believe [,in the case of relapse after HSCT,] the donor immune cells are present but can’t recognize the tumor cells because of inhibitory signals that disguise them,” said study author Matthew Davids, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“By blocking the checkpoint, you allow the donor cells to see the cancer cells.”

Dr Davids and his colleagues tested this theory in 28 patients who had relapsed after allogeneic HSCT. The patients had acute myeloid leukemia (AML, n=12), Hodgkin lymphoma (n=7), non-Hodgkin lymphoma (n=4), myelodysplastic syndromes (MDS, n=2), multiple myeloma (n=1), myeloproliferative neoplasm (n=1), or acute lymphoblastic leukemia (n=1).

Patients had received a median of 3 prior treatment regimens, excluding HSCT (range, 1 to 14), and 20 patients (71%) had received treatment for relapse after transplant. Eight patients (29%) previously had grade 1/2 acute GVHD, and 16 (57%) previously had chronic GVHD.

The median time from transplant to initial treatment with ipilimumab was 675 days (range, 198 to 1830), and the median time from relapse to initial treatment with ipilimumab was 97 days (range, 0 to

1415).

Patients received induction therapy with ipilimumab at a dose of 3 mg/kg or 10 mg/kg every 3 weeks for a total of 4 doses. Those who had a clinical benefit received additional doses every 12 weeks for up to 60 weeks.

Safety

Five patients discontinued ipilimumab due to dose-limiting toxic effects. Four of these patients had GVHD, and 1 had severe immune-related adverse events.

Dose-limiting GVHD presented as chronic GVHD of the liver in 3 patients and acute GVHD of the gut in 1 patient.

Immune-related adverse events included death (n=1), pneumonitis (2 grade 2 events, 1 grade 4 event), colitis (1 grade 3 event), immune thrombocytopenia (1 grade 2 event), and diarrhea (1 grade 2 event).

Efficacy

There were no responses in patients who received ipilimumab at 3 mg/kg. Among the 22 patients who received ipilimumab at 10 mg/kg, 5 had a complete response, and 2 had a partial response.

Six other patients did not qualify as having responses but had a decrease in their tumor burden. Altogether, ipilimumab reduced tumor burden in 59% of patients.

The complete responses occurred in 4 patients with extramedullary AML and 1 patient with MDS developing into AML. Two of the AML patients remained in complete response at 12 and 15 months, and the patient with MDS remained in complete response at 16 months.

At a median follow-up of 15 months (range, 8 to 27), the median duration of response had not been reached. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells.

The 1-year overall survival rate was 49%.

The investigators said these encouraging results have set the stage for larger trials of checkpoint blockade in this patient population. Further research is planned to determine whether immunotherapy drugs could be given to high-risk patients to prevent relapse.

Early data hint that immune checkpoint inhibitors may be able to restore antitumor activity in patients with hematologic malignancies that have relapsed after allogeneic transplant.

Among 22 patients with relapsed hematologic cancers following allogeneic hematopoietic stem cell transplantation (HSCT) in a phase I/Ib study, treatment with the anti-CTLA-4 antibody ipilimumab (Yervoy) at a dose of 10 mg/kg was associated with complete responses in five patients, partial responses in two, and decreased tumor burden in six, reported Matthew S. Davids, MD, of the Dana-Farber Cancer Institute in Boston, and his colleagues.

“CTLA-4 blockade was a feasible approach for the treatment of patients with relapsed hematologic cancer after transplantation. Complete remissions with some durability were observed, even in patients with refractory myeloid cancers,” they wrote (N Engl J Med. 2016 Jul 14. doi: 10.1056/NEJMoa1601202).

More than one-third of patients who undergo HSCT for hematologic malignancies such as lymphoma, multiple myeloma, or leukemia will experience a relapse, and most will die within a year of relapse despite salvage therapies or retransplantation, the authors noted.

“Immune escape (i.e., tumor evasion of the donor immune system) contributes to relapse after allogeneic HSCT, and immune checkpoint inhibitory pathways probably play an important role,” they wrote.

Selective CTLA-4 blockade has been shown in mouse models to treat late relapse after transplantation by augmenting graft-versus-tumor response without apparent exacerbation of graft-versus-host disease (GVHD). To see whether the use of a CTLA-4 inhibitor could have the same effect in humans, the investigators instituted a single-group, open-label, dose-finding, safety and efficacy study of ipilimumab in 28 patients from six treatment sites.

The patients had all undergone allogeneic HSCT more than 3 months before the start of the study. The diagnoses included acute myeloid leukemia (AML) in 12 patients (including 3 with leukemia cutis and 1 with a myeloid sarcoma), Hodgkin lymphoma in 7, non-Hodgkin lymphoma in 4, myelodysplastic syndrome (MDS) in 2, and multiple myeloma, myeloproliferative neoplasm, and acute lymphoblastic leukemia in 1 patient each. Eight of the patients had previously had either grade I or II acute GVHD; 16 had had chronic GVHD.

Patients received induction therapy with ipilimumab at a dose of either 3 mg/kg (6 patients), or 10 mg/kg (22 patients) every 3 weeks for a total of 4 doses. Patients who experienced a clinical benefit from the drug could receive additional doses every 12 weeks for up to 60 weeks.

There were no clinical responses meeting study criteria in any of the patients who received the 3-mg/kg dose. Among the 22 who received the 10-mg/kg dose, however, the rate of complete responses was 23% (5 of 22), partial responses 9% (2 of 22), and decreased tumor burden 27% (6 of 22). The remaining nine patients experienced disease progression.

Four of the complete responses occurred in patients with extramedullary AML, and one occurred in a patient with MDS transforming into AML.

The safety analysis, which included all 28 patients evaluable for adverse events, showed four discontinuations due to dose-limiting chronic GVHD of the liver in the 3 patients, and acute GVHD of the gut in 1, and to severe immune-related events in one additional patient, leading to the patient’s death.

Other grade 3 or greater adverse events possibly related to ipilimumab included acute kidney injury (one patient) , corneal ulcer (one), thrombocytopenia (nine), neutropenia (three), anemia and pleural effusion (two).

The investigators point out that therapy to stimulate a graft-versus-tumor effect has the potential to promote or exacerbate GVHD, as occurred in four patients in the study. The GVHD in these patients was effectively managed with glucocorticoids, however.

The National Institutes of Health, Leukemia and Lymphoma Society, Pasquarello Tissue Bank, and Dana-Farber Cancer Institute supported the study. Dr. Davids disclosed grants from ASCO, the Pasquarello Tissue Bank, NIH, NCI, and Leukemia and Lymphoma society, and personal fees from several companies outside the study. Several coauthors disclosed relationships with various pharmaceutical companies, including Bristol-Myers Squibb, maker of ipilimumab.

Early data hint that immune checkpoint inhibitors may be able to restore antitumor activity in patients with hematologic malignancies that have relapsed after allogeneic transplant.

Among 22 patients with relapsed hematologic cancers following allogeneic hematopoietic stem cell transplantation (HSCT) in a phase I/Ib study, treatment with the anti-CTLA-4 antibody ipilimumab (Yervoy) at a dose of 10 mg/kg was associated with complete responses in five patients, partial responses in two, and decreased tumor burden in six, reported Matthew S. Davids, MD, of the Dana-Farber Cancer Institute in Boston, and his colleagues.

“CTLA-4 blockade was a feasible approach for the treatment of patients with relapsed hematologic cancer after transplantation. Complete remissions with some durability were observed, even in patients with refractory myeloid cancers,” they wrote (N Engl J Med. 2016 Jul 14. doi: 10.1056/NEJMoa1601202).

More than one-third of patients who undergo HSCT for hematologic malignancies such as lymphoma, multiple myeloma, or leukemia will experience a relapse, and most will die within a year of relapse despite salvage therapies or retransplantation, the authors noted.

“Immune escape (i.e., tumor evasion of the donor immune system) contributes to relapse after allogeneic HSCT, and immune checkpoint inhibitory pathways probably play an important role,” they wrote.

Selective CTLA-4 blockade has been shown in mouse models to treat late relapse after transplantation by augmenting graft-versus-tumor response without apparent exacerbation of graft-versus-host disease (GVHD). To see whether the use of a CTLA-4 inhibitor could have the same effect in humans, the investigators instituted a single-group, open-label, dose-finding, safety and efficacy study of ipilimumab in 28 patients from six treatment sites.

The patients had all undergone allogeneic HSCT more than 3 months before the start of the study. The diagnoses included acute myeloid leukemia (AML) in 12 patients (including 3 with leukemia cutis and 1 with a myeloid sarcoma), Hodgkin lymphoma in 7, non-Hodgkin lymphoma in 4, myelodysplastic syndrome (MDS) in 2, and multiple myeloma, myeloproliferative neoplasm, and acute lymphoblastic leukemia in 1 patient each. Eight of the patients had previously had either grade I or II acute GVHD; 16 had had chronic GVHD.

Patients received induction therapy with ipilimumab at a dose of either 3 mg/kg (6 patients), or 10 mg/kg (22 patients) every 3 weeks for a total of 4 doses. Patients who experienced a clinical benefit from the drug could receive additional doses every 12 weeks for up to 60 weeks.

There were no clinical responses meeting study criteria in any of the patients who received the 3-mg/kg dose. Among the 22 who received the 10-mg/kg dose, however, the rate of complete responses was 23% (5 of 22), partial responses 9% (2 of 22), and decreased tumor burden 27% (6 of 22). The remaining nine patients experienced disease progression.

Four of the complete responses occurred in patients with extramedullary AML, and one occurred in a patient with MDS transforming into AML.

The safety analysis, which included all 28 patients evaluable for adverse events, showed four discontinuations due to dose-limiting chronic GVHD of the liver in the 3 patients, and acute GVHD of the gut in 1, and to severe immune-related events in one additional patient, leading to the patient’s death.

Other grade 3 or greater adverse events possibly related to ipilimumab included acute kidney injury (one patient) , corneal ulcer (one), thrombocytopenia (nine), neutropenia (three), anemia and pleural effusion (two).

The investigators point out that therapy to stimulate a graft-versus-tumor effect has the potential to promote or exacerbate GVHD, as occurred in four patients in the study. The GVHD in these patients was effectively managed with glucocorticoids, however.

The National Institutes of Health, Leukemia and Lymphoma Society, Pasquarello Tissue Bank, and Dana-Farber Cancer Institute supported the study. Dr. Davids disclosed grants from ASCO, the Pasquarello Tissue Bank, NIH, NCI, and Leukemia and Lymphoma society, and personal fees from several companies outside the study. Several coauthors disclosed relationships with various pharmaceutical companies, including Bristol-Myers Squibb, maker of ipilimumab.

Early data hint that immune checkpoint inhibitors may be able to restore antitumor activity in patients with hematologic malignancies that have relapsed after allogeneic transplant.

Among 22 patients with relapsed hematologic cancers following allogeneic hematopoietic stem cell transplantation (HSCT) in a phase I/Ib study, treatment with the anti-CTLA-4 antibody ipilimumab (Yervoy) at a dose of 10 mg/kg was associated with complete responses in five patients, partial responses in two, and decreased tumor burden in six, reported Matthew S. Davids, MD, of the Dana-Farber Cancer Institute in Boston, and his colleagues.

“CTLA-4 blockade was a feasible approach for the treatment of patients with relapsed hematologic cancer after transplantation. Complete remissions with some durability were observed, even in patients with refractory myeloid cancers,” they wrote (N Engl J Med. 2016 Jul 14. doi: 10.1056/NEJMoa1601202).

More than one-third of patients who undergo HSCT for hematologic malignancies such as lymphoma, multiple myeloma, or leukemia will experience a relapse, and most will die within a year of relapse despite salvage therapies or retransplantation, the authors noted.

“Immune escape (i.e., tumor evasion of the donor immune system) contributes to relapse after allogeneic HSCT, and immune checkpoint inhibitory pathways probably play an important role,” they wrote.

Selective CTLA-4 blockade has been shown in mouse models to treat late relapse after transplantation by augmenting graft-versus-tumor response without apparent exacerbation of graft-versus-host disease (GVHD). To see whether the use of a CTLA-4 inhibitor could have the same effect in humans, the investigators instituted a single-group, open-label, dose-finding, safety and efficacy study of ipilimumab in 28 patients from six treatment sites.

The patients had all undergone allogeneic HSCT more than 3 months before the start of the study. The diagnoses included acute myeloid leukemia (AML) in 12 patients (including 3 with leukemia cutis and 1 with a myeloid sarcoma), Hodgkin lymphoma in 7, non-Hodgkin lymphoma in 4, myelodysplastic syndrome (MDS) in 2, and multiple myeloma, myeloproliferative neoplasm, and acute lymphoblastic leukemia in 1 patient each. Eight of the patients had previously had either grade I or II acute GVHD; 16 had had chronic GVHD.

Patients received induction therapy with ipilimumab at a dose of either 3 mg/kg (6 patients), or 10 mg/kg (22 patients) every 3 weeks for a total of 4 doses. Patients who experienced a clinical benefit from the drug could receive additional doses every 12 weeks for up to 60 weeks.

There were no clinical responses meeting study criteria in any of the patients who received the 3-mg/kg dose. Among the 22 who received the 10-mg/kg dose, however, the rate of complete responses was 23% (5 of 22), partial responses 9% (2 of 22), and decreased tumor burden 27% (6 of 22). The remaining nine patients experienced disease progression.

Four of the complete responses occurred in patients with extramedullary AML, and one occurred in a patient with MDS transforming into AML.

The safety analysis, which included all 28 patients evaluable for adverse events, showed four discontinuations due to dose-limiting chronic GVHD of the liver in the 3 patients, and acute GVHD of the gut in 1, and to severe immune-related events in one additional patient, leading to the patient’s death.

Other grade 3 or greater adverse events possibly related to ipilimumab included acute kidney injury (one patient) , corneal ulcer (one), thrombocytopenia (nine), neutropenia (three), anemia and pleural effusion (two).

The investigators point out that therapy to stimulate a graft-versus-tumor effect has the potential to promote or exacerbate GVHD, as occurred in four patients in the study. The GVHD in these patients was effectively managed with glucocorticoids, however.

The National Institutes of Health, Leukemia and Lymphoma Society, Pasquarello Tissue Bank, and Dana-Farber Cancer Institute supported the study. Dr. Davids disclosed grants from ASCO, the Pasquarello Tissue Bank, NIH, NCI, and Leukemia and Lymphoma society, and personal fees from several companies outside the study. Several coauthors disclosed relationships with various pharmaceutical companies, including Bristol-Myers Squibb, maker of ipilimumab.

Standard oncology measures are acceptable indicators of good-quality end of life care for hematologic malignancies, investigators report.

Six out of eight standard end of life (EOL) care measures were deemed acceptable (defined as greater than 55% agreement) based on 349 returned surveys from hematologic oncologists. Hospice enrollment more than 7 days before death, no chemotherapy less than 14 days before death, and no CPR and intubation within the last 30 days of life were acceptable measures to more than 75% of those surveyed.

No more than one hospitalization within 30 days of death and no more than one emergency room visit within 30 days of death did not meet the threshold for acceptance by the oncologists.

“These data suggest that the absence of hematology-specific measures is unlikely to be a major barrier to quality care and that more resources should be directed toward addressing barriers to compliance with established EOL quality measures than toward creating new ones,” Oreofe O. Odejide, MD, of the Dana-Farber Cancer Institute, Boston, and her associates reported (J Clin Oncol. 2016 July. doi: 10.1200/JCO.2016.67.8177).

The top barriers to end of life care were unrealistic patient expectations (97.3%), clinician concern about diminishing patient and family hope (71.3%), and unrealistic clinician expectations (59.0%), according to investigators.

Surveyed oncologists also reported that increasing access to palliative care services (93.7%), increasing access to inpatient hospice facilities (92.2%), and allowing hospice enrollment with disease-directed treatment (90.1%) would be the most helpful interventions to improve end of life care.

The Lymphoma Research Foundation, the Conquer Cancer Foundation, and investigators’ respective institutions funded this research. Dr. Odejide and four of her associates had no disclosures to report. Two investigators reported serving in advisory roles, holding patents, or having stock or ownership interest in UnitedHealthcare, UpToDate, or Recap Information Systems.

jcraig@frontlinemedcom.com

On Twitter @jessnicolecraig

Standard oncology measures are acceptable indicators of good-quality end of life care for hematologic malignancies, investigators report.

Six out of eight standard end of life (EOL) care measures were deemed acceptable (defined as greater than 55% agreement) based on 349 returned surveys from hematologic oncologists. Hospice enrollment more than 7 days before death, no chemotherapy less than 14 days before death, and no CPR and intubation within the last 30 days of life were acceptable measures to more than 75% of those surveyed.

No more than one hospitalization within 30 days of death and no more than one emergency room visit within 30 days of death did not meet the threshold for acceptance by the oncologists.

“These data suggest that the absence of hematology-specific measures is unlikely to be a major barrier to quality care and that more resources should be directed toward addressing barriers to compliance with established EOL quality measures than toward creating new ones,” Oreofe O. Odejide, MD, of the Dana-Farber Cancer Institute, Boston, and her associates reported (J Clin Oncol. 2016 July. doi: 10.1200/JCO.2016.67.8177).

The top barriers to end of life care were unrealistic patient expectations (97.3%), clinician concern about diminishing patient and family hope (71.3%), and unrealistic clinician expectations (59.0%), according to investigators.

Surveyed oncologists also reported that increasing access to palliative care services (93.7%), increasing access to inpatient hospice facilities (92.2%), and allowing hospice enrollment with disease-directed treatment (90.1%) would be the most helpful interventions to improve end of life care.

The Lymphoma Research Foundation, the Conquer Cancer Foundation, and investigators’ respective institutions funded this research. Dr. Odejide and four of her associates had no disclosures to report. Two investigators reported serving in advisory roles, holding patents, or having stock or ownership interest in UnitedHealthcare, UpToDate, or Recap Information Systems.

jcraig@frontlinemedcom.com

On Twitter @jessnicolecraig

Standard oncology measures are acceptable indicators of good-quality end of life care for hematologic malignancies, investigators report.

Six out of eight standard end of life (EOL) care measures were deemed acceptable (defined as greater than 55% agreement) based on 349 returned surveys from hematologic oncologists. Hospice enrollment more than 7 days before death, no chemotherapy less than 14 days before death, and no CPR and intubation within the last 30 days of life were acceptable measures to more than 75% of those surveyed.

No more than one hospitalization within 30 days of death and no more than one emergency room visit within 30 days of death did not meet the threshold for acceptance by the oncologists.

“These data suggest that the absence of hematology-specific measures is unlikely to be a major barrier to quality care and that more resources should be directed toward addressing barriers to compliance with established EOL quality measures than toward creating new ones,” Oreofe O. Odejide, MD, of the Dana-Farber Cancer Institute, Boston, and her associates reported (J Clin Oncol. 2016 July. doi: 10.1200/JCO.2016.67.8177).

The top barriers to end of life care were unrealistic patient expectations (97.3%), clinician concern about diminishing patient and family hope (71.3%), and unrealistic clinician expectations (59.0%), according to investigators.

Surveyed oncologists also reported that increasing access to palliative care services (93.7%), increasing access to inpatient hospice facilities (92.2%), and allowing hospice enrollment with disease-directed treatment (90.1%) would be the most helpful interventions to improve end of life care.

The Lymphoma Research Foundation, the Conquer Cancer Foundation, and investigators’ respective institutions funded this research. Dr. Odejide and four of her associates had no disclosures to report. Two investigators reported serving in advisory roles, holding patents, or having stock or ownership interest in UnitedHealthcare, UpToDate, or Recap Information Systems.

jcraig@frontlinemedcom.com

On Twitter @jessnicolecraig

 

 

Idelalisib (Zydelig)

Photo courtesy of

Gilead Sciences, Inc.

 

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of the PI3Kδ inhibitor idelalisib (Zyedelig) and concluded that the drug’s benefits outweigh its risks in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.

However, the PRAC also confirmed that the drug increases the risk of serious infections, including Pneumocystis jirovecii pneumonia.

And the committee updated its previous recommendations to manage this risk.

The PRAC’s recommendations will now be sent to the Committee for Medicinal Products for Human Use, which will adopt the EMA’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all member states of the European Union (EU).

About idelalisib

In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.

Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

About the review

The PRAC’s review of idelalisib began after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).

Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.

The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indications for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.

The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.

PRAC’s recommendations

The PRAC noted that, although the aforementioned trials did not all use idelalisib as currently authorized, the risk of serious infection is considered relevant to the authorized use.

Therefore, the PRAC recommends that all patients treated with idelalisib receive antibiotics to prevent Pneumocystis jirovecii pneumonia during treatment and for up to 2 to 6 months after treatment has stopped.

Patients should also be monitored for infection and have regular blood tests for white cell counts because low counts can increase their risk of infection.

Furthermore, idelalisib should not be started in patients with a generalized infection.

At the beginning of its review, the PRAC had said idelalisib should not be started in patients with previously untreated CLL and 17p deletion or TP53 mutation.

Now, the PRAC has concluded that idelalisib can be initiated in these patients, provided they cannot take any alternative treatment and that the recommended measures to prevent infection are followed.

 

 

Idelalisib (Zydelig)

Photo courtesy of

Gilead Sciences, Inc.

 

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of the PI3Kδ inhibitor idelalisib (Zyedelig) and concluded that the drug’s benefits outweigh its risks in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.

However, the PRAC also confirmed that the drug increases the risk of serious infections, including Pneumocystis jirovecii pneumonia.

And the committee updated its previous recommendations to manage this risk.

The PRAC’s recommendations will now be sent to the Committee for Medicinal Products for Human Use, which will adopt the EMA’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all member states of the European Union (EU).

About idelalisib

In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.

Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

About the review

The PRAC’s review of idelalisib began after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).

Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.

The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indications for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.

The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.

PRAC’s recommendations

The PRAC noted that, although the aforementioned trials did not all use idelalisib as currently authorized, the risk of serious infection is considered relevant to the authorized use.

Therefore, the PRAC recommends that all patients treated with idelalisib receive antibiotics to prevent Pneumocystis jirovecii pneumonia during treatment and for up to 2 to 6 months after treatment has stopped.

Patients should also be monitored for infection and have regular blood tests for white cell counts because low counts can increase their risk of infection.

Furthermore, idelalisib should not be started in patients with a generalized infection.

At the beginning of its review, the PRAC had said idelalisib should not be started in patients with previously untreated CLL and 17p deletion or TP53 mutation.

Now, the PRAC has concluded that idelalisib can be initiated in these patients, provided they cannot take any alternative treatment and that the recommended measures to prevent infection are followed.

 

 

Idelalisib (Zydelig)

Photo courtesy of

Gilead Sciences, Inc.

 

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of the PI3Kδ inhibitor idelalisib (Zyedelig) and concluded that the drug’s benefits outweigh its risks in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.

However, the PRAC also confirmed that the drug increases the risk of serious infections, including Pneumocystis jirovecii pneumonia.

And the committee updated its previous recommendations to manage this risk.

The PRAC’s recommendations will now be sent to the Committee for Medicinal Products for Human Use, which will adopt the EMA’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all member states of the European Union (EU).

About idelalisib

In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.

Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

About the review

The PRAC’s review of idelalisib began after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).

Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.

The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indications for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.

The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.

PRAC’s recommendations

The PRAC noted that, although the aforementioned trials did not all use idelalisib as currently authorized, the risk of serious infection is considered relevant to the authorized use.

Therefore, the PRAC recommends that all patients treated with idelalisib receive antibiotics to prevent Pneumocystis jirovecii pneumonia during treatment and for up to 2 to 6 months after treatment has stopped.

Patients should also be monitored for infection and have regular blood tests for white cell counts because low counts can increase their risk of infection.

Furthermore, idelalisib should not be started in patients with a generalized infection.

At the beginning of its review, the PRAC had said idelalisib should not be started in patients with previously untreated CLL and 17p deletion or TP53 mutation.

Now, the PRAC has concluded that idelalisib can be initiated in these patients, provided they cannot take any alternative treatment and that the recommended measures to prevent infection are followed.

Long-term follow-up from two randomized trials shows that the treatment advantage initially seen by adding radiotherapy to the CHOP regimen in patients with limited-stage diffuse large B-cell lymphoma disappeared over time.

After a median follow-up of nearly 18 years, there were no significant differences in either progression-free survival (PFS) or overall survival between patients who had received standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) for 8 cycles (CHOP8), or 3 cycles of CHOP with involved-field radiotherapy (CHOP3RT), reported Deborah M. Stephens, DO, of the University of Utah in Salt Lake City, and her colleagues.

The addition of rituximab to CHOP plus involved-field radiotherapy (IFRT) in a separate cohort did not appear to reduce the continued relapse risk, the investigators noted (J Clin Oncol. 2016 Jul. doi: 10.1200/JCO.2015.65.4582).

The findings suggest that long-term follow-up of patients enrolled in clinical trials may provide clinically important additional information, and that limited-stage diffuse large B-cell lymphoma (DLBCL) may have a biology that is distinctly different from that of advanced stage DLBCL, the investigators wrote.

Initial results from the SWOG (Southwest Oncology Group) Study 8736, published after a median follow-up of 4.4 years, showed that CHOP3RT was associated with significantly better 5-year PFS and OS rates, compared with patients treated with CHOP8.

A second trial, SWOG Study 0014, looked at the addition of rituximab (Rituxan) to CHOP plus IFRT in patients with high-risk DLBCL with at least one adverse feature of the stage-modified International Prognostic Index. In this trial, after a median follow-up of 5.3 years, 4-year PFS was 88%, and 4-year OS was 92%.

5 years not enough

Results of both trials were published around the 5-year follow-up mark. However, an analysis of 10-year follow-up data from the S8736 trial, published only as an abstract (Blood. 98:724a-725a, 2001; abstr 3024), showed that “the survival curves for CHOP8 and CHOP3RT, surprisingly, began to overlap,” Dr. Stephens and her colleagues wrote.

“Additionally, for both S8736 and S0014, no plateau had been reached in the PFS curves. These data contrasted the expected cure rates for advanced-stage DLBCL, leading to the hypothesis that limited-stage DLBCL may have a unique biology from its advanced-stage counterpart,” they added.

Although more than half of patients with advanced-stage diffuse large B-cell lymphoma (DLBCL) can be cured with anthracycline-based chemotherapy, cure rates are markedly lower among patients with limited-stage disease, defined as Ann Arbor stage I or II, confined to a single irradiation field. Limited-stage disease accounts for approximately one-third DLBCL cases.

To see whether the trends observed at 10 years continued, the investigators conducted a survival analysis from S8736 and compared the data from similar patients in the S0014 study.

They found that after a median follow-up of 17.7 years in S8736, median PFS was 12.0 years for patients treated with CHOP8, and 11.1 years for patients treated with CHOP3RT, a difference that was not statistically significant.

Median OS was 13.0 and 13.7 years, respectively, and was also not significant.

In S0014, after a median follow-up of 12 years, the 5-year OS rate was 82%, and 10-year rate was 67%. In this trial, the investigators observed “a persistent pattern of relapse despite the addition of rituximab.”

“The populations were not entirely identical; however, even the addition of rituximab as per S0014 to combined-modality therapy did not seem to mitigate the continued relapse risk, underscoring the value of prolonged observation of clinical trial patients and possible unique biology of limited-stage DLBCL,” Dr. Stephens and her associates wrote.

The study was sponsored by grants from the National Institutes of Health. Dr. Stephens reported having no financial disclosures. Several coauthors disclosed research funding, consulting, speakers’ bureau participation or travel expenses from various oncology drug makers.

Long-term follow-up from two randomized trials shows that the treatment advantage initially seen by adding radiotherapy to the CHOP regimen in patients with limited-stage diffuse large B-cell lymphoma disappeared over time.

After a median follow-up of nearly 18 years, there were no significant differences in either progression-free survival (PFS) or overall survival between patients who had received standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) for 8 cycles (CHOP8), or 3 cycles of CHOP with involved-field radiotherapy (CHOP3RT), reported Deborah M. Stephens, DO, of the University of Utah in Salt Lake City, and her colleagues.

The addition of rituximab to CHOP plus involved-field radiotherapy (IFRT) in a separate cohort did not appear to reduce the continued relapse risk, the investigators noted (J Clin Oncol. 2016 Jul. doi: 10.1200/JCO.2015.65.4582).

The findings suggest that long-term follow-up of patients enrolled in clinical trials may provide clinically important additional information, and that limited-stage diffuse large B-cell lymphoma (DLBCL) may have a biology that is distinctly different from that of advanced stage DLBCL, the investigators wrote.

Initial results from the SWOG (Southwest Oncology Group) Study 8736, published after a median follow-up of 4.4 years, showed that CHOP3RT was associated with significantly better 5-year PFS and OS rates, compared with patients treated with CHOP8.

A second trial, SWOG Study 0014, looked at the addition of rituximab (Rituxan) to CHOP plus IFRT in patients with high-risk DLBCL with at least one adverse feature of the stage-modified International Prognostic Index. In this trial, after a median follow-up of 5.3 years, 4-year PFS was 88%, and 4-year OS was 92%.

5 years not enough

Results of both trials were published around the 5-year follow-up mark. However, an analysis of 10-year follow-up data from the S8736 trial, published only as an abstract (Blood. 98:724a-725a, 2001; abstr 3024), showed that “the survival curves for CHOP8 and CHOP3RT, surprisingly, began to overlap,” Dr. Stephens and her colleagues wrote.

“Additionally, for both S8736 and S0014, no plateau had been reached in the PFS curves. These data contrasted the expected cure rates for advanced-stage DLBCL, leading to the hypothesis that limited-stage DLBCL may have a unique biology from its advanced-stage counterpart,” they added.

Although more than half of patients with advanced-stage diffuse large B-cell lymphoma (DLBCL) can be cured with anthracycline-based chemotherapy, cure rates are markedly lower among patients with limited-stage disease, defined as Ann Arbor stage I or II, confined to a single irradiation field. Limited-stage disease accounts for approximately one-third DLBCL cases.

To see whether the trends observed at 10 years continued, the investigators conducted a survival analysis from S8736 and compared the data from similar patients in the S0014 study.

They found that after a median follow-up of 17.7 years in S8736, median PFS was 12.0 years for patients treated with CHOP8, and 11.1 years for patients treated with CHOP3RT, a difference that was not statistically significant.

Median OS was 13.0 and 13.7 years, respectively, and was also not significant.

In S0014, after a median follow-up of 12 years, the 5-year OS rate was 82%, and 10-year rate was 67%. In this trial, the investigators observed “a persistent pattern of relapse despite the addition of rituximab.”

“The populations were not entirely identical; however, even the addition of rituximab as per S0014 to combined-modality therapy did not seem to mitigate the continued relapse risk, underscoring the value of prolonged observation of clinical trial patients and possible unique biology of limited-stage DLBCL,” Dr. Stephens and her associates wrote.

The study was sponsored by grants from the National Institutes of Health. Dr. Stephens reported having no financial disclosures. Several coauthors disclosed research funding, consulting, speakers’ bureau participation or travel expenses from various oncology drug makers.

Long-term follow-up from two randomized trials shows that the treatment advantage initially seen by adding radiotherapy to the CHOP regimen in patients with limited-stage diffuse large B-cell lymphoma disappeared over time.

After a median follow-up of nearly 18 years, there were no significant differences in either progression-free survival (PFS) or overall survival between patients who had received standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) for 8 cycles (CHOP8), or 3 cycles of CHOP with involved-field radiotherapy (CHOP3RT), reported Deborah M. Stephens, DO, of the University of Utah in Salt Lake City, and her colleagues.

The addition of rituximab to CHOP plus involved-field radiotherapy (IFRT) in a separate cohort did not appear to reduce the continued relapse risk, the investigators noted (J Clin Oncol. 2016 Jul. doi: 10.1200/JCO.2015.65.4582).

The findings suggest that long-term follow-up of patients enrolled in clinical trials may provide clinically important additional information, and that limited-stage diffuse large B-cell lymphoma (DLBCL) may have a biology that is distinctly different from that of advanced stage DLBCL, the investigators wrote.

Initial results from the SWOG (Southwest Oncology Group) Study 8736, published after a median follow-up of 4.4 years, showed that CHOP3RT was associated with significantly better 5-year PFS and OS rates, compared with patients treated with CHOP8.

A second trial, SWOG Study 0014, looked at the addition of rituximab (Rituxan) to CHOP plus IFRT in patients with high-risk DLBCL with at least one adverse feature of the stage-modified International Prognostic Index. In this trial, after a median follow-up of 5.3 years, 4-year PFS was 88%, and 4-year OS was 92%.

5 years not enough

Results of both trials were published around the 5-year follow-up mark. However, an analysis of 10-year follow-up data from the S8736 trial, published only as an abstract (Blood. 98:724a-725a, 2001; abstr 3024), showed that “the survival curves for CHOP8 and CHOP3RT, surprisingly, began to overlap,” Dr. Stephens and her colleagues wrote.

“Additionally, for both S8736 and S0014, no plateau had been reached in the PFS curves. These data contrasted the expected cure rates for advanced-stage DLBCL, leading to the hypothesis that limited-stage DLBCL may have a unique biology from its advanced-stage counterpart,” they added.

Although more than half of patients with advanced-stage diffuse large B-cell lymphoma (DLBCL) can be cured with anthracycline-based chemotherapy, cure rates are markedly lower among patients with limited-stage disease, defined as Ann Arbor stage I or II, confined to a single irradiation field. Limited-stage disease accounts for approximately one-third DLBCL cases.

To see whether the trends observed at 10 years continued, the investigators conducted a survival analysis from S8736 and compared the data from similar patients in the S0014 study.

They found that after a median follow-up of 17.7 years in S8736, median PFS was 12.0 years for patients treated with CHOP8, and 11.1 years for patients treated with CHOP3RT, a difference that was not statistically significant.

Median OS was 13.0 and 13.7 years, respectively, and was also not significant.

In S0014, after a median follow-up of 12 years, the 5-year OS rate was 82%, and 10-year rate was 67%. In this trial, the investigators observed “a persistent pattern of relapse despite the addition of rituximab.”

“The populations were not entirely identical; however, even the addition of rituximab as per S0014 to combined-modality therapy did not seem to mitigate the continued relapse risk, underscoring the value of prolonged observation of clinical trial patients and possible unique biology of limited-stage DLBCL,” Dr. Stephens and her associates wrote.

The study was sponsored by grants from the National Institutes of Health. Dr. Stephens reported having no financial disclosures. Several coauthors disclosed research funding, consulting, speakers’ bureau participation or travel expenses from various oncology drug makers.

Combination chemotherapy with bendamustine, gemcitabine, and vinorelbine can induce high complete response rates among patients with relapsed or refractory Hodgkin lymphoma (HL) who are candidates for autologous stem cell transplantation, final results of a phase II study show.

Among 59 patients enrolled in the multicenter study, 49 (83%) had responses, including 43 (73%) who achieved a complete response (CR), and 6 (10%) who had a partial response after 4 cycles of chemotherapy with bendamustine (Treanda), gemcitabine (Gemzar), and vinorelbine (BeGEV).

Of the 49 patients with responses, 43 went on to autologous stem cell transplant (ASCT), reported Armando Santoro, MD, from the Humanitas Cancer Center in Rozzano, Italy.

“These findings provide a strong rationale for further development of the BeGEV regimen,” the investigators wrote in a study published online in the Journal of Clinical Oncology (2016 Jul 5. doi: 10.1200/JCO.2016.66.4466).

The investigators had previously shown that a regimen of ifosfamide, gemcitabine, and vinorelbine (IEGV) as salvage chemotherapy prior to ASCT was associated with an 81% overall response rate (ORR) 54% CR rate.

Because bendamustine has shown good activity as monotherapy against relapsed/refractory HL, they conducted a phase II study with an IEGV-like regimen in which bendamustine would be substituted for ifosfamide, to determine whether the substitution could improve response rates.

They enrolled 59 consecutive patients aged 18 years and older with HL that had relapsed or was refractory to one previous line of chemotherapy. Patients were treated with gemcitabine 800 mg/m² on days 1 and 4, vinorelbine 20 mg/m² on day 1, and bendamustine 90 mg/m² on days 2 and 3. Patients also received prednisolone 100 mg/day for days 1 to 4. The patients were treated for four 21-day cycles.

Patients who achieved either a complete or partial response after completion of the four planned cycles then underwent myeloablative therapy with carmustine or fotemustine plus etoposide, cytarabine, and melphalan, followed by reinfusion of mobilized CD34-positive circulating stem cells.

Grade 3 or 4 hematologic toxicities included thrombocytopenia and neutropenia, which occurred in eight patients each. Fifty-five of 57 total evaluable patients had successful mobilization and harvesting of CD34-positive cells, and, as noted before, 43 went on to ASCT.

After a median follow-up of 29 months, the 2-year progression-free survival (PFS) rate for the total population was 62%, and the overall survival rates was nearly 78%. For patients who went on to ASCT, the 2-year PFS rate was 81%, and the 2-year survival rate was 89%.

The authors noted that BeGV was associated with higher CR rates than IEGV, and with “excellent” stem cell mobilization activity and engraftment. Additionally, BeGV has a favorable toxicity profile, because of the absence of ifosfamide which is known to significantly increase risk for hemorrhagic cystitis.

“Because the number of novel agents that may be added in the pretransplantation therapy setting is growing, direct comparisons of combinations incorporating novel agents with BeGEV and other regimens will be necessary to identify the best salvage strategy for relapsed and refractory HL,” the authors wrote.

The study was supported in part by a grant from Mundipharma Pharmaceuticals. Two coauthors disclosed consulting/advisory roles and travel accommodations and expenses from the company.

Combination chemotherapy with bendamustine, gemcitabine, and vinorelbine can induce high complete response rates among patients with relapsed or refractory Hodgkin lymphoma (HL) who are candidates for autologous stem cell transplantation, final results of a phase II study show.

Among 59 patients enrolled in the multicenter study, 49 (83%) had responses, including 43 (73%) who achieved a complete response (CR), and 6 (10%) who had a partial response after 4 cycles of chemotherapy with bendamustine (Treanda), gemcitabine (Gemzar), and vinorelbine (BeGEV).

Of the 49 patients with responses, 43 went on to autologous stem cell transplant (ASCT), reported Armando Santoro, MD, from the Humanitas Cancer Center in Rozzano, Italy.

“These findings provide a strong rationale for further development of the BeGEV regimen,” the investigators wrote in a study published online in the Journal of Clinical Oncology (2016 Jul 5. doi: 10.1200/JCO.2016.66.4466).

The investigators had previously shown that a regimen of ifosfamide, gemcitabine, and vinorelbine (IEGV) as salvage chemotherapy prior to ASCT was associated with an 81% overall response rate (ORR) 54% CR rate.

Because bendamustine has shown good activity as monotherapy against relapsed/refractory HL, they conducted a phase II study with an IEGV-like regimen in which bendamustine would be substituted for ifosfamide, to determine whether the substitution could improve response rates.

They enrolled 59 consecutive patients aged 18 years and older with HL that had relapsed or was refractory to one previous line of chemotherapy. Patients were treated with gemcitabine 800 mg/m² on days 1 and 4, vinorelbine 20 mg/m² on day 1, and bendamustine 90 mg/m² on days 2 and 3. Patients also received prednisolone 100 mg/day for days 1 to 4. The patients were treated for four 21-day cycles.

Patients who achieved either a complete or partial response after completion of the four planned cycles then underwent myeloablative therapy with carmustine or fotemustine plus etoposide, cytarabine, and melphalan, followed by reinfusion of mobilized CD34-positive circulating stem cells.

Grade 3 or 4 hematologic toxicities included thrombocytopenia and neutropenia, which occurred in eight patients each. Fifty-five of 57 total evaluable patients had successful mobilization and harvesting of CD34-positive cells, and, as noted before, 43 went on to ASCT.

After a median follow-up of 29 months, the 2-year progression-free survival (PFS) rate for the total population was 62%, and the overall survival rates was nearly 78%. For patients who went on to ASCT, the 2-year PFS rate was 81%, and the 2-year survival rate was 89%.

The authors noted that BeGV was associated with higher CR rates than IEGV, and with “excellent” stem cell mobilization activity and engraftment. Additionally, BeGV has a favorable toxicity profile, because of the absence of ifosfamide which is known to significantly increase risk for hemorrhagic cystitis.

“Because the number of novel agents that may be added in the pretransplantation therapy setting is growing, direct comparisons of combinations incorporating novel agents with BeGEV and other regimens will be necessary to identify the best salvage strategy for relapsed and refractory HL,” the authors wrote.

The study was supported in part by a grant from Mundipharma Pharmaceuticals. Two coauthors disclosed consulting/advisory roles and travel accommodations and expenses from the company.

Combination chemotherapy with bendamustine, gemcitabine, and vinorelbine can induce high complete response rates among patients with relapsed or refractory Hodgkin lymphoma (HL) who are candidates for autologous stem cell transplantation, final results of a phase II study show.

Among 59 patients enrolled in the multicenter study, 49 (83%) had responses, including 43 (73%) who achieved a complete response (CR), and 6 (10%) who had a partial response after 4 cycles of chemotherapy with bendamustine (Treanda), gemcitabine (Gemzar), and vinorelbine (BeGEV).

Of the 49 patients with responses, 43 went on to autologous stem cell transplant (ASCT), reported Armando Santoro, MD, from the Humanitas Cancer Center in Rozzano, Italy.

“These findings provide a strong rationale for further development of the BeGEV regimen,” the investigators wrote in a study published online in the Journal of Clinical Oncology (2016 Jul 5. doi: 10.1200/JCO.2016.66.4466).

The investigators had previously shown that a regimen of ifosfamide, gemcitabine, and vinorelbine (IEGV) as salvage chemotherapy prior to ASCT was associated with an 81% overall response rate (ORR) 54% CR rate.

Because bendamustine has shown good activity as monotherapy against relapsed/refractory HL, they conducted a phase II study with an IEGV-like regimen in which bendamustine would be substituted for ifosfamide, to determine whether the substitution could improve response rates.

They enrolled 59 consecutive patients aged 18 years and older with HL that had relapsed or was refractory to one previous line of chemotherapy. Patients were treated with gemcitabine 800 mg/m² on days 1 and 4, vinorelbine 20 mg/m² on day 1, and bendamustine 90 mg/m² on days 2 and 3. Patients also received prednisolone 100 mg/day for days 1 to 4. The patients were treated for four 21-day cycles.

Patients who achieved either a complete or partial response after completion of the four planned cycles then underwent myeloablative therapy with carmustine or fotemustine plus etoposide, cytarabine, and melphalan, followed by reinfusion of mobilized CD34-positive circulating stem cells.

Grade 3 or 4 hematologic toxicities included thrombocytopenia and neutropenia, which occurred in eight patients each. Fifty-five of 57 total evaluable patients had successful mobilization and harvesting of CD34-positive cells, and, as noted before, 43 went on to ASCT.

After a median follow-up of 29 months, the 2-year progression-free survival (PFS) rate for the total population was 62%, and the overall survival rates was nearly 78%. For patients who went on to ASCT, the 2-year PFS rate was 81%, and the 2-year survival rate was 89%.

The authors noted that BeGV was associated with higher CR rates than IEGV, and with “excellent” stem cell mobilization activity and engraftment. Additionally, BeGV has a favorable toxicity profile, because of the absence of ifosfamide which is known to significantly increase risk for hemorrhagic cystitis.

“Because the number of novel agents that may be added in the pretransplantation therapy setting is growing, direct comparisons of combinations incorporating novel agents with BeGEV and other regimens will be necessary to identify the best salvage strategy for relapsed and refractory HL,” the authors wrote.

The study was supported in part by a grant from Mundipharma Pharmaceuticals. Two coauthors disclosed consulting/advisory roles and travel accommodations and expenses from the company.

About 1 in 7 cases of multiple myeloma diagnosed in the United States are cases of smoldering disease, according to an analysis of data from the National Cancer Data Base, which represents 70% of cancer cases.

The prevalence of smoldering multiple myeloma varied among various socio- and geodemographic subgroups, but overall survival did not, Aishwarya Ravindran, MBBS, of Mayo Clinic, Rochester, Minn., and colleagues reported at the annual meeting of the American Society of Clinical Oncology. “Our results can be used in the future to study the health care impact of SMM,” the researchers wrote in a poster presentation.

Courtesy Wikimedia Commons/KGH/Creative Commons License

Epidemiologic studies of smoldering multiple myeloma have been limited by the lack of International Classification of Diseases codes specific for smoldering status, the researchers said.

They analyzed 86,327 cases of multiple myeloma, considering socio- and geodemographic subgroups and type of treatment facility. Overall survival was compared for smoldering and active multiple myeloma. The researchers included patients enrolled in the database during 2003-2011; records were examined from the time to initial treatment and they considered reasons for patients not receiving treatment.

Patients who did not require treatment within the first 120 days after diagnosis were considered to have smoldering disease. This group comprised almost 14% of the cases.

The proportion of cases that were smoldering disease did not change significantly during the study period (P = .23 and .34, respectively). Smoldering disease was more likely to be diagnosed among women, black patients, older patients (median age at diagnosis was 67 years), and less educated patients. Smoldering disease was more common in patients with fewer medical comorbidities, those living closer to a treatment facility, and those evaluated for their disease in the Northeast United States. The proportions of cases diagnosed at academic and nonacademic facilities were similar.

The median overall survival for smoldering disease was 63 months; for active disease, 33 months. Overall survival in those with smoldering disease did not differ among the racial groups (P = .27).

The researchers had no financial conflicts.

mdales@frontlinemedcom.com

On Twitter @maryjodales

About 1 in 7 cases of multiple myeloma diagnosed in the United States are cases of smoldering disease, according to an analysis of data from the National Cancer Data Base, which represents 70% of cancer cases.

The prevalence of smoldering multiple myeloma varied among various socio- and geodemographic subgroups, but overall survival did not, Aishwarya Ravindran, MBBS, of Mayo Clinic, Rochester, Minn., and colleagues reported at the annual meeting of the American Society of Clinical Oncology. “Our results can be used in the future to study the health care impact of SMM,” the researchers wrote in a poster presentation.

Courtesy Wikimedia Commons/KGH/Creative Commons License

Epidemiologic studies of smoldering multiple myeloma have been limited by the lack of International Classification of Diseases codes specific for smoldering status, the researchers said.

They analyzed 86,327 cases of multiple myeloma, considering socio- and geodemographic subgroups and type of treatment facility. Overall survival was compared for smoldering and active multiple myeloma. The researchers included patients enrolled in the database during 2003-2011; records were examined from the time to initial treatment and they considered reasons for patients not receiving treatment.

Patients who did not require treatment within the first 120 days after diagnosis were considered to have smoldering disease. This group comprised almost 14% of the cases.

The proportion of cases that were smoldering disease did not change significantly during the study period (P = .23 and .34, respectively). Smoldering disease was more likely to be diagnosed among women, black patients, older patients (median age at diagnosis was 67 years), and less educated patients. Smoldering disease was more common in patients with fewer medical comorbidities, those living closer to a treatment facility, and those evaluated for their disease in the Northeast United States. The proportions of cases diagnosed at academic and nonacademic facilities were similar.

The median overall survival for smoldering disease was 63 months; for active disease, 33 months. Overall survival in those with smoldering disease did not differ among the racial groups (P = .27).

The researchers had no financial conflicts.

mdales@frontlinemedcom.com

On Twitter @maryjodales

About 1 in 7 cases of multiple myeloma diagnosed in the United States are cases of smoldering disease, according to an analysis of data from the National Cancer Data Base, which represents 70% of cancer cases.

The prevalence of smoldering multiple myeloma varied among various socio- and geodemographic subgroups, but overall survival did not, Aishwarya Ravindran, MBBS, of Mayo Clinic, Rochester, Minn., and colleagues reported at the annual meeting of the American Society of Clinical Oncology. “Our results can be used in the future to study the health care impact of SMM,” the researchers wrote in a poster presentation.

Courtesy Wikimedia Commons/KGH/Creative Commons License

Epidemiologic studies of smoldering multiple myeloma have been limited by the lack of International Classification of Diseases codes specific for smoldering status, the researchers said.

They analyzed 86,327 cases of multiple myeloma, considering socio- and geodemographic subgroups and type of treatment facility. Overall survival was compared for smoldering and active multiple myeloma. The researchers included patients enrolled in the database during 2003-2011; records were examined from the time to initial treatment and they considered reasons for patients not receiving treatment.

Patients who did not require treatment within the first 120 days after diagnosis were considered to have smoldering disease. This group comprised almost 14% of the cases.

The proportion of cases that were smoldering disease did not change significantly during the study period (P = .23 and .34, respectively). Smoldering disease was more likely to be diagnosed among women, black patients, older patients (median age at diagnosis was 67 years), and less educated patients. Smoldering disease was more common in patients with fewer medical comorbidities, those living closer to a treatment facility, and those evaluated for their disease in the Northeast United States. The proportions of cases diagnosed at academic and nonacademic facilities were similar.

The median overall survival for smoldering disease was 63 months; for active disease, 33 months. Overall survival in those with smoldering disease did not differ among the racial groups (P = .27).

The researchers had no financial conflicts.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Drug release in a cancer cell

Image from PNAS

A study published in Cell has shown that patient-derived cancer cell lines harbor most of the same genetic changes found in patients’ tumors and could therefore be used to learn how cancers are likely to respond to new drugs.

Researchers believe this discovery could help advance personalized cancer medicine by leading to results that help doctors predict the best available drugs or the most suitable clinical trials for each individual patient.

“We need better ways to figure out which groups of patients are more likely to respond to a new drug before we run complex and expensive clinical trials,” said study author Ultan McDermott, MD, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.

“Our research shows that cancer cell lines do capture the molecular alterations found in tumors and so can be predictive of how a tumor will respond to a drug. This means the cell lines could tell us much more about how a tumor is likely to respond to a new drug before we try to test it in patients. We hope this information will ultimately help in the design of clinical trials that target those patients with the greatest likelihood of benefiting from treatment.”

The researchers said this is the first systematic, large-scale study to combine molecular data from patients, cancer cell lines, and drug sensitivity.

For the study, the team looked at genetic mutations known to cause cancer in more than 11,000 patient samples of 29 different cancer types, including acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, and multiple myeloma.

The researchers built a catalogue of the genetic changes that cause cancer in patients and mapped these alterations onto 1000 cancer cell lines. Next, they tested the cell lines for sensitivity to 265 different cancer drugs to understand which of these changes affect sensitivity.

This revealed that the majority of molecular abnormalities found in patients’ cancers are also found in cancer cells in the laboratory.

The work also showed that many of the molecular abnormalities detected in the thousands of patient samples can, both individually and in combination, have a strong effect on whether a particular drug affects a cancer cell’s survival.

The results suggest cancer cell lines could be better exploited to learn which drugs offer the most effective treatment to which patients.

“If a cell line has the same genetic features as a patient’s tumor, and that cell line responded to a specific drug, we can focus new research on this finding,” said study author Francesco Iorio, PhD, of the European Bioinformatics Institute in Cambridge, UK.

“This could ultimately help assign cancer patients into more precise groups based on how likely they are to respond to therapy. This resource can really help cancer research. Most importantly, it can be used to create tools for doctors to select a clinical trial which is most promising for their cancer patient. That is still a way off, but we are heading in the right direction.”

Drug release in a cancer cell

Image from PNAS

A study published in Cell has shown that patient-derived cancer cell lines harbor most of the same genetic changes found in patients’ tumors and could therefore be used to learn how cancers are likely to respond to new drugs.

Researchers believe this discovery could help advance personalized cancer medicine by leading to results that help doctors predict the best available drugs or the most suitable clinical trials for each individual patient.

“We need better ways to figure out which groups of patients are more likely to respond to a new drug before we run complex and expensive clinical trials,” said study author Ultan McDermott, MD, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.

“Our research shows that cancer cell lines do capture the molecular alterations found in tumors and so can be predictive of how a tumor will respond to a drug. This means the cell lines could tell us much more about how a tumor is likely to respond to a new drug before we try to test it in patients. We hope this information will ultimately help in the design of clinical trials that target those patients with the greatest likelihood of benefiting from treatment.”

The researchers said this is the first systematic, large-scale study to combine molecular data from patients, cancer cell lines, and drug sensitivity.

For the study, the team looked at genetic mutations known to cause cancer in more than 11,000 patient samples of 29 different cancer types, including acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, and multiple myeloma.

The researchers built a catalogue of the genetic changes that cause cancer in patients and mapped these alterations onto 1000 cancer cell lines. Next, they tested the cell lines for sensitivity to 265 different cancer drugs to understand which of these changes affect sensitivity.

This revealed that the majority of molecular abnormalities found in patients’ cancers are also found in cancer cells in the laboratory.

The work also showed that many of the molecular abnormalities detected in the thousands of patient samples can, both individually and in combination, have a strong effect on whether a particular drug affects a cancer cell’s survival.

The results suggest cancer cell lines could be better exploited to learn which drugs offer the most effective treatment to which patients.

“If a cell line has the same genetic features as a patient’s tumor, and that cell line responded to a specific drug, we can focus new research on this finding,” said study author Francesco Iorio, PhD, of the European Bioinformatics Institute in Cambridge, UK.

“This could ultimately help assign cancer patients into more precise groups based on how likely they are to respond to therapy. This resource can really help cancer research. Most importantly, it can be used to create tools for doctors to select a clinical trial which is most promising for their cancer patient. That is still a way off, but we are heading in the right direction.”

Drug release in a cancer cell

Image from PNAS

A study published in Cell has shown that patient-derived cancer cell lines harbor most of the same genetic changes found in patients’ tumors and could therefore be used to learn how cancers are likely to respond to new drugs.

Researchers believe this discovery could help advance personalized cancer medicine by leading to results that help doctors predict the best available drugs or the most suitable clinical trials for each individual patient.

“We need better ways to figure out which groups of patients are more likely to respond to a new drug before we run complex and expensive clinical trials,” said study author Ultan McDermott, MD, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.

“Our research shows that cancer cell lines do capture the molecular alterations found in tumors and so can be predictive of how a tumor will respond to a drug. This means the cell lines could tell us much more about how a tumor is likely to respond to a new drug before we try to test it in patients. We hope this information will ultimately help in the design of clinical trials that target those patients with the greatest likelihood of benefiting from treatment.”

The researchers said this is the first systematic, large-scale study to combine molecular data from patients, cancer cell lines, and drug sensitivity.

For the study, the team looked at genetic mutations known to cause cancer in more than 11,000 patient samples of 29 different cancer types, including acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, and multiple myeloma.

The researchers built a catalogue of the genetic changes that cause cancer in patients and mapped these alterations onto 1000 cancer cell lines. Next, they tested the cell lines for sensitivity to 265 different cancer drugs to understand which of these changes affect sensitivity.

This revealed that the majority of molecular abnormalities found in patients’ cancers are also found in cancer cells in the laboratory.

The work also showed that many of the molecular abnormalities detected in the thousands of patient samples can, both individually and in combination, have a strong effect on whether a particular drug affects a cancer cell’s survival.

The results suggest cancer cell lines could be better exploited to learn which drugs offer the most effective treatment to which patients.

“If a cell line has the same genetic features as a patient’s tumor, and that cell line responded to a specific drug, we can focus new research on this finding,” said study author Francesco Iorio, PhD, of the European Bioinformatics Institute in Cambridge, UK.

“This could ultimately help assign cancer patients into more precise groups based on how likely they are to respond to therapy. This resource can really help cancer research. Most importantly, it can be used to create tools for doctors to select a clinical trial which is most promising for their cancer patient. That is still a way off, but we are heading in the right direction.”

Brentuximab vedotin

Photo from Business Wire

The European Commission (EC) has extended the current conditional marketing authorization of brentuximab vedotin (Adcetris) to include the treatment of adults with CD30+ Hodgkin lymphoma (HL) who are at an increased risk of relapse or progression following autologous stem cell transplant (ASCT).

Conditional marketing authorizations are valid for 1 year and are reviewed annually.

The company developing the drug is required to provide comprehensive data confirming the drug’s benefit-risk balance is positive. Once these data are available, the marketing authorization may be converted into a standard marketing authorization.

Drugs are eligible for conditional marketing authorization if they are designated as orphan medicines, intended for use in emergency situations, or designed to treat, prevent, or diagnose seriously debilitating or life-threatening diseases.

The EC previously granted brentuximab vedotin conditional marketing authorization for 2 indications:

• To treat adults with relapsed or refractory CD30+ HL after ASCT or following at least 2 prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
• To treat adults with relapsed or refractory systemic anaplastic large-cell lymphoma (sALCL).

In January 2016, the EC approved a Type II variation to include data on the retreatment of adult patients with HL or sALCL who previously responded to brentuximab vedotin and later relapsed.

Brentuximab vedotin is under joint development by Seattle Genetics and Takeda Pharmaceutical Company Limited.

AETHERA trial

The EC’s decision to extend the conditional marketing authorization of brentuximab vedotin is based on results from the phase 3 AETHERA trial.

The trial was designed to compare brentuximab vedotin to placebo, both administered for up to 16 cycles (approximately 1 year) every 3 weeks following ASCT. Results from the trial were published in The Lancet in March 2015 and presented at the 2014 ASH Annual Meeting.

The study enrolled 329 HL patients at risk of relapse or progression, including 165 on the brentuximab vedotin arm and 164 on the placebo arm.

Patients were eligible for enrollment if they had a history of primary refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-ASCT relapse.

Brentuximab vedotin conferred a significant increase in progression-free survival over placebo, with a hazard ratio of 0.57 (P=0.001). The median progression-free survival was 43 months for patients who received brentuximab vedotin and 24 months for those who received placebo.

The most common adverse events (≥20%), of any grade and regardless of causality, in the brentuximab vedotin arm were neutropenia (78%), peripheral sensory neuropathy (56%), thrombocytopenia (41%), anemia (27%), upper respiratory tract infection (26%), fatigue (24%), peripheral motor neuropathy (23%), nausea (22%), cough (21%), and diarrhea (20%).

The most common adverse events (≥20%), of any grade and regardless of causality, in the placebo arm were neutropenia (34%), upper respiratory tract infection (23%), and thrombocytopenia (20%).

In all, 67% of patients on the brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution (59%) or partial improvement (26%) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range, 0.1-138).

Brentuximab vedotin

Photo from Business Wire

The European Commission (EC) has extended the current conditional marketing authorization of brentuximab vedotin (Adcetris) to include the treatment of adults with CD30+ Hodgkin lymphoma (HL) who are at an increased risk of relapse or progression following autologous stem cell transplant (ASCT).

Conditional marketing authorizations are valid for 1 year and are reviewed annually.

The company developing the drug is required to provide comprehensive data confirming the drug’s benefit-risk balance is positive. Once these data are available, the marketing authorization may be converted into a standard marketing authorization.

Drugs are eligible for conditional marketing authorization if they are designated as orphan medicines, intended for use in emergency situations, or designed to treat, prevent, or diagnose seriously debilitating or life-threatening diseases.

The EC previously granted brentuximab vedotin conditional marketing authorization for 2 indications:

• To treat adults with relapsed or refractory CD30+ HL after ASCT or following at least 2 prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
• To treat adults with relapsed or refractory systemic anaplastic large-cell lymphoma (sALCL).

In January 2016, the EC approved a Type II variation to include data on the retreatment of adult patients with HL or sALCL who previously responded to brentuximab vedotin and later relapsed.

Brentuximab vedotin is under joint development by Seattle Genetics and Takeda Pharmaceutical Company Limited.

AETHERA trial

The EC’s decision to extend the conditional marketing authorization of brentuximab vedotin is based on results from the phase 3 AETHERA trial.

The trial was designed to compare brentuximab vedotin to placebo, both administered for up to 16 cycles (approximately 1 year) every 3 weeks following ASCT. Results from the trial were published in The Lancet in March 2015 and presented at the 2014 ASH Annual Meeting.

The study enrolled 329 HL patients at risk of relapse or progression, including 165 on the brentuximab vedotin arm and 164 on the placebo arm.

Patients were eligible for enrollment if they had a history of primary refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-ASCT relapse.

Brentuximab vedotin conferred a significant increase in progression-free survival over placebo, with a hazard ratio of 0.57 (P=0.001). The median progression-free survival was 43 months for patients who received brentuximab vedotin and 24 months for those who received placebo.

The most common adverse events (≥20%), of any grade and regardless of causality, in the brentuximab vedotin arm were neutropenia (78%), peripheral sensory neuropathy (56%), thrombocytopenia (41%), anemia (27%), upper respiratory tract infection (26%), fatigue (24%), peripheral motor neuropathy (23%), nausea (22%), cough (21%), and diarrhea (20%).

The most common adverse events (≥20%), of any grade and regardless of causality, in the placebo arm were neutropenia (34%), upper respiratory tract infection (23%), and thrombocytopenia (20%).

In all, 67% of patients on the brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution (59%) or partial improvement (26%) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range, 0.1-138).

Brentuximab vedotin

Photo from Business Wire

The European Commission (EC) has extended the current conditional marketing authorization of brentuximab vedotin (Adcetris) to include the treatment of adults with CD30+ Hodgkin lymphoma (HL) who are at an increased risk of relapse or progression following autologous stem cell transplant (ASCT).

Conditional marketing authorizations are valid for 1 year and are reviewed annually.

The company developing the drug is required to provide comprehensive data confirming the drug’s benefit-risk balance is positive. Once these data are available, the marketing authorization may be converted into a standard marketing authorization.

Drugs are eligible for conditional marketing authorization if they are designated as orphan medicines, intended for use in emergency situations, or designed to treat, prevent, or diagnose seriously debilitating or life-threatening diseases.

The EC previously granted brentuximab vedotin conditional marketing authorization for 2 indications:

• To treat adults with relapsed or refractory CD30+ HL after ASCT or following at least 2 prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
• To treat adults with relapsed or refractory systemic anaplastic large-cell lymphoma (sALCL).

In January 2016, the EC approved a Type II variation to include data on the retreatment of adult patients with HL or sALCL who previously responded to brentuximab vedotin and later relapsed.

Brentuximab vedotin is under joint development by Seattle Genetics and Takeda Pharmaceutical Company Limited.

AETHERA trial

The EC’s decision to extend the conditional marketing authorization of brentuximab vedotin is based on results from the phase 3 AETHERA trial.

The trial was designed to compare brentuximab vedotin to placebo, both administered for up to 16 cycles (approximately 1 year) every 3 weeks following ASCT. Results from the trial were published in The Lancet in March 2015 and presented at the 2014 ASH Annual Meeting.

The study enrolled 329 HL patients at risk of relapse or progression, including 165 on the brentuximab vedotin arm and 164 on the placebo arm.

Patients were eligible for enrollment if they had a history of primary refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-ASCT relapse.

Brentuximab vedotin conferred a significant increase in progression-free survival over placebo, with a hazard ratio of 0.57 (P=0.001). The median progression-free survival was 43 months for patients who received brentuximab vedotin and 24 months for those who received placebo.

The most common adverse events (≥20%), of any grade and regardless of causality, in the brentuximab vedotin arm were neutropenia (78%), peripheral sensory neuropathy (56%), thrombocytopenia (41%), anemia (27%), upper respiratory tract infection (26%), fatigue (24%), peripheral motor neuropathy (23%), nausea (22%), cough (21%), and diarrhea (20%).

The most common adverse events (≥20%), of any grade and regardless of causality, in the placebo arm were neutropenia (34%), upper respiratory tract infection (23%), and thrombocytopenia (20%).

In all, 67% of patients on the brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution (59%) or partial improvement (26%) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range, 0.1-138).