Cellular Therapy

Early mortality after autologous hematopoietic stem cell transplantation (ASCT) for light-chain amyloidosis has declined dramatically in recent years, and 5-year survival is now deemed “excellent” at 77%, according to a report published online Sept. 14 in Journal of Clinical Oncology.

Light-chain amyloidosis results in deposition of insoluble amyloid fibers in many tissues, particularly the heart and kidneys, and can lead to organ failure and death. While medical therapies target the plasma cell clone that is the source of the amyloid, treatments have minimal effect on amyloid that has already accumulated in tissues. Alternatively, ASCT can produce durable hematologic responses and has resulted in improved function of affected organs, based on several single-center studies.

However, the only large, prospective randomized clinical trial to compare ASCT and medical therapy was done in 2007. That study showed autotransplantation carried a high (24%) early mortality, which contributed heavily to inferior overall survival, said Dr. Anita D’Souza of the division of hematology and oncology, Medical College of Wisconsin, Milwaukee, and her associates.

Since that study, supportive care during the peritransplantation period has greatly improved. Large U.S. transplant centers now report that early mortality is less than 5%.

©Nephron/Wikimedia Commons/CC BY-SA 3.0

To assess time trends in autotransplantation mortality, Dr. D’Souza and her associates analyzed data from the Center for International Blood & Marrow Transplant Research, a registry that collects transplant data from 320 centers worldwide and captures information concerning most U.S. procedures. They focused on 1,536 North American patients with light-chain amyloidosis who underwent ASCT during three successive 5-year periods: 1995-2000, 2001-2006, and 2007-2012. The median follow-up was 56 months.

Over time, 30-day mortality declined from 11% to 5% to 3%, respectively; and 100-day mortality declined from 20% to 11% to 5%. One-year overall survival rose from 75% to 85% to 90%, and 5-year overall survival improved from 55% to 61% to 77%.

Even among patients with renal amyloidosis, 3-year overall survival improved over time from 78% during the earliest study period to 89% during the most recent time period. However, mortality did not improve significantly over time among patients with cardiac involvement, which continues to be the single most-important variable associated with poor outcomes, the researchers said (J Clin Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4015]).

A transplant center’s experience with this procedure proved to be of crucial importance to early patient mortality. Centers that performed a low volume of ASCT for light-chain amyloidosis, defined as fewer than four transplants per year, had a 30-day mortality of 5% and a 100-day mortality of 7%, while centers that performed more than four procedures per year had significantly lower mortalities of 1% and 3%, respectively. There were no significant differences between low- and high-volume centers regarding patient, organ, or medication factors, which “led us to believe that high-volume centers do not necessarily select fitter patients for transplantation. Rather, they may be more experienced in supporting and treating these patients in the early posttransplantation period,” Dr. D’Souza and her associates said.

These “reassuring” findings, together with the recent development of novel plasma-cell–targeting agents such as bortezomib, suggest that it is time to consider performing a more current multicenter prospective study comparing autotransplantation against medical therapy, they added.

Early mortality after autologous hematopoietic stem cell transplantation (ASCT) for light-chain amyloidosis has declined dramatically in recent years, and 5-year survival is now deemed “excellent” at 77%, according to a report published online Sept. 14 in Journal of Clinical Oncology.

Light-chain amyloidosis results in deposition of insoluble amyloid fibers in many tissues, particularly the heart and kidneys, and can lead to organ failure and death. While medical therapies target the plasma cell clone that is the source of the amyloid, treatments have minimal effect on amyloid that has already accumulated in tissues. Alternatively, ASCT can produce durable hematologic responses and has resulted in improved function of affected organs, based on several single-center studies.

However, the only large, prospective randomized clinical trial to compare ASCT and medical therapy was done in 2007. That study showed autotransplantation carried a high (24%) early mortality, which contributed heavily to inferior overall survival, said Dr. Anita D’Souza of the division of hematology and oncology, Medical College of Wisconsin, Milwaukee, and her associates.

Since that study, supportive care during the peritransplantation period has greatly improved. Large U.S. transplant centers now report that early mortality is less than 5%.

©Nephron/Wikimedia Commons/CC BY-SA 3.0

To assess time trends in autotransplantation mortality, Dr. D’Souza and her associates analyzed data from the Center for International Blood & Marrow Transplant Research, a registry that collects transplant data from 320 centers worldwide and captures information concerning most U.S. procedures. They focused on 1,536 North American patients with light-chain amyloidosis who underwent ASCT during three successive 5-year periods: 1995-2000, 2001-2006, and 2007-2012. The median follow-up was 56 months.

Over time, 30-day mortality declined from 11% to 5% to 3%, respectively; and 100-day mortality declined from 20% to 11% to 5%. One-year overall survival rose from 75% to 85% to 90%, and 5-year overall survival improved from 55% to 61% to 77%.

Even among patients with renal amyloidosis, 3-year overall survival improved over time from 78% during the earliest study period to 89% during the most recent time period. However, mortality did not improve significantly over time among patients with cardiac involvement, which continues to be the single most-important variable associated with poor outcomes, the researchers said (J Clin Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4015]).

A transplant center’s experience with this procedure proved to be of crucial importance to early patient mortality. Centers that performed a low volume of ASCT for light-chain amyloidosis, defined as fewer than four transplants per year, had a 30-day mortality of 5% and a 100-day mortality of 7%, while centers that performed more than four procedures per year had significantly lower mortalities of 1% and 3%, respectively. There were no significant differences between low- and high-volume centers regarding patient, organ, or medication factors, which “led us to believe that high-volume centers do not necessarily select fitter patients for transplantation. Rather, they may be more experienced in supporting and treating these patients in the early posttransplantation period,” Dr. D’Souza and her associates said.

These “reassuring” findings, together with the recent development of novel plasma-cell–targeting agents such as bortezomib, suggest that it is time to consider performing a more current multicenter prospective study comparing autotransplantation against medical therapy, they added.

Early mortality after autologous hematopoietic stem cell transplantation (ASCT) for light-chain amyloidosis has declined dramatically in recent years, and 5-year survival is now deemed “excellent” at 77%, according to a report published online Sept. 14 in Journal of Clinical Oncology.

Light-chain amyloidosis results in deposition of insoluble amyloid fibers in many tissues, particularly the heart and kidneys, and can lead to organ failure and death. While medical therapies target the plasma cell clone that is the source of the amyloid, treatments have minimal effect on amyloid that has already accumulated in tissues. Alternatively, ASCT can produce durable hematologic responses and has resulted in improved function of affected organs, based on several single-center studies.

However, the only large, prospective randomized clinical trial to compare ASCT and medical therapy was done in 2007. That study showed autotransplantation carried a high (24%) early mortality, which contributed heavily to inferior overall survival, said Dr. Anita D’Souza of the division of hematology and oncology, Medical College of Wisconsin, Milwaukee, and her associates.

Since that study, supportive care during the peritransplantation period has greatly improved. Large U.S. transplant centers now report that early mortality is less than 5%.

©Nephron/Wikimedia Commons/CC BY-SA 3.0

To assess time trends in autotransplantation mortality, Dr. D’Souza and her associates analyzed data from the Center for International Blood & Marrow Transplant Research, a registry that collects transplant data from 320 centers worldwide and captures information concerning most U.S. procedures. They focused on 1,536 North American patients with light-chain amyloidosis who underwent ASCT during three successive 5-year periods: 1995-2000, 2001-2006, and 2007-2012. The median follow-up was 56 months.

Over time, 30-day mortality declined from 11% to 5% to 3%, respectively; and 100-day mortality declined from 20% to 11% to 5%. One-year overall survival rose from 75% to 85% to 90%, and 5-year overall survival improved from 55% to 61% to 77%.

Even among patients with renal amyloidosis, 3-year overall survival improved over time from 78% during the earliest study period to 89% during the most recent time period. However, mortality did not improve significantly over time among patients with cardiac involvement, which continues to be the single most-important variable associated with poor outcomes, the researchers said (J Clin Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4015]).

A transplant center’s experience with this procedure proved to be of crucial importance to early patient mortality. Centers that performed a low volume of ASCT for light-chain amyloidosis, defined as fewer than four transplants per year, had a 30-day mortality of 5% and a 100-day mortality of 7%, while centers that performed more than four procedures per year had significantly lower mortalities of 1% and 3%, respectively. There were no significant differences between low- and high-volume centers regarding patient, organ, or medication factors, which “led us to believe that high-volume centers do not necessarily select fitter patients for transplantation. Rather, they may be more experienced in supporting and treating these patients in the early posttransplantation period,” Dr. D’Souza and her associates said.

These “reassuring” findings, together with the recent development of novel plasma-cell–targeting agents such as bortezomib, suggest that it is time to consider performing a more current multicenter prospective study comparing autotransplantation against medical therapy, they added.

The first recipient of CTL019 for advanced refractory multiple myeloma achieved a durable complete response without developing cytokine release syndrome, according to a study published Sept. 9 in the New England Journal of Medicine.

“Twelve months after transplantation, the patient had no evidence of monoclonal immunoglobulin on serum and urine immunofixation and no clinical signs or symptoms of multiple myeloma,” said Dr. Alfred Garfall and his associates at the University of Pennsylvania in Philadelphia. “This response was achieved despite the absence of CD19 expression in 99.95% of the patient’s neoplastic plasma cells.”

Courtesy Wikimedia Commons/KGH/Creative Commons License

CTL019 consists of autologous T cells modified to express an anti-CD19 chimeric antigen receptor (CAR) from a lentiviral vector. The cell therapy has yielded promising results in relapsed/refractory CLL and ALL,but was overlooked in MM because it was thought to infrequently express CD19, the researchers said.

“Several reports, however, have suggested that a minor component of the MM clone with drug-resistant, disease-propagating properties has a B-cell (i.e., CD19-positive) phenotype,” they noted. “In addition, our unpublished observations suggest that neoplastic plasma cells express low levels of CD19” (N Engl J Med. 2015 Sep 9;373:1040-7).

In response, they designed a pilot trial of adults whose MM relapsed or progressed within a year after initial autologous stem cell transplant. The first participant, a 43-year-old woman with IgA kappa MM, partially responded to lenalidomide, bortezomib, and dexamethasone but progressed when therapy was paused to collect stem cells for transplant. She then partially responded to cisplatin, doxorubicin, cyclophosphamide, and etoposide followed by high-dose melphalan and ASCT, but progressed again and continued to worsen despite a total of nine lines of therapy. A bone marrow sample revealed more than 95% plasma cells when the patient began the CTL019 trial, the researchers said.

For the study, the patient received a lower melphalan dose (140 mg/m² of body surface area), followed by ASCT, CTL019 starting 2 weeks later, and maintenance lenalidomide. On day 100, her tumor burden had dropped by 5-log10, the researchers said. She also did not develop cytokine release syndrome, they added.

So far, 10 patients have been treated on study, of whom six remain progression free, according to the investigators. “The only additional CTL019-attributable toxic effects observed have been one instance of grade 1 cytokine release syndrome and one instance of grade 3 enterocolitis due to autologous graft-versus-host disease,” they reported.

Novartis supported the study and approved the manuscript. The work was also funded by the National Institutes of Health, the International Society for Advancement of Cytometry, the University of Pennsylvania Institute or Translational Medicine and Therapeutics, and a Conquer Cancer Foundation Young Investigator Award. The University of Pennsylvania has licensed technologies involved in this trial to Novartis. Several scientists involved in this trial hold patents for these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and these inventors have benefited financially or may benefit in the future.

The first recipient of CTL019 for advanced refractory multiple myeloma achieved a durable complete response without developing cytokine release syndrome, according to a study published Sept. 9 in the New England Journal of Medicine.

“Twelve months after transplantation, the patient had no evidence of monoclonal immunoglobulin on serum and urine immunofixation and no clinical signs or symptoms of multiple myeloma,” said Dr. Alfred Garfall and his associates at the University of Pennsylvania in Philadelphia. “This response was achieved despite the absence of CD19 expression in 99.95% of the patient’s neoplastic plasma cells.”

Courtesy Wikimedia Commons/KGH/Creative Commons License

CTL019 consists of autologous T cells modified to express an anti-CD19 chimeric antigen receptor (CAR) from a lentiviral vector. The cell therapy has yielded promising results in relapsed/refractory CLL and ALL,but was overlooked in MM because it was thought to infrequently express CD19, the researchers said.

“Several reports, however, have suggested that a minor component of the MM clone with drug-resistant, disease-propagating properties has a B-cell (i.e., CD19-positive) phenotype,” they noted. “In addition, our unpublished observations suggest that neoplastic plasma cells express low levels of CD19” (N Engl J Med. 2015 Sep 9;373:1040-7).

In response, they designed a pilot trial of adults whose MM relapsed or progressed within a year after initial autologous stem cell transplant. The first participant, a 43-year-old woman with IgA kappa MM, partially responded to lenalidomide, bortezomib, and dexamethasone but progressed when therapy was paused to collect stem cells for transplant. She then partially responded to cisplatin, doxorubicin, cyclophosphamide, and etoposide followed by high-dose melphalan and ASCT, but progressed again and continued to worsen despite a total of nine lines of therapy. A bone marrow sample revealed more than 95% plasma cells when the patient began the CTL019 trial, the researchers said.

For the study, the patient received a lower melphalan dose (140 mg/m² of body surface area), followed by ASCT, CTL019 starting 2 weeks later, and maintenance lenalidomide. On day 100, her tumor burden had dropped by 5-log10, the researchers said. She also did not develop cytokine release syndrome, they added.

So far, 10 patients have been treated on study, of whom six remain progression free, according to the investigators. “The only additional CTL019-attributable toxic effects observed have been one instance of grade 1 cytokine release syndrome and one instance of grade 3 enterocolitis due to autologous graft-versus-host disease,” they reported.

Novartis supported the study and approved the manuscript. The work was also funded by the National Institutes of Health, the International Society for Advancement of Cytometry, the University of Pennsylvania Institute or Translational Medicine and Therapeutics, and a Conquer Cancer Foundation Young Investigator Award. The University of Pennsylvania has licensed technologies involved in this trial to Novartis. Several scientists involved in this trial hold patents for these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and these inventors have benefited financially or may benefit in the future.

The first recipient of CTL019 for advanced refractory multiple myeloma achieved a durable complete response without developing cytokine release syndrome, according to a study published Sept. 9 in the New England Journal of Medicine.

“Twelve months after transplantation, the patient had no evidence of monoclonal immunoglobulin on serum and urine immunofixation and no clinical signs or symptoms of multiple myeloma,” said Dr. Alfred Garfall and his associates at the University of Pennsylvania in Philadelphia. “This response was achieved despite the absence of CD19 expression in 99.95% of the patient’s neoplastic plasma cells.”

Courtesy Wikimedia Commons/KGH/Creative Commons License

CTL019 consists of autologous T cells modified to express an anti-CD19 chimeric antigen receptor (CAR) from a lentiviral vector. The cell therapy has yielded promising results in relapsed/refractory CLL and ALL,but was overlooked in MM because it was thought to infrequently express CD19, the researchers said.

“Several reports, however, have suggested that a minor component of the MM clone with drug-resistant, disease-propagating properties has a B-cell (i.e., CD19-positive) phenotype,” they noted. “In addition, our unpublished observations suggest that neoplastic plasma cells express low levels of CD19” (N Engl J Med. 2015 Sep 9;373:1040-7).

In response, they designed a pilot trial of adults whose MM relapsed or progressed within a year after initial autologous stem cell transplant. The first participant, a 43-year-old woman with IgA kappa MM, partially responded to lenalidomide, bortezomib, and dexamethasone but progressed when therapy was paused to collect stem cells for transplant. She then partially responded to cisplatin, doxorubicin, cyclophosphamide, and etoposide followed by high-dose melphalan and ASCT, but progressed again and continued to worsen despite a total of nine lines of therapy. A bone marrow sample revealed more than 95% plasma cells when the patient began the CTL019 trial, the researchers said.

For the study, the patient received a lower melphalan dose (140 mg/m² of body surface area), followed by ASCT, CTL019 starting 2 weeks later, and maintenance lenalidomide. On day 100, her tumor burden had dropped by 5-log10, the researchers said. She also did not develop cytokine release syndrome, they added.

So far, 10 patients have been treated on study, of whom six remain progression free, according to the investigators. “The only additional CTL019-attributable toxic effects observed have been one instance of grade 1 cytokine release syndrome and one instance of grade 3 enterocolitis due to autologous graft-versus-host disease,” they reported.

Novartis supported the study and approved the manuscript. The work was also funded by the National Institutes of Health, the International Society for Advancement of Cytometry, the University of Pennsylvania Institute or Translational Medicine and Therapeutics, and a Conquer Cancer Foundation Young Investigator Award. The University of Pennsylvania has licensed technologies involved in this trial to Novartis. Several scientists involved in this trial hold patents for these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and these inventors have benefited financially or may benefit in the future.

Hematopoietic colony-stimulating factors should now be considered for patients who are over age 64 years, have diffuse aggressive lymphoma, and are receiving curative chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab), particularly those who have comorbidities.

This is one of several recommendations noted in the American Society of Clinical Oncology’s updated practice guidelines, published online in the Journal of Clinical Oncology, on the use of hematopoietic colony-stimulating factors (CSFs) to prevent or treat neutropenia and its complications in adults and children receiving chemotherapy.

This “moderately strong” recommendation is based on a single randomized clinical trial that found pegfilgrastim significantly reduced the risk of febrile neutropenia in this patient population, according to the guidelines (J. Clin. Oncol. 2015 July 13 [doi:10.1200/JCO.2015.62.3488]).

The updated guideline incorporates new evidence from 66 randomized controlled trials and meta-analyses published since its last update in 2006, said cochair Dr. Thomas J. Smith of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, and his associates on the update committee.

In addition to pegfilgrastim and filgrastim, the guideline now addresses the use of tbo-filgrastim, filgrastim-sndz, and other biosimilars as they become available. These new agents are effective at preventing chemotherapy-related febrile neutropenia, so the choice of agent depends on convenience, cost, and clinical factors, and in some cases may be dictated by the patient’s treatment schedule. Certain off-label uses of pegfilgrastim can now be considered, such as giving it on the same day as chemotherapy if that is the only feasible timing for some patients.

CSFs should only be used to enable dose-dense chemotherapy regimens “if supported by convincing efficacy data or within an appropriately designed clinical trial” – for example, to support treatment of urothelial cancer or high-risk breast cancer targeted with high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin.

In contrast, the use of CSFs to enable dose-dense chemotherapy for Hodgkin lymphoma is not recommended at this time because the current data supporting such use are limited and conflicting. Similarly, the current evidence strongly argues against giving CSFs to enable dose-dense chemotherapy for other lymphomas, lung cancer, ovarian cancer, osteosarcoma, or sarcoma.

The guideline update was supported by the American Society of Clinical Oncology. Dr. Smith reported stock or other ownership in United Healthcare; his associates reported ties to numerous industry sources.

The full guideline and supplementary material, including slide sets and clinical tools, are available at www.asco.org/guidelines/wbcgf.

Hematopoietic colony-stimulating factors should now be considered for patients who are over age 64 years, have diffuse aggressive lymphoma, and are receiving curative chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab), particularly those who have comorbidities.

This is one of several recommendations noted in the American Society of Clinical Oncology’s updated practice guidelines, published online in the Journal of Clinical Oncology, on the use of hematopoietic colony-stimulating factors (CSFs) to prevent or treat neutropenia and its complications in adults and children receiving chemotherapy.

This “moderately strong” recommendation is based on a single randomized clinical trial that found pegfilgrastim significantly reduced the risk of febrile neutropenia in this patient population, according to the guidelines (J. Clin. Oncol. 2015 July 13 [doi:10.1200/JCO.2015.62.3488]).

The updated guideline incorporates new evidence from 66 randomized controlled trials and meta-analyses published since its last update in 2006, said cochair Dr. Thomas J. Smith of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, and his associates on the update committee.

In addition to pegfilgrastim and filgrastim, the guideline now addresses the use of tbo-filgrastim, filgrastim-sndz, and other biosimilars as they become available. These new agents are effective at preventing chemotherapy-related febrile neutropenia, so the choice of agent depends on convenience, cost, and clinical factors, and in some cases may be dictated by the patient’s treatment schedule. Certain off-label uses of pegfilgrastim can now be considered, such as giving it on the same day as chemotherapy if that is the only feasible timing for some patients.

CSFs should only be used to enable dose-dense chemotherapy regimens “if supported by convincing efficacy data or within an appropriately designed clinical trial” – for example, to support treatment of urothelial cancer or high-risk breast cancer targeted with high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin.

In contrast, the use of CSFs to enable dose-dense chemotherapy for Hodgkin lymphoma is not recommended at this time because the current data supporting such use are limited and conflicting. Similarly, the current evidence strongly argues against giving CSFs to enable dose-dense chemotherapy for other lymphomas, lung cancer, ovarian cancer, osteosarcoma, or sarcoma.

The guideline update was supported by the American Society of Clinical Oncology. Dr. Smith reported stock or other ownership in United Healthcare; his associates reported ties to numerous industry sources.

The full guideline and supplementary material, including slide sets and clinical tools, are available at www.asco.org/guidelines/wbcgf.

Hematopoietic colony-stimulating factors should now be considered for patients who are over age 64 years, have diffuse aggressive lymphoma, and are receiving curative chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab), particularly those who have comorbidities.

This is one of several recommendations noted in the American Society of Clinical Oncology’s updated practice guidelines, published online in the Journal of Clinical Oncology, on the use of hematopoietic colony-stimulating factors (CSFs) to prevent or treat neutropenia and its complications in adults and children receiving chemotherapy.

This “moderately strong” recommendation is based on a single randomized clinical trial that found pegfilgrastim significantly reduced the risk of febrile neutropenia in this patient population, according to the guidelines (J. Clin. Oncol. 2015 July 13 [doi:10.1200/JCO.2015.62.3488]).

The updated guideline incorporates new evidence from 66 randomized controlled trials and meta-analyses published since its last update in 2006, said cochair Dr. Thomas J. Smith of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, and his associates on the update committee.

In addition to pegfilgrastim and filgrastim, the guideline now addresses the use of tbo-filgrastim, filgrastim-sndz, and other biosimilars as they become available. These new agents are effective at preventing chemotherapy-related febrile neutropenia, so the choice of agent depends on convenience, cost, and clinical factors, and in some cases may be dictated by the patient’s treatment schedule. Certain off-label uses of pegfilgrastim can now be considered, such as giving it on the same day as chemotherapy if that is the only feasible timing for some patients.

CSFs should only be used to enable dose-dense chemotherapy regimens “if supported by convincing efficacy data or within an appropriately designed clinical trial” – for example, to support treatment of urothelial cancer or high-risk breast cancer targeted with high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin.

In contrast, the use of CSFs to enable dose-dense chemotherapy for Hodgkin lymphoma is not recommended at this time because the current data supporting such use are limited and conflicting. Similarly, the current evidence strongly argues against giving CSFs to enable dose-dense chemotherapy for other lymphomas, lung cancer, ovarian cancer, osteosarcoma, or sarcoma.

The guideline update was supported by the American Society of Clinical Oncology. Dr. Smith reported stock or other ownership in United Healthcare; his associates reported ties to numerous industry sources.

The full guideline and supplementary material, including slide sets and clinical tools, are available at www.asco.org/guidelines/wbcgf.

Peripheral blood stem cell (PBSC) grafts with high doses of CD8 cells were associated with significantly lower relapse risk and improved survival in patients who were treated for hematologic malignancies with reduced-intensity conditioning (RIC) hematopoietic allogeneic stem cell transplantation (allo-HSCT), according to a report online in the Journal of Clinical Oncology.

A multivariate analysis showed that CD8 cell dose was an independent predictor of relapse (adjusted hazard ratio [aHR], 0.43; P = .009), relapse-free survival (aHR, 0.50; P = .006), and overall survival (aHR, 0.57; P = .04). The data showed a linear association between CD8 cell dose and outcomes, and further analysis identified an optimum cutoff of CD8 cell dose (0.72 x 10⁸ CD8 cells per kg) to segregate survival outcomes. Patients who received grafts with CD8 cell doses above the cutoff had significantly improved regression-free and overall survival (P = .005 and P = .007, respectively).

“These findings indicate that improved survival after RIC transplantations could be achieved by optimizing donor selection and PBSC collection to increase the likelihood of mobilizing grafts containing high CD8 cell doses,” wrote Dr. Ran Reshef of the department of medicine at the Hospital of the University of Pennsylvania, Philadelphia, and colleagues (Journ. Clin. Onc. 2015 June 8 [doi:10.1200/JCO.2014.60.1203]).

Younger donors were more likely to have CD8 cell doses above the cutoff (CD8^hi), however, only 53% of donors younger than 30 years had CD8^hi grafts. To find methods to predict graft composition during donor screening, the investigators studied 21 randomly selected allo-HSCT donors. They found no correlations between CD8 graft content and clinical variables such as weight, sex, viral serologies, or apheresis parameters. Donors with a higher proportion of CD8 cells donated grafts with higher CD8 cell dose, but the presence of higher CD4 counts negated this. Screening for the relative proportions of CD8 and CD4 cells identifies donors most likely to mobilize CD8^hi grafts.

“This is also a practical consideration because the assay is rapid, is routinely performed in clinical laboratories, and can easily be done at the time of confirmatory HLA [human leukocyte antigen] typing,” the authors noted. Since the relationship between CD8 dose and survival is linear, the higher the dose the better, even if it is below the cutoff.

Previous studies showed conflicting results regarding the outcome of RIC transplantation with younger unrelated donors versus older sibling donors. Donor age inversely correlates with CD8 cell dose, and the results of this study showed that overall survival was significantly better with younger unrelated donors with a CD8^hi graft, compared with older sibling donors (P = .03). No such benefit was observed with younger unrelated donors with CD8^lo grafts (P = .28), indicating the benefit may rely on CD8 cell dose.

The study evaluated 200 patients with hematologic malignancy who underwent allo-HSCT with fludarabine plus busulfan conditioning from 2007 to 2014 at the Abramson Cancer Center, University of Pennsylvania in Philadelphia. The cumulative relapse incidence was 42% at 1 year and 47% at 5 years. The most common diseases in the cohort were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma.

High CD8 dose was associated with an increased, but nonsignificant risk of chronic graft-versus-host disease (GVHD); the risk for nonrelapse mortality was not associated with cell doses.

Peripheral blood stem cell (PBSC) grafts with high doses of CD8 cells were associated with significantly lower relapse risk and improved survival in patients who were treated for hematologic malignancies with reduced-intensity conditioning (RIC) hematopoietic allogeneic stem cell transplantation (allo-HSCT), according to a report online in the Journal of Clinical Oncology.

A multivariate analysis showed that CD8 cell dose was an independent predictor of relapse (adjusted hazard ratio [aHR], 0.43; P = .009), relapse-free survival (aHR, 0.50; P = .006), and overall survival (aHR, 0.57; P = .04). The data showed a linear association between CD8 cell dose and outcomes, and further analysis identified an optimum cutoff of CD8 cell dose (0.72 x 10⁸ CD8 cells per kg) to segregate survival outcomes. Patients who received grafts with CD8 cell doses above the cutoff had significantly improved regression-free and overall survival (P = .005 and P = .007, respectively).

“These findings indicate that improved survival after RIC transplantations could be achieved by optimizing donor selection and PBSC collection to increase the likelihood of mobilizing grafts containing high CD8 cell doses,” wrote Dr. Ran Reshef of the department of medicine at the Hospital of the University of Pennsylvania, Philadelphia, and colleagues (Journ. Clin. Onc. 2015 June 8 [doi:10.1200/JCO.2014.60.1203]).

Younger donors were more likely to have CD8 cell doses above the cutoff (CD8^hi), however, only 53% of donors younger than 30 years had CD8^hi grafts. To find methods to predict graft composition during donor screening, the investigators studied 21 randomly selected allo-HSCT donors. They found no correlations between CD8 graft content and clinical variables such as weight, sex, viral serologies, or apheresis parameters. Donors with a higher proportion of CD8 cells donated grafts with higher CD8 cell dose, but the presence of higher CD4 counts negated this. Screening for the relative proportions of CD8 and CD4 cells identifies donors most likely to mobilize CD8^hi grafts.

“This is also a practical consideration because the assay is rapid, is routinely performed in clinical laboratories, and can easily be done at the time of confirmatory HLA [human leukocyte antigen] typing,” the authors noted. Since the relationship between CD8 dose and survival is linear, the higher the dose the better, even if it is below the cutoff.

Previous studies showed conflicting results regarding the outcome of RIC transplantation with younger unrelated donors versus older sibling donors. Donor age inversely correlates with CD8 cell dose, and the results of this study showed that overall survival was significantly better with younger unrelated donors with a CD8^hi graft, compared with older sibling donors (P = .03). No such benefit was observed with younger unrelated donors with CD8^lo grafts (P = .28), indicating the benefit may rely on CD8 cell dose.

The study evaluated 200 patients with hematologic malignancy who underwent allo-HSCT with fludarabine plus busulfan conditioning from 2007 to 2014 at the Abramson Cancer Center, University of Pennsylvania in Philadelphia. The cumulative relapse incidence was 42% at 1 year and 47% at 5 years. The most common diseases in the cohort were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma.

High CD8 dose was associated with an increased, but nonsignificant risk of chronic graft-versus-host disease (GVHD); the risk for nonrelapse mortality was not associated with cell doses.

Peripheral blood stem cell (PBSC) grafts with high doses of CD8 cells were associated with significantly lower relapse risk and improved survival in patients who were treated for hematologic malignancies with reduced-intensity conditioning (RIC) hematopoietic allogeneic stem cell transplantation (allo-HSCT), according to a report online in the Journal of Clinical Oncology.

A multivariate analysis showed that CD8 cell dose was an independent predictor of relapse (adjusted hazard ratio [aHR], 0.43; P = .009), relapse-free survival (aHR, 0.50; P = .006), and overall survival (aHR, 0.57; P = .04). The data showed a linear association between CD8 cell dose and outcomes, and further analysis identified an optimum cutoff of CD8 cell dose (0.72 x 10⁸ CD8 cells per kg) to segregate survival outcomes. Patients who received grafts with CD8 cell doses above the cutoff had significantly improved regression-free and overall survival (P = .005 and P = .007, respectively).

“These findings indicate that improved survival after RIC transplantations could be achieved by optimizing donor selection and PBSC collection to increase the likelihood of mobilizing grafts containing high CD8 cell doses,” wrote Dr. Ran Reshef of the department of medicine at the Hospital of the University of Pennsylvania, Philadelphia, and colleagues (Journ. Clin. Onc. 2015 June 8 [doi:10.1200/JCO.2014.60.1203]).

Younger donors were more likely to have CD8 cell doses above the cutoff (CD8^hi), however, only 53% of donors younger than 30 years had CD8^hi grafts. To find methods to predict graft composition during donor screening, the investigators studied 21 randomly selected allo-HSCT donors. They found no correlations between CD8 graft content and clinical variables such as weight, sex, viral serologies, or apheresis parameters. Donors with a higher proportion of CD8 cells donated grafts with higher CD8 cell dose, but the presence of higher CD4 counts negated this. Screening for the relative proportions of CD8 and CD4 cells identifies donors most likely to mobilize CD8^hi grafts.

“This is also a practical consideration because the assay is rapid, is routinely performed in clinical laboratories, and can easily be done at the time of confirmatory HLA [human leukocyte antigen] typing,” the authors noted. Since the relationship between CD8 dose and survival is linear, the higher the dose the better, even if it is below the cutoff.

Previous studies showed conflicting results regarding the outcome of RIC transplantation with younger unrelated donors versus older sibling donors. Donor age inversely correlates with CD8 cell dose, and the results of this study showed that overall survival was significantly better with younger unrelated donors with a CD8^hi graft, compared with older sibling donors (P = .03). No such benefit was observed with younger unrelated donors with CD8^lo grafts (P = .28), indicating the benefit may rely on CD8 cell dose.

The study evaluated 200 patients with hematologic malignancy who underwent allo-HSCT with fludarabine plus busulfan conditioning from 2007 to 2014 at the Abramson Cancer Center, University of Pennsylvania in Philadelphia. The cumulative relapse incidence was 42% at 1 year and 47% at 5 years. The most common diseases in the cohort were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma.

High CD8 dose was associated with an increased, but nonsignificant risk of chronic graft-versus-host disease (GVHD); the risk for nonrelapse mortality was not associated with cell doses.

In a population of patients with hematologic malignancies who refuse blood product transfusions, high-dose chemotherapy (HDC) followed by autologous stem-cell transplantation (ASCT) in the absence of hematopoietic support was shown to be relatively safe, according to a report published online April 13 in the Journal of Clinical Oncology.

From May of 1996 to March of 2014 at Pennsylvania Hospital, 125 Jehovah’s Witness patients with lymphoma (n = 55), multiple myeloma (n = 68), or amyloidosis (n = 2) were treated with HDC and ASCT without transfusion through the use of basic blood management techniques. These techniques included priming pretransplantation hemoglobin with erythropoiesis stimulating agents and intravenous iron, limiting iatrogenic blood loss by minimizing phlebotomy, and controlling or preventing bleeding with hemostatic agents, according to Dr. Patricia Ford and her colleagues at the hospital.

They described the low incidence of bleeding even in the absence of prophylactic platelet transfusions, which, they noted, challenges current American Society of Clinical Oncology guidelines that recommend transfusions at platelet counts less than 10 x 10³/mcL. “The absence of major bleeding events observed at platelet counts greater than 5 x 10³/mcL … suggests that a transfusion threshold trigger of 5 x 10³/mcL may be appropriate in a select patient population,” they wrote (J. Clin. Oncol. 2015 April 13 [doi: 10.1200/JCO.2014.57.9912]).

Among the patients treated with HDC and ASCT, those with multiple myeloma (n = 68) received melphalan 200 mg/m²,and those with lymphoma (n = 55) received carmustine 300mg/m² day 1, cyclophosphamide 1,500 mg/m² days 2-5, and VP16 700 mg/m² per day on days 2-4.

At 100 days post transplantation, 115 patients (92%) were still alive. Treatment-related mortality due to anemia, sepsis, pancytopenia, or cardiac events occurred in six patients (4.8%).

Out of 18 bleeding episodes, 2 were major (one grade 4 hemorrhagic temporal infarction with retinal hemorrhages and one grade 3 GI bleed) and 16 were minor. There were no bleeding-associated fatalities.

Cardiac complications occurred at an unexpectedly high rate of 32% (40 patients) and resulted in three treatment-related deaths. Subsequently, all candidates older than 50 years or at risk for cardiac disease were required to undergo cardiac consultation prior to transplantation. Given the cardiovascular risk associated with this population, in addition to ECHO testing, stress testing in patients with suspected coronary artery disease is recommended, the researchers wrote.

On the basis of the observed low mortality and morbidity, Dr. Ford and her associates suggested that HDC followed by ASCT be offered to certain patients who refuse or who have medical contraindications to transfusions, stating that simple blood management strategies were an effective alternative in select patients.

In a population of patients with hematologic malignancies who refuse blood product transfusions, high-dose chemotherapy (HDC) followed by autologous stem-cell transplantation (ASCT) in the absence of hematopoietic support was shown to be relatively safe, according to a report published online April 13 in the Journal of Clinical Oncology.

From May of 1996 to March of 2014 at Pennsylvania Hospital, 125 Jehovah’s Witness patients with lymphoma (n = 55), multiple myeloma (n = 68), or amyloidosis (n = 2) were treated with HDC and ASCT without transfusion through the use of basic blood management techniques. These techniques included priming pretransplantation hemoglobin with erythropoiesis stimulating agents and intravenous iron, limiting iatrogenic blood loss by minimizing phlebotomy, and controlling or preventing bleeding with hemostatic agents, according to Dr. Patricia Ford and her colleagues at the hospital.

They described the low incidence of bleeding even in the absence of prophylactic platelet transfusions, which, they noted, challenges current American Society of Clinical Oncology guidelines that recommend transfusions at platelet counts less than 10 x 10³/mcL. “The absence of major bleeding events observed at platelet counts greater than 5 x 10³/mcL … suggests that a transfusion threshold trigger of 5 x 10³/mcL may be appropriate in a select patient population,” they wrote (J. Clin. Oncol. 2015 April 13 [doi: 10.1200/JCO.2014.57.9912]).

Among the patients treated with HDC and ASCT, those with multiple myeloma (n = 68) received melphalan 200 mg/m²,and those with lymphoma (n = 55) received carmustine 300mg/m² day 1, cyclophosphamide 1,500 mg/m² days 2-5, and VP16 700 mg/m² per day on days 2-4.

At 100 days post transplantation, 115 patients (92%) were still alive. Treatment-related mortality due to anemia, sepsis, pancytopenia, or cardiac events occurred in six patients (4.8%).

Out of 18 bleeding episodes, 2 were major (one grade 4 hemorrhagic temporal infarction with retinal hemorrhages and one grade 3 GI bleed) and 16 were minor. There were no bleeding-associated fatalities.

Cardiac complications occurred at an unexpectedly high rate of 32% (40 patients) and resulted in three treatment-related deaths. Subsequently, all candidates older than 50 years or at risk for cardiac disease were required to undergo cardiac consultation prior to transplantation. Given the cardiovascular risk associated with this population, in addition to ECHO testing, stress testing in patients with suspected coronary artery disease is recommended, the researchers wrote.

On the basis of the observed low mortality and morbidity, Dr. Ford and her associates suggested that HDC followed by ASCT be offered to certain patients who refuse or who have medical contraindications to transfusions, stating that simple blood management strategies were an effective alternative in select patients.

In a population of patients with hematologic malignancies who refuse blood product transfusions, high-dose chemotherapy (HDC) followed by autologous stem-cell transplantation (ASCT) in the absence of hematopoietic support was shown to be relatively safe, according to a report published online April 13 in the Journal of Clinical Oncology.

From May of 1996 to March of 2014 at Pennsylvania Hospital, 125 Jehovah’s Witness patients with lymphoma (n = 55), multiple myeloma (n = 68), or amyloidosis (n = 2) were treated with HDC and ASCT without transfusion through the use of basic blood management techniques. These techniques included priming pretransplantation hemoglobin with erythropoiesis stimulating agents and intravenous iron, limiting iatrogenic blood loss by minimizing phlebotomy, and controlling or preventing bleeding with hemostatic agents, according to Dr. Patricia Ford and her colleagues at the hospital.

They described the low incidence of bleeding even in the absence of prophylactic platelet transfusions, which, they noted, challenges current American Society of Clinical Oncology guidelines that recommend transfusions at platelet counts less than 10 x 10³/mcL. “The absence of major bleeding events observed at platelet counts greater than 5 x 10³/mcL … suggests that a transfusion threshold trigger of 5 x 10³/mcL may be appropriate in a select patient population,” they wrote (J. Clin. Oncol. 2015 April 13 [doi: 10.1200/JCO.2014.57.9912]).

Among the patients treated with HDC and ASCT, those with multiple myeloma (n = 68) received melphalan 200 mg/m²,and those with lymphoma (n = 55) received carmustine 300mg/m² day 1, cyclophosphamide 1,500 mg/m² days 2-5, and VP16 700 mg/m² per day on days 2-4.

At 100 days post transplantation, 115 patients (92%) were still alive. Treatment-related mortality due to anemia, sepsis, pancytopenia, or cardiac events occurred in six patients (4.8%).

Out of 18 bleeding episodes, 2 were major (one grade 4 hemorrhagic temporal infarction with retinal hemorrhages and one grade 3 GI bleed) and 16 were minor. There were no bleeding-associated fatalities.

Cardiac complications occurred at an unexpectedly high rate of 32% (40 patients) and resulted in three treatment-related deaths. Subsequently, all candidates older than 50 years or at risk for cardiac disease were required to undergo cardiac consultation prior to transplantation. Given the cardiovascular risk associated with this population, in addition to ECHO testing, stress testing in patients with suspected coronary artery disease is recommended, the researchers wrote.

On the basis of the observed low mortality and morbidity, Dr. Ford and her associates suggested that HDC followed by ASCT be offered to certain patients who refuse or who have medical contraindications to transfusions, stating that simple blood management strategies were an effective alternative in select patients.

Unlike for those with acute leukemia, patients with chronic lymphocytic leukemia who had disease progression after undergoing transplantation had a relatively good prognosis, with 2- and 5-year overall survival rates of 67% and 38%, investigators reported online April 6 in the Journal of Clinical Oncology.*

Patients with chronic lymphocytic leukemia (CLL) who experienced acute or chronic graft-versus-host disease (GVHD) had significantly longer overall survival (OS) than those who did not have GVHD (P = .04 and P = .05, respectively). “Nearly half our patients with active CLL after transplantation had chronic GVHD, and the association of chronic GVHD with achieving cure and its power to predict OS among patients for whom transplantation failed suggests that the GVL (graft-versus-leukemia) effect contributes to prolonged survival even in patients with a high burden of disease,” wrote Dr. Uri Rozovski and associates at the University of Texas MD Anderson Cancer Center, Houston (J. Clin. Oncol. 2015 Apr. 6 [doi:10.1200/JCO.2014.58.6750]).

A matched-pair analysis showed that patients who underwent allogeneic stem cell transplant (SCT) about the same time and did not relapse also had higher rates of acute and chronic GVHD (P = .004 and P = .011, respectively).

The retrospective review of the Bone Marrow Transplantation Program database identified 358 patients with CLL or RT who underwent SCT from 1998 to 2011. The study evaluated 72 patients who had disease progression at a median 74 months after SCT, most of whom received one to eight lines of treatment after relapse and had a median OS of almost 3 years from the time of progression. Multivariate analysis showed that low hemoglobin levels and the presence of Richter’s transformation (RT) were associated with shorter OS; chronic GVHD and response to the first post-SCT treatment predicted longer OS.

Patients with RT had a worse prognosis, with a median OS of 15 months (95% confidence interval, 2-28 months) and 2- and 5-year survival rates of 36% and 0%. Transplantation carried a significant risk for transformation: 16 (30%) patients with CLL developed RT after allogeneic SCT. Conversely, four patients with RT developed CLL after transplantation.

The authors note that even in patients who did not maintain a durable response, SCT was beneficial. The study cohort received a variety of salvage treatments, and patients who received ibrutinib responded well. “Because of the favorable outcomes with ibrutinib in relapsed/refractory CLL, we believe that ibrutinib might have a role in the treatment of disease progression following transplantation failure,” they wrote.

*Correction, 4/8/2015: A previous version of this article misstated the type of leukemia referenced in the study.

Unlike for those with acute leukemia, patients with chronic lymphocytic leukemia who had disease progression after undergoing transplantation had a relatively good prognosis, with 2- and 5-year overall survival rates of 67% and 38%, investigators reported online April 6 in the Journal of Clinical Oncology.*

Patients with chronic lymphocytic leukemia (CLL) who experienced acute or chronic graft-versus-host disease (GVHD) had significantly longer overall survival (OS) than those who did not have GVHD (P = .04 and P = .05, respectively). “Nearly half our patients with active CLL after transplantation had chronic GVHD, and the association of chronic GVHD with achieving cure and its power to predict OS among patients for whom transplantation failed suggests that the GVL (graft-versus-leukemia) effect contributes to prolonged survival even in patients with a high burden of disease,” wrote Dr. Uri Rozovski and associates at the University of Texas MD Anderson Cancer Center, Houston (J. Clin. Oncol. 2015 Apr. 6 [doi:10.1200/JCO.2014.58.6750]).

A matched-pair analysis showed that patients who underwent allogeneic stem cell transplant (SCT) about the same time and did not relapse also had higher rates of acute and chronic GVHD (P = .004 and P = .011, respectively).

The retrospective review of the Bone Marrow Transplantation Program database identified 358 patients with CLL or RT who underwent SCT from 1998 to 2011. The study evaluated 72 patients who had disease progression at a median 74 months after SCT, most of whom received one to eight lines of treatment after relapse and had a median OS of almost 3 years from the time of progression. Multivariate analysis showed that low hemoglobin levels and the presence of Richter’s transformation (RT) were associated with shorter OS; chronic GVHD and response to the first post-SCT treatment predicted longer OS.

Patients with RT had a worse prognosis, with a median OS of 15 months (95% confidence interval, 2-28 months) and 2- and 5-year survival rates of 36% and 0%. Transplantation carried a significant risk for transformation: 16 (30%) patients with CLL developed RT after allogeneic SCT. Conversely, four patients with RT developed CLL after transplantation.

The authors note that even in patients who did not maintain a durable response, SCT was beneficial. The study cohort received a variety of salvage treatments, and patients who received ibrutinib responded well. “Because of the favorable outcomes with ibrutinib in relapsed/refractory CLL, we believe that ibrutinib might have a role in the treatment of disease progression following transplantation failure,” they wrote.

*Correction, 4/8/2015: A previous version of this article misstated the type of leukemia referenced in the study.

Unlike for those with acute leukemia, patients with chronic lymphocytic leukemia who had disease progression after undergoing transplantation had a relatively good prognosis, with 2- and 5-year overall survival rates of 67% and 38%, investigators reported online April 6 in the Journal of Clinical Oncology.*

Patients with chronic lymphocytic leukemia (CLL) who experienced acute or chronic graft-versus-host disease (GVHD) had significantly longer overall survival (OS) than those who did not have GVHD (P = .04 and P = .05, respectively). “Nearly half our patients with active CLL after transplantation had chronic GVHD, and the association of chronic GVHD with achieving cure and its power to predict OS among patients for whom transplantation failed suggests that the GVL (graft-versus-leukemia) effect contributes to prolonged survival even in patients with a high burden of disease,” wrote Dr. Uri Rozovski and associates at the University of Texas MD Anderson Cancer Center, Houston (J. Clin. Oncol. 2015 Apr. 6 [doi:10.1200/JCO.2014.58.6750]).

A matched-pair analysis showed that patients who underwent allogeneic stem cell transplant (SCT) about the same time and did not relapse also had higher rates of acute and chronic GVHD (P = .004 and P = .011, respectively).

The retrospective review of the Bone Marrow Transplantation Program database identified 358 patients with CLL or RT who underwent SCT from 1998 to 2011. The study evaluated 72 patients who had disease progression at a median 74 months after SCT, most of whom received one to eight lines of treatment after relapse and had a median OS of almost 3 years from the time of progression. Multivariate analysis showed that low hemoglobin levels and the presence of Richter’s transformation (RT) were associated with shorter OS; chronic GVHD and response to the first post-SCT treatment predicted longer OS.

Patients with RT had a worse prognosis, with a median OS of 15 months (95% confidence interval, 2-28 months) and 2- and 5-year survival rates of 36% and 0%. Transplantation carried a significant risk for transformation: 16 (30%) patients with CLL developed RT after allogeneic SCT. Conversely, four patients with RT developed CLL after transplantation.

The authors note that even in patients who did not maintain a durable response, SCT was beneficial. The study cohort received a variety of salvage treatments, and patients who received ibrutinib responded well. “Because of the favorable outcomes with ibrutinib in relapsed/refractory CLL, we believe that ibrutinib might have a role in the treatment of disease progression following transplantation failure,” they wrote.

*Correction, 4/8/2015: A previous version of this article misstated the type of leukemia referenced in the study.

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

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

Patrice Wendling/Frontline Medical News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

Patrice Wendling/Frontline Medical News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

Patrice Wendling/Frontline Medical News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.

The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.

More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).

The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.

Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.

Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”

“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.

He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.

Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.

“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.

VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.

In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.

When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.

There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).

In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).

“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”

During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”

Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.

Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.

Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.

Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.

[email protected]

SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.

The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.

More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).

The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.

Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.

Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”

“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.

He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.

Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.

“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.

VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.

In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.

When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.

There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).

In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).

“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”

During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”

Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.

Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.

Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.

Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.

[email protected]

SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.

The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.

More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).

The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.

Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.

Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”

“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.

He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.

Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.

“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.

VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.

In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.

When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.

There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).

In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).

“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”

During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”

Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.

Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.

Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.

Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.

[email protected]

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

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

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

Patrice Wendling/Frontline Medical News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

Patrice Wendling/Frontline Medical News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

Patrice Wendling/Frontline Medical News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

The development of vitiligo or alopecia areata is not common in patients with chronic graft-versus-host disease, but it is significantly more likely to occur when the donor was female, especially when the recipient was male, according to a report published online Sept. 10 in JAMA Dermatology.

Fifteen case reports and small series in the literature have reported the development of vitiligo or alopecia areata after allogeneic hematopoietic stem cell transplantation, most often among patients who first developed chronic graft-versus-host disease (GVHD) after the procedure. To further explore the frequency of these two skin autoimmune manifestations in GVHD and to identify associated risk factors, researchers performed a retrospective cross-sectional analysis involving 282 adult and pediatric patients referred to the National Institutes of Health Clinical Center for GVHD in 2004-2013.

Courtesy Wikimedia Commons/Grook Da Oger/Creative Commons License

They identified 15 GVHD patients with vitiligo (4.9%) and 2 with alopecia areata (0.7%); one of these patients had both skin disorders. Most of the 15 patients had undergone stem-cell transplantation to treat chronic myelogenous leukemia (CML) (5 patients) or acute leukemia or myelodysplastic syndrome (5 patients), and most had had a human leukocyte antigen–identical donor. Twelve of the 15 developed the skin disorder after having GVHD for more than 1 year, said Rena C. Zuo of the National Cancer Institute’s dermatology branch and her associates.

"Notably, CML accounts for only about 300 of 7,892 (3.8%) allogeneic hematopoietic stem-cell transplantations per year in the United States, a relative minority among indicated diseases," they said.

In what they described as the first study to identify an association between donor/recipient sex mismatch and the development of concomitant autoimmunity in patients with chronic GVHD, the investigators found that 14 of the 15 patients who developed vitiligo or alopecia areata had female donors, 2 of whom had previously given birth; the gender of the donor in the 15th case was unknown. Nine of these 14 recipients were male, "resulting in a female-to-male sex mismatch in [at least] 64% of cases," Ms. Zuo and her colleagues said (JAMA Dermatol. 2014 Sept. 10 [doi:10.1001/jamadermatol.2014.1550]).

Both parous female donors and donor-recipient sex mismatch are known risk factors for GVHD. The risk of autoimmunity in female-to-male transplants "may reflect the activity of skin-homing donor T cells specific for recipient minor histocompatibility antigens encoded by Y-chromosome genes, a mechanism previously implicated in both GVHD and graft-versus-tumor responses," the investigators added.

This study was supported by the National Institutes of Health and the National Cancer Institute. Ms. Zuo and her associates reported no financial conflicts of interest.

The development of vitiligo or alopecia areata is not common in patients with chronic graft-versus-host disease, but it is significantly more likely to occur when the donor was female, especially when the recipient was male, according to a report published online Sept. 10 in JAMA Dermatology.

Fifteen case reports and small series in the literature have reported the development of vitiligo or alopecia areata after allogeneic hematopoietic stem cell transplantation, most often among patients who first developed chronic graft-versus-host disease (GVHD) after the procedure. To further explore the frequency of these two skin autoimmune manifestations in GVHD and to identify associated risk factors, researchers performed a retrospective cross-sectional analysis involving 282 adult and pediatric patients referred to the National Institutes of Health Clinical Center for GVHD in 2004-2013.

Courtesy Wikimedia Commons/Grook Da Oger/Creative Commons License

They identified 15 GVHD patients with vitiligo (4.9%) and 2 with alopecia areata (0.7%); one of these patients had both skin disorders. Most of the 15 patients had undergone stem-cell transplantation to treat chronic myelogenous leukemia (CML) (5 patients) or acute leukemia or myelodysplastic syndrome (5 patients), and most had had a human leukocyte antigen–identical donor. Twelve of the 15 developed the skin disorder after having GVHD for more than 1 year, said Rena C. Zuo of the National Cancer Institute’s dermatology branch and her associates.

"Notably, CML accounts for only about 300 of 7,892 (3.8%) allogeneic hematopoietic stem-cell transplantations per year in the United States, a relative minority among indicated diseases," they said.

In what they described as the first study to identify an association between donor/recipient sex mismatch and the development of concomitant autoimmunity in patients with chronic GVHD, the investigators found that 14 of the 15 patients who developed vitiligo or alopecia areata had female donors, 2 of whom had previously given birth; the gender of the donor in the 15th case was unknown. Nine of these 14 recipients were male, "resulting in a female-to-male sex mismatch in [at least] 64% of cases," Ms. Zuo and her colleagues said (JAMA Dermatol. 2014 Sept. 10 [doi:10.1001/jamadermatol.2014.1550]).

Both parous female donors and donor-recipient sex mismatch are known risk factors for GVHD. The risk of autoimmunity in female-to-male transplants "may reflect the activity of skin-homing donor T cells specific for recipient minor histocompatibility antigens encoded by Y-chromosome genes, a mechanism previously implicated in both GVHD and graft-versus-tumor responses," the investigators added.

This study was supported by the National Institutes of Health and the National Cancer Institute. Ms. Zuo and her associates reported no financial conflicts of interest.

The development of vitiligo or alopecia areata is not common in patients with chronic graft-versus-host disease, but it is significantly more likely to occur when the donor was female, especially when the recipient was male, according to a report published online Sept. 10 in JAMA Dermatology.

Fifteen case reports and small series in the literature have reported the development of vitiligo or alopecia areata after allogeneic hematopoietic stem cell transplantation, most often among patients who first developed chronic graft-versus-host disease (GVHD) after the procedure. To further explore the frequency of these two skin autoimmune manifestations in GVHD and to identify associated risk factors, researchers performed a retrospective cross-sectional analysis involving 282 adult and pediatric patients referred to the National Institutes of Health Clinical Center for GVHD in 2004-2013.

Courtesy Wikimedia Commons/Grook Da Oger/Creative Commons License

They identified 15 GVHD patients with vitiligo (4.9%) and 2 with alopecia areata (0.7%); one of these patients had both skin disorders. Most of the 15 patients had undergone stem-cell transplantation to treat chronic myelogenous leukemia (CML) (5 patients) or acute leukemia or myelodysplastic syndrome (5 patients), and most had had a human leukocyte antigen–identical donor. Twelve of the 15 developed the skin disorder after having GVHD for more than 1 year, said Rena C. Zuo of the National Cancer Institute’s dermatology branch and her associates.

"Notably, CML accounts for only about 300 of 7,892 (3.8%) allogeneic hematopoietic stem-cell transplantations per year in the United States, a relative minority among indicated diseases," they said.

In what they described as the first study to identify an association between donor/recipient sex mismatch and the development of concomitant autoimmunity in patients with chronic GVHD, the investigators found that 14 of the 15 patients who developed vitiligo or alopecia areata had female donors, 2 of whom had previously given birth; the gender of the donor in the 15th case was unknown. Nine of these 14 recipients were male, "resulting in a female-to-male sex mismatch in [at least] 64% of cases," Ms. Zuo and her colleagues said (JAMA Dermatol. 2014 Sept. 10 [doi:10.1001/jamadermatol.2014.1550]).

Both parous female donors and donor-recipient sex mismatch are known risk factors for GVHD. The risk of autoimmunity in female-to-male transplants "may reflect the activity of skin-homing donor T cells specific for recipient minor histocompatibility antigens encoded by Y-chromosome genes, a mechanism previously implicated in both GVHD and graft-versus-tumor responses," the investigators added.

This study was supported by the National Institutes of Health and the National Cancer Institute. Ms. Zuo and her associates reported no financial conflicts of interest.