Lab mouse

Researchers say they have discovered why patients with chronic lymphocytic leukemia (CLL) often relapse.

Using a mouse model, the team demonstrated that crosstalk between leukemic cells and a group of stromal cells in the spleen is crucial for tumor growth.

The group also found a way to prevent leukemic cell proliferation and stop the cells from entering the spleen, thereby identifying new targets for future therapies in CLL.

Kristina Heinig, of Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues reported these findings in Cancer Discovery.

The team theorized that the processes that normally regulate the migration of B lymphocytes into the B-cell follicle are also the reason for the migration of leukemia cells into the lymphoid organs. Hence, within the B-cell follicle, the survival and growth of malignant B cells may depend on the contact of leukemia cells with follicular dendritic cells (FDCs).

The researchers validated this theory with their mouse model. They found the chemokine CXCL13 and its receptor, CXCR5, on the surface of the leukemia cells are needed to ensure that leukemia cells can reach the spleen. With the aid of this homing receptor, the cancer cells are lured into the B-cell follicle of the spleen, where the FDCs secrete CXCL13.

When the researchers blocked CXCR5 in the mice, the leukemia cells could no longer migrate into the stromal cell niche and proliferated much more slowly.

In a second step, the group studied the consequences of the interaction between malignant B cells and the FDCs in the B-cell follicle. They found the close contact between the leukemia cells and the FDC network stimulates the cancer cells to increasingly produce another signaling substance, lymphotoxin.

The lymphotoxin binds to the lymphotoxin-beta receptor on the FDCs, which then increasingly secrete CXCL13. This creates a positive feedback loop because CXCL13 plays a major role in the recruitment of leukemia cells in the B-cell follicles.

The FDCs also provide growth factors that promote the proliferation of leukemia cells in the stromal niche.

When the researchers inhibited the binding of the lymphotoxin to the lymphotoxin-beta receptor on the FDCs with an immunologically active substance, they were able to end this ping-pong match between leukemia cells and the FDCs and dramatically reduce tumor growth.

The team thus identified two different targets that may complement the chemotherapy currently used to treat CLL. The first is blocking the chemokine/homing receptor CXCR5 on the leukemia cells, which prevents the cancer cells from lodging in the B-cell follicle.

The second is blocking the lymphotoxin-beta receptor on the FDCs so the reciprocal crosstalk between the leukemia cells and the FDCs is interrupted and tumor development is reduced.

From the results of their study, the researchers infer that chemotherapies already in clinical use combined with immune therapies that interrupt the crosstalk between leukemia cells and the FDCs may be beneficial.

This combination could prevent the residual leukemia cells that have escaped chemotherapy or radiation therapy from recovering in the stromal cell niche and from triggering a relapse.

Lab mouse

Researchers say they have discovered why patients with chronic lymphocytic leukemia (CLL) often relapse.

Using a mouse model, the team demonstrated that crosstalk between leukemic cells and a group of stromal cells in the spleen is crucial for tumor growth.

The group also found a way to prevent leukemic cell proliferation and stop the cells from entering the spleen, thereby identifying new targets for future therapies in CLL.

Kristina Heinig, of Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues reported these findings in Cancer Discovery.

The team theorized that the processes that normally regulate the migration of B lymphocytes into the B-cell follicle are also the reason for the migration of leukemia cells into the lymphoid organs. Hence, within the B-cell follicle, the survival and growth of malignant B cells may depend on the contact of leukemia cells with follicular dendritic cells (FDCs).

The researchers validated this theory with their mouse model. They found the chemokine CXCL13 and its receptor, CXCR5, on the surface of the leukemia cells are needed to ensure that leukemia cells can reach the spleen. With the aid of this homing receptor, the cancer cells are lured into the B-cell follicle of the spleen, where the FDCs secrete CXCL13.

When the researchers blocked CXCR5 in the mice, the leukemia cells could no longer migrate into the stromal cell niche and proliferated much more slowly.

In a second step, the group studied the consequences of the interaction between malignant B cells and the FDCs in the B-cell follicle. They found the close contact between the leukemia cells and the FDC network stimulates the cancer cells to increasingly produce another signaling substance, lymphotoxin.

The lymphotoxin binds to the lymphotoxin-beta receptor on the FDCs, which then increasingly secrete CXCL13. This creates a positive feedback loop because CXCL13 plays a major role in the recruitment of leukemia cells in the B-cell follicles.

The FDCs also provide growth factors that promote the proliferation of leukemia cells in the stromal niche.

When the researchers inhibited the binding of the lymphotoxin to the lymphotoxin-beta receptor on the FDCs with an immunologically active substance, they were able to end this ping-pong match between leukemia cells and the FDCs and dramatically reduce tumor growth.

The team thus identified two different targets that may complement the chemotherapy currently used to treat CLL. The first is blocking the chemokine/homing receptor CXCR5 on the leukemia cells, which prevents the cancer cells from lodging in the B-cell follicle.

The second is blocking the lymphotoxin-beta receptor on the FDCs so the reciprocal crosstalk between the leukemia cells and the FDCs is interrupted and tumor development is reduced.

From the results of their study, the researchers infer that chemotherapies already in clinical use combined with immune therapies that interrupt the crosstalk between leukemia cells and the FDCs may be beneficial.

This combination could prevent the residual leukemia cells that have escaped chemotherapy or radiation therapy from recovering in the stromal cell niche and from triggering a relapse.

Lab mouse

Researchers say they have discovered why patients with chronic lymphocytic leukemia (CLL) often relapse.

Using a mouse model, the team demonstrated that crosstalk between leukemic cells and a group of stromal cells in the spleen is crucial for tumor growth.

The group also found a way to prevent leukemic cell proliferation and stop the cells from entering the spleen, thereby identifying new targets for future therapies in CLL.

Kristina Heinig, of Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues reported these findings in Cancer Discovery.

The team theorized that the processes that normally regulate the migration of B lymphocytes into the B-cell follicle are also the reason for the migration of leukemia cells into the lymphoid organs. Hence, within the B-cell follicle, the survival and growth of malignant B cells may depend on the contact of leukemia cells with follicular dendritic cells (FDCs).

The researchers validated this theory with their mouse model. They found the chemokine CXCL13 and its receptor, CXCR5, on the surface of the leukemia cells are needed to ensure that leukemia cells can reach the spleen. With the aid of this homing receptor, the cancer cells are lured into the B-cell follicle of the spleen, where the FDCs secrete CXCL13.

When the researchers blocked CXCR5 in the mice, the leukemia cells could no longer migrate into the stromal cell niche and proliferated much more slowly.

In a second step, the group studied the consequences of the interaction between malignant B cells and the FDCs in the B-cell follicle. They found the close contact between the leukemia cells and the FDC network stimulates the cancer cells to increasingly produce another signaling substance, lymphotoxin.

The lymphotoxin binds to the lymphotoxin-beta receptor on the FDCs, which then increasingly secrete CXCL13. This creates a positive feedback loop because CXCL13 plays a major role in the recruitment of leukemia cells in the B-cell follicles.

The FDCs also provide growth factors that promote the proliferation of leukemia cells in the stromal niche.

When the researchers inhibited the binding of the lymphotoxin to the lymphotoxin-beta receptor on the FDCs with an immunologically active substance, they were able to end this ping-pong match between leukemia cells and the FDCs and dramatically reduce tumor growth.

The team thus identified two different targets that may complement the chemotherapy currently used to treat CLL. The first is blocking the chemokine/homing receptor CXCR5 on the leukemia cells, which prevents the cancer cells from lodging in the B-cell follicle.

The second is blocking the lymphotoxin-beta receptor on the FDCs so the reciprocal crosstalk between the leukemia cells and the FDCs is interrupted and tumor development is reduced.

From the results of their study, the researchers infer that chemotherapies already in clinical use combined with immune therapies that interrupt the crosstalk between leukemia cells and the FDCs may be beneficial.

This combination could prevent the residual leukemia cells that have escaped chemotherapy or radiation therapy from recovering in the stromal cell niche and from triggering a relapse.

SAN FRANCISCO – Ofatumumab maintenance therapy nearly doubled progression-free survival in patients with relapsed CLL, according to a preplanned interim analysis of the phase III PROLONG study.

At a median follow-up of 19.1 months, progression-free survival was 15.2 months with the standard approach of observation alone and 29.4 months with maintenance ofatumumab (Hazard ratio, 0.50; P < .0001).

Ofatumumab (Arzerra) also significantly increased the median time to next treatment from 31.1 months to 38 months (HR, 0.66; P = .0108), Dr. Marinus van Oers reported at the annual meeting of the American Society of Hematology.

The benefit in progression-free survival (PFS) with maintenance was “statistically significant and clinical relevant” and was present in all subgroups, he said. It was independent of age, gender, number and type of prior treatment, minimal residual disease status at study entry, and “response at study entry, although we have the impression that it’s more effective in patients on PR [partial response] than in patients on CR [complete response],” he added.

The rationale for the trial lies in the fact that despite recent advances, there is still no curative treatment for chronic lymphocytic leukemia (CLL). Ofatumumab, a type 1 CD20 monoclonal antibody, has a role as maintenance in follicular lymphoma (FL), which shares similarities in biological behavior with CLL. This role is debated, but a recent meta-analysis shows ofatumumab maintenance prolongs PFS and tends to prolong overall survival in relapsed patients with FL, Dr. van Oers of the Academic Medical Center in Amsterdam, The Netherlands, observed.

PROLONG randomized 474 patients with relapsed CLL to observation or ofatumumab 300 mg in week 1 and 1,000 mg in week 2, and every 8 weeks for 2 years. All patients were in second or third remission and within 3 months of response assessment after the last reinduction treatment. Patients with refractory disease or prior maintenance therapy or stem cell transplantation were excluded.

At baseline, the median age was about 65 years, 70% had at least two prior treatments, 80% were in partial remission from their last CLL treatment, and less than 10% had poor-risk cytogenetics 11p or 17p deletions. At the time of the analysis, 25% of patients had received all 13 cycles of ofatumumab.

Adverse events of any grade were increased with the addition of ofatumumab versus placebo (86% vs. 72%; P < .0001). Sixty percent were related to study treatment, but none resulted in study withdrawal, Dr. van Oers said. In all, 17 patients on the experimental arm dropped out due to physician decision or patient wish.

Among grade 3 events, neutropenia was significantly increased with maintenance therapy versus placebo (24% vs. 10%; P < .0001) and there was a non-significant increase in infections (13% vs. 8%). Five deaths occurred in the observation arm and two in the ofatumumab arm, one due to sepsis two months after the end of treatment and the other due to unrelated GI obstruction.

Median overall survival has not been reached for either arm (HR, 0.85; P = .487), he reported on behalf of HOVON and the NORDIC CLL group, co-developers of the study.

[email protected]

SAN FRANCISCO – Ofatumumab maintenance therapy nearly doubled progression-free survival in patients with relapsed CLL, according to a preplanned interim analysis of the phase III PROLONG study.

At a median follow-up of 19.1 months, progression-free survival was 15.2 months with the standard approach of observation alone and 29.4 months with maintenance ofatumumab (Hazard ratio, 0.50; P < .0001).

Ofatumumab (Arzerra) also significantly increased the median time to next treatment from 31.1 months to 38 months (HR, 0.66; P = .0108), Dr. Marinus van Oers reported at the annual meeting of the American Society of Hematology.

The benefit in progression-free survival (PFS) with maintenance was “statistically significant and clinical relevant” and was present in all subgroups, he said. It was independent of age, gender, number and type of prior treatment, minimal residual disease status at study entry, and “response at study entry, although we have the impression that it’s more effective in patients on PR [partial response] than in patients on CR [complete response],” he added.

The rationale for the trial lies in the fact that despite recent advances, there is still no curative treatment for chronic lymphocytic leukemia (CLL). Ofatumumab, a type 1 CD20 monoclonal antibody, has a role as maintenance in follicular lymphoma (FL), which shares similarities in biological behavior with CLL. This role is debated, but a recent meta-analysis shows ofatumumab maintenance prolongs PFS and tends to prolong overall survival in relapsed patients with FL, Dr. van Oers of the Academic Medical Center in Amsterdam, The Netherlands, observed.

PROLONG randomized 474 patients with relapsed CLL to observation or ofatumumab 300 mg in week 1 and 1,000 mg in week 2, and every 8 weeks for 2 years. All patients were in second or third remission and within 3 months of response assessment after the last reinduction treatment. Patients with refractory disease or prior maintenance therapy or stem cell transplantation were excluded.

At baseline, the median age was about 65 years, 70% had at least two prior treatments, 80% were in partial remission from their last CLL treatment, and less than 10% had poor-risk cytogenetics 11p or 17p deletions. At the time of the analysis, 25% of patients had received all 13 cycles of ofatumumab.

Adverse events of any grade were increased with the addition of ofatumumab versus placebo (86% vs. 72%; P < .0001). Sixty percent were related to study treatment, but none resulted in study withdrawal, Dr. van Oers said. In all, 17 patients on the experimental arm dropped out due to physician decision or patient wish.

Among grade 3 events, neutropenia was significantly increased with maintenance therapy versus placebo (24% vs. 10%; P < .0001) and there was a non-significant increase in infections (13% vs. 8%). Five deaths occurred in the observation arm and two in the ofatumumab arm, one due to sepsis two months after the end of treatment and the other due to unrelated GI obstruction.

Median overall survival has not been reached for either arm (HR, 0.85; P = .487), he reported on behalf of HOVON and the NORDIC CLL group, co-developers of the study.

[email protected]

SAN FRANCISCO – Ofatumumab maintenance therapy nearly doubled progression-free survival in patients with relapsed CLL, according to a preplanned interim analysis of the phase III PROLONG study.

At a median follow-up of 19.1 months, progression-free survival was 15.2 months with the standard approach of observation alone and 29.4 months with maintenance ofatumumab (Hazard ratio, 0.50; P < .0001).

Ofatumumab (Arzerra) also significantly increased the median time to next treatment from 31.1 months to 38 months (HR, 0.66; P = .0108), Dr. Marinus van Oers reported at the annual meeting of the American Society of Hematology.

The benefit in progression-free survival (PFS) with maintenance was “statistically significant and clinical relevant” and was present in all subgroups, he said. It was independent of age, gender, number and type of prior treatment, minimal residual disease status at study entry, and “response at study entry, although we have the impression that it’s more effective in patients on PR [partial response] than in patients on CR [complete response],” he added.

The rationale for the trial lies in the fact that despite recent advances, there is still no curative treatment for chronic lymphocytic leukemia (CLL). Ofatumumab, a type 1 CD20 monoclonal antibody, has a role as maintenance in follicular lymphoma (FL), which shares similarities in biological behavior with CLL. This role is debated, but a recent meta-analysis shows ofatumumab maintenance prolongs PFS and tends to prolong overall survival in relapsed patients with FL, Dr. van Oers of the Academic Medical Center in Amsterdam, The Netherlands, observed.

PROLONG randomized 474 patients with relapsed CLL to observation or ofatumumab 300 mg in week 1 and 1,000 mg in week 2, and every 8 weeks for 2 years. All patients were in second or third remission and within 3 months of response assessment after the last reinduction treatment. Patients with refractory disease or prior maintenance therapy or stem cell transplantation were excluded.

At baseline, the median age was about 65 years, 70% had at least two prior treatments, 80% were in partial remission from their last CLL treatment, and less than 10% had poor-risk cytogenetics 11p or 17p deletions. At the time of the analysis, 25% of patients had received all 13 cycles of ofatumumab.

Adverse events of any grade were increased with the addition of ofatumumab versus placebo (86% vs. 72%; P < .0001). Sixty percent were related to study treatment, but none resulted in study withdrawal, Dr. van Oers said. In all, 17 patients on the experimental arm dropped out due to physician decision or patient wish.

Among grade 3 events, neutropenia was significantly increased with maintenance therapy versus placebo (24% vs. 10%; P < .0001) and there was a non-significant increase in infections (13% vs. 8%). Five deaths occurred in the observation arm and two in the ofatumumab arm, one due to sepsis two months after the end of treatment and the other due to unrelated GI obstruction.

Median overall survival has not been reached for either arm (HR, 0.85; P = .487), he reported on behalf of HOVON and the NORDIC CLL group, co-developers of the study.

[email protected]

SAN FRANCISCO – Early post-transplant brentuximab vedotin dramatically slows Hodgkin’s lymphoma progression in patients at high risk for relapse or progression, the phase III AETHERA study shows.

After a median follow-up of about 28 months, the primary end point of progression-free survival (PFS) per independent review increased from a median of 24 months with placebo and best supportive care (BSC) to 43 months with brentuximab and BSC (Hazard ratio, 0.57; P = .001).

Per investigator assessment, median PFS was 16 months with placebo and had not been reached with brentuximab (HR, 0.50),Dr. Craig Moskowitz reported at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

The benefit of brentuximab maintenance was consistent across every subgroup. Historically, roughly half of patients who undergo an autologous stem cell transplant will relapse.

“Once this study is published, in patients who met eligibility criteria to be on this study - and once again I’ll remind you that’s remission duration less than one year, disease outside the lymph node system, or primary refractory disease - in my opinion, this will be the standard of care,” Dr. Moskowitz said during a press briefing.

Brentuximab, an anti-CD30 antibody conjugate, is already approved in the U.S. for the management of Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT) or at least two prior lines of multi-agent chemotherapy in patients ineligible for ASCT.

Brentuximab is also indicated for systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen.

In September it was announced that AETHERA met its primary end point, but this was the first full look at the absolute survival rates and safety data.

The 2-year PFS rate for the brentuximab and placebo groups is now 63% vs. 51% per independent review and 65% vs. 45% per investigator.

“The bottom line is there’s a 20% difference in progression-free survival at 2 years upon investigator review. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin lymphoma,” Dr. Moskowitz, clinical director of hematology oncology at Memorial Sloan-Kettering Cancer Center in New York City, said.

Overall survival data are immature, but was the same in both groups at 2 years (P = .62). The likelihood of showing a survival difference was not expected because 85% of patients who relapsed on the placebo arm crossed over to brentuximab, as allowed per protocol, and it’s known that brentuximab alone in auto-transplant failures improves outcomes by at least a year, he said. Also, twice as many patients who failed placebo received a second transplant.

Dr. Moskowitz stressed that nearly every patient in the trial had at least three risk factors that would place them at high risk of treatment failure and that studies have shown that for patients with this many risk factors, the chance of being cured by an auto-transplant is about 25%. The risk factors are: relapsed less than 12 months or refractory to frontline therapy, best response of partial remission or stable disease to most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse, or two or more prior salvage therapies.

Press briefing moderator Dr. Brad Kahl of the University of Wisconsin-Madison, said Aethera is the first study to show a significant benefit for a post-transplant strategy.

“The biggest question in my mind is whether the application of maintenance brentuximab vedotin is just delaying the inevitable relapse, so the patients will still relapse, just later, or has the brentuximab taken patients who are destined to relapse and turned them into a cured patient,” Dr. Kahl said. “We don’t know the answer to that question. That will become apparent with more time.”

Dr. Moscowitz observed that relapses almost never happen after two year, adding, “So if you’re in remission at two years after stem cell transplantation for Hodgkin lymphoma, you are likely to be cured.”

AETHERA enrolled 329 patients with Hodgkin’s lymphoma and randomly assigned them after ASCT to brentuximab vedotin 1.8 mg/kg or placebo given every 3 weeks for up to 16 cycles, plus BSC. All patients were required to have achieved a complete response, partial remission, or stable disease to salvage therapy prior to ASCT. Their median age was 32 years and 53% were male.

Roughly 60% were refractory to upfront therapy, 43% in the brentuximab arm and 48% of controls had received 2 or more prior systemic therapies, and a third in each arm had extranodal involvement.

Consolidation therapy with brentuximab was generally well tolerated, Dr. Moskowitz said. Peripheral sensory neuropathy was the most common side effect, experienced at any grade in 67% on brentuximab vs. 19% of controls and at grade 3 in 13% vs. 1%. There were no grade 4 events and 85% of patients had resolution or improvement with dose reductions or stopping the drug.

Other adverse events in the brentuximab and control groups were neutropenia (35% vs. 12%), upper respiratory tract infections (26% vs. 23%), and fatigue (24% vs. 18%). Two patients died within 40 days of dosing with brentuximab, one from treatment-related acute respiratory distress syndrome associated with pneumonitis and one following an episode of treatment-related acute pancreatitis that had resolved at the time of death, he reported.

Based on the results, study sponsor Seattle Genetics is expected to seek approval for brentuximab in this consolidation setting in the first half of 2015, according to a statement from the company. The ongoing phase III ECHELON-1 and ECHELON 2 trials in HL and mature T-cell lymphomas are looking at the use of brentuximab in frontline disease.

[email protected]

SAN FRANCISCO – Early post-transplant brentuximab vedotin dramatically slows Hodgkin’s lymphoma progression in patients at high risk for relapse or progression, the phase III AETHERA study shows.

After a median follow-up of about 28 months, the primary end point of progression-free survival (PFS) per independent review increased from a median of 24 months with placebo and best supportive care (BSC) to 43 months with brentuximab and BSC (Hazard ratio, 0.57; P = .001).

Per investigator assessment, median PFS was 16 months with placebo and had not been reached with brentuximab (HR, 0.50),Dr. Craig Moskowitz reported at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

The benefit of brentuximab maintenance was consistent across every subgroup. Historically, roughly half of patients who undergo an autologous stem cell transplant will relapse.

“Once this study is published, in patients who met eligibility criteria to be on this study - and once again I’ll remind you that’s remission duration less than one year, disease outside the lymph node system, or primary refractory disease - in my opinion, this will be the standard of care,” Dr. Moskowitz said during a press briefing.

Brentuximab, an anti-CD30 antibody conjugate, is already approved in the U.S. for the management of Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT) or at least two prior lines of multi-agent chemotherapy in patients ineligible for ASCT.

Brentuximab is also indicated for systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen.

In September it was announced that AETHERA met its primary end point, but this was the first full look at the absolute survival rates and safety data.

The 2-year PFS rate for the brentuximab and placebo groups is now 63% vs. 51% per independent review and 65% vs. 45% per investigator.

“The bottom line is there’s a 20% difference in progression-free survival at 2 years upon investigator review. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin lymphoma,” Dr. Moskowitz, clinical director of hematology oncology at Memorial Sloan-Kettering Cancer Center in New York City, said.

Overall survival data are immature, but was the same in both groups at 2 years (P = .62). The likelihood of showing a survival difference was not expected because 85% of patients who relapsed on the placebo arm crossed over to brentuximab, as allowed per protocol, and it’s known that brentuximab alone in auto-transplant failures improves outcomes by at least a year, he said. Also, twice as many patients who failed placebo received a second transplant.

Dr. Moskowitz stressed that nearly every patient in the trial had at least three risk factors that would place them at high risk of treatment failure and that studies have shown that for patients with this many risk factors, the chance of being cured by an auto-transplant is about 25%. The risk factors are: relapsed less than 12 months or refractory to frontline therapy, best response of partial remission or stable disease to most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse, or two or more prior salvage therapies.

Press briefing moderator Dr. Brad Kahl of the University of Wisconsin-Madison, said Aethera is the first study to show a significant benefit for a post-transplant strategy.

“The biggest question in my mind is whether the application of maintenance brentuximab vedotin is just delaying the inevitable relapse, so the patients will still relapse, just later, or has the brentuximab taken patients who are destined to relapse and turned them into a cured patient,” Dr. Kahl said. “We don’t know the answer to that question. That will become apparent with more time.”

Dr. Moscowitz observed that relapses almost never happen after two year, adding, “So if you’re in remission at two years after stem cell transplantation for Hodgkin lymphoma, you are likely to be cured.”

AETHERA enrolled 329 patients with Hodgkin’s lymphoma and randomly assigned them after ASCT to brentuximab vedotin 1.8 mg/kg or placebo given every 3 weeks for up to 16 cycles, plus BSC. All patients were required to have achieved a complete response, partial remission, or stable disease to salvage therapy prior to ASCT. Their median age was 32 years and 53% were male.

Roughly 60% were refractory to upfront therapy, 43% in the brentuximab arm and 48% of controls had received 2 or more prior systemic therapies, and a third in each arm had extranodal involvement.

Consolidation therapy with brentuximab was generally well tolerated, Dr. Moskowitz said. Peripheral sensory neuropathy was the most common side effect, experienced at any grade in 67% on brentuximab vs. 19% of controls and at grade 3 in 13% vs. 1%. There were no grade 4 events and 85% of patients had resolution or improvement with dose reductions or stopping the drug.

Other adverse events in the brentuximab and control groups were neutropenia (35% vs. 12%), upper respiratory tract infections (26% vs. 23%), and fatigue (24% vs. 18%). Two patients died within 40 days of dosing with brentuximab, one from treatment-related acute respiratory distress syndrome associated with pneumonitis and one following an episode of treatment-related acute pancreatitis that had resolved at the time of death, he reported.

Based on the results, study sponsor Seattle Genetics is expected to seek approval for brentuximab in this consolidation setting in the first half of 2015, according to a statement from the company. The ongoing phase III ECHELON-1 and ECHELON 2 trials in HL and mature T-cell lymphomas are looking at the use of brentuximab in frontline disease.

[email protected]

SAN FRANCISCO – Early post-transplant brentuximab vedotin dramatically slows Hodgkin’s lymphoma progression in patients at high risk for relapse or progression, the phase III AETHERA study shows.

After a median follow-up of about 28 months, the primary end point of progression-free survival (PFS) per independent review increased from a median of 24 months with placebo and best supportive care (BSC) to 43 months with brentuximab and BSC (Hazard ratio, 0.57; P = .001).

Per investigator assessment, median PFS was 16 months with placebo and had not been reached with brentuximab (HR, 0.50),Dr. Craig Moskowitz reported at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

The benefit of brentuximab maintenance was consistent across every subgroup. Historically, roughly half of patients who undergo an autologous stem cell transplant will relapse.

“Once this study is published, in patients who met eligibility criteria to be on this study - and once again I’ll remind you that’s remission duration less than one year, disease outside the lymph node system, or primary refractory disease - in my opinion, this will be the standard of care,” Dr. Moskowitz said during a press briefing.

Brentuximab, an anti-CD30 antibody conjugate, is already approved in the U.S. for the management of Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT) or at least two prior lines of multi-agent chemotherapy in patients ineligible for ASCT.

Brentuximab is also indicated for systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen.

In September it was announced that AETHERA met its primary end point, but this was the first full look at the absolute survival rates and safety data.

The 2-year PFS rate for the brentuximab and placebo groups is now 63% vs. 51% per independent review and 65% vs. 45% per investigator.

“The bottom line is there’s a 20% difference in progression-free survival at 2 years upon investigator review. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin lymphoma,” Dr. Moskowitz, clinical director of hematology oncology at Memorial Sloan-Kettering Cancer Center in New York City, said.

Overall survival data are immature, but was the same in both groups at 2 years (P = .62). The likelihood of showing a survival difference was not expected because 85% of patients who relapsed on the placebo arm crossed over to brentuximab, as allowed per protocol, and it’s known that brentuximab alone in auto-transplant failures improves outcomes by at least a year, he said. Also, twice as many patients who failed placebo received a second transplant.

Dr. Moskowitz stressed that nearly every patient in the trial had at least three risk factors that would place them at high risk of treatment failure and that studies have shown that for patients with this many risk factors, the chance of being cured by an auto-transplant is about 25%. The risk factors are: relapsed less than 12 months or refractory to frontline therapy, best response of partial remission or stable disease to most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse, or two or more prior salvage therapies.

Press briefing moderator Dr. Brad Kahl of the University of Wisconsin-Madison, said Aethera is the first study to show a significant benefit for a post-transplant strategy.

“The biggest question in my mind is whether the application of maintenance brentuximab vedotin is just delaying the inevitable relapse, so the patients will still relapse, just later, or has the brentuximab taken patients who are destined to relapse and turned them into a cured patient,” Dr. Kahl said. “We don’t know the answer to that question. That will become apparent with more time.”

Dr. Moscowitz observed that relapses almost never happen after two year, adding, “So if you’re in remission at two years after stem cell transplantation for Hodgkin lymphoma, you are likely to be cured.”

AETHERA enrolled 329 patients with Hodgkin’s lymphoma and randomly assigned them after ASCT to brentuximab vedotin 1.8 mg/kg or placebo given every 3 weeks for up to 16 cycles, plus BSC. All patients were required to have achieved a complete response, partial remission, or stable disease to salvage therapy prior to ASCT. Their median age was 32 years and 53% were male.

Roughly 60% were refractory to upfront therapy, 43% in the brentuximab arm and 48% of controls had received 2 or more prior systemic therapies, and a third in each arm had extranodal involvement.

Consolidation therapy with brentuximab was generally well tolerated, Dr. Moskowitz said. Peripheral sensory neuropathy was the most common side effect, experienced at any grade in 67% on brentuximab vs. 19% of controls and at grade 3 in 13% vs. 1%. There were no grade 4 events and 85% of patients had resolution or improvement with dose reductions or stopping the drug.

Other adverse events in the brentuximab and control groups were neutropenia (35% vs. 12%), upper respiratory tract infections (26% vs. 23%), and fatigue (24% vs. 18%). Two patients died within 40 days of dosing with brentuximab, one from treatment-related acute respiratory distress syndrome associated with pneumonitis and one following an episode of treatment-related acute pancreatitis that had resolved at the time of death, he reported.

Based on the results, study sponsor Seattle Genetics is expected to seek approval for brentuximab in this consolidation setting in the first half of 2015, according to a statement from the company. The ongoing phase III ECHELON-1 and ECHELON 2 trials in HL and mature T-cell lymphomas are looking at the use of brentuximab in frontline disease.

[email protected]

CORONADO, CALIF.– Compared with elastography, ultrasound predictors of malignancy were more specific for presurgical diagnosis and in differentiating between benign and malignant thyroid nodules, results from a pooled analysis showed.

“Elastography is controversial,” Dr. Parisha Bhatia said in an interview during the annual meeting of the American Thyroid Association. “Some studies have reported that it has better sensitivity and specificity, compared with conventional ultrasound, but others have found it not to be helpful.”

In an effort to compare the efficacy of elastography and ultrasound in determining benign and malignant thyroid nodules, and to determine if elastography has a complementary role to fine needle aspiration (FNA), Dr. Bhatia and her associates searched Embase and PubMed databases for articles involving more than 50 nodules using specimen histology as the reference standard. They discovered 14 prospective studies and organized them into one of two groups. Group 1 included nodules with FNA cytology–proven “benign/malignant” result. Group 2 included nodules with FNA cytology as “intermediate.” The elasticity score was compared with ultrasound features such as taller than wide, irregular margins, internal vascularity, calcification, and absence of halo to determine validity measures and likelihood ratios.

Dr. Bhatia, an endocrine surgeon at Tulane University, New Orleans, reported on findings from 2,732 nodules in the pooled analysis. Of these, 64% were benign, 25% were malignant, and 11% were indeterminate.

In group 1, elastography showed a sensitivity of 75%, a specificity of 80%, a positive predictive value (PPV) of 61%, a negative predictive value (NPV) of 89%, and a likelihood ratio of 5.7, with a higher predictive value for nodules smaller than 1 cm in diameter (PPV of 79% and NPV of 83%). The strongest ultrasound-related predictor of malignancies was “taller than wide” (a specificity of 92%, a NPV of 51%, yet a sensitivity of only 24%), followed by irregular margins (a specificity of 91%, sensitivity of 48%, and a PPV of 64%). Combination of elastography and ultrasound had the highest sensitivity (96%) and NPV (96%), yet lower specificity (46%) and PPV (46%).

In group 2, elastography yielded a higher sensitivity (90%) and NPV (92%), while ultrasound features were highly specific, with the highest values for “taller than wide” shape (85%) in these thyroid nodules.

“Ultrasound predictors of malignancy prove to be more specific for presurgical diagnosis and differentiation of benign and malignant thyroid nodules,” the researchers wrote in their abstract. “When used as an adjunct, the higher sensitivity and NPV of combination of both the techniques can lead to better selection of candidates for FNA.”

Dr. Bhatia acknowledged certain limitations of the study, including the fact that the pooled data contained little information on indeterminate thyroid nodules. She reported having no financial disclosures.

[email protected]

On Twitter @dougbrunk

CORONADO, CALIF.– Compared with elastography, ultrasound predictors of malignancy were more specific for presurgical diagnosis and in differentiating between benign and malignant thyroid nodules, results from a pooled analysis showed.

“Elastography is controversial,” Dr. Parisha Bhatia said in an interview during the annual meeting of the American Thyroid Association. “Some studies have reported that it has better sensitivity and specificity, compared with conventional ultrasound, but others have found it not to be helpful.”

In an effort to compare the efficacy of elastography and ultrasound in determining benign and malignant thyroid nodules, and to determine if elastography has a complementary role to fine needle aspiration (FNA), Dr. Bhatia and her associates searched Embase and PubMed databases for articles involving more than 50 nodules using specimen histology as the reference standard. They discovered 14 prospective studies and organized them into one of two groups. Group 1 included nodules with FNA cytology–proven “benign/malignant” result. Group 2 included nodules with FNA cytology as “intermediate.” The elasticity score was compared with ultrasound features such as taller than wide, irregular margins, internal vascularity, calcification, and absence of halo to determine validity measures and likelihood ratios.

Dr. Bhatia, an endocrine surgeon at Tulane University, New Orleans, reported on findings from 2,732 nodules in the pooled analysis. Of these, 64% were benign, 25% were malignant, and 11% were indeterminate.

In group 1, elastography showed a sensitivity of 75%, a specificity of 80%, a positive predictive value (PPV) of 61%, a negative predictive value (NPV) of 89%, and a likelihood ratio of 5.7, with a higher predictive value for nodules smaller than 1 cm in diameter (PPV of 79% and NPV of 83%). The strongest ultrasound-related predictor of malignancies was “taller than wide” (a specificity of 92%, a NPV of 51%, yet a sensitivity of only 24%), followed by irregular margins (a specificity of 91%, sensitivity of 48%, and a PPV of 64%). Combination of elastography and ultrasound had the highest sensitivity (96%) and NPV (96%), yet lower specificity (46%) and PPV (46%).

In group 2, elastography yielded a higher sensitivity (90%) and NPV (92%), while ultrasound features were highly specific, with the highest values for “taller than wide” shape (85%) in these thyroid nodules.

“Ultrasound predictors of malignancy prove to be more specific for presurgical diagnosis and differentiation of benign and malignant thyroid nodules,” the researchers wrote in their abstract. “When used as an adjunct, the higher sensitivity and NPV of combination of both the techniques can lead to better selection of candidates for FNA.”

Dr. Bhatia acknowledged certain limitations of the study, including the fact that the pooled data contained little information on indeterminate thyroid nodules. She reported having no financial disclosures.

[email protected]

On Twitter @dougbrunk

CORONADO, CALIF.– Compared with elastography, ultrasound predictors of malignancy were more specific for presurgical diagnosis and in differentiating between benign and malignant thyroid nodules, results from a pooled analysis showed.

“Elastography is controversial,” Dr. Parisha Bhatia said in an interview during the annual meeting of the American Thyroid Association. “Some studies have reported that it has better sensitivity and specificity, compared with conventional ultrasound, but others have found it not to be helpful.”

In an effort to compare the efficacy of elastography and ultrasound in determining benign and malignant thyroid nodules, and to determine if elastography has a complementary role to fine needle aspiration (FNA), Dr. Bhatia and her associates searched Embase and PubMed databases for articles involving more than 50 nodules using specimen histology as the reference standard. They discovered 14 prospective studies and organized them into one of two groups. Group 1 included nodules with FNA cytology–proven “benign/malignant” result. Group 2 included nodules with FNA cytology as “intermediate.” The elasticity score was compared with ultrasound features such as taller than wide, irregular margins, internal vascularity, calcification, and absence of halo to determine validity measures and likelihood ratios.

Dr. Bhatia, an endocrine surgeon at Tulane University, New Orleans, reported on findings from 2,732 nodules in the pooled analysis. Of these, 64% were benign, 25% were malignant, and 11% were indeterminate.

In group 1, elastography showed a sensitivity of 75%, a specificity of 80%, a positive predictive value (PPV) of 61%, a negative predictive value (NPV) of 89%, and a likelihood ratio of 5.7, with a higher predictive value for nodules smaller than 1 cm in diameter (PPV of 79% and NPV of 83%). The strongest ultrasound-related predictor of malignancies was “taller than wide” (a specificity of 92%, a NPV of 51%, yet a sensitivity of only 24%), followed by irregular margins (a specificity of 91%, sensitivity of 48%, and a PPV of 64%). Combination of elastography and ultrasound had the highest sensitivity (96%) and NPV (96%), yet lower specificity (46%) and PPV (46%).

In group 2, elastography yielded a higher sensitivity (90%) and NPV (92%), while ultrasound features were highly specific, with the highest values for “taller than wide” shape (85%) in these thyroid nodules.

“Ultrasound predictors of malignancy prove to be more specific for presurgical diagnosis and differentiation of benign and malignant thyroid nodules,” the researchers wrote in their abstract. “When used as an adjunct, the higher sensitivity and NPV of combination of both the techniques can lead to better selection of candidates for FNA.”

Dr. Bhatia acknowledged certain limitations of the study, including the fact that the pooled data contained little information on indeterminate thyroid nodules. She reported having no financial disclosures.

[email protected]

On Twitter @dougbrunk

It’s a scene you’re all too familiar with – you’ve gone to a lot of trouble to give your children a well-prepared and nutritious meal, but a lot of it never leaves the plate. It’s frustrating, and you worry about their health, but according to the Cornell Food and Brand Lab, this is not unusual behavior.

When an adult serves him or herself food, it almost all gets eaten, according to a study from Brian Wansink, Ph.D., director of the Cornell Food and Brand Lab in Ithaca, N.Y., with the average adult eating 92% of the food served. However, the same study also found that children eat only about 60% of the food they serve to themselves, indicating a broad difference in how adults and children approach food.

Adults know what they like, and if they try something new, they might only take a little bit in case they don’t like it. Children tend not to fully understand their limits and may take a lot of something they’ve never had before because it looks appetizing, try it, realize they don’t like it, and not finish it. “It’s natural, for them to make some mistakes and take a food they don’t like or to serve too much,” Dr. Wansink said.

Dr. Wansink noted that the children in the study were not eating with their parents, and perhaps they would have eaten more if their parents had been there, but not enough to account for the vast discrepancy between the two groups. Other possible factors in children eating less include uncertainty toward how much will make them full, whether or not they are eating with utensils, the presence of friends, and whether they are introverted or extroverted.

So for all the frustrated parents out there“who want his/her noncooperating children to be vegetable-eating members of the clean plate club,” there is good news in these results. “They show that children who only eat half to two-thirds of the food they serve themselves aren’t being wasteful, belligerent, or disrespectful,” Dr. Wansink concluded. It’s a matter of kids just being kids.

[email protected]

It’s a scene you’re all too familiar with – you’ve gone to a lot of trouble to give your children a well-prepared and nutritious meal, but a lot of it never leaves the plate. It’s frustrating, and you worry about their health, but according to the Cornell Food and Brand Lab, this is not unusual behavior.

When an adult serves him or herself food, it almost all gets eaten, according to a study from Brian Wansink, Ph.D., director of the Cornell Food and Brand Lab in Ithaca, N.Y., with the average adult eating 92% of the food served. However, the same study also found that children eat only about 60% of the food they serve to themselves, indicating a broad difference in how adults and children approach food.

Adults know what they like, and if they try something new, they might only take a little bit in case they don’t like it. Children tend not to fully understand their limits and may take a lot of something they’ve never had before because it looks appetizing, try it, realize they don’t like it, and not finish it. “It’s natural, for them to make some mistakes and take a food they don’t like or to serve too much,” Dr. Wansink said.

Dr. Wansink noted that the children in the study were not eating with their parents, and perhaps they would have eaten more if their parents had been there, but not enough to account for the vast discrepancy between the two groups. Other possible factors in children eating less include uncertainty toward how much will make them full, whether or not they are eating with utensils, the presence of friends, and whether they are introverted or extroverted.

So for all the frustrated parents out there“who want his/her noncooperating children to be vegetable-eating members of the clean plate club,” there is good news in these results. “They show that children who only eat half to two-thirds of the food they serve themselves aren’t being wasteful, belligerent, or disrespectful,” Dr. Wansink concluded. It’s a matter of kids just being kids.

[email protected]

It’s a scene you’re all too familiar with – you’ve gone to a lot of trouble to give your children a well-prepared and nutritious meal, but a lot of it never leaves the plate. It’s frustrating, and you worry about their health, but according to the Cornell Food and Brand Lab, this is not unusual behavior.

When an adult serves him or herself food, it almost all gets eaten, according to a study from Brian Wansink, Ph.D., director of the Cornell Food and Brand Lab in Ithaca, N.Y., with the average adult eating 92% of the food served. However, the same study also found that children eat only about 60% of the food they serve to themselves, indicating a broad difference in how adults and children approach food.

Adults know what they like, and if they try something new, they might only take a little bit in case they don’t like it. Children tend not to fully understand their limits and may take a lot of something they’ve never had before because it looks appetizing, try it, realize they don’t like it, and not finish it. “It’s natural, for them to make some mistakes and take a food they don’t like or to serve too much,” Dr. Wansink said.

Dr. Wansink noted that the children in the study were not eating with their parents, and perhaps they would have eaten more if their parents had been there, but not enough to account for the vast discrepancy between the two groups. Other possible factors in children eating less include uncertainty toward how much will make them full, whether or not they are eating with utensils, the presence of friends, and whether they are introverted or extroverted.

So for all the frustrated parents out there“who want his/her noncooperating children to be vegetable-eating members of the clean plate club,” there is good news in these results. “They show that children who only eat half to two-thirds of the food they serve themselves aren’t being wasteful, belligerent, or disrespectful,” Dr. Wansink concluded. It’s a matter of kids just being kids.

[email protected]

SAN FRANCISCO– PD-1 checkpoint inhibitors, which have shown remarkable efficacy against advanced malignant melanoma, appear to hold similar promise in the treatment of relapsed or refractory Hodgkin’s lymphoma, results from two early studies suggest.

In a phase I study, the PD-1 blocking antibody nivolumab produced an 87% response rate in 23 heavily pre-treated patients with relapsed Hodgkin’s lymphoma (HL). In a separate phase Ib study, pembrolizumab, which blocks the PD-1 and PD-2 ligands, produced a 66% overall response rate, 21% complete remission rate, and 86% clinical benefit rate among 29 patients with HL for whom therapy with brentuximab vedotin (Adcetris) had failed.

The studies were presented at a media briefing prior to the presentation of data in oral sessions at the annual meeting of the American Society of Hematology.

“Classical Hodgkin lymphoma appears to be a tumor with genetically determined vulnerability to PD-1 blockade. We hope that PD-1 blockade in the future can become an important part of the treatment of patients with Hodgkin lymphoma,” said Dr. Phillipe Armand from the Dana-Farber Cancer Institute in Boston, an investigator for the nivolumab study.

Neil Osterweil/Frontline Medical News

Evidence from preclinical studies suggests that the Reed-Sternberg malignant cells characteristic of HL may use the PD-1 (programmed death 1) pathway to evade detection by immune cells, as suggested by pathologic studies showing the cells surrounded by an extensive but ineffective infiltrate of inflammatory cells.

“We’ve wondered for a long time how Hodgkin lymphoma could attract such a brisk immune response and yet have this immune response fail to kill the tumor,” he said.

Genetic Achilles heel

Genetic analyses had shown that HL frequently has a mutation that results in amplification of a region on chromosome 9 (9p24.1) which leads to increased expression of PD-1 ligands 1 and 2, and leads to a downregulation or weakening of the immune response. The mutation appears to work through the Janus kinase (JAK)-signal transducer and activator transcription (STAT) signalling. These findings suggested to researchers that classical HL has a genetically driven and, ideally, targetable dependence on the PD-1 pathway for survival, Dr. Armand explained.

To test this idea, he and colleagues studied 23 patients with relapsed or refractory HL that had been heavily pre-treated who were part of an independent expansion cohort of a study of nivolumab in hematologic malignancies. Of these patients, 78% were enrolled after a relapse following autologous stem cell transplantation, and 22% after treatment with brentuximab vedotin had failed.

The patients received nivolumab 3 mg/kg every 2 weeks until they had either a complete response, tumor progression, or excessive side effects. In all, 20 of the 23 patients (87%) had an objective response to the single-agent therapy, including 4 (17%) complete responses and 16 (70%) partial responses. The remaining three patients (13%) had stable disease.

The longest time on study at the data cutoff point was 72 weeks. Among all responders, 60% had a response by 8 weeks of therapy, 48% are ongoing, and 43% of patients are still on treatment.

Drug-related adverse events were reported in 18 patients, most commonly rash and decreased platelet count. Five patients had grade 3 events. There were no drug-related grade 4 events or deaths.

In an editorial accompanying the study, which was also published online in The New England Journal of Medicine, Dr. Mario Sznoll and Dr. Dan L. Longo from the Yale University School of Medicine in New Haven, Connecticut write that “with recent data showing impressive clinical activity of PD-1 or PD-L1 antagonists in subgroups of patients with a variety of different cancers, the critical and foundational role of immune interventions in cancer treatment is no longer deniable,” (NEJM, Dec. 6, 2014 [DOI: 10.1056/NEJMoa1411087]).

Pembrolizumab trial

Dr. Craig H. Moskowitz from Memorial Sloan-Kettering Cancer Center in New York City discussed results of the second study, dubbed KEYNOTE-013 (A Phase Ib Multi-Cohort Trial of MK-3475 in Subjects With Hematologic Malignancies).

In this study, patients with HL who were not transplant eligible or for whom transplant had failed and who either had a relapse or were refractory to therapy with brentuximab vedotin received 19 mg/kg IV infusion of pembrolizumab every 2 weeks until complete response, partial response/stable disease, or disease progression.

Of the 31 patients enrolled, 29 were available for the analysis. As of the data cutoff in November 2014, 6 patients (21%) had achieved a complete remission, and 13 (45%) had a partial response, for an overall response rate of 66%. The median time to response was 12 weeks, and as of the data cutoff 17 of 19 patients had ongoing responses. The median response duration has not yet been reached. An additional 6 patients (21%) had stable disease, leading to an overall clinical benefit rate (responses plus stable disease) of 86%.

The patients generally tolerated the drug well. There were 4 treatment-related adverse events in 3 patients, including axillary pain, hypoxia, joint swelling, and pneumonitis. There were no grade 4 treatment-related events or deaths.

Of the tumor samples evaluable, all expressed PD-L1, supporting the rationale for PD-1 blockade in this population, Dr. Moskowitz said.

The results of both his and Dr. Armand’s study support the continued development of PD-1 inhibitors in various subsets of patients with classical Hodgkin’s lymphoma, he said.

SAN FRANCISCO– PD-1 checkpoint inhibitors, which have shown remarkable efficacy against advanced malignant melanoma, appear to hold similar promise in the treatment of relapsed or refractory Hodgkin’s lymphoma, results from two early studies suggest.

In a phase I study, the PD-1 blocking antibody nivolumab produced an 87% response rate in 23 heavily pre-treated patients with relapsed Hodgkin’s lymphoma (HL). In a separate phase Ib study, pembrolizumab, which blocks the PD-1 and PD-2 ligands, produced a 66% overall response rate, 21% complete remission rate, and 86% clinical benefit rate among 29 patients with HL for whom therapy with brentuximab vedotin (Adcetris) had failed.

The studies were presented at a media briefing prior to the presentation of data in oral sessions at the annual meeting of the American Society of Hematology.

“Classical Hodgkin lymphoma appears to be a tumor with genetically determined vulnerability to PD-1 blockade. We hope that PD-1 blockade in the future can become an important part of the treatment of patients with Hodgkin lymphoma,” said Dr. Phillipe Armand from the Dana-Farber Cancer Institute in Boston, an investigator for the nivolumab study.

Neil Osterweil/Frontline Medical News

Evidence from preclinical studies suggests that the Reed-Sternberg malignant cells characteristic of HL may use the PD-1 (programmed death 1) pathway to evade detection by immune cells, as suggested by pathologic studies showing the cells surrounded by an extensive but ineffective infiltrate of inflammatory cells.

“We’ve wondered for a long time how Hodgkin lymphoma could attract such a brisk immune response and yet have this immune response fail to kill the tumor,” he said.

Genetic Achilles heel

Genetic analyses had shown that HL frequently has a mutation that results in amplification of a region on chromosome 9 (9p24.1) which leads to increased expression of PD-1 ligands 1 and 2, and leads to a downregulation or weakening of the immune response. The mutation appears to work through the Janus kinase (JAK)-signal transducer and activator transcription (STAT) signalling. These findings suggested to researchers that classical HL has a genetically driven and, ideally, targetable dependence on the PD-1 pathway for survival, Dr. Armand explained.

To test this idea, he and colleagues studied 23 patients with relapsed or refractory HL that had been heavily pre-treated who were part of an independent expansion cohort of a study of nivolumab in hematologic malignancies. Of these patients, 78% were enrolled after a relapse following autologous stem cell transplantation, and 22% after treatment with brentuximab vedotin had failed.

The patients received nivolumab 3 mg/kg every 2 weeks until they had either a complete response, tumor progression, or excessive side effects. In all, 20 of the 23 patients (87%) had an objective response to the single-agent therapy, including 4 (17%) complete responses and 16 (70%) partial responses. The remaining three patients (13%) had stable disease.

The longest time on study at the data cutoff point was 72 weeks. Among all responders, 60% had a response by 8 weeks of therapy, 48% are ongoing, and 43% of patients are still on treatment.

Drug-related adverse events were reported in 18 patients, most commonly rash and decreased platelet count. Five patients had grade 3 events. There were no drug-related grade 4 events or deaths.

In an editorial accompanying the study, which was also published online in The New England Journal of Medicine, Dr. Mario Sznoll and Dr. Dan L. Longo from the Yale University School of Medicine in New Haven, Connecticut write that “with recent data showing impressive clinical activity of PD-1 or PD-L1 antagonists in subgroups of patients with a variety of different cancers, the critical and foundational role of immune interventions in cancer treatment is no longer deniable,” (NEJM, Dec. 6, 2014 [DOI: 10.1056/NEJMoa1411087]).

Pembrolizumab trial

Dr. Craig H. Moskowitz from Memorial Sloan-Kettering Cancer Center in New York City discussed results of the second study, dubbed KEYNOTE-013 (A Phase Ib Multi-Cohort Trial of MK-3475 in Subjects With Hematologic Malignancies).

In this study, patients with HL who were not transplant eligible or for whom transplant had failed and who either had a relapse or were refractory to therapy with brentuximab vedotin received 19 mg/kg IV infusion of pembrolizumab every 2 weeks until complete response, partial response/stable disease, or disease progression.

Of the 31 patients enrolled, 29 were available for the analysis. As of the data cutoff in November 2014, 6 patients (21%) had achieved a complete remission, and 13 (45%) had a partial response, for an overall response rate of 66%. The median time to response was 12 weeks, and as of the data cutoff 17 of 19 patients had ongoing responses. The median response duration has not yet been reached. An additional 6 patients (21%) had stable disease, leading to an overall clinical benefit rate (responses plus stable disease) of 86%.

The patients generally tolerated the drug well. There were 4 treatment-related adverse events in 3 patients, including axillary pain, hypoxia, joint swelling, and pneumonitis. There were no grade 4 treatment-related events or deaths.

Of the tumor samples evaluable, all expressed PD-L1, supporting the rationale for PD-1 blockade in this population, Dr. Moskowitz said.

The results of both his and Dr. Armand’s study support the continued development of PD-1 inhibitors in various subsets of patients with classical Hodgkin’s lymphoma, he said.

SAN FRANCISCO– PD-1 checkpoint inhibitors, which have shown remarkable efficacy against advanced malignant melanoma, appear to hold similar promise in the treatment of relapsed or refractory Hodgkin’s lymphoma, results from two early studies suggest.

In a phase I study, the PD-1 blocking antibody nivolumab produced an 87% response rate in 23 heavily pre-treated patients with relapsed Hodgkin’s lymphoma (HL). In a separate phase Ib study, pembrolizumab, which blocks the PD-1 and PD-2 ligands, produced a 66% overall response rate, 21% complete remission rate, and 86% clinical benefit rate among 29 patients with HL for whom therapy with brentuximab vedotin (Adcetris) had failed.

The studies were presented at a media briefing prior to the presentation of data in oral sessions at the annual meeting of the American Society of Hematology.

“Classical Hodgkin lymphoma appears to be a tumor with genetically determined vulnerability to PD-1 blockade. We hope that PD-1 blockade in the future can become an important part of the treatment of patients with Hodgkin lymphoma,” said Dr. Phillipe Armand from the Dana-Farber Cancer Institute in Boston, an investigator for the nivolumab study.

Neil Osterweil/Frontline Medical News

Evidence from preclinical studies suggests that the Reed-Sternberg malignant cells characteristic of HL may use the PD-1 (programmed death 1) pathway to evade detection by immune cells, as suggested by pathologic studies showing the cells surrounded by an extensive but ineffective infiltrate of inflammatory cells.

“We’ve wondered for a long time how Hodgkin lymphoma could attract such a brisk immune response and yet have this immune response fail to kill the tumor,” he said.

Genetic Achilles heel

Genetic analyses had shown that HL frequently has a mutation that results in amplification of a region on chromosome 9 (9p24.1) which leads to increased expression of PD-1 ligands 1 and 2, and leads to a downregulation or weakening of the immune response. The mutation appears to work through the Janus kinase (JAK)-signal transducer and activator transcription (STAT) signalling. These findings suggested to researchers that classical HL has a genetically driven and, ideally, targetable dependence on the PD-1 pathway for survival, Dr. Armand explained.

To test this idea, he and colleagues studied 23 patients with relapsed or refractory HL that had been heavily pre-treated who were part of an independent expansion cohort of a study of nivolumab in hematologic malignancies. Of these patients, 78% were enrolled after a relapse following autologous stem cell transplantation, and 22% after treatment with brentuximab vedotin had failed.

The patients received nivolumab 3 mg/kg every 2 weeks until they had either a complete response, tumor progression, or excessive side effects. In all, 20 of the 23 patients (87%) had an objective response to the single-agent therapy, including 4 (17%) complete responses and 16 (70%) partial responses. The remaining three patients (13%) had stable disease.

The longest time on study at the data cutoff point was 72 weeks. Among all responders, 60% had a response by 8 weeks of therapy, 48% are ongoing, and 43% of patients are still on treatment.

Drug-related adverse events were reported in 18 patients, most commonly rash and decreased platelet count. Five patients had grade 3 events. There were no drug-related grade 4 events or deaths.

In an editorial accompanying the study, which was also published online in The New England Journal of Medicine, Dr. Mario Sznoll and Dr. Dan L. Longo from the Yale University School of Medicine in New Haven, Connecticut write that “with recent data showing impressive clinical activity of PD-1 or PD-L1 antagonists in subgroups of patients with a variety of different cancers, the critical and foundational role of immune interventions in cancer treatment is no longer deniable,” (NEJM, Dec. 6, 2014 [DOI: 10.1056/NEJMoa1411087]).

Pembrolizumab trial

Dr. Craig H. Moskowitz from Memorial Sloan-Kettering Cancer Center in New York City discussed results of the second study, dubbed KEYNOTE-013 (A Phase Ib Multi-Cohort Trial of MK-3475 in Subjects With Hematologic Malignancies).

In this study, patients with HL who were not transplant eligible or for whom transplant had failed and who either had a relapse or were refractory to therapy with brentuximab vedotin received 19 mg/kg IV infusion of pembrolizumab every 2 weeks until complete response, partial response/stable disease, or disease progression.

Of the 31 patients enrolled, 29 were available for the analysis. As of the data cutoff in November 2014, 6 patients (21%) had achieved a complete remission, and 13 (45%) had a partial response, for an overall response rate of 66%. The median time to response was 12 weeks, and as of the data cutoff 17 of 19 patients had ongoing responses. The median response duration has not yet been reached. An additional 6 patients (21%) had stable disease, leading to an overall clinical benefit rate (responses plus stable disease) of 86%.

The patients generally tolerated the drug well. There were 4 treatment-related adverse events in 3 patients, including axillary pain, hypoxia, joint swelling, and pneumonitis. There were no grade 4 treatment-related events or deaths.

Of the tumor samples evaluable, all expressed PD-L1, supporting the rationale for PD-1 blockade in this population, Dr. Moskowitz said.

The results of both his and Dr. Armand’s study support the continued development of PD-1 inhibitors in various subsets of patients with classical Hodgkin’s lymphoma, he said.

CLL cells

Health Canada recently approved the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica) for the treatment of chronic lymphocytic leukemia (CLL).

The drug can now be used to treat CLL patients, including those with 17p deletion, who have received at least one prior therapy. It can also be used as frontline treatment in CLL patients with 17p deletion.

Health Canada’s approval of ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.

The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.

The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.

Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

Ibrutinib is being developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics, Inc. Janssen will commercialize the drug in Canada, and Janssen affiliates will commercialize it around the world, except in the US, where Pharmacyclics and Janssen Biotech, Inc. co-market it.

CLL cells

Health Canada recently approved the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica) for the treatment of chronic lymphocytic leukemia (CLL).

The drug can now be used to treat CLL patients, including those with 17p deletion, who have received at least one prior therapy. It can also be used as frontline treatment in CLL patients with 17p deletion.

Health Canada’s approval of ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.

The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.

The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.

Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

Ibrutinib is being developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics, Inc. Janssen will commercialize the drug in Canada, and Janssen affiliates will commercialize it around the world, except in the US, where Pharmacyclics and Janssen Biotech, Inc. co-market it.

CLL cells

Health Canada recently approved the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica) for the treatment of chronic lymphocytic leukemia (CLL).

The drug can now be used to treat CLL patients, including those with 17p deletion, who have received at least one prior therapy. It can also be used as frontline treatment in CLL patients with 17p deletion.

Health Canada’s approval of ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.

The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.

The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.

Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

Ibrutinib is being developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics, Inc. Janssen will commercialize the drug in Canada, and Janssen affiliates will commercialize it around the world, except in the US, where Pharmacyclics and Janssen Biotech, Inc. co-market it.

Doctor and patient

Credit: NIH

People could be putting their lives at risk by dismissing potential warning signs of cancer as less serious symptoms, according to a study published in PLOS ONE.

In a survey of about 1700 people, more than half of respondents said they had experienced at least

one red-flag cancer “alarm” symptom—such as persistent, unexplained pain or an unexplained lump—during the previous 3 months, but

only 2% of them thought cancer was a possible cause.

The survey had been sent to people aged 50 and older who were registered with 3 London general practices. The questionnaire listed 17 symptoms, including 10 widely publicized potential cancer warning signs, such as an unexplained cough, bleeding, and a persistent change in bowel or bladder habits.

Cancer was not mentioned, but the survey asked which of the symptoms subjects had experienced, what they thought caused them, if they were concerned that symptoms were serious, and whether they had consulted their doctor.

Of the 1724 subjects who responded, 53% had experienced at least one cancer “alarm” symptom in the previous 3 months.

This included unexplained cough or hoarseness; persistent change in bowel habits; persistent, unexplained pain; persistent change in bladder habits; unexplained lump; a change in the appearance of a mole; a sore that does not heal; unexplained bleeding; unexplained weight loss; and persistent difficulty swallowing.

Persistent cough (20%) and persistent change in bowel habits (18%) were the most common symptoms. Difficulty swallowing and unexplained weight loss (both 4%) were least common.

Overall, subjects appraised the cancer warning “alarm” symptoms as more serious than “non-alarm” symptoms, such as sore throat and feeling tired. Fifty-nine percent of respondents said they contacted a doctor about their “alarm” symptoms.

However, subjects rarely attributed potential signs of cancer to the disease, putting them down to other reasons, such as age, infection, arthritis, piles, and cysts.

“Most people with potential warning symptoms don’t have cancer, but some will, and others may have other diseases that would benefit from early attention,” said study author Katriina Whitaker, PhD, of University College London in the UK.

“That’s why it’s important that these symptoms are checked out, especially if they don’t go away. But people could delay seeing a doctor if they don’t acknowledge cancer as a possible cause. It’s worrying that even the more obvious warning symptoms, such as unexplained lumps or changes to the appearance of a mole, were rarely attributed to cancer, although they are often well recognized in surveys that assess the public’s knowledge of the disease.”

“Even when people thought warning symptoms might be serious, cancer didn’t tend to spring to mind. This might be because people were frightened and reluctant to mention cancer, thought cancer wouldn’t happen to them, or believed other causes were more likely.”

Doctor and patient

Credit: NIH

People could be putting their lives at risk by dismissing potential warning signs of cancer as less serious symptoms, according to a study published in PLOS ONE.

In a survey of about 1700 people, more than half of respondents said they had experienced at least

one red-flag cancer “alarm” symptom—such as persistent, unexplained pain or an unexplained lump—during the previous 3 months, but

only 2% of them thought cancer was a possible cause.

The survey had been sent to people aged 50 and older who were registered with 3 London general practices. The questionnaire listed 17 symptoms, including 10 widely publicized potential cancer warning signs, such as an unexplained cough, bleeding, and a persistent change in bowel or bladder habits.

Cancer was not mentioned, but the survey asked which of the symptoms subjects had experienced, what they thought caused them, if they were concerned that symptoms were serious, and whether they had consulted their doctor.

Of the 1724 subjects who responded, 53% had experienced at least one cancer “alarm” symptom in the previous 3 months.

This included unexplained cough or hoarseness; persistent change in bowel habits; persistent, unexplained pain; persistent change in bladder habits; unexplained lump; a change in the appearance of a mole; a sore that does not heal; unexplained bleeding; unexplained weight loss; and persistent difficulty swallowing.

Persistent cough (20%) and persistent change in bowel habits (18%) were the most common symptoms. Difficulty swallowing and unexplained weight loss (both 4%) were least common.

Overall, subjects appraised the cancer warning “alarm” symptoms as more serious than “non-alarm” symptoms, such as sore throat and feeling tired. Fifty-nine percent of respondents said they contacted a doctor about their “alarm” symptoms.

However, subjects rarely attributed potential signs of cancer to the disease, putting them down to other reasons, such as age, infection, arthritis, piles, and cysts.

“Most people with potential warning symptoms don’t have cancer, but some will, and others may have other diseases that would benefit from early attention,” said study author Katriina Whitaker, PhD, of University College London in the UK.

“That’s why it’s important that these symptoms are checked out, especially if they don’t go away. But people could delay seeing a doctor if they don’t acknowledge cancer as a possible cause. It’s worrying that even the more obvious warning symptoms, such as unexplained lumps or changes to the appearance of a mole, were rarely attributed to cancer, although they are often well recognized in surveys that assess the public’s knowledge of the disease.”

“Even when people thought warning symptoms might be serious, cancer didn’t tend to spring to mind. This might be because people were frightened and reluctant to mention cancer, thought cancer wouldn’t happen to them, or believed other causes were more likely.”

Doctor and patient

Credit: NIH

People could be putting their lives at risk by dismissing potential warning signs of cancer as less serious symptoms, according to a study published in PLOS ONE.

In a survey of about 1700 people, more than half of respondents said they had experienced at least

one red-flag cancer “alarm” symptom—such as persistent, unexplained pain or an unexplained lump—during the previous 3 months, but

only 2% of them thought cancer was a possible cause.

The survey had been sent to people aged 50 and older who were registered with 3 London general practices. The questionnaire listed 17 symptoms, including 10 widely publicized potential cancer warning signs, such as an unexplained cough, bleeding, and a persistent change in bowel or bladder habits.

Cancer was not mentioned, but the survey asked which of the symptoms subjects had experienced, what they thought caused them, if they were concerned that symptoms were serious, and whether they had consulted their doctor.

Of the 1724 subjects who responded, 53% had experienced at least one cancer “alarm” symptom in the previous 3 months.

This included unexplained cough or hoarseness; persistent change in bowel habits; persistent, unexplained pain; persistent change in bladder habits; unexplained lump; a change in the appearance of a mole; a sore that does not heal; unexplained bleeding; unexplained weight loss; and persistent difficulty swallowing.

Persistent cough (20%) and persistent change in bowel habits (18%) were the most common symptoms. Difficulty swallowing and unexplained weight loss (both 4%) were least common.

Overall, subjects appraised the cancer warning “alarm” symptoms as more serious than “non-alarm” symptoms, such as sore throat and feeling tired. Fifty-nine percent of respondents said they contacted a doctor about their “alarm” symptoms.

However, subjects rarely attributed potential signs of cancer to the disease, putting them down to other reasons, such as age, infection, arthritis, piles, and cysts.

“Most people with potential warning symptoms don’t have cancer, but some will, and others may have other diseases that would benefit from early attention,” said study author Katriina Whitaker, PhD, of University College London in the UK.

“That’s why it’s important that these symptoms are checked out, especially if they don’t go away. But people could delay seeing a doctor if they don’t acknowledge cancer as a possible cause. It’s worrying that even the more obvious warning symptoms, such as unexplained lumps or changes to the appearance of a mole, were rarely attributed to cancer, although they are often well recognized in surveys that assess the public’s knowledge of the disease.”

“Even when people thought warning symptoms might be serious, cancer didn’t tend to spring to mind. This might be because people were frightened and reluctant to mention cancer, thought cancer wouldn’t happen to them, or believed other causes were more likely.”

CHICAGO – Patients with atrial fibrillation who start treatment with a new oral anticoagulant may spend more on their medication than if they were prescribed generic warfarin, but their overall health care costs may wind up being about the same, based on an analysis of health care expense records for more than 4,500 U.S. patients.

“Despite higher anticoagulant costs, total all-cause and atrial fibrillation–related costs remain comparable” between patients prescribed warfarin and those who received the new oral anticoagulant rivaroxaban (Xarelto), said Concetta Crivera, Pharm.D., at the American Heart Association Scientific Sessions. Higher drug costs for daily treatment with rivaroxaban were offset by reduced hospital lengths of stays and hence reduced hospitalization costs, said Dr. Crivera, director of cardiovascular health economics and outcomes research at Janssen in Raritan, N.J., the company that markets rivaroxaban along with Bayer.

Mitchel L. Zoler/Frontline Medical News

“I can believe that hospitalized days would be reduced because patients treated with rivaroxaban or any of the other new oral anticoagulants don’t need to remain in the hospital while you wait for their international normalized ratio to enter the therapeutic range,” which is what happens with patients treated with warfarin, commented Dr. Jeffrey Weitz, professor of medicine and director of the Juravinski Hospital and Cancer Centre of McMaster University in Hamilton, Ont.

The new findings by Dr. Crivera “are not definitive on their own, but they add to a growing body of data that indicate that all the new oral anticoagulants are cost effective,” said Dr. Weitz, who specializes in thrombosis and anticoagulants. “The worst time for a patient on warfarin is when they start treatment. You do a disservice to patients with new-onset atrial fibrillation by using warfarin, because some patients will get into the therapeutic range but others never will. That’s why the new oral anticoagulants are better, because everybody gets into therapeutic range,” he said in an interview.

Dr. Crivera and her associates conducted a retrospective study of health records for 2,253 patients with nonvalvular atrial fibrillation (AF) who started anticoagulation treatment with rivaroxaban during the period of November 2011 (when the drug received U.S. marketing approval) through December 2012. The data came from the patient records of Humana, a U.S. HMO and insurer that covers both commercially insured patients and those covered by Medicare. The researchers matched each of the patients initiating rivaroxaban treatment with a similar patient from the Humana database with nonvalvular AF who started on warfarin during the same period. The average age of patients in the study was about 74 years, and patients in the two groups were closely matched for their demographic and clinical characteristics, including comorbidities. Data on health care use were available for patients for an average of about 4 months following their start of anticoagulant treatment.

The analysis showed that during the first months on treatment, patients prescribed rivaroxaban averaged 2.11 days of hospitalization for an AF-related episode, compared with 3.02 days for those prescribed warfarin, a statistically significant difference. Hospitalizations for any cause averaged a total of 2.71 days in the rivaroxaban group and 3.87 days in the patients on warfarin, also a significant difference, Dr. Crivera reported.

This difference in days hospitalized translated into reduced hospitalization costs, a roughly $2,000 average difference per patient in actual hospitalization costs in favor of the rivaroxaban patients for all-cause hospitalizations, and an average $1,300 difference per patient for hospitalization costs directly related to AF.

Although the rivaroxaban patients spent an average of $2,700 more per patient on pharmaceuticals for all causes, and an average $2,200 more for AF-related drugs, the total average all-cause and AF-related costs for drugs, hospitalizations, outpatient visits, and emergency department visits were similar in the two subgroups: an average total of $17,590 per patient for the rivaroxaban patients and $18,676 for warfarin patients for all causes, and an average of $7,394 for the rivaroxaban patients and $7,319 for those on warfarin for AF-related care. The between-group differences for both sets of total costs were not statistically significant.

The study was sponsored by Janssen, which along with Bayer markets rivaroxaban (Xarelto). Dr. Crivera is a Janssen employee. Dr. Weitz has been an adviser or a consultant to Janssen and Bayer and to Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Merck, Pfizer, and Portola.

[email protected]

On Twitter @mitchelzoler

CHICAGO – Patients with atrial fibrillation who start treatment with a new oral anticoagulant may spend more on their medication than if they were prescribed generic warfarin, but their overall health care costs may wind up being about the same, based on an analysis of health care expense records for more than 4,500 U.S. patients.

“Despite higher anticoagulant costs, total all-cause and atrial fibrillation–related costs remain comparable” between patients prescribed warfarin and those who received the new oral anticoagulant rivaroxaban (Xarelto), said Concetta Crivera, Pharm.D., at the American Heart Association Scientific Sessions. Higher drug costs for daily treatment with rivaroxaban were offset by reduced hospital lengths of stays and hence reduced hospitalization costs, said Dr. Crivera, director of cardiovascular health economics and outcomes research at Janssen in Raritan, N.J., the company that markets rivaroxaban along with Bayer.

Mitchel L. Zoler/Frontline Medical News

“I can believe that hospitalized days would be reduced because patients treated with rivaroxaban or any of the other new oral anticoagulants don’t need to remain in the hospital while you wait for their international normalized ratio to enter the therapeutic range,” which is what happens with patients treated with warfarin, commented Dr. Jeffrey Weitz, professor of medicine and director of the Juravinski Hospital and Cancer Centre of McMaster University in Hamilton, Ont.

The new findings by Dr. Crivera “are not definitive on their own, but they add to a growing body of data that indicate that all the new oral anticoagulants are cost effective,” said Dr. Weitz, who specializes in thrombosis and anticoagulants. “The worst time for a patient on warfarin is when they start treatment. You do a disservice to patients with new-onset atrial fibrillation by using warfarin, because some patients will get into the therapeutic range but others never will. That’s why the new oral anticoagulants are better, because everybody gets into therapeutic range,” he said in an interview.

Dr. Crivera and her associates conducted a retrospective study of health records for 2,253 patients with nonvalvular atrial fibrillation (AF) who started anticoagulation treatment with rivaroxaban during the period of November 2011 (when the drug received U.S. marketing approval) through December 2012. The data came from the patient records of Humana, a U.S. HMO and insurer that covers both commercially insured patients and those covered by Medicare. The researchers matched each of the patients initiating rivaroxaban treatment with a similar patient from the Humana database with nonvalvular AF who started on warfarin during the same period. The average age of patients in the study was about 74 years, and patients in the two groups were closely matched for their demographic and clinical characteristics, including comorbidities. Data on health care use were available for patients for an average of about 4 months following their start of anticoagulant treatment.

The analysis showed that during the first months on treatment, patients prescribed rivaroxaban averaged 2.11 days of hospitalization for an AF-related episode, compared with 3.02 days for those prescribed warfarin, a statistically significant difference. Hospitalizations for any cause averaged a total of 2.71 days in the rivaroxaban group and 3.87 days in the patients on warfarin, also a significant difference, Dr. Crivera reported.

This difference in days hospitalized translated into reduced hospitalization costs, a roughly $2,000 average difference per patient in actual hospitalization costs in favor of the rivaroxaban patients for all-cause hospitalizations, and an average $1,300 difference per patient for hospitalization costs directly related to AF.

Although the rivaroxaban patients spent an average of $2,700 more per patient on pharmaceuticals for all causes, and an average $2,200 more for AF-related drugs, the total average all-cause and AF-related costs for drugs, hospitalizations, outpatient visits, and emergency department visits were similar in the two subgroups: an average total of $17,590 per patient for the rivaroxaban patients and $18,676 for warfarin patients for all causes, and an average of $7,394 for the rivaroxaban patients and $7,319 for those on warfarin for AF-related care. The between-group differences for both sets of total costs were not statistically significant.

The study was sponsored by Janssen, which along with Bayer markets rivaroxaban (Xarelto). Dr. Crivera is a Janssen employee. Dr. Weitz has been an adviser or a consultant to Janssen and Bayer and to Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Merck, Pfizer, and Portola.

[email protected]

On Twitter @mitchelzoler

CHICAGO – Patients with atrial fibrillation who start treatment with a new oral anticoagulant may spend more on their medication than if they were prescribed generic warfarin, but their overall health care costs may wind up being about the same, based on an analysis of health care expense records for more than 4,500 U.S. patients.

“Despite higher anticoagulant costs, total all-cause and atrial fibrillation–related costs remain comparable” between patients prescribed warfarin and those who received the new oral anticoagulant rivaroxaban (Xarelto), said Concetta Crivera, Pharm.D., at the American Heart Association Scientific Sessions. Higher drug costs for daily treatment with rivaroxaban were offset by reduced hospital lengths of stays and hence reduced hospitalization costs, said Dr. Crivera, director of cardiovascular health economics and outcomes research at Janssen in Raritan, N.J., the company that markets rivaroxaban along with Bayer.

Mitchel L. Zoler/Frontline Medical News

“I can believe that hospitalized days would be reduced because patients treated with rivaroxaban or any of the other new oral anticoagulants don’t need to remain in the hospital while you wait for their international normalized ratio to enter the therapeutic range,” which is what happens with patients treated with warfarin, commented Dr. Jeffrey Weitz, professor of medicine and director of the Juravinski Hospital and Cancer Centre of McMaster University in Hamilton, Ont.

The new findings by Dr. Crivera “are not definitive on their own, but they add to a growing body of data that indicate that all the new oral anticoagulants are cost effective,” said Dr. Weitz, who specializes in thrombosis and anticoagulants. “The worst time for a patient on warfarin is when they start treatment. You do a disservice to patients with new-onset atrial fibrillation by using warfarin, because some patients will get into the therapeutic range but others never will. That’s why the new oral anticoagulants are better, because everybody gets into therapeutic range,” he said in an interview.

Dr. Crivera and her associates conducted a retrospective study of health records for 2,253 patients with nonvalvular atrial fibrillation (AF) who started anticoagulation treatment with rivaroxaban during the period of November 2011 (when the drug received U.S. marketing approval) through December 2012. The data came from the patient records of Humana, a U.S. HMO and insurer that covers both commercially insured patients and those covered by Medicare. The researchers matched each of the patients initiating rivaroxaban treatment with a similar patient from the Humana database with nonvalvular AF who started on warfarin during the same period. The average age of patients in the study was about 74 years, and patients in the two groups were closely matched for their demographic and clinical characteristics, including comorbidities. Data on health care use were available for patients for an average of about 4 months following their start of anticoagulant treatment.

The analysis showed that during the first months on treatment, patients prescribed rivaroxaban averaged 2.11 days of hospitalization for an AF-related episode, compared with 3.02 days for those prescribed warfarin, a statistically significant difference. Hospitalizations for any cause averaged a total of 2.71 days in the rivaroxaban group and 3.87 days in the patients on warfarin, also a significant difference, Dr. Crivera reported.

This difference in days hospitalized translated into reduced hospitalization costs, a roughly $2,000 average difference per patient in actual hospitalization costs in favor of the rivaroxaban patients for all-cause hospitalizations, and an average $1,300 difference per patient for hospitalization costs directly related to AF.

Although the rivaroxaban patients spent an average of $2,700 more per patient on pharmaceuticals for all causes, and an average $2,200 more for AF-related drugs, the total average all-cause and AF-related costs for drugs, hospitalizations, outpatient visits, and emergency department visits were similar in the two subgroups: an average total of $17,590 per patient for the rivaroxaban patients and $18,676 for warfarin patients for all causes, and an average of $7,394 for the rivaroxaban patients and $7,319 for those on warfarin for AF-related care. The between-group differences for both sets of total costs were not statistically significant.

The study was sponsored by Janssen, which along with Bayer markets rivaroxaban (Xarelto). Dr. Crivera is a Janssen employee. Dr. Weitz has been an adviser or a consultant to Janssen and Bayer and to Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Merck, Pfizer, and Portola.

[email protected]

On Twitter @mitchelzoler