Jane Salodof MacNeil

ORLANDO – Allogeneic stem cell transplantation failed to boost overall survival or progression-free survival rates at 3 years when added to autologous stem cell transplantation and compared with tandem autologous transplants among patients with standard-risk myeloma.

Disappointing at best, the experimental strategy dubbed "auto-allo" by investigators also increased treatment-related mortality in this first report from a much-anticipated phase III trial that enrolled 710 patients at 43 centers in the United States.

Yet researchers are holding out hope that with longer follow-up, auto-allo might begin to pay off for patients with standard or high-risk disease. Tandem "auto-auto" transplants are known to improve survival, but they are not curative, explained lead author Dr. Amrita Krishnan, director of the multiple myeloma program at the City of Hope cancer center in Duarte, Calif.

"Ultimately, [auto-allo] may lead to a cure for these patients," she said, when pressed to explain the continued interest in the approach. Dr. Krishnan’s presentation at the annual meeting of the American Society of Hematology generated extensive discussion. If there was any audience agreement, it was that for now, use of auto-allo transplants should be confined to clinical trials.

"This is a preliminary result but it certainly is not supportive of routine use of nonmyeloablative allogeneic transplant in the standard-risk patients. ... With longer-term follow-up, if these results hold out, then I think our enthusiasm will [disappear]," said session moderator Dr. Edward A. Stadtmauer, a coinvestigator, professor of medicine, and codirector of the bone marrow and stem cell transplant programs at the University of Pennsylvania in Philadelphia.

The Blood and Marrow Transplant Clinical Trials Network enrolled multiple myeloma patients from December 2003 to March 2007, and assigned them to trial arms based on whether they had an HLA-matched sibling donor at the time of enrollment. All patients received high-dose melphalan 200 mg/m2 and an autologous stem cell transplant. This was followed by a second autologous transplant with melphalan in 484 patients without a sibling match. The 226 patients who had a match received a nonmyeloablative conditioning regimen followed by allogeneic transplant and 2 Gy of total body irradiation. In each group, 82% went on to a second transplant.

Progression-free survival rates at 3 years were 46% in the auto-auto arm and 43% in the auto-allo arm (47% and 44%, respectively, when only patients who received second transplants were analyzed). Overall survival rates, likewise, were similar at 80% and 77%, respectively, as were progression/relapse rates of 46% with auto-auto and 43% with auto-allo.

Only treatment-related mortality was significantly different, at 4% with auto-auto and 12% with auto-allo (P less than .001), a split that Dr. Krishnan attributed to graft-vs.-host effect and graft failure in the allo-allo arm. Myeloma accounted for 70% of deaths in the auto-auto group vs. 38% in the experimental group, she noted.

Patients in the auto-allo group also received maintenance therapy with thalidomide and dexamethasone, but the regimen proved intolerable for 84% of those assigned to it.

The National Heart, Lung, and Blood Institute and the National Cancer Institute fund the Blood and Marrow Transplant Clinical Trials Network. Dr. Krishnan and Dr. Stadtmauer disclosed being on the Celgene speakers bureau.

ORLANDO – Allogeneic stem cell transplantation failed to boost overall survival or progression-free survival rates at 3 years when added to autologous stem cell transplantation and compared with tandem autologous transplants among patients with standard-risk myeloma.

Disappointing at best, the experimental strategy dubbed "auto-allo" by investigators also increased treatment-related mortality in this first report from a much-anticipated phase III trial that enrolled 710 patients at 43 centers in the United States.

Yet researchers are holding out hope that with longer follow-up, auto-allo might begin to pay off for patients with standard or high-risk disease. Tandem "auto-auto" transplants are known to improve survival, but they are not curative, explained lead author Dr. Amrita Krishnan, director of the multiple myeloma program at the City of Hope cancer center in Duarte, Calif.

"Ultimately, [auto-allo] may lead to a cure for these patients," she said, when pressed to explain the continued interest in the approach. Dr. Krishnan’s presentation at the annual meeting of the American Society of Hematology generated extensive discussion. If there was any audience agreement, it was that for now, use of auto-allo transplants should be confined to clinical trials.

"This is a preliminary result but it certainly is not supportive of routine use of nonmyeloablative allogeneic transplant in the standard-risk patients. ... With longer-term follow-up, if these results hold out, then I think our enthusiasm will [disappear]," said session moderator Dr. Edward A. Stadtmauer, a coinvestigator, professor of medicine, and codirector of the bone marrow and stem cell transplant programs at the University of Pennsylvania in Philadelphia.

The Blood and Marrow Transplant Clinical Trials Network enrolled multiple myeloma patients from December 2003 to March 2007, and assigned them to trial arms based on whether they had an HLA-matched sibling donor at the time of enrollment. All patients received high-dose melphalan 200 mg/m2 and an autologous stem cell transplant. This was followed by a second autologous transplant with melphalan in 484 patients without a sibling match. The 226 patients who had a match received a nonmyeloablative conditioning regimen followed by allogeneic transplant and 2 Gy of total body irradiation. In each group, 82% went on to a second transplant.

Progression-free survival rates at 3 years were 46% in the auto-auto arm and 43% in the auto-allo arm (47% and 44%, respectively, when only patients who received second transplants were analyzed). Overall survival rates, likewise, were similar at 80% and 77%, respectively, as were progression/relapse rates of 46% with auto-auto and 43% with auto-allo.

Only treatment-related mortality was significantly different, at 4% with auto-auto and 12% with auto-allo (P less than .001), a split that Dr. Krishnan attributed to graft-vs.-host effect and graft failure in the allo-allo arm. Myeloma accounted for 70% of deaths in the auto-auto group vs. 38% in the experimental group, she noted.

Patients in the auto-allo group also received maintenance therapy with thalidomide and dexamethasone, but the regimen proved intolerable for 84% of those assigned to it.

The National Heart, Lung, and Blood Institute and the National Cancer Institute fund the Blood and Marrow Transplant Clinical Trials Network. Dr. Krishnan and Dr. Stadtmauer disclosed being on the Celgene speakers bureau.

ORLANDO – Allogeneic stem cell transplantation failed to boost overall survival or progression-free survival rates at 3 years when added to autologous stem cell transplantation and compared with tandem autologous transplants among patients with standard-risk myeloma.

Disappointing at best, the experimental strategy dubbed "auto-allo" by investigators also increased treatment-related mortality in this first report from a much-anticipated phase III trial that enrolled 710 patients at 43 centers in the United States.

Yet researchers are holding out hope that with longer follow-up, auto-allo might begin to pay off for patients with standard or high-risk disease. Tandem "auto-auto" transplants are known to improve survival, but they are not curative, explained lead author Dr. Amrita Krishnan, director of the multiple myeloma program at the City of Hope cancer center in Duarte, Calif.

"Ultimately, [auto-allo] may lead to a cure for these patients," she said, when pressed to explain the continued interest in the approach. Dr. Krishnan’s presentation at the annual meeting of the American Society of Hematology generated extensive discussion. If there was any audience agreement, it was that for now, use of auto-allo transplants should be confined to clinical trials.

"This is a preliminary result but it certainly is not supportive of routine use of nonmyeloablative allogeneic transplant in the standard-risk patients. ... With longer-term follow-up, if these results hold out, then I think our enthusiasm will [disappear]," said session moderator Dr. Edward A. Stadtmauer, a coinvestigator, professor of medicine, and codirector of the bone marrow and stem cell transplant programs at the University of Pennsylvania in Philadelphia.

The Blood and Marrow Transplant Clinical Trials Network enrolled multiple myeloma patients from December 2003 to March 2007, and assigned them to trial arms based on whether they had an HLA-matched sibling donor at the time of enrollment. All patients received high-dose melphalan 200 mg/m2 and an autologous stem cell transplant. This was followed by a second autologous transplant with melphalan in 484 patients without a sibling match. The 226 patients who had a match received a nonmyeloablative conditioning regimen followed by allogeneic transplant and 2 Gy of total body irradiation. In each group, 82% went on to a second transplant.

Progression-free survival rates at 3 years were 46% in the auto-auto arm and 43% in the auto-allo arm (47% and 44%, respectively, when only patients who received second transplants were analyzed). Overall survival rates, likewise, were similar at 80% and 77%, respectively, as were progression/relapse rates of 46% with auto-auto and 43% with auto-allo.

Only treatment-related mortality was significantly different, at 4% with auto-auto and 12% with auto-allo (P less than .001), a split that Dr. Krishnan attributed to graft-vs.-host effect and graft failure in the allo-allo arm. Myeloma accounted for 70% of deaths in the auto-auto group vs. 38% in the experimental group, she noted.

Patients in the auto-allo group also received maintenance therapy with thalidomide and dexamethasone, but the regimen proved intolerable for 84% of those assigned to it.

The National Heart, Lung, and Blood Institute and the National Cancer Institute fund the Blood and Marrow Transplant Clinical Trials Network. Dr. Krishnan and Dr. Stadtmauer disclosed being on the Celgene speakers bureau.

ORLANDO – Despite missing its primary end point for complete cytogenetic response, a phase III trial suggests that the novel agent bosutinib has comparable efficacy to other drugs that were approved for first-line use in newly diagnosed chronic-phase chronic myeloid leukemia.

For most outcomes, bosutinib outperformed imatinib (Gleevec) in the multinational BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial reported by Dr. Carlo Gambacorti-Passerini at the annual meeting of the American Society of Hematology.

[Check out our comprehensive coverage of the American Society of Hematology's annual meeting.]

"Bosutinib may offer a new therapeutic option for patients with Philadelphia chromosome–positive CML," he concluded, after presenting mixed results from the open-label study sponsored by Pfizer Inc. The trial randomized 250 newly diagnosed patients to 500 mg/day of bosutinib and 252 patients to 400 mg/day of imatinib.

At 12 months, the major molecular response rate was superior with bosutinib (39%) compared with 26% with imatinib (P = .002) in an intent-to-treat analysis by Dr. Gambacorti-Passerini, professor of internal medicine and director of the clinical research unit in hematology at the University of Milan-Bicocca in Monza, Italy.

Treatment-failure rates were lower with bosutinib (3% vs. 10%), as were the rates of transformation to resulting from CML progression (1% vs. 3%).

The complete cytogenetic response rate was only slightly higher at 70% vs. 68%, however, and the difference did not reach statistical significance – a shortcoming Dr. Gambacorti-Passerini suggested may have been the result of 8%-9% of patients on bosutinib going off treatment before the first assessment.

What distinguished bosutinib from other tyrosine kinase inhibitors (TKIs) was its toxicity profile. GI side effects were more common, although not serious, and adverse events were the leading cause of treatment discontinuation, accounting for 19% in the experimental arm.

Dr. Gambacorti-Passerini attributed the discontinuations to most participating physicians’ unfamiliarity with bosutinib. Unlike imatinib and other approved TKIs, such as dasatinib (Sprycel) and nilotinib (Tasigna), bosutinib has not previously been used outside of clinical trials.

"I think we are paying ... the price of this relative lack of familiarity with the drug," he said, suggesting in an interview that at least part of the observed toxicity was because of poor management of side effects. "Patients in centers that had no previous experience with the novel drug had a 30% higher probability of dropping a patient for adverse events."

Paradoxically, bosutinib has a mild toxicity profile that is also different from those of the approved drugs, according to Dr. Gambacorti-Passerini. Patients in the experimental arm had significantly more diarrhea (68% of patients on bosutinib experienced this toxicity), vomiting, pyrexia, upper abdominal pain, and abdominal pain than did those in the imatinib arm. In contrast, patients on imatinib had significantly more bone pain, muscle cramps, and periorbital edema.

Except for diarrhea in patients who were treated with bosutinib, grade 3/4 events were uncommon. The median duration of diarrhea was 30 days, he noted, and no one dropped out as result. Moreover, more serious side effects such as arrhythmia and pleural effusions were not seen. Compared with imatinib, bosutinib was associated with less neutropenia and more transaminase elevation, but no liver injury was seen.

"I think the safety profile is the safest" among the second-generation TKIs, he said.

The toxicity profile "may or may not be a problem," according to session moderator Dr. Kimmo Porkka, a professor of hematology at Helsinki University. "We need to really learn to manage the different toxicities with these different agents. ... The toxicity profile may help determine which we will end up using," he said, noting the bosutinib seems similar in efficacy to the approved drugs.

Dr. Mark Shapiro, a hematology team leader with Pfizer, said that the company plans to apply for first-line approval in Europe based on the BELA trial and for second- and third-line approval in the United States based on phase II trials.

ORLANDO – Despite missing its primary end point for complete cytogenetic response, a phase III trial suggests that the novel agent bosutinib has comparable efficacy to other drugs that were approved for first-line use in newly diagnosed chronic-phase chronic myeloid leukemia.

For most outcomes, bosutinib outperformed imatinib (Gleevec) in the multinational BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial reported by Dr. Carlo Gambacorti-Passerini at the annual meeting of the American Society of Hematology.

[Check out our comprehensive coverage of the American Society of Hematology's annual meeting.]

"Bosutinib may offer a new therapeutic option for patients with Philadelphia chromosome–positive CML," he concluded, after presenting mixed results from the open-label study sponsored by Pfizer Inc. The trial randomized 250 newly diagnosed patients to 500 mg/day of bosutinib and 252 patients to 400 mg/day of imatinib.

At 12 months, the major molecular response rate was superior with bosutinib (39%) compared with 26% with imatinib (P = .002) in an intent-to-treat analysis by Dr. Gambacorti-Passerini, professor of internal medicine and director of the clinical research unit in hematology at the University of Milan-Bicocca in Monza, Italy.

Treatment-failure rates were lower with bosutinib (3% vs. 10%), as were the rates of transformation to resulting from CML progression (1% vs. 3%).

The complete cytogenetic response rate was only slightly higher at 70% vs. 68%, however, and the difference did not reach statistical significance – a shortcoming Dr. Gambacorti-Passerini suggested may have been the result of 8%-9% of patients on bosutinib going off treatment before the first assessment.

What distinguished bosutinib from other tyrosine kinase inhibitors (TKIs) was its toxicity profile. GI side effects were more common, although not serious, and adverse events were the leading cause of treatment discontinuation, accounting for 19% in the experimental arm.

Dr. Gambacorti-Passerini attributed the discontinuations to most participating physicians’ unfamiliarity with bosutinib. Unlike imatinib and other approved TKIs, such as dasatinib (Sprycel) and nilotinib (Tasigna), bosutinib has not previously been used outside of clinical trials.

"I think we are paying ... the price of this relative lack of familiarity with the drug," he said, suggesting in an interview that at least part of the observed toxicity was because of poor management of side effects. "Patients in centers that had no previous experience with the novel drug had a 30% higher probability of dropping a patient for adverse events."

Paradoxically, bosutinib has a mild toxicity profile that is also different from those of the approved drugs, according to Dr. Gambacorti-Passerini. Patients in the experimental arm had significantly more diarrhea (68% of patients on bosutinib experienced this toxicity), vomiting, pyrexia, upper abdominal pain, and abdominal pain than did those in the imatinib arm. In contrast, patients on imatinib had significantly more bone pain, muscle cramps, and periorbital edema.

Except for diarrhea in patients who were treated with bosutinib, grade 3/4 events were uncommon. The median duration of diarrhea was 30 days, he noted, and no one dropped out as result. Moreover, more serious side effects such as arrhythmia and pleural effusions were not seen. Compared with imatinib, bosutinib was associated with less neutropenia and more transaminase elevation, but no liver injury was seen.

"I think the safety profile is the safest" among the second-generation TKIs, he said.

The toxicity profile "may or may not be a problem," according to session moderator Dr. Kimmo Porkka, a professor of hematology at Helsinki University. "We need to really learn to manage the different toxicities with these different agents. ... The toxicity profile may help determine which we will end up using," he said, noting the bosutinib seems similar in efficacy to the approved drugs.

Dr. Mark Shapiro, a hematology team leader with Pfizer, said that the company plans to apply for first-line approval in Europe based on the BELA trial and for second- and third-line approval in the United States based on phase II trials.

ORLANDO – Despite missing its primary end point for complete cytogenetic response, a phase III trial suggests that the novel agent bosutinib has comparable efficacy to other drugs that were approved for first-line use in newly diagnosed chronic-phase chronic myeloid leukemia.

For most outcomes, bosutinib outperformed imatinib (Gleevec) in the multinational BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial reported by Dr. Carlo Gambacorti-Passerini at the annual meeting of the American Society of Hematology.

[Check out our comprehensive coverage of the American Society of Hematology's annual meeting.]

"Bosutinib may offer a new therapeutic option for patients with Philadelphia chromosome–positive CML," he concluded, after presenting mixed results from the open-label study sponsored by Pfizer Inc. The trial randomized 250 newly diagnosed patients to 500 mg/day of bosutinib and 252 patients to 400 mg/day of imatinib.

At 12 months, the major molecular response rate was superior with bosutinib (39%) compared with 26% with imatinib (P = .002) in an intent-to-treat analysis by Dr. Gambacorti-Passerini, professor of internal medicine and director of the clinical research unit in hematology at the University of Milan-Bicocca in Monza, Italy.

Treatment-failure rates were lower with bosutinib (3% vs. 10%), as were the rates of transformation to resulting from CML progression (1% vs. 3%).

The complete cytogenetic response rate was only slightly higher at 70% vs. 68%, however, and the difference did not reach statistical significance – a shortcoming Dr. Gambacorti-Passerini suggested may have been the result of 8%-9% of patients on bosutinib going off treatment before the first assessment.

What distinguished bosutinib from other tyrosine kinase inhibitors (TKIs) was its toxicity profile. GI side effects were more common, although not serious, and adverse events were the leading cause of treatment discontinuation, accounting for 19% in the experimental arm.

Dr. Gambacorti-Passerini attributed the discontinuations to most participating physicians’ unfamiliarity with bosutinib. Unlike imatinib and other approved TKIs, such as dasatinib (Sprycel) and nilotinib (Tasigna), bosutinib has not previously been used outside of clinical trials.

"I think we are paying ... the price of this relative lack of familiarity with the drug," he said, suggesting in an interview that at least part of the observed toxicity was because of poor management of side effects. "Patients in centers that had no previous experience with the novel drug had a 30% higher probability of dropping a patient for adverse events."

Paradoxically, bosutinib has a mild toxicity profile that is also different from those of the approved drugs, according to Dr. Gambacorti-Passerini. Patients in the experimental arm had significantly more diarrhea (68% of patients on bosutinib experienced this toxicity), vomiting, pyrexia, upper abdominal pain, and abdominal pain than did those in the imatinib arm. In contrast, patients on imatinib had significantly more bone pain, muscle cramps, and periorbital edema.

Except for diarrhea in patients who were treated with bosutinib, grade 3/4 events were uncommon. The median duration of diarrhea was 30 days, he noted, and no one dropped out as result. Moreover, more serious side effects such as arrhythmia and pleural effusions were not seen. Compared with imatinib, bosutinib was associated with less neutropenia and more transaminase elevation, but no liver injury was seen.

"I think the safety profile is the safest" among the second-generation TKIs, he said.

The toxicity profile "may or may not be a problem," according to session moderator Dr. Kimmo Porkka, a professor of hematology at Helsinki University. "We need to really learn to manage the different toxicities with these different agents. ... The toxicity profile may help determine which we will end up using," he said, noting the bosutinib seems similar in efficacy to the approved drugs.

Dr. Mark Shapiro, a hematology team leader with Pfizer, said that the company plans to apply for first-line approval in Europe based on the BELA trial and for second- and third-line approval in the United States based on phase II trials.

ORLANDO – A large retrospective analysis of adult patients with acute leukemia suggests that double-unit transplantation of cord blood from two unrelated donors may be better than single-unit transplants despite more graft-vs.-host disease among the double-unit recipients.

Patients given two units of cord blood while in their first complete remission had a significantly higher rate of leukemia-free survival and lower rate of relapse compared with single-unit recipients, Dr. Vanderson Rocha reported at the annual meeting of the American Society of Hematology. No benefit was seen among patients transplanted when they were in second or third remissions.

The study confirms that double-unit transplants are feasible and can lead to better outcomes, but the results still need to be confirmed by randomized trials already underway in Europe and the United States, according to Dr. Rocha, scientific director of the Eurocord Registry at Hôpital St. Louis in Paris.

Transplantation of hematopoietic stem cells from umbilical cord blood was initially done in children. Although the practice has spread to adult patients, the number of cells in a single unit of cord blood often is not sufficient for larger recipients. Hence, many centers have started to do double-unit unrelated cord blood transplantation, which was found to be beneficial in research from the University of Minnesota (Blood 2009;113:2410-5).

Eurocord and the Acute Leukemia Working Party (a part of the European Group for Blood and Marrow Transplantation) undertook the retrospective analysis to see whether the Minnesota results would be reproducible in a registry-based study. Collecting data on adult patients with acute myeloid or lymphoblastic leukemias, the investigators found 230 who had undergone double-unit transplants and 377 given single units in European centers from 1998 to 2009.

Although the overall rates of leukemia-free survival were not significantly different statistically at 2 years, the double-unit group fared better at 44% vs. 35% of the single-unit recipients. Separating the population by number of remissions, the investigators found significant benefits for the double-units among early leukemia patients transplanted while in their first remissions.

Dr. Rocha reported the 2-year incidence of relapse was 15% in this group vs. 25% (P = .03) in the single-unit group. The leukemia-free survival rate was also improved at 53% vs. 39% (hazard ratio, 0.57; P = .04).

Double-unit recipients paid a price in more grade II-IV acute graft vs. host disease – 36% vs. 25% in the single-unit group (P = .007). Dr. Rocha noted that mortality was not higher, however, at 33% with two units and 32% in the single-unit group.

Review of the patient populations showed that those receiving double units tended to be larger with a median of 68 kg vs. 65 kg in the single-unit group (P less than .001). The double-unit transplants also tended to be more recent and have a shorter follow-up at a median of 14 months vs. 20 months for the single unit group. Median age was similar, however, at 37 years and 35 years, respectively, as were most other patient characteristics, including distribution of leukemia by type, status by first, second, or third remission at time of transplant.

More poor-risk cytogenetics were seen in the single-unit group (36% vs. 32%, P = .02). The single-unit group also was significantly more likely to have myeloablative conditioning, antithymocyte globulin/antilymphocyte globulin (ATG/ALG), and graft-vs.-host disease prophylaxis (P less than .001).

Not surprisingly, the double-unit recipients were infused with more nucleated cell: 3.7 x 107 vs. 2.6 x 107 (P less than .001). In response to audience questions, Dr. Rocha said the investigators looked for a cell-dose effect, but could not find a cell-dose cut-off based on the retrospective analysis. Time to neutrophil recovery was similar.

Dr. Armand Keating, professor of medicine, director of the division of hematology, and Epstein Chair in cell therapy and transplantation at the University of Toronto, described the study as important during a press briefing which he moderated. It suggests that mortality may be the same, he said, but leukemia-free survival could be superior. Like Dr. Rocha, he anticipated that the ongoing randomized trials could resolve the issue.

Even if double-cord blood transplants prove superior, the investigators noted that cost could be an obstacle. Storing large inventories of cord blood is expensive – so much so that another press briefing panelist, Dr. Joseph H. Antin of the Dana-Farber Cancer Institute, Boston, said his institution considered setting up a program only to find it would cost 10 years to recoup the initial cost.

The price of a single unit of cord-blood ranges from €20,000 to €25,000 (euros) in Europe and $30,000 to $35,000 in the United States, Dr. Rocha said, adding that some centers might discount the price of a second unit in a double transplant.

The investigators reported no conflicts of interest.

ORLANDO – A large retrospective analysis of adult patients with acute leukemia suggests that double-unit transplantation of cord blood from two unrelated donors may be better than single-unit transplants despite more graft-vs.-host disease among the double-unit recipients.

Patients given two units of cord blood while in their first complete remission had a significantly higher rate of leukemia-free survival and lower rate of relapse compared with single-unit recipients, Dr. Vanderson Rocha reported at the annual meeting of the American Society of Hematology. No benefit was seen among patients transplanted when they were in second or third remissions.

The study confirms that double-unit transplants are feasible and can lead to better outcomes, but the results still need to be confirmed by randomized trials already underway in Europe and the United States, according to Dr. Rocha, scientific director of the Eurocord Registry at Hôpital St. Louis in Paris.

Transplantation of hematopoietic stem cells from umbilical cord blood was initially done in children. Although the practice has spread to adult patients, the number of cells in a single unit of cord blood often is not sufficient for larger recipients. Hence, many centers have started to do double-unit unrelated cord blood transplantation, which was found to be beneficial in research from the University of Minnesota (Blood 2009;113:2410-5).

Eurocord and the Acute Leukemia Working Party (a part of the European Group for Blood and Marrow Transplantation) undertook the retrospective analysis to see whether the Minnesota results would be reproducible in a registry-based study. Collecting data on adult patients with acute myeloid or lymphoblastic leukemias, the investigators found 230 who had undergone double-unit transplants and 377 given single units in European centers from 1998 to 2009.

Although the overall rates of leukemia-free survival were not significantly different statistically at 2 years, the double-unit group fared better at 44% vs. 35% of the single-unit recipients. Separating the population by number of remissions, the investigators found significant benefits for the double-units among early leukemia patients transplanted while in their first remissions.

Dr. Rocha reported the 2-year incidence of relapse was 15% in this group vs. 25% (P = .03) in the single-unit group. The leukemia-free survival rate was also improved at 53% vs. 39% (hazard ratio, 0.57; P = .04).

Double-unit recipients paid a price in more grade II-IV acute graft vs. host disease – 36% vs. 25% in the single-unit group (P = .007). Dr. Rocha noted that mortality was not higher, however, at 33% with two units and 32% in the single-unit group.

Review of the patient populations showed that those receiving double units tended to be larger with a median of 68 kg vs. 65 kg in the single-unit group (P less than .001). The double-unit transplants also tended to be more recent and have a shorter follow-up at a median of 14 months vs. 20 months for the single unit group. Median age was similar, however, at 37 years and 35 years, respectively, as were most other patient characteristics, including distribution of leukemia by type, status by first, second, or third remission at time of transplant.

More poor-risk cytogenetics were seen in the single-unit group (36% vs. 32%, P = .02). The single-unit group also was significantly more likely to have myeloablative conditioning, antithymocyte globulin/antilymphocyte globulin (ATG/ALG), and graft-vs.-host disease prophylaxis (P less than .001).

Not surprisingly, the double-unit recipients were infused with more nucleated cell: 3.7 x 107 vs. 2.6 x 107 (P less than .001). In response to audience questions, Dr. Rocha said the investigators looked for a cell-dose effect, but could not find a cell-dose cut-off based on the retrospective analysis. Time to neutrophil recovery was similar.

Dr. Armand Keating, professor of medicine, director of the division of hematology, and Epstein Chair in cell therapy and transplantation at the University of Toronto, described the study as important during a press briefing which he moderated. It suggests that mortality may be the same, he said, but leukemia-free survival could be superior. Like Dr. Rocha, he anticipated that the ongoing randomized trials could resolve the issue.

Even if double-cord blood transplants prove superior, the investigators noted that cost could be an obstacle. Storing large inventories of cord blood is expensive – so much so that another press briefing panelist, Dr. Joseph H. Antin of the Dana-Farber Cancer Institute, Boston, said his institution considered setting up a program only to find it would cost 10 years to recoup the initial cost.

The price of a single unit of cord-blood ranges from €20,000 to €25,000 (euros) in Europe and $30,000 to $35,000 in the United States, Dr. Rocha said, adding that some centers might discount the price of a second unit in a double transplant.

The investigators reported no conflicts of interest.

ORLANDO – A large retrospective analysis of adult patients with acute leukemia suggests that double-unit transplantation of cord blood from two unrelated donors may be better than single-unit transplants despite more graft-vs.-host disease among the double-unit recipients.

Patients given two units of cord blood while in their first complete remission had a significantly higher rate of leukemia-free survival and lower rate of relapse compared with single-unit recipients, Dr. Vanderson Rocha reported at the annual meeting of the American Society of Hematology. No benefit was seen among patients transplanted when they were in second or third remissions.

The study confirms that double-unit transplants are feasible and can lead to better outcomes, but the results still need to be confirmed by randomized trials already underway in Europe and the United States, according to Dr. Rocha, scientific director of the Eurocord Registry at Hôpital St. Louis in Paris.

Transplantation of hematopoietic stem cells from umbilical cord blood was initially done in children. Although the practice has spread to adult patients, the number of cells in a single unit of cord blood often is not sufficient for larger recipients. Hence, many centers have started to do double-unit unrelated cord blood transplantation, which was found to be beneficial in research from the University of Minnesota (Blood 2009;113:2410-5).

Eurocord and the Acute Leukemia Working Party (a part of the European Group for Blood and Marrow Transplantation) undertook the retrospective analysis to see whether the Minnesota results would be reproducible in a registry-based study. Collecting data on adult patients with acute myeloid or lymphoblastic leukemias, the investigators found 230 who had undergone double-unit transplants and 377 given single units in European centers from 1998 to 2009.

Although the overall rates of leukemia-free survival were not significantly different statistically at 2 years, the double-unit group fared better at 44% vs. 35% of the single-unit recipients. Separating the population by number of remissions, the investigators found significant benefits for the double-units among early leukemia patients transplanted while in their first remissions.

Dr. Rocha reported the 2-year incidence of relapse was 15% in this group vs. 25% (P = .03) in the single-unit group. The leukemia-free survival rate was also improved at 53% vs. 39% (hazard ratio, 0.57; P = .04).

Double-unit recipients paid a price in more grade II-IV acute graft vs. host disease – 36% vs. 25% in the single-unit group (P = .007). Dr. Rocha noted that mortality was not higher, however, at 33% with two units and 32% in the single-unit group.

Review of the patient populations showed that those receiving double units tended to be larger with a median of 68 kg vs. 65 kg in the single-unit group (P less than .001). The double-unit transplants also tended to be more recent and have a shorter follow-up at a median of 14 months vs. 20 months for the single unit group. Median age was similar, however, at 37 years and 35 years, respectively, as were most other patient characteristics, including distribution of leukemia by type, status by first, second, or third remission at time of transplant.

More poor-risk cytogenetics were seen in the single-unit group (36% vs. 32%, P = .02). The single-unit group also was significantly more likely to have myeloablative conditioning, antithymocyte globulin/antilymphocyte globulin (ATG/ALG), and graft-vs.-host disease prophylaxis (P less than .001).

Not surprisingly, the double-unit recipients were infused with more nucleated cell: 3.7 x 107 vs. 2.6 x 107 (P less than .001). In response to audience questions, Dr. Rocha said the investigators looked for a cell-dose effect, but could not find a cell-dose cut-off based on the retrospective analysis. Time to neutrophil recovery was similar.

Dr. Armand Keating, professor of medicine, director of the division of hematology, and Epstein Chair in cell therapy and transplantation at the University of Toronto, described the study as important during a press briefing which he moderated. It suggests that mortality may be the same, he said, but leukemia-free survival could be superior. Like Dr. Rocha, he anticipated that the ongoing randomized trials could resolve the issue.

Even if double-cord blood transplants prove superior, the investigators noted that cost could be an obstacle. Storing large inventories of cord blood is expensive – so much so that another press briefing panelist, Dr. Joseph H. Antin of the Dana-Farber Cancer Institute, Boston, said his institution considered setting up a program only to find it would cost 10 years to recoup the initial cost.

The price of a single unit of cord-blood ranges from €20,000 to €25,000 (euros) in Europe and $30,000 to $35,000 in the United States, Dr. Rocha said, adding that some centers might discount the price of a second unit in a double transplant.

The investigators reported no conflicts of interest.

ORLANDO – Stopping the cycle by which the Plasmodium parasite spreads from people to mosquitoes and back to people could be the key to controlling malaria, according to scientists who have developed what may be a strategy for doing just that.

Dr. John G. Quigley and his coinvestigators are targeting a protein called FLVCR that mosquitoes express after feasting on blood. FLVCR protects cells from the toxicity of excess heme, or iron, a part of hemoglobin that binds and transports oxygen in red blood cells.

The ongoing study aims to induce oxidative stress in the midgut of malaria-transmitting mosquitoes by inhibiting the heme-exporting function of FLVCR. As a consequence, the midgut should become inhospitable to the blood-borne parasite, causing it to die instead of reproducing, Dr. Quigley explained in a plenary presentation at the annual meeting of the American Society of Hematology.

Ultimately, the goal is to create an FLVCR-suppressing vaccine for use in humans in areas where malaria is widespread, he said. The vaccine would not protect the person who is already infected, but it would break the cycle of transmission if that person is bitten by a mosquito.

"It’s called the altruistic vaccine because it’s not actually protecting you, but it is preventing the mosquito from infecting the next person," Dr. Quigley of the University of Illinois at Chicago said in an interview.

FLVCR – an abbreviation for feline leukemia virus subgroup C receptor – was initially isolated as a cause of severe anemia in cats, he said. Working with two common malaria-transmitting mosquitoes (Anopheles gambiae and A. stephensi), the Chicago-based group of scientists at the University of Illinois and Loyola University isolated the gene encoding mosquito FLVCR proteins.

The researchers conducted a series of studies, verifying that the proteins export heme and could protect cells from the oxidative stress that results when too much free heme overloads cells with reactive oxygen species (ROS). They also showed that anopheline FLVCR is highly expressed after a mosquito gorges on blood.

If the mosquito bites an infected person, this blood will contain anywhere from 10,000 to 100,000 parasites, most of which are unable to reproduce, according to Dr. Quigley. Only 20-100 will be fertilized successfully and invade the midgut, but their fertilized eggs develop into Plasmodium cysts (or oocysts) that release thousands of parasites after maturing for 1-3 weeks in the mosquito gut. These offspring then travel to the mosquito’s salivary gland from which they are transmitted via the insect’s next bite.

"You are trying to kill the parasite ... the idea is to interfere with the invasion of the gut epithelium," Dr. Quigley said, characterizing the blood drinking as "a major bottleneck" and "the weakest point" in the process.

The researchers so far have developed an antibody "that appears to bind (and likely inhibit) FLVCR in vivo." They also have used gene-silencing techniques to "knock down" FLVCR gene expression. The next step will be to analyze the effects on parasite transmission, and if those show FLVCR is required, develop a vaccine to block transmission. If this is successful, the mosquito would no longer be a womb but a tomb for Plasmodium.

"Disruption of FLVCR function may be an ‘Achilles heel’ of blood-eating disease vectors," Dr. Quigley said.

Such a vaccine could have a major impact on public health globally, commented Dr. Alexis Thompson, who moderated a press briefing on the research. Malaria infects 250 million people, causing 1 million deaths annually, noted Dr. Thompson, director of hematology services at Children’s Memorial Hospital, Chicago.

"This is a global problem that the United States really has an opportunity to contribute to solving," she said. Even in the United States, she added, despite widespread belief that draining swamps in Florida and Louisiana eliminated malaria, a small number of cases are seen each year.

The authors said they had no relevant conflicts to disclose.

ORLANDO – Stopping the cycle by which the Plasmodium parasite spreads from people to mosquitoes and back to people could be the key to controlling malaria, according to scientists who have developed what may be a strategy for doing just that.

Dr. John G. Quigley and his coinvestigators are targeting a protein called FLVCR that mosquitoes express after feasting on blood. FLVCR protects cells from the toxicity of excess heme, or iron, a part of hemoglobin that binds and transports oxygen in red blood cells.

The ongoing study aims to induce oxidative stress in the midgut of malaria-transmitting mosquitoes by inhibiting the heme-exporting function of FLVCR. As a consequence, the midgut should become inhospitable to the blood-borne parasite, causing it to die instead of reproducing, Dr. Quigley explained in a plenary presentation at the annual meeting of the American Society of Hematology.

Ultimately, the goal is to create an FLVCR-suppressing vaccine for use in humans in areas where malaria is widespread, he said. The vaccine would not protect the person who is already infected, but it would break the cycle of transmission if that person is bitten by a mosquito.

"It’s called the altruistic vaccine because it’s not actually protecting you, but it is preventing the mosquito from infecting the next person," Dr. Quigley of the University of Illinois at Chicago said in an interview.

FLVCR – an abbreviation for feline leukemia virus subgroup C receptor – was initially isolated as a cause of severe anemia in cats, he said. Working with two common malaria-transmitting mosquitoes (Anopheles gambiae and A. stephensi), the Chicago-based group of scientists at the University of Illinois and Loyola University isolated the gene encoding mosquito FLVCR proteins.

The researchers conducted a series of studies, verifying that the proteins export heme and could protect cells from the oxidative stress that results when too much free heme overloads cells with reactive oxygen species (ROS). They also showed that anopheline FLVCR is highly expressed after a mosquito gorges on blood.

If the mosquito bites an infected person, this blood will contain anywhere from 10,000 to 100,000 parasites, most of which are unable to reproduce, according to Dr. Quigley. Only 20-100 will be fertilized successfully and invade the midgut, but their fertilized eggs develop into Plasmodium cysts (or oocysts) that release thousands of parasites after maturing for 1-3 weeks in the mosquito gut. These offspring then travel to the mosquito’s salivary gland from which they are transmitted via the insect’s next bite.

"You are trying to kill the parasite ... the idea is to interfere with the invasion of the gut epithelium," Dr. Quigley said, characterizing the blood drinking as "a major bottleneck" and "the weakest point" in the process.

The researchers so far have developed an antibody "that appears to bind (and likely inhibit) FLVCR in vivo." They also have used gene-silencing techniques to "knock down" FLVCR gene expression. The next step will be to analyze the effects on parasite transmission, and if those show FLVCR is required, develop a vaccine to block transmission. If this is successful, the mosquito would no longer be a womb but a tomb for Plasmodium.

"Disruption of FLVCR function may be an ‘Achilles heel’ of blood-eating disease vectors," Dr. Quigley said.

Such a vaccine could have a major impact on public health globally, commented Dr. Alexis Thompson, who moderated a press briefing on the research. Malaria infects 250 million people, causing 1 million deaths annually, noted Dr. Thompson, director of hematology services at Children’s Memorial Hospital, Chicago.

"This is a global problem that the United States really has an opportunity to contribute to solving," she said. Even in the United States, she added, despite widespread belief that draining swamps in Florida and Louisiana eliminated malaria, a small number of cases are seen each year.

The authors said they had no relevant conflicts to disclose.

ORLANDO – Stopping the cycle by which the Plasmodium parasite spreads from people to mosquitoes and back to people could be the key to controlling malaria, according to scientists who have developed what may be a strategy for doing just that.

Dr. John G. Quigley and his coinvestigators are targeting a protein called FLVCR that mosquitoes express after feasting on blood. FLVCR protects cells from the toxicity of excess heme, or iron, a part of hemoglobin that binds and transports oxygen in red blood cells.

The ongoing study aims to induce oxidative stress in the midgut of malaria-transmitting mosquitoes by inhibiting the heme-exporting function of FLVCR. As a consequence, the midgut should become inhospitable to the blood-borne parasite, causing it to die instead of reproducing, Dr. Quigley explained in a plenary presentation at the annual meeting of the American Society of Hematology.

Ultimately, the goal is to create an FLVCR-suppressing vaccine for use in humans in areas where malaria is widespread, he said. The vaccine would not protect the person who is already infected, but it would break the cycle of transmission if that person is bitten by a mosquito.

"It’s called the altruistic vaccine because it’s not actually protecting you, but it is preventing the mosquito from infecting the next person," Dr. Quigley of the University of Illinois at Chicago said in an interview.

FLVCR – an abbreviation for feline leukemia virus subgroup C receptor – was initially isolated as a cause of severe anemia in cats, he said. Working with two common malaria-transmitting mosquitoes (Anopheles gambiae and A. stephensi), the Chicago-based group of scientists at the University of Illinois and Loyola University isolated the gene encoding mosquito FLVCR proteins.

The researchers conducted a series of studies, verifying that the proteins export heme and could protect cells from the oxidative stress that results when too much free heme overloads cells with reactive oxygen species (ROS). They also showed that anopheline FLVCR is highly expressed after a mosquito gorges on blood.

If the mosquito bites an infected person, this blood will contain anywhere from 10,000 to 100,000 parasites, most of which are unable to reproduce, according to Dr. Quigley. Only 20-100 will be fertilized successfully and invade the midgut, but their fertilized eggs develop into Plasmodium cysts (or oocysts) that release thousands of parasites after maturing for 1-3 weeks in the mosquito gut. These offspring then travel to the mosquito’s salivary gland from which they are transmitted via the insect’s next bite.

"You are trying to kill the parasite ... the idea is to interfere with the invasion of the gut epithelium," Dr. Quigley said, characterizing the blood drinking as "a major bottleneck" and "the weakest point" in the process.

The researchers so far have developed an antibody "that appears to bind (and likely inhibit) FLVCR in vivo." They also have used gene-silencing techniques to "knock down" FLVCR gene expression. The next step will be to analyze the effects on parasite transmission, and if those show FLVCR is required, develop a vaccine to block transmission. If this is successful, the mosquito would no longer be a womb but a tomb for Plasmodium.

"Disruption of FLVCR function may be an ‘Achilles heel’ of blood-eating disease vectors," Dr. Quigley said.

Such a vaccine could have a major impact on public health globally, commented Dr. Alexis Thompson, who moderated a press briefing on the research. Malaria infects 250 million people, causing 1 million deaths annually, noted Dr. Thompson, director of hematology services at Children’s Memorial Hospital, Chicago.

"This is a global problem that the United States really has an opportunity to contribute to solving," she said. Even in the United States, she added, despite widespread belief that draining swamps in Florida and Louisiana eliminated malaria, a small number of cases are seen each year.

The authors said they had no relevant conflicts to disclose.

ORLANDO – Stopping the cycle by which the Plasmodium parasite spreads from people to mosquitoes and back to people could be the key to controlling malaria, according to scientists who have developed what may be a strategy for doing just that.

Dr. John G. Quigley and his coinvestigators are targeting a protein called FLVCR that mosquitoes express after feasting on blood. FLVCR protects cells from the toxicity of excess heme, or iron, a part of hemoglobin that binds and transports oxygen in red blood cells.

The ongoing study aims to induce oxidative stress in the midgut of malaria-transmitting mosquitoes by inhibiting the heme-exporting function of FLVCR. As a consequence, the midgut should become inhospitable to the blood-borne parasite, causing it to die instead of reproducing, Dr. Quigley explained in a plenary presentation at the annual meeting of the American Society of Hematology.

Ultimately, the goal is to create an FLVCR-suppressing vaccine for use in humans in areas where malaria is widespread, he said. The vaccine would not protect the person who is already infected, but it would break the cycle of transmission if that person is bitten by a mosquito.

"It’s called the altruistic vaccine because it’s not actually protecting you, but it is preventing the mosquito from infecting the next person," Dr. Quigley of the University of Illinois at Chicago said in an interview.

FLVCR – an abbreviation for feline leukemia virus subgroup C receptor – was initially isolated as a cause of severe anemia in cats, he said. Working with two common malaria-transmitting mosquitoes (Anopheles gambiae and A. stephensi), the Chicago-based group of scientists at the University of Illinois and Loyola University isolated the gene encoding mosquito FLVCR proteins.

The researchers conducted a series of studies, verifying that the proteins export heme and could protect cells from the oxidative stress that results when too much free heme overloads cells with reactive oxygen species (ROS). They also showed that anopheline FLVCR is highly expressed after a mosquito gorges on blood.

If the mosquito bites an infected person, this blood will contain anywhere from 10,000 to 100,000 parasites, most of which are unable to reproduce, according to Dr. Quigley. Only 20-100 will be fertilized successfully and invade the midgut, but their fertilized eggs develop into Plasmodium cysts (or oocysts) that release thousands of parasites after maturing for 1-3 weeks in the mosquito gut. These offspring then travel to the mosquito’s salivary gland from which they are transmitted via the insect’s next bite.

"You are trying to kill the parasite ... the idea is to interfere with the invasion of the gut epithelium," Dr. Quigley said, characterizing the blood drinking as "a major bottleneck" and "the weakest point" in the process.

The researchers so far have developed an antibody "that appears to bind (and likely inhibit) FLVCR in vivo." They also have used gene-silencing techniques to "knock down" FLVCR gene expression. The next step will be to analyze the effects on parasite transmission, and if those show FLVCR is required, develop a vaccine to block transmission. If this is successful, the mosquito would no longer be a womb but a tomb for Plasmodium.

"Disruption of FLVCR function may be an ‘Achilles heel’ of blood-eating disease vectors," Dr. Quigley said.

Such a vaccine could have a major impact on public health globally, commented Dr. Alexis Thompson, who moderated a press briefing on the research. Malaria infects 250 million people, causing 1 million deaths annually, noted Dr. Thompson, director of hematology services at Children’s Memorial Hospital, Chicago.

"This is a global problem that the United States really has an opportunity to contribute to solving," she said. Even in the United States, she added, despite widespread belief that draining swamps in Florida and Louisiana eliminated malaria, a small number of cases are seen each year.

The authors said they had no relevant conflicts to disclose.

ORLANDO – Stopping the cycle by which the Plasmodium parasite spreads from people to mosquitoes and back to people could be the key to controlling malaria, according to scientists who have developed what may be a strategy for doing just that.

Dr. John G. Quigley and his coinvestigators are targeting a protein called FLVCR that mosquitoes express after feasting on blood. FLVCR protects cells from the toxicity of excess heme, or iron, a part of hemoglobin that binds and transports oxygen in red blood cells.

The ongoing study aims to induce oxidative stress in the midgut of malaria-transmitting mosquitoes by inhibiting the heme-exporting function of FLVCR. As a consequence, the midgut should become inhospitable to the blood-borne parasite, causing it to die instead of reproducing, Dr. Quigley explained in a plenary presentation at the annual meeting of the American Society of Hematology.

Ultimately, the goal is to create an FLVCR-suppressing vaccine for use in humans in areas where malaria is widespread, he said. The vaccine would not protect the person who is already infected, but it would break the cycle of transmission if that person is bitten by a mosquito.

"It’s called the altruistic vaccine because it’s not actually protecting you, but it is preventing the mosquito from infecting the next person," Dr. Quigley of the University of Illinois at Chicago said in an interview.

FLVCR – an abbreviation for feline leukemia virus subgroup C receptor – was initially isolated as a cause of severe anemia in cats, he said. Working with two common malaria-transmitting mosquitoes (Anopheles gambiae and A. stephensi), the Chicago-based group of scientists at the University of Illinois and Loyola University isolated the gene encoding mosquito FLVCR proteins.

The researchers conducted a series of studies, verifying that the proteins export heme and could protect cells from the oxidative stress that results when too much free heme overloads cells with reactive oxygen species (ROS). They also showed that anopheline FLVCR is highly expressed after a mosquito gorges on blood.

If the mosquito bites an infected person, this blood will contain anywhere from 10,000 to 100,000 parasites, most of which are unable to reproduce, according to Dr. Quigley. Only 20-100 will be fertilized successfully and invade the midgut, but their fertilized eggs develop into Plasmodium cysts (or oocysts) that release thousands of parasites after maturing for 1-3 weeks in the mosquito gut. These offspring then travel to the mosquito’s salivary gland from which they are transmitted via the insect’s next bite.

"You are trying to kill the parasite ... the idea is to interfere with the invasion of the gut epithelium," Dr. Quigley said, characterizing the blood drinking as "a major bottleneck" and "the weakest point" in the process.

The researchers so far have developed an antibody "that appears to bind (and likely inhibit) FLVCR in vivo." They also have used gene-silencing techniques to "knock down" FLVCR gene expression. The next step will be to analyze the effects on parasite transmission, and if those show FLVCR is required, develop a vaccine to block transmission. If this is successful, the mosquito would no longer be a womb but a tomb for Plasmodium.

"Disruption of FLVCR function may be an ‘Achilles heel’ of blood-eating disease vectors," Dr. Quigley said.

Such a vaccine could have a major impact on public health globally, commented Dr. Alexis Thompson, who moderated a press briefing on the research. Malaria infects 250 million people, causing 1 million deaths annually, noted Dr. Thompson, director of hematology services at Children’s Memorial Hospital, Chicago.

"This is a global problem that the United States really has an opportunity to contribute to solving," she said. Even in the United States, she added, despite widespread belief that draining swamps in Florida and Louisiana eliminated malaria, a small number of cases are seen each year.

The authors said they had no relevant conflicts to disclose.

ORLANDO – Stopping the cycle by which the Plasmodium parasite spreads from people to mosquitoes and back to people could be the key to controlling malaria, according to scientists who have developed what may be a strategy for doing just that.

Dr. John G. Quigley and his coinvestigators are targeting a protein called FLVCR that mosquitoes express after feasting on blood. FLVCR protects cells from the toxicity of excess heme, or iron, a part of hemoglobin that binds and transports oxygen in red blood cells.

The ongoing study aims to induce oxidative stress in the midgut of malaria-transmitting mosquitoes by inhibiting the heme-exporting function of FLVCR. As a consequence, the midgut should become inhospitable to the blood-borne parasite, causing it to die instead of reproducing, Dr. Quigley explained in a plenary presentation at the annual meeting of the American Society of Hematology.

Ultimately, the goal is to create an FLVCR-suppressing vaccine for use in humans in areas where malaria is widespread, he said. The vaccine would not protect the person who is already infected, but it would break the cycle of transmission if that person is bitten by a mosquito.

"It’s called the altruistic vaccine because it’s not actually protecting you, but it is preventing the mosquito from infecting the next person," Dr. Quigley of the University of Illinois at Chicago said in an interview.

FLVCR – an abbreviation for feline leukemia virus subgroup C receptor – was initially isolated as a cause of severe anemia in cats, he said. Working with two common malaria-transmitting mosquitoes (Anopheles gambiae and A. stephensi), the Chicago-based group of scientists at the University of Illinois and Loyola University isolated the gene encoding mosquito FLVCR proteins.

The researchers conducted a series of studies, verifying that the proteins export heme and could protect cells from the oxidative stress that results when too much free heme overloads cells with reactive oxygen species (ROS). They also showed that anopheline FLVCR is highly expressed after a mosquito gorges on blood.

If the mosquito bites an infected person, this blood will contain anywhere from 10,000 to 100,000 parasites, most of which are unable to reproduce, according to Dr. Quigley. Only 20-100 will be fertilized successfully and invade the midgut, but their fertilized eggs develop into Plasmodium cysts (or oocysts) that release thousands of parasites after maturing for 1-3 weeks in the mosquito gut. These offspring then travel to the mosquito’s salivary gland from which they are transmitted via the insect’s next bite.

"You are trying to kill the parasite ... the idea is to interfere with the invasion of the gut epithelium," Dr. Quigley said, characterizing the blood drinking as "a major bottleneck" and "the weakest point" in the process.

The researchers so far have developed an antibody "that appears to bind (and likely inhibit) FLVCR in vivo." They also have used gene-silencing techniques to "knock down" FLVCR gene expression. The next step will be to analyze the effects on parasite transmission, and if those show FLVCR is required, develop a vaccine to block transmission. If this is successful, the mosquito would no longer be a womb but a tomb for Plasmodium.

"Disruption of FLVCR function may be an ‘Achilles heel’ of blood-eating disease vectors," Dr. Quigley said.

Such a vaccine could have a major impact on public health globally, commented Dr. Alexis Thompson, who moderated a press briefing on the research. Malaria infects 250 million people, causing 1 million deaths annually, noted Dr. Thompson, director of hematology services at Children’s Memorial Hospital, Chicago.

"This is a global problem that the United States really has an opportunity to contribute to solving," she said. Even in the United States, she added, despite widespread belief that draining swamps in Florida and Louisiana eliminated malaria, a small number of cases are seen each year.

The authors said they had no relevant conflicts to disclose.

ORLANDO – The novel oral drug ponatinib may provide a much-needed therapeutic option for patients who develop resistance to at least two approved therapies for Philadelphia chromosome-positive chronic myeloid leukemia, a study has shown.

Results from an open-label phase I dose-escalation trial show major cytogenetic response rates as high as 66% in this heavily pretreated population.

In addition, all 11 patients with the dreaded T315I mutation that responds to none of the approved therapies had complete hematologic responses with ponatinib (also known as AP24534), and 9 had had a major cytogenetic response (8 of which were complete). The T315I subgroup included patients with other Philadelphia-positive (Ph+) blood cancers.

The trial followed laboratory studies that demonstrated ponatinib, a multitargeted tyrosine kinase inhibitor, can eliminate cells with "this very tough mutation" in the test tube, the lead author, Dr. Jorge Cortes, noted at a press briefing in advance of a presentation Dec. 6 at the annual meeting of the American Society of Hematology. The preclinical work also showed the new agent could prevent the emergence of cells with mutations that make them resistant to the existing CML drugs.

"So that made us think it could be a very valuable drug for these patients," said Dr. Cortes, professor of medicine at the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators enrolled 74 patients with refractory hematologic cancers in the trial, for which he reported data as of Oct. 15. The malignancies included acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), but the large majority of patients had Ph+ CML.

Nearly all (95%) of the Ph+ CML patients had experienced failures of more than two previous therapies, and 64%, more than three – these included imatinib (Gleevec, 96%); dasatinib (Sprycel, 89%); and nilotinib (Tasigna, 55%). All patients were assigned to daily doses of ponatinib in the trial, which identified the maximum tolerated dose as 45 mg/day. Men comprised just over half of the population, and the median age was 56 years (range, 26-85).

Among 55 evaluable patients, 38 had CML in the chronic phase. Of these, 36 (95%) had a complete hematologic response, and 25 (66%) had a major cytogenetic response; the latter included 20 (53%) patients with complete cytogenetic responses.

When 17 Ph+ patients were grouped together regardless of disease or stage of disease, 6 (35%) had a major hematologic response, and 4 (24%) had a major cytogenetic response, including 2 (12%) with a complete cytogenetic response.

The investigators projected that the sustained major cytogenetic response rate would be 78% at 1 year, with the median not yet reached.

Based on these results, Dr. Cortes announced that a phase II study called PACE has already been started to look at treating "all patients with Philadelphia-positive diseases in all stages of the disease."

At this point imatinib, dasatinib, and nilotinib have been approved as first- and second-line therapies for Ph+ CML, and at least two other drugs, bosutinib and omacetaxine mepesuccinate, are in development. Despite the success of the approved tyrosine kinase inhibitors, more drugs are needed, Dr. Cortes said, because they do not cure everyone.

"We need to recognize [that as good as] results so far are, we are not curing everybody," he said.

For physicians, the challenge will be to select the right drugs for each patient, he added in an interview. "We are going to have to be smart enough to learn how to integrate more of these options into treatment with algorithms to identify which patients are more likely to respond to one drug than another."

More drugs are needed, agreed Dr. Peter Emanuel, moderator of the press briefing, but the number and efficacy of drugs raises questions about which will continue to be used. "The burning question is whether imatinib will eventually become a historical drug," said Dr. Emanuel, director of the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences in Little Rock.

Dr. Cortes disclosed receiving funding from Ariad Pharmaceuticals, which sponsored the trial. Seven coauthors disclosed relationships with the company. In addition, several coauthors disclosed relationships with Novartis and other companies.

ORLANDO – The novel oral drug ponatinib may provide a much-needed therapeutic option for patients who develop resistance to at least two approved therapies for Philadelphia chromosome-positive chronic myeloid leukemia, a study has shown.

Results from an open-label phase I dose-escalation trial show major cytogenetic response rates as high as 66% in this heavily pretreated population.

In addition, all 11 patients with the dreaded T315I mutation that responds to none of the approved therapies had complete hematologic responses with ponatinib (also known as AP24534), and 9 had had a major cytogenetic response (8 of which were complete). The T315I subgroup included patients with other Philadelphia-positive (Ph+) blood cancers.

The trial followed laboratory studies that demonstrated ponatinib, a multitargeted tyrosine kinase inhibitor, can eliminate cells with "this very tough mutation" in the test tube, the lead author, Dr. Jorge Cortes, noted at a press briefing in advance of a presentation Dec. 6 at the annual meeting of the American Society of Hematology. The preclinical work also showed the new agent could prevent the emergence of cells with mutations that make them resistant to the existing CML drugs.

"So that made us think it could be a very valuable drug for these patients," said Dr. Cortes, professor of medicine at the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators enrolled 74 patients with refractory hematologic cancers in the trial, for which he reported data as of Oct. 15. The malignancies included acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), but the large majority of patients had Ph+ CML.

Nearly all (95%) of the Ph+ CML patients had experienced failures of more than two previous therapies, and 64%, more than three – these included imatinib (Gleevec, 96%); dasatinib (Sprycel, 89%); and nilotinib (Tasigna, 55%). All patients were assigned to daily doses of ponatinib in the trial, which identified the maximum tolerated dose as 45 mg/day. Men comprised just over half of the population, and the median age was 56 years (range, 26-85).

Among 55 evaluable patients, 38 had CML in the chronic phase. Of these, 36 (95%) had a complete hematologic response, and 25 (66%) had a major cytogenetic response; the latter included 20 (53%) patients with complete cytogenetic responses.

When 17 Ph+ patients were grouped together regardless of disease or stage of disease, 6 (35%) had a major hematologic response, and 4 (24%) had a major cytogenetic response, including 2 (12%) with a complete cytogenetic response.

The investigators projected that the sustained major cytogenetic response rate would be 78% at 1 year, with the median not yet reached.

Based on these results, Dr. Cortes announced that a phase II study called PACE has already been started to look at treating "all patients with Philadelphia-positive diseases in all stages of the disease."

At this point imatinib, dasatinib, and nilotinib have been approved as first- and second-line therapies for Ph+ CML, and at least two other drugs, bosutinib and omacetaxine mepesuccinate, are in development. Despite the success of the approved tyrosine kinase inhibitors, more drugs are needed, Dr. Cortes said, because they do not cure everyone.

"We need to recognize [that as good as] results so far are, we are not curing everybody," he said.

For physicians, the challenge will be to select the right drugs for each patient, he added in an interview. "We are going to have to be smart enough to learn how to integrate more of these options into treatment with algorithms to identify which patients are more likely to respond to one drug than another."

More drugs are needed, agreed Dr. Peter Emanuel, moderator of the press briefing, but the number and efficacy of drugs raises questions about which will continue to be used. "The burning question is whether imatinib will eventually become a historical drug," said Dr. Emanuel, director of the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences in Little Rock.

Dr. Cortes disclosed receiving funding from Ariad Pharmaceuticals, which sponsored the trial. Seven coauthors disclosed relationships with the company. In addition, several coauthors disclosed relationships with Novartis and other companies.

ORLANDO – The novel oral drug ponatinib may provide a much-needed therapeutic option for patients who develop resistance to at least two approved therapies for Philadelphia chromosome-positive chronic myeloid leukemia, a study has shown.

Results from an open-label phase I dose-escalation trial show major cytogenetic response rates as high as 66% in this heavily pretreated population.

In addition, all 11 patients with the dreaded T315I mutation that responds to none of the approved therapies had complete hematologic responses with ponatinib (also known as AP24534), and 9 had had a major cytogenetic response (8 of which were complete). The T315I subgroup included patients with other Philadelphia-positive (Ph+) blood cancers.

The trial followed laboratory studies that demonstrated ponatinib, a multitargeted tyrosine kinase inhibitor, can eliminate cells with "this very tough mutation" in the test tube, the lead author, Dr. Jorge Cortes, noted at a press briefing in advance of a presentation Dec. 6 at the annual meeting of the American Society of Hematology. The preclinical work also showed the new agent could prevent the emergence of cells with mutations that make them resistant to the existing CML drugs.

"So that made us think it could be a very valuable drug for these patients," said Dr. Cortes, professor of medicine at the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators enrolled 74 patients with refractory hematologic cancers in the trial, for which he reported data as of Oct. 15. The malignancies included acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), but the large majority of patients had Ph+ CML.

Nearly all (95%) of the Ph+ CML patients had experienced failures of more than two previous therapies, and 64%, more than three – these included imatinib (Gleevec, 96%); dasatinib (Sprycel, 89%); and nilotinib (Tasigna, 55%). All patients were assigned to daily doses of ponatinib in the trial, which identified the maximum tolerated dose as 45 mg/day. Men comprised just over half of the population, and the median age was 56 years (range, 26-85).

Among 55 evaluable patients, 38 had CML in the chronic phase. Of these, 36 (95%) had a complete hematologic response, and 25 (66%) had a major cytogenetic response; the latter included 20 (53%) patients with complete cytogenetic responses.

When 17 Ph+ patients were grouped together regardless of disease or stage of disease, 6 (35%) had a major hematologic response, and 4 (24%) had a major cytogenetic response, including 2 (12%) with a complete cytogenetic response.

The investigators projected that the sustained major cytogenetic response rate would be 78% at 1 year, with the median not yet reached.

Based on these results, Dr. Cortes announced that a phase II study called PACE has already been started to look at treating "all patients with Philadelphia-positive diseases in all stages of the disease."

At this point imatinib, dasatinib, and nilotinib have been approved as first- and second-line therapies for Ph+ CML, and at least two other drugs, bosutinib and omacetaxine mepesuccinate, are in development. Despite the success of the approved tyrosine kinase inhibitors, more drugs are needed, Dr. Cortes said, because they do not cure everyone.

"We need to recognize [that as good as] results so far are, we are not curing everybody," he said.

For physicians, the challenge will be to select the right drugs for each patient, he added in an interview. "We are going to have to be smart enough to learn how to integrate more of these options into treatment with algorithms to identify which patients are more likely to respond to one drug than another."

More drugs are needed, agreed Dr. Peter Emanuel, moderator of the press briefing, but the number and efficacy of drugs raises questions about which will continue to be used. "The burning question is whether imatinib will eventually become a historical drug," said Dr. Emanuel, director of the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences in Little Rock.

Dr. Cortes disclosed receiving funding from Ariad Pharmaceuticals, which sponsored the trial. Seven coauthors disclosed relationships with the company. In addition, several coauthors disclosed relationships with Novartis and other companies.

Oncologists have a new Food and Drug Administration–approved option, eribulin mesylate, for patients with metastatic breast cancer that has stopped responding to at least two chemotherapy regimens for early- or late-stage disease.

An injectable microtubule inhibitor, eribulin is a synthetic version of a compound derived from the sea sponge Halichondria okadai. It will be marketed as Halaven by Eisai Inc., a Japanese-owned company based in Woodcliff Lake, N.J.

Before eribulin is introduced, patients should have been treated with taxane- and anthracycline-based regimens, according to the FDA announcement. The agency skipped review by its Oncologic Drugs Advisory Committee, after the new drug proved superior to other single-drug regimens in a company-sponsored phase III clinical trial presented at the American Society of Clinical Oncology’s annual meeting earlier this year.

"There are limited treatment options for women with aggressive forms of late-stage breast cancer who have already received other therapies," said Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, in the FDA statement. "Halaven shows a clear survival benefit and is an important new option for women."

In the EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus Eribulin) trial, eribulin therapy extended overall survival from 10.65 months in a control arm to 13.12 months (P = .041). Eribulin 1.4 mg/m2 was administered on days 1 and 8 every 21 days.

Women in the control group received single-agent treatments chosen by their physicians. Vinorelbine was the most frequent choice, followed by gemcitabine, capecitabine, taxanes, and anthracyclines, Dr. Christopher Twelves, a professor at the University of Leeds in the United Kingdom, reported at the ASCO meeting. The overall response rate was 12.2% for eribulin vs. 4.7% for physician’s choice, he said.

Dr. Twelves described eribulin’s safety profile as consistent with phase II trial data, showing an increase in grade 3 or 4 neutropenia (21% grade 3, 24% grade 4), febrile neutropenia (3%, 1%), fatigue (8%, 0.6%), and neuropathy (7.8%, 0.4%).

According to the FDA announcement, the most common side effects reported by women treated with eribulin include neutropenia, anemia, leukopenia, alopecia, fatigue, nausea, asthenia, peripheral neuropathy, and constipation.

Eisai has announced that eribulin should be available in the United States within 10 business days after approval. In addition, the company said it has applied for approvals in the treatment of metastatic breast cancer in Japan, the European Union, Switzerland, and Singapore.

Oncologists have a new Food and Drug Administration–approved option, eribulin mesylate, for patients with metastatic breast cancer that has stopped responding to at least two chemotherapy regimens for early- or late-stage disease.

An injectable microtubule inhibitor, eribulin is a synthetic version of a compound derived from the sea sponge Halichondria okadai. It will be marketed as Halaven by Eisai Inc., a Japanese-owned company based in Woodcliff Lake, N.J.

Before eribulin is introduced, patients should have been treated with taxane- and anthracycline-based regimens, according to the FDA announcement. The agency skipped review by its Oncologic Drugs Advisory Committee, after the new drug proved superior to other single-drug regimens in a company-sponsored phase III clinical trial presented at the American Society of Clinical Oncology’s annual meeting earlier this year.

"There are limited treatment options for women with aggressive forms of late-stage breast cancer who have already received other therapies," said Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, in the FDA statement. "Halaven shows a clear survival benefit and is an important new option for women."

In the EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus Eribulin) trial, eribulin therapy extended overall survival from 10.65 months in a control arm to 13.12 months (P = .041). Eribulin 1.4 mg/m2 was administered on days 1 and 8 every 21 days.

Women in the control group received single-agent treatments chosen by their physicians. Vinorelbine was the most frequent choice, followed by gemcitabine, capecitabine, taxanes, and anthracyclines, Dr. Christopher Twelves, a professor at the University of Leeds in the United Kingdom, reported at the ASCO meeting. The overall response rate was 12.2% for eribulin vs. 4.7% for physician’s choice, he said.

Dr. Twelves described eribulin’s safety profile as consistent with phase II trial data, showing an increase in grade 3 or 4 neutropenia (21% grade 3, 24% grade 4), febrile neutropenia (3%, 1%), fatigue (8%, 0.6%), and neuropathy (7.8%, 0.4%).

According to the FDA announcement, the most common side effects reported by women treated with eribulin include neutropenia, anemia, leukopenia, alopecia, fatigue, nausea, asthenia, peripheral neuropathy, and constipation.

Eisai has announced that eribulin should be available in the United States within 10 business days after approval. In addition, the company said it has applied for approvals in the treatment of metastatic breast cancer in Japan, the European Union, Switzerland, and Singapore.

Oncologists have a new Food and Drug Administration–approved option, eribulin mesylate, for patients with metastatic breast cancer that has stopped responding to at least two chemotherapy regimens for early- or late-stage disease.

An injectable microtubule inhibitor, eribulin is a synthetic version of a compound derived from the sea sponge Halichondria okadai. It will be marketed as Halaven by Eisai Inc., a Japanese-owned company based in Woodcliff Lake, N.J.

Before eribulin is introduced, patients should have been treated with taxane- and anthracycline-based regimens, according to the FDA announcement. The agency skipped review by its Oncologic Drugs Advisory Committee, after the new drug proved superior to other single-drug regimens in a company-sponsored phase III clinical trial presented at the American Society of Clinical Oncology’s annual meeting earlier this year.

"There are limited treatment options for women with aggressive forms of late-stage breast cancer who have already received other therapies," said Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, in the FDA statement. "Halaven shows a clear survival benefit and is an important new option for women."

In the EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus Eribulin) trial, eribulin therapy extended overall survival from 10.65 months in a control arm to 13.12 months (P = .041). Eribulin 1.4 mg/m2 was administered on days 1 and 8 every 21 days.

Women in the control group received single-agent treatments chosen by their physicians. Vinorelbine was the most frequent choice, followed by gemcitabine, capecitabine, taxanes, and anthracyclines, Dr. Christopher Twelves, a professor at the University of Leeds in the United Kingdom, reported at the ASCO meeting. The overall response rate was 12.2% for eribulin vs. 4.7% for physician’s choice, he said.

Dr. Twelves described eribulin’s safety profile as consistent with phase II trial data, showing an increase in grade 3 or 4 neutropenia (21% grade 3, 24% grade 4), febrile neutropenia (3%, 1%), fatigue (8%, 0.6%), and neuropathy (7.8%, 0.4%).

According to the FDA announcement, the most common side effects reported by women treated with eribulin include neutropenia, anemia, leukopenia, alopecia, fatigue, nausea, asthenia, peripheral neuropathy, and constipation.

Eisai has announced that eribulin should be available in the United States within 10 business days after approval. In addition, the company said it has applied for approvals in the treatment of metastatic breast cancer in Japan, the European Union, Switzerland, and Singapore.

Trastuzumab-DM1 produced higher response rates with less toxicity than did a combination of trastuzumab and docetaxel in the first randomized trial of the novel agent as first-line therapy for metastatic HER2-positive breast cancer.

At a median six months’ follow-up, overall response rates were 48% in the trastuzumab-DM1 (T-DM1) arm and 41% in the trastuzumab (Herceptin) – docetaxel (Taxotere) arm of the open-label phase II trial. Three of 67 women treated with the novel drug had complete responses, compared with 1 of 70 women given trastuzumab and docetaxel.

Serious adverse events of grade 3 or higher in the T-DM1 arm were about half as frequent with T-DM1 as in the control arm (37% vs. 75%), but 1 treatment-related death was reported in the experimental arm. The most common adverse events were nausea, fatigue, and pyrexia in women treated with T-DM1.

Dr. Edith Perez of the Mayo Clinic in Jacksonville, Fla. will report the preliminary data Oct. 11 in Milan at the annual meeting of the European Society for Clinical Oncology. A professor of medicine at the Mayo Medical School, she is principal investigator of the ongoing study. A larger three-armed phase III trial called MARIANNE is comparing T-DM1 monotherapy to trastuzumab plus a taxane and to T-DM1 plus pertuzumab, which also targets HER2.

The Food and Drug Administration recently refused a request from Roche to fast-track T-DM1 based on positive single-arm studies. Although the women in those studies had been heavily pretreated, the agency said they had not exhausted all options.

T-DM1 combines two lines of attack in one agent: the anti-HER2 activity of trastuzumab, a monoclonal antibody, with the targeted intracellular delivery of DM1, a potent antimicrotubule agent. The DM1 component is licensed by ImmunoGen, Inc.

In a press statement, Dr. Fabrice Andr? from Institut Gustave Roussy in Villejuif, France, described the results to be reported by Dr. Perez as important for two reasons.

“Firstly, they confirm that in coming years chemotherapy could be replaced by a less toxic compound .... These results suggest that, with the same efficacy, T-DM1 could dramatically reduce the toxicities related to chemotherapy."”

Secondly, Dr. Andr? observed that the study offers proof of concept for the linking of a monoclonal antibody to a cytotoxic drug in an anti-cancer therapy. “This could have several implications beyond drugs that target HER2,” Dr Andr? said.

Dr. Perez declared no conflicts of interest. Several of her coauthors disclosed receiving research support from Roche/Genentech and three identified themselves as employees and stockholders of Roche.☐

Trastuzumab-DM1 produced higher response rates with less toxicity than did a combination of trastuzumab and docetaxel in the first randomized trial of the novel agent as first-line therapy for metastatic HER2-positive breast cancer.

At a median six months’ follow-up, overall response rates were 48% in the trastuzumab-DM1 (T-DM1) arm and 41% in the trastuzumab (Herceptin) – docetaxel (Taxotere) arm of the open-label phase II trial. Three of 67 women treated with the novel drug had complete responses, compared with 1 of 70 women given trastuzumab and docetaxel.

Serious adverse events of grade 3 or higher in the T-DM1 arm were about half as frequent with T-DM1 as in the control arm (37% vs. 75%), but 1 treatment-related death was reported in the experimental arm. The most common adverse events were nausea, fatigue, and pyrexia in women treated with T-DM1.

Dr. Edith Perez of the Mayo Clinic in Jacksonville, Fla. will report the preliminary data Oct. 11 in Milan at the annual meeting of the European Society for Clinical Oncology. A professor of medicine at the Mayo Medical School, she is principal investigator of the ongoing study. A larger three-armed phase III trial called MARIANNE is comparing T-DM1 monotherapy to trastuzumab plus a taxane and to T-DM1 plus pertuzumab, which also targets HER2.

The Food and Drug Administration recently refused a request from Roche to fast-track T-DM1 based on positive single-arm studies. Although the women in those studies had been heavily pretreated, the agency said they had not exhausted all options.

T-DM1 combines two lines of attack in one agent: the anti-HER2 activity of trastuzumab, a monoclonal antibody, with the targeted intracellular delivery of DM1, a potent antimicrotubule agent. The DM1 component is licensed by ImmunoGen, Inc.

In a press statement, Dr. Fabrice Andr? from Institut Gustave Roussy in Villejuif, France, described the results to be reported by Dr. Perez as important for two reasons.

“Firstly, they confirm that in coming years chemotherapy could be replaced by a less toxic compound .... These results suggest that, with the same efficacy, T-DM1 could dramatically reduce the toxicities related to chemotherapy."”

Secondly, Dr. Andr? observed that the study offers proof of concept for the linking of a monoclonal antibody to a cytotoxic drug in an anti-cancer therapy. “This could have several implications beyond drugs that target HER2,” Dr Andr? said.

Dr. Perez declared no conflicts of interest. Several of her coauthors disclosed receiving research support from Roche/Genentech and three identified themselves as employees and stockholders of Roche.☐

Trastuzumab-DM1 produced higher response rates with less toxicity than did a combination of trastuzumab and docetaxel in the first randomized trial of the novel agent as first-line therapy for metastatic HER2-positive breast cancer.

At a median six months’ follow-up, overall response rates were 48% in the trastuzumab-DM1 (T-DM1) arm and 41% in the trastuzumab (Herceptin) – docetaxel (Taxotere) arm of the open-label phase II trial. Three of 67 women treated with the novel drug had complete responses, compared with 1 of 70 women given trastuzumab and docetaxel.

Serious adverse events of grade 3 or higher in the T-DM1 arm were about half as frequent with T-DM1 as in the control arm (37% vs. 75%), but 1 treatment-related death was reported in the experimental arm. The most common adverse events were nausea, fatigue, and pyrexia in women treated with T-DM1.

Dr. Edith Perez of the Mayo Clinic in Jacksonville, Fla. will report the preliminary data Oct. 11 in Milan at the annual meeting of the European Society for Clinical Oncology. A professor of medicine at the Mayo Medical School, she is principal investigator of the ongoing study. A larger three-armed phase III trial called MARIANNE is comparing T-DM1 monotherapy to trastuzumab plus a taxane and to T-DM1 plus pertuzumab, which also targets HER2.

The Food and Drug Administration recently refused a request from Roche to fast-track T-DM1 based on positive single-arm studies. Although the women in those studies had been heavily pretreated, the agency said they had not exhausted all options.

T-DM1 combines two lines of attack in one agent: the anti-HER2 activity of trastuzumab, a monoclonal antibody, with the targeted intracellular delivery of DM1, a potent antimicrotubule agent. The DM1 component is licensed by ImmunoGen, Inc.

In a press statement, Dr. Fabrice Andr? from Institut Gustave Roussy in Villejuif, France, described the results to be reported by Dr. Perez as important for two reasons.

“Firstly, they confirm that in coming years chemotherapy could be replaced by a less toxic compound .... These results suggest that, with the same efficacy, T-DM1 could dramatically reduce the toxicities related to chemotherapy."”

Secondly, Dr. Andr? observed that the study offers proof of concept for the linking of a monoclonal antibody to a cytotoxic drug in an anti-cancer therapy. “This could have several implications beyond drugs that target HER2,” Dr Andr? said.

Dr. Perez declared no conflicts of interest. Several of her coauthors disclosed receiving research support from Roche/Genentech and three identified themselves as employees and stockholders of Roche.☐

Trabedersen, a novel TGF-beta 2 inhibitor, performed well when compared with standard chemotherapy for high-grade gliomas in a phase IIb trial that enrolled 145 patients with recurrent or refractory stage III or IV disease.

Patients with anaplastic astrocytomas had the best results, Dr. Piotr Jachimczak said in a telephone call from Germany to a press briefing at the meeting in Washington, where the data were presented.

Younger patients with glioblastoma also fared better than controls treated with temozolomide or vincristine, said Dr. Jachimczak, senior scientific adviser at Antisense Pharma, the drug's developer, in Regensburg. Other study investigators also are employees of the company.

Trabedersen has orphan drug status in the United States and Europe for glioma, a brain tumor that often overexpresses TGF-beta 2. A phosphorothioate antisense oligonucleotide, the drug is administered intra-tumorally via convection-enhanced delivery. This enables trabedersen to cross the blood-brain barrier, Dr. Jachimczak said.

Patients in the study received trabedersen in 10 mcM or 80 mcM doses 7 days on and 7 days off, for up to 11 cycles or standard therapy. The investigators reported the lower dose of trabedersen was “superior in efficacy and safety.”

Among patients with anaplastic astrocytomas, the survival rate at 24 months was 83.3% with the low dose, 53.3% with the high dose, and 41.7% with standard therapy. Responses lasted about 3 times longer in the low-dose cohort than in the standard chemotherapy group: 29.1 months vs. 8.0 months. Both trabedersen groups had better median overall survival than the control group, with the benefit in the low-dose group reported as a gain of 17.4 months.

The overall benefit in glioblastoma patients was described as being “as efficacious as standard chemotherapy.” In a prespecified subgroup of patients who were less than 55 years of age and had Karnofsky performance scores of less than 80%; however, trabedersen-treated patients had a 2-year survival rate of 40% vs. 13.3% with standard chemotherapy.

Investigators are enrolling glioma patients for a randomized, multinational phase III trial of trabedersen called the SAPPHIRE study.

My Take

Astrocytoma Results Are 'Encouraging'

Previous attempts to cross the blood-brain barrier by infusing therapeutic agents into the tumor and the surrounding brain using convection enhanced delivery have been largely unsuccessful. However, this study with trabedersen, administered by convection-enhanced delivery, suggests that this approach may have promise. Repeated administration was feasible and appeared to be safe. Trabedersen had only modest activity in patients with glioblastomas but the results with anaplastic astrocytomas (AAs) were encouraging. The significant increase in survival for patients with AA treated with trabedersen, compared with standard chemotherapy, is striking. Nonetheless, the results must be interpreted with caution because of the small numbers of patients in each group (less than 20), and the possibility of selection bias.

PATRICK Y. WEN, M.D., is director of the Center for Neuro-Oncology at the Dana-Farber/Brigham and Women's Cancer Center, Boston.

Trabedersen, a novel TGF-beta 2 inhibitor, performed well when compared with standard chemotherapy for high-grade gliomas in a phase IIb trial that enrolled 145 patients with recurrent or refractory stage III or IV disease.

Patients with anaplastic astrocytomas had the best results, Dr. Piotr Jachimczak said in a telephone call from Germany to a press briefing at the meeting in Washington, where the data were presented.

Younger patients with glioblastoma also fared better than controls treated with temozolomide or vincristine, said Dr. Jachimczak, senior scientific adviser at Antisense Pharma, the drug's developer, in Regensburg. Other study investigators also are employees of the company.

Trabedersen has orphan drug status in the United States and Europe for glioma, a brain tumor that often overexpresses TGF-beta 2. A phosphorothioate antisense oligonucleotide, the drug is administered intra-tumorally via convection-enhanced delivery. This enables trabedersen to cross the blood-brain barrier, Dr. Jachimczak said.

Patients in the study received trabedersen in 10 mcM or 80 mcM doses 7 days on and 7 days off, for up to 11 cycles or standard therapy. The investigators reported the lower dose of trabedersen was “superior in efficacy and safety.”

Among patients with anaplastic astrocytomas, the survival rate at 24 months was 83.3% with the low dose, 53.3% with the high dose, and 41.7% with standard therapy. Responses lasted about 3 times longer in the low-dose cohort than in the standard chemotherapy group: 29.1 months vs. 8.0 months. Both trabedersen groups had better median overall survival than the control group, with the benefit in the low-dose group reported as a gain of 17.4 months.

The overall benefit in glioblastoma patients was described as being “as efficacious as standard chemotherapy.” In a prespecified subgroup of patients who were less than 55 years of age and had Karnofsky performance scores of less than 80%; however, trabedersen-treated patients had a 2-year survival rate of 40% vs. 13.3% with standard chemotherapy.

Investigators are enrolling glioma patients for a randomized, multinational phase III trial of trabedersen called the SAPPHIRE study.

My Take

Astrocytoma Results Are 'Encouraging'

Previous attempts to cross the blood-brain barrier by infusing therapeutic agents into the tumor and the surrounding brain using convection enhanced delivery have been largely unsuccessful. However, this study with trabedersen, administered by convection-enhanced delivery, suggests that this approach may have promise. Repeated administration was feasible and appeared to be safe. Trabedersen had only modest activity in patients with glioblastomas but the results with anaplastic astrocytomas (AAs) were encouraging. The significant increase in survival for patients with AA treated with trabedersen, compared with standard chemotherapy, is striking. Nonetheless, the results must be interpreted with caution because of the small numbers of patients in each group (less than 20), and the possibility of selection bias.

PATRICK Y. WEN, M.D., is director of the Center for Neuro-Oncology at the Dana-Farber/Brigham and Women's Cancer Center, Boston.

Trabedersen, a novel TGF-beta 2 inhibitor, performed well when compared with standard chemotherapy for high-grade gliomas in a phase IIb trial that enrolled 145 patients with recurrent or refractory stage III or IV disease.

Patients with anaplastic astrocytomas had the best results, Dr. Piotr Jachimczak said in a telephone call from Germany to a press briefing at the meeting in Washington, where the data were presented.

Younger patients with glioblastoma also fared better than controls treated with temozolomide or vincristine, said Dr. Jachimczak, senior scientific adviser at Antisense Pharma, the drug's developer, in Regensburg. Other study investigators also are employees of the company.

Trabedersen has orphan drug status in the United States and Europe for glioma, a brain tumor that often overexpresses TGF-beta 2. A phosphorothioate antisense oligonucleotide, the drug is administered intra-tumorally via convection-enhanced delivery. This enables trabedersen to cross the blood-brain barrier, Dr. Jachimczak said.

Patients in the study received trabedersen in 10 mcM or 80 mcM doses 7 days on and 7 days off, for up to 11 cycles or standard therapy. The investigators reported the lower dose of trabedersen was “superior in efficacy and safety.”

Among patients with anaplastic astrocytomas, the survival rate at 24 months was 83.3% with the low dose, 53.3% with the high dose, and 41.7% with standard therapy. Responses lasted about 3 times longer in the low-dose cohort than in the standard chemotherapy group: 29.1 months vs. 8.0 months. Both trabedersen groups had better median overall survival than the control group, with the benefit in the low-dose group reported as a gain of 17.4 months.

The overall benefit in glioblastoma patients was described as being “as efficacious as standard chemotherapy.” In a prespecified subgroup of patients who were less than 55 years of age and had Karnofsky performance scores of less than 80%; however, trabedersen-treated patients had a 2-year survival rate of 40% vs. 13.3% with standard chemotherapy.

Investigators are enrolling glioma patients for a randomized, multinational phase III trial of trabedersen called the SAPPHIRE study.

My Take

Astrocytoma Results Are 'Encouraging'

Previous attempts to cross the blood-brain barrier by infusing therapeutic agents into the tumor and the surrounding brain using convection enhanced delivery have been largely unsuccessful. However, this study with trabedersen, administered by convection-enhanced delivery, suggests that this approach may have promise. Repeated administration was feasible and appeared to be safe. Trabedersen had only modest activity in patients with glioblastomas but the results with anaplastic astrocytomas (AAs) were encouraging. The significant increase in survival for patients with AA treated with trabedersen, compared with standard chemotherapy, is striking. Nonetheless, the results must be interpreted with caution because of the small numbers of patients in each group (less than 20), and the possibility of selection bias.

PATRICK Y. WEN, M.D., is director of the Center for Neuro-Oncology at the Dana-Farber/Brigham and Women's Cancer Center, Boston.

CHICAGO — After a 30-year drought during which 70 randomized trials failed to improve outcomes in advanced melanoma, the first agent in a new class of drugs has prolonged survival of advanced, pretreated patients in a large international phase III clinical trial.

“This is the first time we have shown a survival benefit in metastatic melanoma,” Dr. Steven O'Day, the lead investigator, announced at the annual meeting of the American Society of Clinical Oncology.

The new agent, ipilimumab, is a monoclonal antibody targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a gene that limits the ability of T cells to attack cancerous cells.

Median overall survival reached 10.1 months in 137 patients whose only active treatment was ipilimumab and 10 months in 403 patients given ipilimumab with an experimental vaccine. It was 6.4 months in 136 patients who received the vaccine without ipilimumab'a length of time that falls within the 6–9 month life expectancy for patients with metastatic melanoma, according to Dr. O'Day, chief of research and director of the melanoma program at the Angeles Clinic and Research Institute in Los Angeles.

The difference between the study arms treated with ipilimumab and patients who received only the vaccine was highly significant with a hazard ratio of 0.68 (P = .0004).

The one-year survival rate was nearly twice as high in the ipilimumab arms (46% vs. 25%), as was the two-year rate (24% vs. 14%). Some long-term survivors continue to be followed 4.5 years after treatment.

Disease-control rates were also significantly higher in the two ipilimumab arms (28.5% with ipilimumab alone and 20.1% with ipilimumab plus vaccine vs. 11% with the vaccine alone). Best overall response rates likewise were higher (10.9% and 5.7%, respectively, vs. 1.5%).

Addition of the GP 100 peptide vaccine did not appear to improve outcomes, Dr. O'Day noted. The investigators chose it for the control arm because it had drawn responses in a previous trial, and there is no standard of care for these patients. Dacarbazine (DTIC) has long and often been used, but no randomized trial has ever proven it superior to best supportive care.

Disclosures included that the research funding was provided by Medarex and Bristol-Myers Squibb, which is developing ipilimumab.

CHICAGO — After a 30-year drought during which 70 randomized trials failed to improve outcomes in advanced melanoma, the first agent in a new class of drugs has prolonged survival of advanced, pretreated patients in a large international phase III clinical trial.

“This is the first time we have shown a survival benefit in metastatic melanoma,” Dr. Steven O'Day, the lead investigator, announced at the annual meeting of the American Society of Clinical Oncology.

The new agent, ipilimumab, is a monoclonal antibody targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a gene that limits the ability of T cells to attack cancerous cells.

Median overall survival reached 10.1 months in 137 patients whose only active treatment was ipilimumab and 10 months in 403 patients given ipilimumab with an experimental vaccine. It was 6.4 months in 136 patients who received the vaccine without ipilimumab'a length of time that falls within the 6–9 month life expectancy for patients with metastatic melanoma, according to Dr. O'Day, chief of research and director of the melanoma program at the Angeles Clinic and Research Institute in Los Angeles.

The difference between the study arms treated with ipilimumab and patients who received only the vaccine was highly significant with a hazard ratio of 0.68 (P = .0004).

The one-year survival rate was nearly twice as high in the ipilimumab arms (46% vs. 25%), as was the two-year rate (24% vs. 14%). Some long-term survivors continue to be followed 4.5 years after treatment.

Disease-control rates were also significantly higher in the two ipilimumab arms (28.5% with ipilimumab alone and 20.1% with ipilimumab plus vaccine vs. 11% with the vaccine alone). Best overall response rates likewise were higher (10.9% and 5.7%, respectively, vs. 1.5%).

Addition of the GP 100 peptide vaccine did not appear to improve outcomes, Dr. O'Day noted. The investigators chose it for the control arm because it had drawn responses in a previous trial, and there is no standard of care for these patients. Dacarbazine (DTIC) has long and often been used, but no randomized trial has ever proven it superior to best supportive care.

Disclosures included that the research funding was provided by Medarex and Bristol-Myers Squibb, which is developing ipilimumab.

CHICAGO — After a 30-year drought during which 70 randomized trials failed to improve outcomes in advanced melanoma, the first agent in a new class of drugs has prolonged survival of advanced, pretreated patients in a large international phase III clinical trial.

“This is the first time we have shown a survival benefit in metastatic melanoma,” Dr. Steven O'Day, the lead investigator, announced at the annual meeting of the American Society of Clinical Oncology.

The new agent, ipilimumab, is a monoclonal antibody targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a gene that limits the ability of T cells to attack cancerous cells.

Median overall survival reached 10.1 months in 137 patients whose only active treatment was ipilimumab and 10 months in 403 patients given ipilimumab with an experimental vaccine. It was 6.4 months in 136 patients who received the vaccine without ipilimumab'a length of time that falls within the 6–9 month life expectancy for patients with metastatic melanoma, according to Dr. O'Day, chief of research and director of the melanoma program at the Angeles Clinic and Research Institute in Los Angeles.

The difference between the study arms treated with ipilimumab and patients who received only the vaccine was highly significant with a hazard ratio of 0.68 (P = .0004).

The one-year survival rate was nearly twice as high in the ipilimumab arms (46% vs. 25%), as was the two-year rate (24% vs. 14%). Some long-term survivors continue to be followed 4.5 years after treatment.

Disease-control rates were also significantly higher in the two ipilimumab arms (28.5% with ipilimumab alone and 20.1% with ipilimumab plus vaccine vs. 11% with the vaccine alone). Best overall response rates likewise were higher (10.9% and 5.7%, respectively, vs. 1.5%).

Addition of the GP 100 peptide vaccine did not appear to improve outcomes, Dr. O'Day noted. The investigators chose it for the control arm because it had drawn responses in a previous trial, and there is no standard of care for these patients. Dacarbazine (DTIC) has long and often been used, but no randomized trial has ever proven it superior to best supportive care.

Disclosures included that the research funding was provided by Medarex and Bristol-Myers Squibb, which is developing ipilimumab.