ASH 2013

NEW ORLEANS – For patients with newly diagnosed multiple myeloma who are not eligible for stem cell transplants, continuous treatment with lenalidomide and low-dose dexamethasone was associated with significant overall survival and progression-free survival benefits, compared with melphalan-prednisone-thalidomide.

"Overall, we should congratulate [the investigators] for having a new standard of care that is active, convenient, and with excellent tolerability," said invited discussant Dr. Jesús San Miguel from the cancer center at the Hospital Universitario de Salamanca, Spain.

Initial results from the phase III FIRST trial (Front-Line Investigation of Revlimid/Dexamethasone vs. Standard Thalidomide) showed that lenalidomide (Revlimid [RD]) plus low-dose dexamethasone used until disease progression was associated with a median progression-free survival (PFS, the primary endpoint) of 25.5 months, compared with 20.7 months for patients treated with the same combination for 18 cycles over 72 weeks (RD18), and 21.2 months for patients treated with melphalan-prednisone-thalidomide (MPT) for 12 cycles over 72 weeks, reported Dr. Thierry Facon of the Service des Maladies du Sang, Hôpital Claude Huriez and CHRU Lille, France.

At the first interim analysis, patients treated with continuous RD had better overall survival than patients treated with MPT, with a hazard ratio favoring RD of 0.78 (P = .0168). However, there were no significant differences in overall survival between the RD and RD18 groups or between the RD18 and MPT groups, Dr. Facon said at the American Society of Hematology annual meeting.

The FIRST trial investigators enrolled 1,623 patients aged 65 years or older from 246 centers in 18 countries in North America, Europe, Asia, and Australia/New Zealand. Patients were randomly assigned to either continuous RD (535), RD18 (541), or MPT (547). Median follow-up as of May 24, 2013, was 37 months.

Continuous RD offered significantly better PFS, compared with either RD18 or MPT. At 3 years, 42% of patients on continuous RD remained progression free, compared with 23% each in the other two groups. The hazard ratio for continuous RD vs. MPT was 0.72 (P = .00006), and vs. RD18 was 0.70 (P = .00001). There was no significant difference in progression-free survival between RD18 and MPT.

Estimated 4-year overall survival rates were 59.4% in the continuous RD group, 55.7% in the RD18 group, and 51.4% in the MPT group.

"RD was superior to MPT across all other efficacy secondary endpoints," Dr. Facon said in the plenary session. Those secondary endpoints included response, duration of response, time to response, time to treatment failure, time to second-line anti–multiple myeloma therapy, time to progression, safety, and quality of life.

Both versions of the RD regimen were generally comparable to MPT in safety profile, although infections were more frequent with RD, and peripheral sensory neuropathy was more frequent with continuous RD (1.1% vs. 0.4% for the other two regimens).

The incidence of second primary malignancies was lower in both RD groups, consisting of one case each of acute myeloid leukemia and myelodysplasia in each group, compared with four cases of acute myeloid leukemia, six of myelodysplasia, and two cases of myelodysplasia converting to acute myeloid leukemia in the MPT group.

Current treatment approaches for elderly, newly diagnosed patients with multiple myeloma include MPT, which is associated with a PFS of 20.3 months; and bortezomib (Velcade), melphalan, and prednisone (VMP), with a PFS of 18.3 months. MPT and VMP are the preferred regimens recommend by the National Comprehensive Cancer Network for patients who are ineligible for stem cell transplants because of age or other factors, Dr. Facon noted. Typically, drug therapy in this patient population has had a fixed duration because of f concern for toxicities associated with long-term therapy.

Dr. San Miguel noted that the excellent results were achieved without the use of an alkylating agent such as melphalan or cyclophosphamide, which might lead some clinicians to question whether alkylating agents still have a role in this population. He pointed out, however, that the study was not designed to answer that question. To do so, it would be necessary to compare RD with and without an alkylator for the same treatment duration.

"Probably the most challenging question is the duration of the lenalidomide treatment. The data indicate that the best option is to treat until progression. Nevertheless, it would be interesting to know the outcome according to response, because it could be that in patients taking lenalidomide and dexamethasone for 1 year or [1 1/2 years] will achieve a complete response with prolonged disease stability. Additional treatment may not add too much, and this could contribute to increased cost and toxicities of unnecessary prolonged treatment," he said.

Questions that still need to be answered include benefits for specific populations, such as high-risk patients, the very elderly, and those with renal insufficiency. It’s also unclear whether the reduced risk of secondary malignancies is because of the absence of melphalan or the presence of dexamethasone.

It will also be important to find a way to indentify, as early as possible, the 25% of patients who will not achieve at least a partial response, he said.

The study was supported by Celegene Corporation and by the Intergroupe Francophone du Myelome. Dr. Facon disclosed serving on the speakers bureau and being a member on a board of directors/advisory committee for Celgene. Dr. San Miguel reported having no disclosures.

NEW ORLEANS – For patients with newly diagnosed multiple myeloma who are not eligible for stem cell transplants, continuous treatment with lenalidomide and low-dose dexamethasone was associated with significant overall survival and progression-free survival benefits, compared with melphalan-prednisone-thalidomide.

"Overall, we should congratulate [the investigators] for having a new standard of care that is active, convenient, and with excellent tolerability," said invited discussant Dr. Jesús San Miguel from the cancer center at the Hospital Universitario de Salamanca, Spain.

Initial results from the phase III FIRST trial (Front-Line Investigation of Revlimid/Dexamethasone vs. Standard Thalidomide) showed that lenalidomide (Revlimid [RD]) plus low-dose dexamethasone used until disease progression was associated with a median progression-free survival (PFS, the primary endpoint) of 25.5 months, compared with 20.7 months for patients treated with the same combination for 18 cycles over 72 weeks (RD18), and 21.2 months for patients treated with melphalan-prednisone-thalidomide (MPT) for 12 cycles over 72 weeks, reported Dr. Thierry Facon of the Service des Maladies du Sang, Hôpital Claude Huriez and CHRU Lille, France.

At the first interim analysis, patients treated with continuous RD had better overall survival than patients treated with MPT, with a hazard ratio favoring RD of 0.78 (P = .0168). However, there were no significant differences in overall survival between the RD and RD18 groups or between the RD18 and MPT groups, Dr. Facon said at the American Society of Hematology annual meeting.

The FIRST trial investigators enrolled 1,623 patients aged 65 years or older from 246 centers in 18 countries in North America, Europe, Asia, and Australia/New Zealand. Patients were randomly assigned to either continuous RD (535), RD18 (541), or MPT (547). Median follow-up as of May 24, 2013, was 37 months.

Continuous RD offered significantly better PFS, compared with either RD18 or MPT. At 3 years, 42% of patients on continuous RD remained progression free, compared with 23% each in the other two groups. The hazard ratio for continuous RD vs. MPT was 0.72 (P = .00006), and vs. RD18 was 0.70 (P = .00001). There was no significant difference in progression-free survival between RD18 and MPT.

Estimated 4-year overall survival rates were 59.4% in the continuous RD group, 55.7% in the RD18 group, and 51.4% in the MPT group.

"RD was superior to MPT across all other efficacy secondary endpoints," Dr. Facon said in the plenary session. Those secondary endpoints included response, duration of response, time to response, time to treatment failure, time to second-line anti–multiple myeloma therapy, time to progression, safety, and quality of life.

Both versions of the RD regimen were generally comparable to MPT in safety profile, although infections were more frequent with RD, and peripheral sensory neuropathy was more frequent with continuous RD (1.1% vs. 0.4% for the other two regimens).

The incidence of second primary malignancies was lower in both RD groups, consisting of one case each of acute myeloid leukemia and myelodysplasia in each group, compared with four cases of acute myeloid leukemia, six of myelodysplasia, and two cases of myelodysplasia converting to acute myeloid leukemia in the MPT group.

Current treatment approaches for elderly, newly diagnosed patients with multiple myeloma include MPT, which is associated with a PFS of 20.3 months; and bortezomib (Velcade), melphalan, and prednisone (VMP), with a PFS of 18.3 months. MPT and VMP are the preferred regimens recommend by the National Comprehensive Cancer Network for patients who are ineligible for stem cell transplants because of age or other factors, Dr. Facon noted. Typically, drug therapy in this patient population has had a fixed duration because of f concern for toxicities associated with long-term therapy.

Dr. San Miguel noted that the excellent results were achieved without the use of an alkylating agent such as melphalan or cyclophosphamide, which might lead some clinicians to question whether alkylating agents still have a role in this population. He pointed out, however, that the study was not designed to answer that question. To do so, it would be necessary to compare RD with and without an alkylator for the same treatment duration.

"Probably the most challenging question is the duration of the lenalidomide treatment. The data indicate that the best option is to treat until progression. Nevertheless, it would be interesting to know the outcome according to response, because it could be that in patients taking lenalidomide and dexamethasone for 1 year or [1 1/2 years] will achieve a complete response with prolonged disease stability. Additional treatment may not add too much, and this could contribute to increased cost and toxicities of unnecessary prolonged treatment," he said.

Questions that still need to be answered include benefits for specific populations, such as high-risk patients, the very elderly, and those with renal insufficiency. It’s also unclear whether the reduced risk of secondary malignancies is because of the absence of melphalan or the presence of dexamethasone.

It will also be important to find a way to indentify, as early as possible, the 25% of patients who will not achieve at least a partial response, he said.

The study was supported by Celegene Corporation and by the Intergroupe Francophone du Myelome. Dr. Facon disclosed serving on the speakers bureau and being a member on a board of directors/advisory committee for Celgene. Dr. San Miguel reported having no disclosures.

NEW ORLEANS – For patients with newly diagnosed multiple myeloma who are not eligible for stem cell transplants, continuous treatment with lenalidomide and low-dose dexamethasone was associated with significant overall survival and progression-free survival benefits, compared with melphalan-prednisone-thalidomide.

"Overall, we should congratulate [the investigators] for having a new standard of care that is active, convenient, and with excellent tolerability," said invited discussant Dr. Jesús San Miguel from the cancer center at the Hospital Universitario de Salamanca, Spain.

Initial results from the phase III FIRST trial (Front-Line Investigation of Revlimid/Dexamethasone vs. Standard Thalidomide) showed that lenalidomide (Revlimid [RD]) plus low-dose dexamethasone used until disease progression was associated with a median progression-free survival (PFS, the primary endpoint) of 25.5 months, compared with 20.7 months for patients treated with the same combination for 18 cycles over 72 weeks (RD18), and 21.2 months for patients treated with melphalan-prednisone-thalidomide (MPT) for 12 cycles over 72 weeks, reported Dr. Thierry Facon of the Service des Maladies du Sang, Hôpital Claude Huriez and CHRU Lille, France.

At the first interim analysis, patients treated with continuous RD had better overall survival than patients treated with MPT, with a hazard ratio favoring RD of 0.78 (P = .0168). However, there were no significant differences in overall survival between the RD and RD18 groups or between the RD18 and MPT groups, Dr. Facon said at the American Society of Hematology annual meeting.

The FIRST trial investigators enrolled 1,623 patients aged 65 years or older from 246 centers in 18 countries in North America, Europe, Asia, and Australia/New Zealand. Patients were randomly assigned to either continuous RD (535), RD18 (541), or MPT (547). Median follow-up as of May 24, 2013, was 37 months.

Continuous RD offered significantly better PFS, compared with either RD18 or MPT. At 3 years, 42% of patients on continuous RD remained progression free, compared with 23% each in the other two groups. The hazard ratio for continuous RD vs. MPT was 0.72 (P = .00006), and vs. RD18 was 0.70 (P = .00001). There was no significant difference in progression-free survival between RD18 and MPT.

Estimated 4-year overall survival rates were 59.4% in the continuous RD group, 55.7% in the RD18 group, and 51.4% in the MPT group.

"RD was superior to MPT across all other efficacy secondary endpoints," Dr. Facon said in the plenary session. Those secondary endpoints included response, duration of response, time to response, time to treatment failure, time to second-line anti–multiple myeloma therapy, time to progression, safety, and quality of life.

Both versions of the RD regimen were generally comparable to MPT in safety profile, although infections were more frequent with RD, and peripheral sensory neuropathy was more frequent with continuous RD (1.1% vs. 0.4% for the other two regimens).

The incidence of second primary malignancies was lower in both RD groups, consisting of one case each of acute myeloid leukemia and myelodysplasia in each group, compared with four cases of acute myeloid leukemia, six of myelodysplasia, and two cases of myelodysplasia converting to acute myeloid leukemia in the MPT group.

Current treatment approaches for elderly, newly diagnosed patients with multiple myeloma include MPT, which is associated with a PFS of 20.3 months; and bortezomib (Velcade), melphalan, and prednisone (VMP), with a PFS of 18.3 months. MPT and VMP are the preferred regimens recommend by the National Comprehensive Cancer Network for patients who are ineligible for stem cell transplants because of age or other factors, Dr. Facon noted. Typically, drug therapy in this patient population has had a fixed duration because of f concern for toxicities associated with long-term therapy.

Dr. San Miguel noted that the excellent results were achieved without the use of an alkylating agent such as melphalan or cyclophosphamide, which might lead some clinicians to question whether alkylating agents still have a role in this population. He pointed out, however, that the study was not designed to answer that question. To do so, it would be necessary to compare RD with and without an alkylator for the same treatment duration.

"Probably the most challenging question is the duration of the lenalidomide treatment. The data indicate that the best option is to treat until progression. Nevertheless, it would be interesting to know the outcome according to response, because it could be that in patients taking lenalidomide and dexamethasone for 1 year or [1 1/2 years] will achieve a complete response with prolonged disease stability. Additional treatment may not add too much, and this could contribute to increased cost and toxicities of unnecessary prolonged treatment," he said.

Questions that still need to be answered include benefits for specific populations, such as high-risk patients, the very elderly, and those with renal insufficiency. It’s also unclear whether the reduced risk of secondary malignancies is because of the absence of melphalan or the presence of dexamethasone.

It will also be important to find a way to indentify, as early as possible, the 25% of patients who will not achieve at least a partial response, he said.

The study was supported by Celegene Corporation and by the Intergroupe Francophone du Myelome. Dr. Facon disclosed serving on the speakers bureau and being a member on a board of directors/advisory committee for Celgene. Dr. San Miguel reported having no disclosures.

NEW ORLEANS – The glycoengineered CD20-antibody obinutuzumab is already being hailed as a breakthrough first-line therapy for chronic lymphocytic leukemia, and clinicians finally got to see the full data behind the accolades and its recent approval.

In the CLL11 study of older chronic lymphocytic leukemia (CLL) patients with coexisting medical problems, obinutuzumab (Gazyva) pushed the overall response rate to 78%, compared with 65% with rituximab (Rituxan) (P less than .0001). Both drugs were used in combination with chlorambucil chemotherapy.

Complete remission occurred in 21% of patients given obinutuzumab, formerly known as GA101, and 7% on rituximab.

More patients receiving obinutuzumab also achieved minimal residual disease in bone marrow (19.5% vs. 2.6%) and blood (37.7% vs. 3.3%); both differences were statistically significant at P less than .0001), Dr. Valentin Goede reported during a plenary session at the annual meeting of the American Society of Hematology.

Obinutuzumab significantly extended the study’s primary endpoint of progression-free survival to 26.7 months from 15.2 months with combination rituximab (hazard ratio, 0.39; P less than .0001), and delivered a huge 15-month advantage in median progression-free survival over chlorambucil alone(11.1 months vs. 26.7 months; HR, 0.18; P less than .0001).

Overall survival data are still immature at about 18 months but look promising, with 28 deaths on obinutuzumab (8%) and 41 (12%) on rituximab (HR, 0.66; P = .08), said Dr. Goede of the German CLL Study Group and University Hospital Cologne, Germany.

During a press conference, he described the results of the CLL11 trial as practice-changing for older CLL patients, who comprise the bulk of patients clinicians see, but not for all patients with CLL.

"If we combine GA101 or rituximab with a weaker chemotherapy backbone, GA101 obviously is superior to rituximab in this setting, and will substitute for rituximab," he said. "It is more difficult to give an estimation for younger patients, where as you know, rituximab is combined with much more aggressive chemotherapy backbones. We know that these therapies are very effective in these patients and we don’t know how much GA101 adds to the efficacy when replacing rituximab."

Dr. Jennifer R. Brown, press briefing moderator and director of the chronic lymphocytic leukemia center at the Dana-Farber Cancer Institute in Boston, said there has been a great deal of skepticism prior to CLL11 that any CD20 antibody would beat rituximab so definitively in a head-to-head study.

"The results are very impressive and in this patient population, obinutuzumab clearly beat rituximab. So going forward, it will be of great interest to study [obinutuzumab] in other contexts," she said.

Almost 40% of the 663 patients in the head-to-head comparison were older than 75 years (median age, 73 years) and all had common comorbidities such as cardiovascular disease, diabetes mellitus, dyslipidemia, and chronic obstructive pulmonary disease.

All 781 patients in the CLL11 study had previously untreated CLL and a total Cumulative Illness Rating Scale score of more than 6 and/or a creatinine clearance rate of less than 70 mL/min.

Results from the first stage of the phase III study comparing chlorambucil alone with obinutuzumab were reported earlier this year at the annual meeting of the American Society of Clinical Oncology.

Obinutuzumab was approved in November in combination with chlorambucil for the first-line treatment of CLL, and carries boxed warnings regarding the potential for hepatitis B reactivation and progressive multifocal leukoencephalopathy, which have been reported in rare cases in other obinutuzumab trials. These adverse events have not been seen so far in CLL11, but were added to the label because they are known risks with other monoclonal antibodies including rituximab, Dr. Goede said in an interview.

Overall grade 3/4 adverse events were more common with obinutuzumab than rituximab (70% vs. 55%), primarily driven by infusion-related reactions (20% vs. 4%). These reactions occurred only during the first infusion and should be managed with corticosteroid prophylaxis and a slow initial infusion rate, he said. Neutropenia was also increased (33% vs. 28%) but did not lead to an increase in infections.

Dr. Goede reported honoraria from Mundipharma and Hoffman-La Roche; several coauthors reported financial relationships including board membership and employment with Roche, parent company of Genentech, which makes obinutuzumab.

pwendling@frontlinemedcom.com

NEW ORLEANS – The glycoengineered CD20-antibody obinutuzumab is already being hailed as a breakthrough first-line therapy for chronic lymphocytic leukemia, and clinicians finally got to see the full data behind the accolades and its recent approval.

In the CLL11 study of older chronic lymphocytic leukemia (CLL) patients with coexisting medical problems, obinutuzumab (Gazyva) pushed the overall response rate to 78%, compared with 65% with rituximab (Rituxan) (P less than .0001). Both drugs were used in combination with chlorambucil chemotherapy.

Complete remission occurred in 21% of patients given obinutuzumab, formerly known as GA101, and 7% on rituximab.

More patients receiving obinutuzumab also achieved minimal residual disease in bone marrow (19.5% vs. 2.6%) and blood (37.7% vs. 3.3%); both differences were statistically significant at P less than .0001), Dr. Valentin Goede reported during a plenary session at the annual meeting of the American Society of Hematology.

Obinutuzumab significantly extended the study’s primary endpoint of progression-free survival to 26.7 months from 15.2 months with combination rituximab (hazard ratio, 0.39; P less than .0001), and delivered a huge 15-month advantage in median progression-free survival over chlorambucil alone(11.1 months vs. 26.7 months; HR, 0.18; P less than .0001).

Overall survival data are still immature at about 18 months but look promising, with 28 deaths on obinutuzumab (8%) and 41 (12%) on rituximab (HR, 0.66; P = .08), said Dr. Goede of the German CLL Study Group and University Hospital Cologne, Germany.

During a press conference, he described the results of the CLL11 trial as practice-changing for older CLL patients, who comprise the bulk of patients clinicians see, but not for all patients with CLL.

"If we combine GA101 or rituximab with a weaker chemotherapy backbone, GA101 obviously is superior to rituximab in this setting, and will substitute for rituximab," he said. "It is more difficult to give an estimation for younger patients, where as you know, rituximab is combined with much more aggressive chemotherapy backbones. We know that these therapies are very effective in these patients and we don’t know how much GA101 adds to the efficacy when replacing rituximab."

Dr. Jennifer R. Brown, press briefing moderator and director of the chronic lymphocytic leukemia center at the Dana-Farber Cancer Institute in Boston, said there has been a great deal of skepticism prior to CLL11 that any CD20 antibody would beat rituximab so definitively in a head-to-head study.

"The results are very impressive and in this patient population, obinutuzumab clearly beat rituximab. So going forward, it will be of great interest to study [obinutuzumab] in other contexts," she said.

Almost 40% of the 663 patients in the head-to-head comparison were older than 75 years (median age, 73 years) and all had common comorbidities such as cardiovascular disease, diabetes mellitus, dyslipidemia, and chronic obstructive pulmonary disease.

All 781 patients in the CLL11 study had previously untreated CLL and a total Cumulative Illness Rating Scale score of more than 6 and/or a creatinine clearance rate of less than 70 mL/min.

Results from the first stage of the phase III study comparing chlorambucil alone with obinutuzumab were reported earlier this year at the annual meeting of the American Society of Clinical Oncology.

Obinutuzumab was approved in November in combination with chlorambucil for the first-line treatment of CLL, and carries boxed warnings regarding the potential for hepatitis B reactivation and progressive multifocal leukoencephalopathy, which have been reported in rare cases in other obinutuzumab trials. These adverse events have not been seen so far in CLL11, but were added to the label because they are known risks with other monoclonal antibodies including rituximab, Dr. Goede said in an interview.

Overall grade 3/4 adverse events were more common with obinutuzumab than rituximab (70% vs. 55%), primarily driven by infusion-related reactions (20% vs. 4%). These reactions occurred only during the first infusion and should be managed with corticosteroid prophylaxis and a slow initial infusion rate, he said. Neutropenia was also increased (33% vs. 28%) but did not lead to an increase in infections.

Dr. Goede reported honoraria from Mundipharma and Hoffman-La Roche; several coauthors reported financial relationships including board membership and employment with Roche, parent company of Genentech, which makes obinutuzumab.

pwendling@frontlinemedcom.com

NEW ORLEANS – The glycoengineered CD20-antibody obinutuzumab is already being hailed as a breakthrough first-line therapy for chronic lymphocytic leukemia, and clinicians finally got to see the full data behind the accolades and its recent approval.

In the CLL11 study of older chronic lymphocytic leukemia (CLL) patients with coexisting medical problems, obinutuzumab (Gazyva) pushed the overall response rate to 78%, compared with 65% with rituximab (Rituxan) (P less than .0001). Both drugs were used in combination with chlorambucil chemotherapy.

Complete remission occurred in 21% of patients given obinutuzumab, formerly known as GA101, and 7% on rituximab.

More patients receiving obinutuzumab also achieved minimal residual disease in bone marrow (19.5% vs. 2.6%) and blood (37.7% vs. 3.3%); both differences were statistically significant at P less than .0001), Dr. Valentin Goede reported during a plenary session at the annual meeting of the American Society of Hematology.

Obinutuzumab significantly extended the study’s primary endpoint of progression-free survival to 26.7 months from 15.2 months with combination rituximab (hazard ratio, 0.39; P less than .0001), and delivered a huge 15-month advantage in median progression-free survival over chlorambucil alone(11.1 months vs. 26.7 months; HR, 0.18; P less than .0001).

Overall survival data are still immature at about 18 months but look promising, with 28 deaths on obinutuzumab (8%) and 41 (12%) on rituximab (HR, 0.66; P = .08), said Dr. Goede of the German CLL Study Group and University Hospital Cologne, Germany.

During a press conference, he described the results of the CLL11 trial as practice-changing for older CLL patients, who comprise the bulk of patients clinicians see, but not for all patients with CLL.

"If we combine GA101 or rituximab with a weaker chemotherapy backbone, GA101 obviously is superior to rituximab in this setting, and will substitute for rituximab," he said. "It is more difficult to give an estimation for younger patients, where as you know, rituximab is combined with much more aggressive chemotherapy backbones. We know that these therapies are very effective in these patients and we don’t know how much GA101 adds to the efficacy when replacing rituximab."

Dr. Jennifer R. Brown, press briefing moderator and director of the chronic lymphocytic leukemia center at the Dana-Farber Cancer Institute in Boston, said there has been a great deal of skepticism prior to CLL11 that any CD20 antibody would beat rituximab so definitively in a head-to-head study.

"The results are very impressive and in this patient population, obinutuzumab clearly beat rituximab. So going forward, it will be of great interest to study [obinutuzumab] in other contexts," she said.

Almost 40% of the 663 patients in the head-to-head comparison were older than 75 years (median age, 73 years) and all had common comorbidities such as cardiovascular disease, diabetes mellitus, dyslipidemia, and chronic obstructive pulmonary disease.

All 781 patients in the CLL11 study had previously untreated CLL and a total Cumulative Illness Rating Scale score of more than 6 and/or a creatinine clearance rate of less than 70 mL/min.

Results from the first stage of the phase III study comparing chlorambucil alone with obinutuzumab were reported earlier this year at the annual meeting of the American Society of Clinical Oncology.

Obinutuzumab was approved in November in combination with chlorambucil for the first-line treatment of CLL, and carries boxed warnings regarding the potential for hepatitis B reactivation and progressive multifocal leukoencephalopathy, which have been reported in rare cases in other obinutuzumab trials. These adverse events have not been seen so far in CLL11, but were added to the label because they are known risks with other monoclonal antibodies including rituximab, Dr. Goede said in an interview.

Overall grade 3/4 adverse events were more common with obinutuzumab than rituximab (70% vs. 55%), primarily driven by infusion-related reactions (20% vs. 4%). These reactions occurred only during the first infusion and should be managed with corticosteroid prophylaxis and a slow initial infusion rate, he said. Neutropenia was also increased (33% vs. 28%) but did not lead to an increase in infections.

Dr. Goede reported honoraria from Mundipharma and Hoffman-La Roche; several coauthors reported financial relationships including board membership and employment with Roche, parent company of Genentech, which makes obinutuzumab.

pwendling@frontlinemedcom.com

NEW ORLEANS – Gemtuzumab, an antileukemia antibody withdrawn from the market in 2010, has been shown to reduce relapse risk and improve event-free survival when added to conventional therapy in children with acute myeloid leukemia.

Among 1,022 children with AML who were followed for a median of 3.6 years, 3-year event-free survival rates were 53% for children and young adults treated with gemtuzumab ozogamicin added to a standard chemotherapy induction/intensification regimen, compared with 47% for patients treated with chemotherapy alone, said Dr. Alan Gamis, associate division director of the section of oncology at Children’s Mercy Hospital in Kansas City, Mo.

"It would be our thought that [gemtuzumab] would be added to standard therapy at the time of induction for low-risk patients, and it may be a way to enhance the benefits of stem-cell transplant, as we saw for our high-risk patients," Dr. Gamis said in a briefing at the annual meeting of the American Society of Hematology prior to his presentation of data.

Gemtuzumab (formerly marketed as Mylotarg) is a monoclonal antibody linked to the DNA toxin calicheamicin. The antibody targets the CD33 receptor found on the surface of approximately 80%-85% of acute myeloid leukemia (AML) cells and causes both single-stranded and double-stranded DNA breaks.

The agent was voluntarily withdrawn from the market by Pfizer in 2010 at the urging of the U.S. Food and Drug Administration, following a failure to reach the primary endpoint of complete remission in a phase III clinical trial. In that trial, the addition of gemtuzumab to induction therapy was associated with a significantly higher risk of fatal adverse events.

The findings of the current study, however, suggest that gemtuzumab may be worth another look, Dr. Gamis said.

Survival of childhood AML has been gradually improving due to chemotherapy intensification, stem-cell transplants for high-risk patients, and improved supportive care. However, treatment is limited by a relatively high 10%-19% rate of treatment-related mortality. Further, compared with the general population, patients have a 27-fold increased risk for developing late cardiac toxicities from exposure to anthracyclines such as daunorubicin.

"There is also a ceiling to our success. We still, despite the advances in therapy, are only seeing event-free survival between 46% and 59%, and overall survival between 56% and 74% among the best chemotherapy regimens tested throughout the world," Dr. Gamis said.

In the phase III trial, pediatric and adolescent/young adult patients with newly diagnosed AML were randomized to receive induction therapy with the ADE regimen (cytarabine, daunorubicin, and etoposide), with or without gemtuzumab 3 mg/m² on day 6 of the first induction cycle, and, for those patients not going on to immediate stem-cell transplant, on day 7 of the second intensification cycle. Intensification includes, for some patients, additional cytarabine and etoposide, as well as mitoxantrone.

Patients were risk-stratified following induction, with all low-risk patients and with intermediate-risk patients without matched family donors going on to intensification. Intermediate-risk patients with matched donors went on to stem-cell transplant, and high-risk patients went on to transplant with any suitable donor.

A total of 1,070 patients from infancy to up to age 29 years were enrolled from 181 institutions in the United States and Canada. Of this cohort, 1,022 were eligible for analysis.

Three-year overall survival rates were 69.4% in patients who received gemtuzumab, compared with 65.4% in those who received chemotherapy only, a difference that was not statistically significant.

As noted before, however, 3-year event-free survival was significantly better for patients who received gemtuzumab, with a hazard ratio (HR) of 0.83 (P = .04).

In addition, gemtuzumab was associated with a significantly lower risk of relapse, with a 3-year relapse rate of nearly 33%, compared with slightly more than 41% for no gemtuzumab (HR, 0.73; P = .01).

There were no significant differences in nonleukemic mortality, disease-free survival, or overall survival; there appeared to be a trend in each category favoring gemtuzumab, Dr. Gamis said.

Looking at the individual risk groups, gemtuzumab was significantly associated with a reduced risk for relapse in low-risk patients (HR, 0.58; 95% confidence interval, 0.34-0.97). There was a trend, albeit nonsignificant, toward greater treatment-related mortality, primarily from infections during intensification cycles 2 and 3.

There were no significant differences in intermediate-risk patients or in high-risk patients, although in the latter group there were trends favoring gemtuzumab for reduced relapse risk, disease-free survival, and overall survival.

The risk of relapse was consistently reduced in all groups, Dr. Gamis said, but he noted that in intermediate- and high-risk groups that benefit was limited to transplant recipients. The decreased relapse risk in low-risk patients was offset by increases in treatment-related mortality.

The overall treatment-related mortality rates were 2% during induction and 5% overall, and did not differ by study arm. The incidence of veno-occlusive disease was 3% overall and was severe in 0.6% of patients. There were no differences in incidence of this complication between the study arms.

Dr. Joseph Mikhael, who moderated the briefing, commented that the findings are "exciting" and noted that "this agent not only has efficacy, but is particularly well tolerated in this pediatric population." He is an associate professor of medicine at the Mayo Clinic in Scottsdale, Ariz.

The study was supported by the National Cancer Institute. Dr. Gamis and Dr. Mikhael reported no relevant conflicts of interest.

NEW ORLEANS – Gemtuzumab, an antileukemia antibody withdrawn from the market in 2010, has been shown to reduce relapse risk and improve event-free survival when added to conventional therapy in children with acute myeloid leukemia.

Among 1,022 children with AML who were followed for a median of 3.6 years, 3-year event-free survival rates were 53% for children and young adults treated with gemtuzumab ozogamicin added to a standard chemotherapy induction/intensification regimen, compared with 47% for patients treated with chemotherapy alone, said Dr. Alan Gamis, associate division director of the section of oncology at Children’s Mercy Hospital in Kansas City, Mo.

"It would be our thought that [gemtuzumab] would be added to standard therapy at the time of induction for low-risk patients, and it may be a way to enhance the benefits of stem-cell transplant, as we saw for our high-risk patients," Dr. Gamis said in a briefing at the annual meeting of the American Society of Hematology prior to his presentation of data.

Gemtuzumab (formerly marketed as Mylotarg) is a monoclonal antibody linked to the DNA toxin calicheamicin. The antibody targets the CD33 receptor found on the surface of approximately 80%-85% of acute myeloid leukemia (AML) cells and causes both single-stranded and double-stranded DNA breaks.

The agent was voluntarily withdrawn from the market by Pfizer in 2010 at the urging of the U.S. Food and Drug Administration, following a failure to reach the primary endpoint of complete remission in a phase III clinical trial. In that trial, the addition of gemtuzumab to induction therapy was associated with a significantly higher risk of fatal adverse events.

The findings of the current study, however, suggest that gemtuzumab may be worth another look, Dr. Gamis said.

Survival of childhood AML has been gradually improving due to chemotherapy intensification, stem-cell transplants for high-risk patients, and improved supportive care. However, treatment is limited by a relatively high 10%-19% rate of treatment-related mortality. Further, compared with the general population, patients have a 27-fold increased risk for developing late cardiac toxicities from exposure to anthracyclines such as daunorubicin.

"There is also a ceiling to our success. We still, despite the advances in therapy, are only seeing event-free survival between 46% and 59%, and overall survival between 56% and 74% among the best chemotherapy regimens tested throughout the world," Dr. Gamis said.

In the phase III trial, pediatric and adolescent/young adult patients with newly diagnosed AML were randomized to receive induction therapy with the ADE regimen (cytarabine, daunorubicin, and etoposide), with or without gemtuzumab 3 mg/m² on day 6 of the first induction cycle, and, for those patients not going on to immediate stem-cell transplant, on day 7 of the second intensification cycle. Intensification includes, for some patients, additional cytarabine and etoposide, as well as mitoxantrone.

Patients were risk-stratified following induction, with all low-risk patients and with intermediate-risk patients without matched family donors going on to intensification. Intermediate-risk patients with matched donors went on to stem-cell transplant, and high-risk patients went on to transplant with any suitable donor.

A total of 1,070 patients from infancy to up to age 29 years were enrolled from 181 institutions in the United States and Canada. Of this cohort, 1,022 were eligible for analysis.

Three-year overall survival rates were 69.4% in patients who received gemtuzumab, compared with 65.4% in those who received chemotherapy only, a difference that was not statistically significant.

As noted before, however, 3-year event-free survival was significantly better for patients who received gemtuzumab, with a hazard ratio (HR) of 0.83 (P = .04).

In addition, gemtuzumab was associated with a significantly lower risk of relapse, with a 3-year relapse rate of nearly 33%, compared with slightly more than 41% for no gemtuzumab (HR, 0.73; P = .01).

There were no significant differences in nonleukemic mortality, disease-free survival, or overall survival; there appeared to be a trend in each category favoring gemtuzumab, Dr. Gamis said.

Looking at the individual risk groups, gemtuzumab was significantly associated with a reduced risk for relapse in low-risk patients (HR, 0.58; 95% confidence interval, 0.34-0.97). There was a trend, albeit nonsignificant, toward greater treatment-related mortality, primarily from infections during intensification cycles 2 and 3.

There were no significant differences in intermediate-risk patients or in high-risk patients, although in the latter group there were trends favoring gemtuzumab for reduced relapse risk, disease-free survival, and overall survival.

The risk of relapse was consistently reduced in all groups, Dr. Gamis said, but he noted that in intermediate- and high-risk groups that benefit was limited to transplant recipients. The decreased relapse risk in low-risk patients was offset by increases in treatment-related mortality.

The overall treatment-related mortality rates were 2% during induction and 5% overall, and did not differ by study arm. The incidence of veno-occlusive disease was 3% overall and was severe in 0.6% of patients. There were no differences in incidence of this complication between the study arms.

Dr. Joseph Mikhael, who moderated the briefing, commented that the findings are "exciting" and noted that "this agent not only has efficacy, but is particularly well tolerated in this pediatric population." He is an associate professor of medicine at the Mayo Clinic in Scottsdale, Ariz.

The study was supported by the National Cancer Institute. Dr. Gamis and Dr. Mikhael reported no relevant conflicts of interest.

NEW ORLEANS – Gemtuzumab, an antileukemia antibody withdrawn from the market in 2010, has been shown to reduce relapse risk and improve event-free survival when added to conventional therapy in children with acute myeloid leukemia.

Among 1,022 children with AML who were followed for a median of 3.6 years, 3-year event-free survival rates were 53% for children and young adults treated with gemtuzumab ozogamicin added to a standard chemotherapy induction/intensification regimen, compared with 47% for patients treated with chemotherapy alone, said Dr. Alan Gamis, associate division director of the section of oncology at Children’s Mercy Hospital in Kansas City, Mo.

"It would be our thought that [gemtuzumab] would be added to standard therapy at the time of induction for low-risk patients, and it may be a way to enhance the benefits of stem-cell transplant, as we saw for our high-risk patients," Dr. Gamis said in a briefing at the annual meeting of the American Society of Hematology prior to his presentation of data.

Gemtuzumab (formerly marketed as Mylotarg) is a monoclonal antibody linked to the DNA toxin calicheamicin. The antibody targets the CD33 receptor found on the surface of approximately 80%-85% of acute myeloid leukemia (AML) cells and causes both single-stranded and double-stranded DNA breaks.

The agent was voluntarily withdrawn from the market by Pfizer in 2010 at the urging of the U.S. Food and Drug Administration, following a failure to reach the primary endpoint of complete remission in a phase III clinical trial. In that trial, the addition of gemtuzumab to induction therapy was associated with a significantly higher risk of fatal adverse events.

The findings of the current study, however, suggest that gemtuzumab may be worth another look, Dr. Gamis said.

Survival of childhood AML has been gradually improving due to chemotherapy intensification, stem-cell transplants for high-risk patients, and improved supportive care. However, treatment is limited by a relatively high 10%-19% rate of treatment-related mortality. Further, compared with the general population, patients have a 27-fold increased risk for developing late cardiac toxicities from exposure to anthracyclines such as daunorubicin.

"There is also a ceiling to our success. We still, despite the advances in therapy, are only seeing event-free survival between 46% and 59%, and overall survival between 56% and 74% among the best chemotherapy regimens tested throughout the world," Dr. Gamis said.

In the phase III trial, pediatric and adolescent/young adult patients with newly diagnosed AML were randomized to receive induction therapy with the ADE regimen (cytarabine, daunorubicin, and etoposide), with or without gemtuzumab 3 mg/m² on day 6 of the first induction cycle, and, for those patients not going on to immediate stem-cell transplant, on day 7 of the second intensification cycle. Intensification includes, for some patients, additional cytarabine and etoposide, as well as mitoxantrone.

Patients were risk-stratified following induction, with all low-risk patients and with intermediate-risk patients without matched family donors going on to intensification. Intermediate-risk patients with matched donors went on to stem-cell transplant, and high-risk patients went on to transplant with any suitable donor.

A total of 1,070 patients from infancy to up to age 29 years were enrolled from 181 institutions in the United States and Canada. Of this cohort, 1,022 were eligible for analysis.

Three-year overall survival rates were 69.4% in patients who received gemtuzumab, compared with 65.4% in those who received chemotherapy only, a difference that was not statistically significant.

As noted before, however, 3-year event-free survival was significantly better for patients who received gemtuzumab, with a hazard ratio (HR) of 0.83 (P = .04).

In addition, gemtuzumab was associated with a significantly lower risk of relapse, with a 3-year relapse rate of nearly 33%, compared with slightly more than 41% for no gemtuzumab (HR, 0.73; P = .01).

There were no significant differences in nonleukemic mortality, disease-free survival, or overall survival; there appeared to be a trend in each category favoring gemtuzumab, Dr. Gamis said.

Looking at the individual risk groups, gemtuzumab was significantly associated with a reduced risk for relapse in low-risk patients (HR, 0.58; 95% confidence interval, 0.34-0.97). There was a trend, albeit nonsignificant, toward greater treatment-related mortality, primarily from infections during intensification cycles 2 and 3.

There were no significant differences in intermediate-risk patients or in high-risk patients, although in the latter group there were trends favoring gemtuzumab for reduced relapse risk, disease-free survival, and overall survival.

The risk of relapse was consistently reduced in all groups, Dr. Gamis said, but he noted that in intermediate- and high-risk groups that benefit was limited to transplant recipients. The decreased relapse risk in low-risk patients was offset by increases in treatment-related mortality.

The overall treatment-related mortality rates were 2% during induction and 5% overall, and did not differ by study arm. The incidence of veno-occlusive disease was 3% overall and was severe in 0.6% of patients. There were no differences in incidence of this complication between the study arms.

Dr. Joseph Mikhael, who moderated the briefing, commented that the findings are "exciting" and noted that "this agent not only has efficacy, but is particularly well tolerated in this pediatric population." He is an associate professor of medicine at the Mayo Clinic in Scottsdale, Ariz.

The study was supported by the National Cancer Institute. Dr. Gamis and Dr. Mikhael reported no relevant conflicts of interest.

NEW ORLEANS – Older patients with hematologic malignancies should be offered reduced-intensity haploidentical bone marrow transplants if followed with high-dose cyclophosphamide, a study indicates.

Overall outcomes and toxicities were not only comparable between patients in their 50s, 60s and 70s, but similar to those seen with matched bone marrow transplantation (BMT), Dr. Yvette Kasamon reported at the annual meeting of the American Society of Hematology.

"Since many elderly patients may lack a suitable matched sibling donor, the haplo option becomes even more attractive," Dr. Kasamon, with the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, said during a press briefing.

The current results are likely to spark a dramatic expansion in related haploidentical -- or half-matched -- transplants, which are performed at relatively few transplant centers because of concerns of excessive risk.

"What this adds is another option that is safe in the elderly — and that’s a lot of people," commented Dr. Jeffrey S. Miller, with the University of Minnesota Blood and Marrow Transplant Clinic in Minneapolis. "The incidence of AML goes up with age. So you’re talking about a population, at least with acute myeloid leukemia, where the elderly are the target population for the disease and typically those patients would not get transplants. Now we’re hearing that this is actually the treatment of choice and the outcomes are better."

Recent advances such as cord blood transplants and reduced-intensity conditioning BMT have increased transplants, but another major advance was the introduction of high-dose, post-transplant cyclophosphamide for graft-versus-host disease prophylaxis, Dr. Kasamon said. With post-transplant cyclophosphamide, reduced-intensity haplo BMT has been shown to be safe and effective (Blood 2011;118:282-8).

To examine the impact of older age on this approach, Dr. Kasamon and her colleagues retrospectively analyzed 273 consecutive patients, aged 50-75 years, treated at Johns Hopkins for poor-risk lymphoma (n=153), acute leukemia or myelodysplastic syndrome (n=96), and other hematologic malignancies (n=24). The preconditioning regimen was comprised of cyclophosphamide, fludarabine, and 200 cGy of total body irradiation, with two doses of cyclophosphamide post-transplant. No prior allogeneic* BMT was allowed and post-BMT rituximab (Rituxan) was used in 55 of 126 patients with B-cell lymphoma.

Patients in their 50s, 60s, and 70s had similar estimated 2-year progression-free survival (39%, 36%,and 39%, respectively) and overall survival (51%, 56%, and 44%, respectively).

The risk of non-relapse death was similar at 6 months (11% overall) and the risk was only 3% for severe acute graft-versus-host disease, which makes these risks comparable to what is seen in patients with matched transplants, Dr. Kasamon said.

"With recent advances in how we do these transplants, haploidentical transplants are a very reasonable consideration for patients who don’t have matched donors and who are otherwise in desperate need of transplant," she said.

The procedure will also reduce the time spent hunting for an unrelated match, which is a 50-50 chance for some and even worse odds for African-Americans, who have a limited chance of an unrelated match. Almost every patient has at least one haploidentical relative, often sitting alongside their bed, Dr. Kasamon said.

Based on the data, Johns Hopkins recently lifted its upper age limit of 75 years for transplants, and now looks to performance status and overall functioning to determine a patient’s fitness for transplant. "As long as they can meet our criteria, age is no longer a barrier at our institution," she noted.

Dr. Kasamon and her co-authors reported having no financial disclosures.

pwendling@frontlinemedcom.com

*Correction, 12/16/2013: An earlier version of this story did not specify that patients with prior allogenic bone marrow transplants were excluded from the study. Details related to the risk of non-relapse death also were misstated.

NEW ORLEANS – Older patients with hematologic malignancies should be offered reduced-intensity haploidentical bone marrow transplants if followed with high-dose cyclophosphamide, a study indicates.

Overall outcomes and toxicities were not only comparable between patients in their 50s, 60s and 70s, but similar to those seen with matched bone marrow transplantation (BMT), Dr. Yvette Kasamon reported at the annual meeting of the American Society of Hematology.

"Since many elderly patients may lack a suitable matched sibling donor, the haplo option becomes even more attractive," Dr. Kasamon, with the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, said during a press briefing.

The current results are likely to spark a dramatic expansion in related haploidentical -- or half-matched -- transplants, which are performed at relatively few transplant centers because of concerns of excessive risk.

"What this adds is another option that is safe in the elderly — and that’s a lot of people," commented Dr. Jeffrey S. Miller, with the University of Minnesota Blood and Marrow Transplant Clinic in Minneapolis. "The incidence of AML goes up with age. So you’re talking about a population, at least with acute myeloid leukemia, where the elderly are the target population for the disease and typically those patients would not get transplants. Now we’re hearing that this is actually the treatment of choice and the outcomes are better."

Recent advances such as cord blood transplants and reduced-intensity conditioning BMT have increased transplants, but another major advance was the introduction of high-dose, post-transplant cyclophosphamide for graft-versus-host disease prophylaxis, Dr. Kasamon said. With post-transplant cyclophosphamide, reduced-intensity haplo BMT has been shown to be safe and effective (Blood 2011;118:282-8).

To examine the impact of older age on this approach, Dr. Kasamon and her colleagues retrospectively analyzed 273 consecutive patients, aged 50-75 years, treated at Johns Hopkins for poor-risk lymphoma (n=153), acute leukemia or myelodysplastic syndrome (n=96), and other hematologic malignancies (n=24). The preconditioning regimen was comprised of cyclophosphamide, fludarabine, and 200 cGy of total body irradiation, with two doses of cyclophosphamide post-transplant. No prior allogeneic* BMT was allowed and post-BMT rituximab (Rituxan) was used in 55 of 126 patients with B-cell lymphoma.

Patients in their 50s, 60s, and 70s had similar estimated 2-year progression-free survival (39%, 36%,and 39%, respectively) and overall survival (51%, 56%, and 44%, respectively).

The risk of non-relapse death was similar at 6 months (11% overall) and the risk was only 3% for severe acute graft-versus-host disease, which makes these risks comparable to what is seen in patients with matched transplants, Dr. Kasamon said.

"With recent advances in how we do these transplants, haploidentical transplants are a very reasonable consideration for patients who don’t have matched donors and who are otherwise in desperate need of transplant," she said.

The procedure will also reduce the time spent hunting for an unrelated match, which is a 50-50 chance for some and even worse odds for African-Americans, who have a limited chance of an unrelated match. Almost every patient has at least one haploidentical relative, often sitting alongside their bed, Dr. Kasamon said.

Based on the data, Johns Hopkins recently lifted its upper age limit of 75 years for transplants, and now looks to performance status and overall functioning to determine a patient’s fitness for transplant. "As long as they can meet our criteria, age is no longer a barrier at our institution," she noted.

Dr. Kasamon and her co-authors reported having no financial disclosures.

pwendling@frontlinemedcom.com

*Correction, 12/16/2013: An earlier version of this story did not specify that patients with prior allogenic bone marrow transplants were excluded from the study. Details related to the risk of non-relapse death also were misstated.

NEW ORLEANS – Older patients with hematologic malignancies should be offered reduced-intensity haploidentical bone marrow transplants if followed with high-dose cyclophosphamide, a study indicates.

Overall outcomes and toxicities were not only comparable between patients in their 50s, 60s and 70s, but similar to those seen with matched bone marrow transplantation (BMT), Dr. Yvette Kasamon reported at the annual meeting of the American Society of Hematology.

"Since many elderly patients may lack a suitable matched sibling donor, the haplo option becomes even more attractive," Dr. Kasamon, with the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, said during a press briefing.

The current results are likely to spark a dramatic expansion in related haploidentical -- or half-matched -- transplants, which are performed at relatively few transplant centers because of concerns of excessive risk.

"What this adds is another option that is safe in the elderly — and that’s a lot of people," commented Dr. Jeffrey S. Miller, with the University of Minnesota Blood and Marrow Transplant Clinic in Minneapolis. "The incidence of AML goes up with age. So you’re talking about a population, at least with acute myeloid leukemia, where the elderly are the target population for the disease and typically those patients would not get transplants. Now we’re hearing that this is actually the treatment of choice and the outcomes are better."

Recent advances such as cord blood transplants and reduced-intensity conditioning BMT have increased transplants, but another major advance was the introduction of high-dose, post-transplant cyclophosphamide for graft-versus-host disease prophylaxis, Dr. Kasamon said. With post-transplant cyclophosphamide, reduced-intensity haplo BMT has been shown to be safe and effective (Blood 2011;118:282-8).

To examine the impact of older age on this approach, Dr. Kasamon and her colleagues retrospectively analyzed 273 consecutive patients, aged 50-75 years, treated at Johns Hopkins for poor-risk lymphoma (n=153), acute leukemia or myelodysplastic syndrome (n=96), and other hematologic malignancies (n=24). The preconditioning regimen was comprised of cyclophosphamide, fludarabine, and 200 cGy of total body irradiation, with two doses of cyclophosphamide post-transplant. No prior allogeneic* BMT was allowed and post-BMT rituximab (Rituxan) was used in 55 of 126 patients with B-cell lymphoma.

Patients in their 50s, 60s, and 70s had similar estimated 2-year progression-free survival (39%, 36%,and 39%, respectively) and overall survival (51%, 56%, and 44%, respectively).

The risk of non-relapse death was similar at 6 months (11% overall) and the risk was only 3% for severe acute graft-versus-host disease, which makes these risks comparable to what is seen in patients with matched transplants, Dr. Kasamon said.

"With recent advances in how we do these transplants, haploidentical transplants are a very reasonable consideration for patients who don’t have matched donors and who are otherwise in desperate need of transplant," she said.

The procedure will also reduce the time spent hunting for an unrelated match, which is a 50-50 chance for some and even worse odds for African-Americans, who have a limited chance of an unrelated match. Almost every patient has at least one haploidentical relative, often sitting alongside their bed, Dr. Kasamon said.

Based on the data, Johns Hopkins recently lifted its upper age limit of 75 years for transplants, and now looks to performance status and overall functioning to determine a patient’s fitness for transplant. "As long as they can meet our criteria, age is no longer a barrier at our institution," she noted.

Dr. Kasamon and her co-authors reported having no financial disclosures.

pwendling@frontlinemedcom.com

*Correction, 12/16/2013: An earlier version of this story did not specify that patients with prior allogenic bone marrow transplants were excluded from the study. Details related to the risk of non-relapse death also were misstated.

NEW ORLEANS – A majority of patients with aggressive, treatment-refractory lymphomas had a complete or partial remission after being treated with chemotherapy and T-cells engineered to target the CD-19 receptor, National Cancer Institute investigators reported here.

In a study of 15 patients, 9 of whom had aggressive large-cell lymphomas and 6 of whom had indolent B-cell malignancies, 6 of 13 evaluable patients had a complete remission, 6 had a partial remission, and 1 had stable disease, said Dr. James N. Kochenderfer, an investigator in the Experimental Transplantation and Immunology Branch at the National Cancer Institute in Bethesda, Md.

One patient who, despite having undergone 10 prior therapies -- including 3 rituximab-based chemotherapy regimens -- continued to have lymphoma involvement of the liver and other abdominal areas, remains in complete remission 9 months after treatment with a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19, Dr. Kochenderfer said at the American Society of Hematology annual meeting.

"We’ve chosen to focus on the aggressive large-cell lymphomas, because patients with these lymphomas, such as diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma, have a very poor prognosis if they are refractory to chemotherapy," he said in a briefing prior to his presentation of the results in oral session.

Commenting on the CAR-T cell strategy, Dr. Laurence Cooper of the University of Texas MD Anderson Cancer Center in Houston, who moderated the briefing, noted that "these patients were mortally wounded – they were all going to die, except that these types of engineered T-cell therapies rescued the patients."

The NCI investigators genetically modify each patient’s T-cells in vitro, using a gammaretroviral vector to induce in the cells expression of an anti-CD19 antibody. The process takes 10 days, during which time the patients receive cyclophosphamide and fludarabine to deplete their endogenous leukocytes.

"There’s extensive evidence in multiple animal models and also in humans that shows that depletion of endogenous lymphocytes dramatically enhances the activity of adoptively transferred T-cells. In mouse models, it’s absolutely critical for effectiveness of these CAR T-cells," Dr. Kochenderfer said.

The patients are then infused with the anti-C19-CAR transduced T-cells.

The investigators thus far have treated 15 patients with the technique, including, as noted before, 9 with chemo-refractory large cell lymphomas.

Treatment toxicities included hypotension and neurological toxicities such as confusion, delirium, and transient aphasia.

"Another thing about this therapy that’s amazing is that the patients do become sick; we previously published that the toxicity correlates with serum cytokine levels. [However] they recover very quickly: they can go from being incredibly ill to completely feeling almost normal within 2 days," Dr. Kochenderfer noted.

He and his colleagues also have used the technique in 10 patients who had persistent B-cell malignancies or other cancers following allogeneic stem cell transplantation as an alternative to donor lymphocyte infusions, which have shown inconsistent efficacy and are associated with significant risk for morbidity and mortality for graft-versus-host disease (GvHD).

Of 10 patients treated to date, 3 had "substantial regression" of their malignancies, and one patient with chronic lymphoctic leukemia (CLL) is still in complete remission 12 months after treatment. Another CLL patient had tumor lysis syndrome as he experienced regression of CLL in his bone marrow, blood, and lymph nodes. A patient with the notoriously treatment-refractory mantle cell lymphoma had a partial remission.

As in the first study, toxicities were manageable and consisted mainly of fever, hypotension, and B-cell depletion. No patients developed GvHD after infusion of the altered T-cells.

The study was funded by the National Cancer Institute and by Kite Pharma. Dr. Kochenderfer and Dr. Cooper reported having no conflicts of interest to disclose.

NEW ORLEANS – A majority of patients with aggressive, treatment-refractory lymphomas had a complete or partial remission after being treated with chemotherapy and T-cells engineered to target the CD-19 receptor, National Cancer Institute investigators reported here.

In a study of 15 patients, 9 of whom had aggressive large-cell lymphomas and 6 of whom had indolent B-cell malignancies, 6 of 13 evaluable patients had a complete remission, 6 had a partial remission, and 1 had stable disease, said Dr. James N. Kochenderfer, an investigator in the Experimental Transplantation and Immunology Branch at the National Cancer Institute in Bethesda, Md.

One patient who, despite having undergone 10 prior therapies -- including 3 rituximab-based chemotherapy regimens -- continued to have lymphoma involvement of the liver and other abdominal areas, remains in complete remission 9 months after treatment with a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19, Dr. Kochenderfer said at the American Society of Hematology annual meeting.

"We’ve chosen to focus on the aggressive large-cell lymphomas, because patients with these lymphomas, such as diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma, have a very poor prognosis if they are refractory to chemotherapy," he said in a briefing prior to his presentation of the results in oral session.

Commenting on the CAR-T cell strategy, Dr. Laurence Cooper of the University of Texas MD Anderson Cancer Center in Houston, who moderated the briefing, noted that "these patients were mortally wounded – they were all going to die, except that these types of engineered T-cell therapies rescued the patients."

The NCI investigators genetically modify each patient’s T-cells in vitro, using a gammaretroviral vector to induce in the cells expression of an anti-CD19 antibody. The process takes 10 days, during which time the patients receive cyclophosphamide and fludarabine to deplete their endogenous leukocytes.

"There’s extensive evidence in multiple animal models and also in humans that shows that depletion of endogenous lymphocytes dramatically enhances the activity of adoptively transferred T-cells. In mouse models, it’s absolutely critical for effectiveness of these CAR T-cells," Dr. Kochenderfer said.

The patients are then infused with the anti-C19-CAR transduced T-cells.

The investigators thus far have treated 15 patients with the technique, including, as noted before, 9 with chemo-refractory large cell lymphomas.

Treatment toxicities included hypotension and neurological toxicities such as confusion, delirium, and transient aphasia.

"Another thing about this therapy that’s amazing is that the patients do become sick; we previously published that the toxicity correlates with serum cytokine levels. [However] they recover very quickly: they can go from being incredibly ill to completely feeling almost normal within 2 days," Dr. Kochenderfer noted.

He and his colleagues also have used the technique in 10 patients who had persistent B-cell malignancies or other cancers following allogeneic stem cell transplantation as an alternative to donor lymphocyte infusions, which have shown inconsistent efficacy and are associated with significant risk for morbidity and mortality for graft-versus-host disease (GvHD).

Of 10 patients treated to date, 3 had "substantial regression" of their malignancies, and one patient with chronic lymphoctic leukemia (CLL) is still in complete remission 12 months after treatment. Another CLL patient had tumor lysis syndrome as he experienced regression of CLL in his bone marrow, blood, and lymph nodes. A patient with the notoriously treatment-refractory mantle cell lymphoma had a partial remission.

As in the first study, toxicities were manageable and consisted mainly of fever, hypotension, and B-cell depletion. No patients developed GvHD after infusion of the altered T-cells.

The study was funded by the National Cancer Institute and by Kite Pharma. Dr. Kochenderfer and Dr. Cooper reported having no conflicts of interest to disclose.

NEW ORLEANS – A majority of patients with aggressive, treatment-refractory lymphomas had a complete or partial remission after being treated with chemotherapy and T-cells engineered to target the CD-19 receptor, National Cancer Institute investigators reported here.

In a study of 15 patients, 9 of whom had aggressive large-cell lymphomas and 6 of whom had indolent B-cell malignancies, 6 of 13 evaluable patients had a complete remission, 6 had a partial remission, and 1 had stable disease, said Dr. James N. Kochenderfer, an investigator in the Experimental Transplantation and Immunology Branch at the National Cancer Institute in Bethesda, Md.

One patient who, despite having undergone 10 prior therapies -- including 3 rituximab-based chemotherapy regimens -- continued to have lymphoma involvement of the liver and other abdominal areas, remains in complete remission 9 months after treatment with a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19, Dr. Kochenderfer said at the American Society of Hematology annual meeting.

"We’ve chosen to focus on the aggressive large-cell lymphomas, because patients with these lymphomas, such as diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma, have a very poor prognosis if they are refractory to chemotherapy," he said in a briefing prior to his presentation of the results in oral session.

Commenting on the CAR-T cell strategy, Dr. Laurence Cooper of the University of Texas MD Anderson Cancer Center in Houston, who moderated the briefing, noted that "these patients were mortally wounded – they were all going to die, except that these types of engineered T-cell therapies rescued the patients."

The NCI investigators genetically modify each patient’s T-cells in vitro, using a gammaretroviral vector to induce in the cells expression of an anti-CD19 antibody. The process takes 10 days, during which time the patients receive cyclophosphamide and fludarabine to deplete their endogenous leukocytes.

"There’s extensive evidence in multiple animal models and also in humans that shows that depletion of endogenous lymphocytes dramatically enhances the activity of adoptively transferred T-cells. In mouse models, it’s absolutely critical for effectiveness of these CAR T-cells," Dr. Kochenderfer said.

The patients are then infused with the anti-C19-CAR transduced T-cells.

The investigators thus far have treated 15 patients with the technique, including, as noted before, 9 with chemo-refractory large cell lymphomas.

Treatment toxicities included hypotension and neurological toxicities such as confusion, delirium, and transient aphasia.

"Another thing about this therapy that’s amazing is that the patients do become sick; we previously published that the toxicity correlates with serum cytokine levels. [However] they recover very quickly: they can go from being incredibly ill to completely feeling almost normal within 2 days," Dr. Kochenderfer noted.

He and his colleagues also have used the technique in 10 patients who had persistent B-cell malignancies or other cancers following allogeneic stem cell transplantation as an alternative to donor lymphocyte infusions, which have shown inconsistent efficacy and are associated with significant risk for morbidity and mortality for graft-versus-host disease (GvHD).

Of 10 patients treated to date, 3 had "substantial regression" of their malignancies, and one patient with chronic lymphoctic leukemia (CLL) is still in complete remission 12 months after treatment. Another CLL patient had tumor lysis syndrome as he experienced regression of CLL in his bone marrow, blood, and lymph nodes. A patient with the notoriously treatment-refractory mantle cell lymphoma had a partial remission.

As in the first study, toxicities were manageable and consisted mainly of fever, hypotension, and B-cell depletion. No patients developed GvHD after infusion of the altered T-cells.

The study was funded by the National Cancer Institute and by Kite Pharma. Dr. Kochenderfer and Dr. Cooper reported having no conflicts of interest to disclose.

NEW ORLEANS – The gap appears to be narrowing between white European patients and European patients of other ethnicities regarding times to stem cell transplant and ability to find a matched donor, based on a study conducted in the United Kingdom.

In the study, non-white northern European patients were less likely than white northern European patients to have a fully-matched donor available. Transplant was ultimately achieved by 62% of white and 56% of nonwhite patients in a four-center study of 332 leukemia and lymphoma patients treated in the United Kingdom in concert with Anthony Nolan, the United Kingdom’s blood cancer charity and bone marrow register. Non-white patients comprised 25% of the patient population, Dr. Robert Lown reported during a press conference held at the annual meeting of the American Society of Hematology.

"The use of cord blood and haploidentical transplants is ‘leveling the playing field’ for non-white patients seeking transplants other than with an HLA-identical sibling," said Dr. Lown of the Royal Marsden Hospital, London, and of Anthony Nolan.

Just 20% of non-white patients in the study had a fully-matched donor available, while 69% of white northern European patients did. A suitable donor was identified, however, for 96% of the white European patients and 61% of patients of other ethnicities. Ultimately, transplant was achieved by 62% of white and 56% of other ethnicity patients. Average time to transplant was 110 days for white patients and 132 days for patients of other ethnicities, he said.

The results reflect improvements since a Dutch study of patients treated from 1996-2000 found that 32% of nonwhite and 59% of white northern Europeans achieved transplants. Typically, those patients who could not find a donor were either not transplanted or used less suitable donors, an option associated with more complications and poorer prognosis, he said.

The number of donors listed in registries has expanded, and new sources of stem cells, like cord blood and haploidentical transplantation, are available, Dr. Lown said. Few studies before this one have examined how these changes have affected the ability of transplant centers to get patients to transplant.

The trial results may not reflect general clinical experience, however, Dr. Lown said. Anthony Nolan uses an expert graft identification and advisory service to optimize donor selection and determine which patients are unlikely to find suitable donors. This practice allows timely use of cord blood and haploidentical transplants, Dr. Lown said. 

The Anthony Nolan Research Institute sponsored the study. Dr. Lown did not disclose any financial conflicts of interest. 

NEW ORLEANS – The gap appears to be narrowing between white European patients and European patients of other ethnicities regarding times to stem cell transplant and ability to find a matched donor, based on a study conducted in the United Kingdom.

In the study, non-white northern European patients were less likely than white northern European patients to have a fully-matched donor available. Transplant was ultimately achieved by 62% of white and 56% of nonwhite patients in a four-center study of 332 leukemia and lymphoma patients treated in the United Kingdom in concert with Anthony Nolan, the United Kingdom’s blood cancer charity and bone marrow register. Non-white patients comprised 25% of the patient population, Dr. Robert Lown reported during a press conference held at the annual meeting of the American Society of Hematology.

"The use of cord blood and haploidentical transplants is ‘leveling the playing field’ for non-white patients seeking transplants other than with an HLA-identical sibling," said Dr. Lown of the Royal Marsden Hospital, London, and of Anthony Nolan.

Just 20% of non-white patients in the study had a fully-matched donor available, while 69% of white northern European patients did. A suitable donor was identified, however, for 96% of the white European patients and 61% of patients of other ethnicities. Ultimately, transplant was achieved by 62% of white and 56% of other ethnicity patients. Average time to transplant was 110 days for white patients and 132 days for patients of other ethnicities, he said.

The results reflect improvements since a Dutch study of patients treated from 1996-2000 found that 32% of nonwhite and 59% of white northern Europeans achieved transplants. Typically, those patients who could not find a donor were either not transplanted or used less suitable donors, an option associated with more complications and poorer prognosis, he said.

The number of donors listed in registries has expanded, and new sources of stem cells, like cord blood and haploidentical transplantation, are available, Dr. Lown said. Few studies before this one have examined how these changes have affected the ability of transplant centers to get patients to transplant.

The trial results may not reflect general clinical experience, however, Dr. Lown said. Anthony Nolan uses an expert graft identification and advisory service to optimize donor selection and determine which patients are unlikely to find suitable donors. This practice allows timely use of cord blood and haploidentical transplants, Dr. Lown said. 

The Anthony Nolan Research Institute sponsored the study. Dr. Lown did not disclose any financial conflicts of interest. 

NEW ORLEANS – The gap appears to be narrowing between white European patients and European patients of other ethnicities regarding times to stem cell transplant and ability to find a matched donor, based on a study conducted in the United Kingdom.

In the study, non-white northern European patients were less likely than white northern European patients to have a fully-matched donor available. Transplant was ultimately achieved by 62% of white and 56% of nonwhite patients in a four-center study of 332 leukemia and lymphoma patients treated in the United Kingdom in concert with Anthony Nolan, the United Kingdom’s blood cancer charity and bone marrow register. Non-white patients comprised 25% of the patient population, Dr. Robert Lown reported during a press conference held at the annual meeting of the American Society of Hematology.

"The use of cord blood and haploidentical transplants is ‘leveling the playing field’ for non-white patients seeking transplants other than with an HLA-identical sibling," said Dr. Lown of the Royal Marsden Hospital, London, and of Anthony Nolan.

Just 20% of non-white patients in the study had a fully-matched donor available, while 69% of white northern European patients did. A suitable donor was identified, however, for 96% of the white European patients and 61% of patients of other ethnicities. Ultimately, transplant was achieved by 62% of white and 56% of other ethnicity patients. Average time to transplant was 110 days for white patients and 132 days for patients of other ethnicities, he said.

The results reflect improvements since a Dutch study of patients treated from 1996-2000 found that 32% of nonwhite and 59% of white northern Europeans achieved transplants. Typically, those patients who could not find a donor were either not transplanted or used less suitable donors, an option associated with more complications and poorer prognosis, he said.

The number of donors listed in registries has expanded, and new sources of stem cells, like cord blood and haploidentical transplantation, are available, Dr. Lown said. Few studies before this one have examined how these changes have affected the ability of transplant centers to get patients to transplant.

The trial results may not reflect general clinical experience, however, Dr. Lown said. Anthony Nolan uses an expert graft identification and advisory service to optimize donor selection and determine which patients are unlikely to find suitable donors. This practice allows timely use of cord blood and haploidentical transplants, Dr. Lown said. 

The Anthony Nolan Research Institute sponsored the study. Dr. Lown did not disclose any financial conflicts of interest. 

NEW ORLEANS  – Full-intensity conditioning regimens before stem-cell transplants put patients at risk for cognitive problems afterward, investigators reported.

Compared with healthy controls, men and women who underwent allogeneic hematopoietic stem transplants (HCT) with full-intensity pre-transplant conditioning continued to have deficits in executive function for at least 2 years after transplant.

In contrast, patients who had reduced-intensity conditioning before their transplants had initial cognitive deficits but recovered gradually, continued to have significantly better cognitive function than patients who had undergone full-intensity conditioning (P = .01), and had no significant deficits in executive function compared with controls at 2-year follow-up, reported Dr. Smita Bhatia, professor and chair of the department of population sciences at City of Hope in Duarte, Calif.

The investigators also found preliminary evidence to suggest that the length of telomeres, the caps at the end of chromosomes that protect chromosomal integrity through cellular division, also may be associated with risk for post-transplant cognitive problems -- at least in women.

In women, telomeric shortening before HCT was associated with poorer cognitive functioning after HCT in domains of executive function, processing speed, verbal speed, and working memory, Dr. Bhatia reported at the American Society of Hematology annual meeting.

Those especially at risk for post-transplant cognitive problems include older patients, men, Hispanics, people with lower socioeconomic status, those with high levels of fatigue, and those who undergo a full-intensity pre-transplant conditioning regimen.

"This study has identified vulnerable sub-populations, and there is a need to develop future interventions targeted toward these patients, as well as to understand the pathogenesis of this outcome," Dr. Bhatia said in a briefing before the presentation of results.

Dr. Bhatia stressed that clinicians need to educate patients and families about the cognitive consequences of transplantation.

"When these patients come back, and especially younger patients when they are not performing well in their schools or college settings, very often the family blames these patients for being lazy, and that is something which we need to absolutely negate and say that this is the effect of the treatment they received, and we need to offer them services," she said.

The investigators conducted a 2-year prospective longitudinal study comparing patients scheduled for HCT with age and sex-matched healthy controls.

The participants underwent baseline testing with a 2-hour battery of standardized neurocognitive tests assessing 8 cognitive domains. Scores of healthy controls were used to correct the scores of HCT patients for practice effects.

Patients also had pre-transplant blood draws tested by assay for relative telomere length, defined as the ratio of telomeres to single genes.

As the authors had previously shown, allogeneic HCT recipients overall have poorer cognitive function than controls in domains of executive function, processing speed, verbal fluency, and fine motor dexterity.

For example, in an analysis adjusted for age, race, and income, controls had significantly better executive function scores than did transplant recipients (P = .0008).

When the researchers drilled down a little deeper, however, they found that patients who had undergone full-intensity conditioning did especially poorly in domains of executive function, processing speed, verbal speed, and visual memory.

When they looked at telomere length, they found in an analysis adjusted for age, race, income, IQ, diagnosis, risk of relapse, and remission status that women with short telomeres fared worse than women with long telomeres. At a 2-year follow-up women with short telomeres had significantly poorer executive function scores (P = .004).

There were no significant associations between telomere length and cognitive function among men, however.

Dr. Bhatia noted that chemotherapy and radiation both accelerate telomere shortening and that glial cells, which divide, therefore are susceptible to telomere shortening, offering a potential explanation for the association between telomere length and cognitive function.

Although the investigators have not yet sorted out which components of the conditioning regimen contribute to cognitive problems, it appears to be a combination of total body irradiation and high-myeloablative intensity agents, Dr. Bhatia said.

Clinical trials testing behavioral therapy and pharmacologic therapy with agents that support attention and cognitive processing, such as methylphenidate, are underway, she noted.

Dr. Jeffrey Miller, who moderated the briefing at which Dr. Bhatia presented the data, noted that reduced-intensity pre-transplant conditioning is suitable for older, frailer patients, and in this study was shown to offer cognitive protection compared with full-intensity conditioning.

Reduced-intensity conditioning, however, comes with a significant trade-off in terms of increased risk for relapse, said Dr. Miller, deputy director of the Masonic Cancer Center and the Clinical and Translational Sciences Institute, University of Minnesota, Minneapolis.

Dr. Bhatia commented that the most important clinical consideration is which treatment strategy is likely to offer the best relapse-free survival.

"Then we have the luxury of looking at whether we have a mode of therapy that is less toxic down the road," she said.

The study was supported in part by the Leukemia & Lymphoma Society. Dr. Bhatia and Dr. Miller reported having no relevant conflicts of interest to disclose.

NEW ORLEANS  – Full-intensity conditioning regimens before stem-cell transplants put patients at risk for cognitive problems afterward, investigators reported.

Compared with healthy controls, men and women who underwent allogeneic hematopoietic stem transplants (HCT) with full-intensity pre-transplant conditioning continued to have deficits in executive function for at least 2 years after transplant.

In contrast, patients who had reduced-intensity conditioning before their transplants had initial cognitive deficits but recovered gradually, continued to have significantly better cognitive function than patients who had undergone full-intensity conditioning (P = .01), and had no significant deficits in executive function compared with controls at 2-year follow-up, reported Dr. Smita Bhatia, professor and chair of the department of population sciences at City of Hope in Duarte, Calif.

The investigators also found preliminary evidence to suggest that the length of telomeres, the caps at the end of chromosomes that protect chromosomal integrity through cellular division, also may be associated with risk for post-transplant cognitive problems -- at least in women.

In women, telomeric shortening before HCT was associated with poorer cognitive functioning after HCT in domains of executive function, processing speed, verbal speed, and working memory, Dr. Bhatia reported at the American Society of Hematology annual meeting.

Those especially at risk for post-transplant cognitive problems include older patients, men, Hispanics, people with lower socioeconomic status, those with high levels of fatigue, and those who undergo a full-intensity pre-transplant conditioning regimen.

"This study has identified vulnerable sub-populations, and there is a need to develop future interventions targeted toward these patients, as well as to understand the pathogenesis of this outcome," Dr. Bhatia said in a briefing before the presentation of results.

Dr. Bhatia stressed that clinicians need to educate patients and families about the cognitive consequences of transplantation.

"When these patients come back, and especially younger patients when they are not performing well in their schools or college settings, very often the family blames these patients for being lazy, and that is something which we need to absolutely negate and say that this is the effect of the treatment they received, and we need to offer them services," she said.

The investigators conducted a 2-year prospective longitudinal study comparing patients scheduled for HCT with age and sex-matched healthy controls.

The participants underwent baseline testing with a 2-hour battery of standardized neurocognitive tests assessing 8 cognitive domains. Scores of healthy controls were used to correct the scores of HCT patients for practice effects.

Patients also had pre-transplant blood draws tested by assay for relative telomere length, defined as the ratio of telomeres to single genes.

As the authors had previously shown, allogeneic HCT recipients overall have poorer cognitive function than controls in domains of executive function, processing speed, verbal fluency, and fine motor dexterity.

For example, in an analysis adjusted for age, race, and income, controls had significantly better executive function scores than did transplant recipients (P = .0008).

When the researchers drilled down a little deeper, however, they found that patients who had undergone full-intensity conditioning did especially poorly in domains of executive function, processing speed, verbal speed, and visual memory.

When they looked at telomere length, they found in an analysis adjusted for age, race, income, IQ, diagnosis, risk of relapse, and remission status that women with short telomeres fared worse than women with long telomeres. At a 2-year follow-up women with short telomeres had significantly poorer executive function scores (P = .004).

There were no significant associations between telomere length and cognitive function among men, however.

Dr. Bhatia noted that chemotherapy and radiation both accelerate telomere shortening and that glial cells, which divide, therefore are susceptible to telomere shortening, offering a potential explanation for the association between telomere length and cognitive function.

Although the investigators have not yet sorted out which components of the conditioning regimen contribute to cognitive problems, it appears to be a combination of total body irradiation and high-myeloablative intensity agents, Dr. Bhatia said.

Clinical trials testing behavioral therapy and pharmacologic therapy with agents that support attention and cognitive processing, such as methylphenidate, are underway, she noted.

Dr. Jeffrey Miller, who moderated the briefing at which Dr. Bhatia presented the data, noted that reduced-intensity pre-transplant conditioning is suitable for older, frailer patients, and in this study was shown to offer cognitive protection compared with full-intensity conditioning.

Reduced-intensity conditioning, however, comes with a significant trade-off in terms of increased risk for relapse, said Dr. Miller, deputy director of the Masonic Cancer Center and the Clinical and Translational Sciences Institute, University of Minnesota, Minneapolis.

Dr. Bhatia commented that the most important clinical consideration is which treatment strategy is likely to offer the best relapse-free survival.

"Then we have the luxury of looking at whether we have a mode of therapy that is less toxic down the road," she said.

The study was supported in part by the Leukemia & Lymphoma Society. Dr. Bhatia and Dr. Miller reported having no relevant conflicts of interest to disclose.

NEW ORLEANS  – Full-intensity conditioning regimens before stem-cell transplants put patients at risk for cognitive problems afterward, investigators reported.

Compared with healthy controls, men and women who underwent allogeneic hematopoietic stem transplants (HCT) with full-intensity pre-transplant conditioning continued to have deficits in executive function for at least 2 years after transplant.

In contrast, patients who had reduced-intensity conditioning before their transplants had initial cognitive deficits but recovered gradually, continued to have significantly better cognitive function than patients who had undergone full-intensity conditioning (P = .01), and had no significant deficits in executive function compared with controls at 2-year follow-up, reported Dr. Smita Bhatia, professor and chair of the department of population sciences at City of Hope in Duarte, Calif.

The investigators also found preliminary evidence to suggest that the length of telomeres, the caps at the end of chromosomes that protect chromosomal integrity through cellular division, also may be associated with risk for post-transplant cognitive problems -- at least in women.

In women, telomeric shortening before HCT was associated with poorer cognitive functioning after HCT in domains of executive function, processing speed, verbal speed, and working memory, Dr. Bhatia reported at the American Society of Hematology annual meeting.

Those especially at risk for post-transplant cognitive problems include older patients, men, Hispanics, people with lower socioeconomic status, those with high levels of fatigue, and those who undergo a full-intensity pre-transplant conditioning regimen.

"This study has identified vulnerable sub-populations, and there is a need to develop future interventions targeted toward these patients, as well as to understand the pathogenesis of this outcome," Dr. Bhatia said in a briefing before the presentation of results.

Dr. Bhatia stressed that clinicians need to educate patients and families about the cognitive consequences of transplantation.

"When these patients come back, and especially younger patients when they are not performing well in their schools or college settings, very often the family blames these patients for being lazy, and that is something which we need to absolutely negate and say that this is the effect of the treatment they received, and we need to offer them services," she said.

The investigators conducted a 2-year prospective longitudinal study comparing patients scheduled for HCT with age and sex-matched healthy controls.

The participants underwent baseline testing with a 2-hour battery of standardized neurocognitive tests assessing 8 cognitive domains. Scores of healthy controls were used to correct the scores of HCT patients for practice effects.

Patients also had pre-transplant blood draws tested by assay for relative telomere length, defined as the ratio of telomeres to single genes.

As the authors had previously shown, allogeneic HCT recipients overall have poorer cognitive function than controls in domains of executive function, processing speed, verbal fluency, and fine motor dexterity.

For example, in an analysis adjusted for age, race, and income, controls had significantly better executive function scores than did transplant recipients (P = .0008).

When the researchers drilled down a little deeper, however, they found that patients who had undergone full-intensity conditioning did especially poorly in domains of executive function, processing speed, verbal speed, and visual memory.

When they looked at telomere length, they found in an analysis adjusted for age, race, income, IQ, diagnosis, risk of relapse, and remission status that women with short telomeres fared worse than women with long telomeres. At a 2-year follow-up women with short telomeres had significantly poorer executive function scores (P = .004).

There were no significant associations between telomere length and cognitive function among men, however.

Dr. Bhatia noted that chemotherapy and radiation both accelerate telomere shortening and that glial cells, which divide, therefore are susceptible to telomere shortening, offering a potential explanation for the association between telomere length and cognitive function.

Although the investigators have not yet sorted out which components of the conditioning regimen contribute to cognitive problems, it appears to be a combination of total body irradiation and high-myeloablative intensity agents, Dr. Bhatia said.

Clinical trials testing behavioral therapy and pharmacologic therapy with agents that support attention and cognitive processing, such as methylphenidate, are underway, she noted.

Dr. Jeffrey Miller, who moderated the briefing at which Dr. Bhatia presented the data, noted that reduced-intensity pre-transplant conditioning is suitable for older, frailer patients, and in this study was shown to offer cognitive protection compared with full-intensity conditioning.

Reduced-intensity conditioning, however, comes with a significant trade-off in terms of increased risk for relapse, said Dr. Miller, deputy director of the Masonic Cancer Center and the Clinical and Translational Sciences Institute, University of Minnesota, Minneapolis.

Dr. Bhatia commented that the most important clinical consideration is which treatment strategy is likely to offer the best relapse-free survival.

"Then we have the luxury of looking at whether we have a mode of therapy that is less toxic down the road," she said.

The study was supported in part by the Leukemia & Lymphoma Society. Dr. Bhatia and Dr. Miller reported having no relevant conflicts of interest to disclose.

Our onsite coverage of the American Society of Hematology’s annual meeting in New Orleans begins this weekend, bringing you timely insights on the latest research into the etiology, diagnosis, and treatment of hematologic disorders.

To preview our coverage, enjoy this summary of just a few of the reports scheduled for presentation at the plenary session on Sunday, Dec. 8.

Early TP53 Mutations in Therapy-Related AML

New research suggests that heterozygous TP53 mutations, acquired as a function of normal aging, are selected for in the presence of cytotoxic therapy and result in therapy-related acute myeloid leukemia (AML) and myelodysplastic syndrome. The insights come from the research group that previously reported that there is no evidence that chemotherapy induces genome-wide DNA damage in therapy-related AML, based on their finding of similar total numbers of somatic single nucleotide variants and percentages of transversions in therapy-related and de novo AML.

Dr. Terrence Neal Wong of Washington University, St. Louis, and his colleagues will detail how hematologic stem cells that acquire heterozygous TP53 mutations as a function of normal aging may be selected for in the presence of cytotoxic therapy. Their findings provide a potential mechanism for the high incidence of TP53 mutations in therapy-related AML and myelodysplastic disorder. They speculate that early acquisition of TP53 mutations in the founding clone likely contribute to the cytogenetic abnormalities and poor response to chemotherapy in these disorders.

Final Stage 2 Results of the CLL11 Trial

Obinutuzumab, a CD20 antibody, in combination with chlorambucil, was associated with a higher complete response rate and longer progression-free survival as compared with rituximab and chlorambucil in previously untreated patients with chronic lymphocytic leukemia and comorbidities, based on results to be presented by Dr. Valentin Goede of the German CLL Study Group and the University Hospital Cologne, Germany.

After a median 19 month follow-up, the final stage 2 results of the CLL11 Trial found infusion-related reactions and neutropenia were more common with obinutuzumab and chlorambucil without an increase in infections. The researchers will present data to support their conclusion that the obinutuzumab and chlorambucil combination is superior to rituximab and chlorambucil.

The FIRST (Frontline investigation of lenalidomide + dexamethasone vs. standard thalidomide) Trial

The FIRST trial is a multicenter, open-label, phase III trial comparing the efficacy and safety of lenalidomide + dexamethasone vs. melphalan, prednisone, and thalidomide in newly diagnosed multiple myeloma patients ineligible for stem cell transplants.

Dr. Thierry Facon of Hôpital Claude Huriez, Lille, France, and his colleagues will present data indicating that continuous treatment with the all oral doublet lenalidomide + dexamethasone significantly improved the primary endpoint of progression-free survival, compared with the standard triplet melphalan, prednisone, and thalidomide.

tor@frontlinemedcom.com

Our onsite coverage of the American Society of Hematology’s annual meeting in New Orleans begins this weekend, bringing you timely insights on the latest research into the etiology, diagnosis, and treatment of hematologic disorders.

To preview our coverage, enjoy this summary of just a few of the reports scheduled for presentation at the plenary session on Sunday, Dec. 8.

Early TP53 Mutations in Therapy-Related AML

New research suggests that heterozygous TP53 mutations, acquired as a function of normal aging, are selected for in the presence of cytotoxic therapy and result in therapy-related acute myeloid leukemia (AML) and myelodysplastic syndrome. The insights come from the research group that previously reported that there is no evidence that chemotherapy induces genome-wide DNA damage in therapy-related AML, based on their finding of similar total numbers of somatic single nucleotide variants and percentages of transversions in therapy-related and de novo AML.

Dr. Terrence Neal Wong of Washington University, St. Louis, and his colleagues will detail how hematologic stem cells that acquire heterozygous TP53 mutations as a function of normal aging may be selected for in the presence of cytotoxic therapy. Their findings provide a potential mechanism for the high incidence of TP53 mutations in therapy-related AML and myelodysplastic disorder. They speculate that early acquisition of TP53 mutations in the founding clone likely contribute to the cytogenetic abnormalities and poor response to chemotherapy in these disorders.

Final Stage 2 Results of the CLL11 Trial

Obinutuzumab, a CD20 antibody, in combination with chlorambucil, was associated with a higher complete response rate and longer progression-free survival as compared with rituximab and chlorambucil in previously untreated patients with chronic lymphocytic leukemia and comorbidities, based on results to be presented by Dr. Valentin Goede of the German CLL Study Group and the University Hospital Cologne, Germany.

After a median 19 month follow-up, the final stage 2 results of the CLL11 Trial found infusion-related reactions and neutropenia were more common with obinutuzumab and chlorambucil without an increase in infections. The researchers will present data to support their conclusion that the obinutuzumab and chlorambucil combination is superior to rituximab and chlorambucil.

The FIRST (Frontline investigation of lenalidomide + dexamethasone vs. standard thalidomide) Trial

The FIRST trial is a multicenter, open-label, phase III trial comparing the efficacy and safety of lenalidomide + dexamethasone vs. melphalan, prednisone, and thalidomide in newly diagnosed multiple myeloma patients ineligible for stem cell transplants.

Dr. Thierry Facon of Hôpital Claude Huriez, Lille, France, and his colleagues will present data indicating that continuous treatment with the all oral doublet lenalidomide + dexamethasone significantly improved the primary endpoint of progression-free survival, compared with the standard triplet melphalan, prednisone, and thalidomide.

tor@frontlinemedcom.com

Our onsite coverage of the American Society of Hematology’s annual meeting in New Orleans begins this weekend, bringing you timely insights on the latest research into the etiology, diagnosis, and treatment of hematologic disorders.

To preview our coverage, enjoy this summary of just a few of the reports scheduled for presentation at the plenary session on Sunday, Dec. 8.

Early TP53 Mutations in Therapy-Related AML

New research suggests that heterozygous TP53 mutations, acquired as a function of normal aging, are selected for in the presence of cytotoxic therapy and result in therapy-related acute myeloid leukemia (AML) and myelodysplastic syndrome. The insights come from the research group that previously reported that there is no evidence that chemotherapy induces genome-wide DNA damage in therapy-related AML, based on their finding of similar total numbers of somatic single nucleotide variants and percentages of transversions in therapy-related and de novo AML.

Dr. Terrence Neal Wong of Washington University, St. Louis, and his colleagues will detail how hematologic stem cells that acquire heterozygous TP53 mutations as a function of normal aging may be selected for in the presence of cytotoxic therapy. Their findings provide a potential mechanism for the high incidence of TP53 mutations in therapy-related AML and myelodysplastic disorder. They speculate that early acquisition of TP53 mutations in the founding clone likely contribute to the cytogenetic abnormalities and poor response to chemotherapy in these disorders.

Final Stage 2 Results of the CLL11 Trial

Obinutuzumab, a CD20 antibody, in combination with chlorambucil, was associated with a higher complete response rate and longer progression-free survival as compared with rituximab and chlorambucil in previously untreated patients with chronic lymphocytic leukemia and comorbidities, based on results to be presented by Dr. Valentin Goede of the German CLL Study Group and the University Hospital Cologne, Germany.

After a median 19 month follow-up, the final stage 2 results of the CLL11 Trial found infusion-related reactions and neutropenia were more common with obinutuzumab and chlorambucil without an increase in infections. The researchers will present data to support their conclusion that the obinutuzumab and chlorambucil combination is superior to rituximab and chlorambucil.

The FIRST (Frontline investigation of lenalidomide + dexamethasone vs. standard thalidomide) Trial

The FIRST trial is a multicenter, open-label, phase III trial comparing the efficacy and safety of lenalidomide + dexamethasone vs. melphalan, prednisone, and thalidomide in newly diagnosed multiple myeloma patients ineligible for stem cell transplants.

Dr. Thierry Facon of Hôpital Claude Huriez, Lille, France, and his colleagues will present data indicating that continuous treatment with the all oral doublet lenalidomide + dexamethasone significantly improved the primary endpoint of progression-free survival, compared with the standard triplet melphalan, prednisone, and thalidomide.

tor@frontlinemedcom.com