Neil Osterweil

ORLANDO – The histone deacetylase inhibitor romidepsin showed significant single-agent activity in patients with relapsed or refractory peripheral T-cell lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

In a phase II trial, 130 patients with various subtypes of relapsed/refractory peripheral T-cell lymphoma (PTCL) who received romidepsin (Istodax) had a complete response rate of 13% as determined by an independent review committee (IRC) of radiologists and hematologists, and 16% as judged by study investigators.

Overall objective responses (a composite of complete responses [CR], complete responses unconfirmed [CRu] and partial responses [PR]) were 26% according to the IRC, and 29% according to investigators, said Dr. Bertrand Coiffier, professor of hematology at Hospices Civils de Lyon (France).

The agent "warrants further investigation as front-line therapy in these patients in combination with chemotherapy," Dr. Coiffier said.

Romidepsin is approved in the United States for patients with cutaneous T-cell lymphoma that has relapsed after at least one prior systemic therapy. The drug has demonstrated activity against PTCL in phase I and II trials conducted by the National Cancer Institute, and it has received fast-track status from the Food and Drug Administration for PTCL, as well as an orphan-drug designation in the United States and Europe.

Peripheral T-cell lymphoma is the overall term for a heterogeneous group of non-Hodgkin’s lymphomas arising from clonal proliferation of mature post-thymic lymphocytes. These malignancies tend to be clinically aggressive, respond poorly to chemotherapy, have high relapse rates, and are associated with poor long-term survival.

"We don’t have any standard of care for these patients, and we need to find new drugs," said Dr. Coiffier.

The open-label, single-arm trial involved 130 patients from centers in Australia, France, Germany, Spain, and the United States. Histologies included PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase (ALK)–anaplastic large cell lymphoma (ALCL), ALK-positive ALCL (if stem-cell transplant had failed), enteropathy-type TCL, subcutaneous panniculitis-type TCL, extranodal natural killer/T-cell lymphoma nasal type, and transformed mycosis fungoides.

All patients had relapsed/refractory disease following at least one prior systemic therapy (median 2), and either measurable disease according to International Workshop Criteria or measurable cutaneous disease.

The patients received romidepsin 14 mg/m2 in a 4-hour intravenous infusion on days 1, 8, and 15 of a 28-day cycle for a total of six cycles. Patients who responded to the drug could receive additional treatment cycles at their discretion and that of the investigators. Responses were assessed after every 2 cycles, with follow-up every 2-3 cycles.

The primary end point was the complete response rate as determined by the IRC. It found that 34 patients (26%) had objective responses, and that 17 of these (13% of all patients) were CR (10 patients) or CRu (7 patients). An additional 17 had partial responses, 32 (25%) had stable disease, and 64 (49%) either had progressive disease or were not evaluable.

At the time of the presentation, the median duration of complete responses had not been reached according to the IRC analysis (range less than 1 month to more than 26.3 months). The median duration of objective responses (CR, CRu, and PR) was 12 months. Median time to objective response was 2 months, time to CR was 4 months, and time to progression was 6 months.

Complete responses were seen in 14% of 49 patients whose disease was refractory to the most recent therapy, Dr. Coiffier noted. As of the data cutoff date of March 31, 2010, 9 of the 17 patients with a CR/CRu continued to receive the drug, 5 discontinued it (1 of these patients went on to transplant), and 3 had disease progression, following response durations of 12, 2.2, and 1.9 months.

Treatment-emergent adverse events occurred in nearly all patients (96%). Events occurring in 20% or more of patients included nausea (59%), fatigue (41%), vomiting (38%), thrombocytopenia (38%), diarrhea (35%), pyrexia (34%), neutropenia (30%), anorexia (28%), constipation (28%), anemia (23%), and dysgeusia (21%). Grade 3 or 4 adverse events occurred in 86 patients (66%), and included pyrexia (7%), pneumonia (5%), vomiting (5%), and sepsis (5%). In all, 22 patients (17%) withdrew because of side effects.

There were eight patient deaths within 30 days of the last drug dose: three from progressive disease and five from infections. One patient died from a probable treatment-related case of sepsis and multiple organ failure.

Eight patients had electrocardiographic abnormalities, four of which were prolongation of the QTc interval. None of these patients had concurrent symptoms of either syncope or other cardiac adverse events at the time of the reported abnormality, Dr. Coiffier noted.

Gloucester Pharmaceuticals sponsored the trial. Dr. Coiffier is a consultant to, and has received honoraria from, Gloucester. He has similar relationships with Celgene, which acquired Gloucester 2010; he also declared research funding from Celgene and has served on its speakers bureau. Most of his coauthors had relationships with Celgene and/or Gloucester, and two were Celgene employees. The trial involved off-label use of romidepsin.

ORLANDO – The histone deacetylase inhibitor romidepsin showed significant single-agent activity in patients with relapsed or refractory peripheral T-cell lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

In a phase II trial, 130 patients with various subtypes of relapsed/refractory peripheral T-cell lymphoma (PTCL) who received romidepsin (Istodax) had a complete response rate of 13% as determined by an independent review committee (IRC) of radiologists and hematologists, and 16% as judged by study investigators.

Overall objective responses (a composite of complete responses [CR], complete responses unconfirmed [CRu] and partial responses [PR]) were 26% according to the IRC, and 29% according to investigators, said Dr. Bertrand Coiffier, professor of hematology at Hospices Civils de Lyon (France).

The agent "warrants further investigation as front-line therapy in these patients in combination with chemotherapy," Dr. Coiffier said.

Romidepsin is approved in the United States for patients with cutaneous T-cell lymphoma that has relapsed after at least one prior systemic therapy. The drug has demonstrated activity against PTCL in phase I and II trials conducted by the National Cancer Institute, and it has received fast-track status from the Food and Drug Administration for PTCL, as well as an orphan-drug designation in the United States and Europe.

Peripheral T-cell lymphoma is the overall term for a heterogeneous group of non-Hodgkin’s lymphomas arising from clonal proliferation of mature post-thymic lymphocytes. These malignancies tend to be clinically aggressive, respond poorly to chemotherapy, have high relapse rates, and are associated with poor long-term survival.

"We don’t have any standard of care for these patients, and we need to find new drugs," said Dr. Coiffier.

The open-label, single-arm trial involved 130 patients from centers in Australia, France, Germany, Spain, and the United States. Histologies included PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase (ALK)–anaplastic large cell lymphoma (ALCL), ALK-positive ALCL (if stem-cell transplant had failed), enteropathy-type TCL, subcutaneous panniculitis-type TCL, extranodal natural killer/T-cell lymphoma nasal type, and transformed mycosis fungoides.

All patients had relapsed/refractory disease following at least one prior systemic therapy (median 2), and either measurable disease according to International Workshop Criteria or measurable cutaneous disease.

The patients received romidepsin 14 mg/m2 in a 4-hour intravenous infusion on days 1, 8, and 15 of a 28-day cycle for a total of six cycles. Patients who responded to the drug could receive additional treatment cycles at their discretion and that of the investigators. Responses were assessed after every 2 cycles, with follow-up every 2-3 cycles.

The primary end point was the complete response rate as determined by the IRC. It found that 34 patients (26%) had objective responses, and that 17 of these (13% of all patients) were CR (10 patients) or CRu (7 patients). An additional 17 had partial responses, 32 (25%) had stable disease, and 64 (49%) either had progressive disease or were not evaluable.

At the time of the presentation, the median duration of complete responses had not been reached according to the IRC analysis (range less than 1 month to more than 26.3 months). The median duration of objective responses (CR, CRu, and PR) was 12 months. Median time to objective response was 2 months, time to CR was 4 months, and time to progression was 6 months.

Complete responses were seen in 14% of 49 patients whose disease was refractory to the most recent therapy, Dr. Coiffier noted. As of the data cutoff date of March 31, 2010, 9 of the 17 patients with a CR/CRu continued to receive the drug, 5 discontinued it (1 of these patients went on to transplant), and 3 had disease progression, following response durations of 12, 2.2, and 1.9 months.

Treatment-emergent adverse events occurred in nearly all patients (96%). Events occurring in 20% or more of patients included nausea (59%), fatigue (41%), vomiting (38%), thrombocytopenia (38%), diarrhea (35%), pyrexia (34%), neutropenia (30%), anorexia (28%), constipation (28%), anemia (23%), and dysgeusia (21%). Grade 3 or 4 adverse events occurred in 86 patients (66%), and included pyrexia (7%), pneumonia (5%), vomiting (5%), and sepsis (5%). In all, 22 patients (17%) withdrew because of side effects.

There were eight patient deaths within 30 days of the last drug dose: three from progressive disease and five from infections. One patient died from a probable treatment-related case of sepsis and multiple organ failure.

Eight patients had electrocardiographic abnormalities, four of which were prolongation of the QTc interval. None of these patients had concurrent symptoms of either syncope or other cardiac adverse events at the time of the reported abnormality, Dr. Coiffier noted.

Gloucester Pharmaceuticals sponsored the trial. Dr. Coiffier is a consultant to, and has received honoraria from, Gloucester. He has similar relationships with Celgene, which acquired Gloucester 2010; he also declared research funding from Celgene and has served on its speakers bureau. Most of his coauthors had relationships with Celgene and/or Gloucester, and two were Celgene employees. The trial involved off-label use of romidepsin.

ORLANDO – The histone deacetylase inhibitor romidepsin showed significant single-agent activity in patients with relapsed or refractory peripheral T-cell lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

In a phase II trial, 130 patients with various subtypes of relapsed/refractory peripheral T-cell lymphoma (PTCL) who received romidepsin (Istodax) had a complete response rate of 13% as determined by an independent review committee (IRC) of radiologists and hematologists, and 16% as judged by study investigators.

Overall objective responses (a composite of complete responses [CR], complete responses unconfirmed [CRu] and partial responses [PR]) were 26% according to the IRC, and 29% according to investigators, said Dr. Bertrand Coiffier, professor of hematology at Hospices Civils de Lyon (France).

The agent "warrants further investigation as front-line therapy in these patients in combination with chemotherapy," Dr. Coiffier said.

Romidepsin is approved in the United States for patients with cutaneous T-cell lymphoma that has relapsed after at least one prior systemic therapy. The drug has demonstrated activity against PTCL in phase I and II trials conducted by the National Cancer Institute, and it has received fast-track status from the Food and Drug Administration for PTCL, as well as an orphan-drug designation in the United States and Europe.

Peripheral T-cell lymphoma is the overall term for a heterogeneous group of non-Hodgkin’s lymphomas arising from clonal proliferation of mature post-thymic lymphocytes. These malignancies tend to be clinically aggressive, respond poorly to chemotherapy, have high relapse rates, and are associated with poor long-term survival.

"We don’t have any standard of care for these patients, and we need to find new drugs," said Dr. Coiffier.

The open-label, single-arm trial involved 130 patients from centers in Australia, France, Germany, Spain, and the United States. Histologies included PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase (ALK)–anaplastic large cell lymphoma (ALCL), ALK-positive ALCL (if stem-cell transplant had failed), enteropathy-type TCL, subcutaneous panniculitis-type TCL, extranodal natural killer/T-cell lymphoma nasal type, and transformed mycosis fungoides.

All patients had relapsed/refractory disease following at least one prior systemic therapy (median 2), and either measurable disease according to International Workshop Criteria or measurable cutaneous disease.

The patients received romidepsin 14 mg/m2 in a 4-hour intravenous infusion on days 1, 8, and 15 of a 28-day cycle for a total of six cycles. Patients who responded to the drug could receive additional treatment cycles at their discretion and that of the investigators. Responses were assessed after every 2 cycles, with follow-up every 2-3 cycles.

The primary end point was the complete response rate as determined by the IRC. It found that 34 patients (26%) had objective responses, and that 17 of these (13% of all patients) were CR (10 patients) or CRu (7 patients). An additional 17 had partial responses, 32 (25%) had stable disease, and 64 (49%) either had progressive disease or were not evaluable.

At the time of the presentation, the median duration of complete responses had not been reached according to the IRC analysis (range less than 1 month to more than 26.3 months). The median duration of objective responses (CR, CRu, and PR) was 12 months. Median time to objective response was 2 months, time to CR was 4 months, and time to progression was 6 months.

Complete responses were seen in 14% of 49 patients whose disease was refractory to the most recent therapy, Dr. Coiffier noted. As of the data cutoff date of March 31, 2010, 9 of the 17 patients with a CR/CRu continued to receive the drug, 5 discontinued it (1 of these patients went on to transplant), and 3 had disease progression, following response durations of 12, 2.2, and 1.9 months.

Treatment-emergent adverse events occurred in nearly all patients (96%). Events occurring in 20% or more of patients included nausea (59%), fatigue (41%), vomiting (38%), thrombocytopenia (38%), diarrhea (35%), pyrexia (34%), neutropenia (30%), anorexia (28%), constipation (28%), anemia (23%), and dysgeusia (21%). Grade 3 or 4 adverse events occurred in 86 patients (66%), and included pyrexia (7%), pneumonia (5%), vomiting (5%), and sepsis (5%). In all, 22 patients (17%) withdrew because of side effects.

There were eight patient deaths within 30 days of the last drug dose: three from progressive disease and five from infections. One patient died from a probable treatment-related case of sepsis and multiple organ failure.

Eight patients had electrocardiographic abnormalities, four of which were prolongation of the QTc interval. None of these patients had concurrent symptoms of either syncope or other cardiac adverse events at the time of the reported abnormality, Dr. Coiffier noted.

Gloucester Pharmaceuticals sponsored the trial. Dr. Coiffier is a consultant to, and has received honoraria from, Gloucester. He has similar relationships with Celgene, which acquired Gloucester 2010; he also declared research funding from Celgene and has served on its speakers bureau. Most of his coauthors had relationships with Celgene and/or Gloucester, and two were Celgene employees. The trial involved off-label use of romidepsin.

ORLANDO – Rituximab that was added to the ACVBP regimen was associated with significantly improved overall survival, compared with rituximab added to the CHOP regimen, in patients younger than age 60 with diffuse, large B-cell lymphoma, based on results of a study presented at the annual meeting of the American Society of Hematology.

The 3-year overall survival rate was 92% among patients younger than age 60 years who had diffuse, large B-cell lymphoma (DLBCL) and were assigned to receive R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone). The 3-year overall survival rate was 84% for patients who were assigned to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The difference in survival was significant (R-ACVBP hazard ratio, 0.439; P = .0071), reported Dr. Christian Recher of the Centre Hôpitalier Universitaire (CHU) Purpan in Toulouse, France.

In addition, R-ACVBP was associated with significantly better 3-year event-free survival (81% vs. 67%; HR, 0.559; P = .0035), progression-free survival (87% vs. 73%; HR, 0.482; P = .0015), and disease-free survival among complete responders (91% vs. 80%; HR, 0.393; P = .0019).

"R-ACVBP should be the standard of care for younger patients with this disease," said Dr. Recher on behalf of colleagues in the GELA (Groupe d'Étude des Lymphomes de l'Adulte) LNH03-2B study.

Although R-CHOP has changed the prognosis of DLBCL for the better, many patients are refractory to initial therapy or may relapse after achieving a complete response, he said. One recent study suggests that patients who experience relapse or have refractory disease after R-CHOP have poor outcomes, with a 3-year event-free survival rate of 21% (J. Clin. Oncol. 2010;28;4184-90).

Critical questions in the care of these patients include the optimal rituximab dosage and schedule, and the optimal chemotherapy to match it with, Dr. Recher said.

The randomized, open-label trial compared R-CHOP with R-ACVBP in 380 patients aged 18-59 years (median age, 47 in the R-ACVBP arm and 48 in the R-CHOP arm), with an age-adjusted IPI (International Prognostic Index) score of 1.

Patients who were randomized to R-ACVBP received induction with four cycles delivered every 2 weeks, plus intrathecal methotrexate on day 2, with granulocyte colony-stimulating factor (G-CSF) support from day 6 to day 13 of each cycle. These patients then received sequential consolidation therapy consisting of two courses of methotrexate plus leucovorin rescue, followed by four courses of rituximab, etoposide, and ifosfamide on day 1 and two courses of cytosine-arabinoside for 4 days, with consolidation courses administered at 14-day intervals.

Patients who were randomized to R-CHOP received eight cycles for 21 days each, along with intrathecal methotrexate on day 1 of the first four cycles.

The primary end point was event-free survival. Secondary end points were response rate (evaluated according to the Cheson criteria of 1999), progression-free survival, disease-free survival for complete responders, overall survival, neuromeningeal relapse rate, and toxicities. Both the safety and efficacy analyses were by intention to treat. Of the 380 patients enrolled, 161 in the R-ACVBP group and 165 in the R-CHOP group completed treatment.

There were no significant differences in the overall response rates at the end of treatment, with 84% of patients who received R-ACVBP having a complete response (CR) or complete response unconfirmed (CRu), and 8% having a partial response (overall response rate, 92%). In the R-CHOP arm, 80% of patients had a CR or CRu, and 8% had a partial response (ORR, 88%).

Grade 3 or 4 hematologic toxicities were more frequent among patients who received R-ACVBP vs. R-CHOP, with neutropenia occurring in 78% vs. 64% and febrile neutropenia in 38% and 9%, respectively; anemia in 35% vs. 5%, and thrombocytopenia in 30% vs. 3%. In addition, 51% of patients in the R-ACVBP arm required red blood cell transfusions, compared with 7% of R-CHOP patients, and 13% required platelet transfusions, compared with 1%.

The only grade 3 or greater general toxicity that occurred in more than 10% of patients was mucositis, which affected 18% of those on R-ACVBP but no patients on R-CHOP. Vomiting, infections, and neurologic toxicities were also more frequent among patients on R-ACVBP, but liver and lung toxicities were identical in the two groups. Cardiotoxicity was seen in 1% of R-CHOP patients, but not among R-ACVBP patients.

In all, 2.6% of patients on R-ACVBP died from toxicities that were attributable to treatment, as did 1.6% of those on R-CHOP.

The study was sponsored by GELA. Dr. Recher had no financial disclosures. Coauthors Dr. Bertrand Coiffier, Dr. Christian Gisselbrecht, and Dr. Andre Bosly disclosed receiving honoraria, research funding, and/or serving in an advisory role to Roche, maker of rituximab.

ORLANDO – Rituximab that was added to the ACVBP regimen was associated with significantly improved overall survival, compared with rituximab added to the CHOP regimen, in patients younger than age 60 with diffuse, large B-cell lymphoma, based on results of a study presented at the annual meeting of the American Society of Hematology.

The 3-year overall survival rate was 92% among patients younger than age 60 years who had diffuse, large B-cell lymphoma (DLBCL) and were assigned to receive R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone). The 3-year overall survival rate was 84% for patients who were assigned to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The difference in survival was significant (R-ACVBP hazard ratio, 0.439; P = .0071), reported Dr. Christian Recher of the Centre Hôpitalier Universitaire (CHU) Purpan in Toulouse, France.

In addition, R-ACVBP was associated with significantly better 3-year event-free survival (81% vs. 67%; HR, 0.559; P = .0035), progression-free survival (87% vs. 73%; HR, 0.482; P = .0015), and disease-free survival among complete responders (91% vs. 80%; HR, 0.393; P = .0019).

"R-ACVBP should be the standard of care for younger patients with this disease," said Dr. Recher on behalf of colleagues in the GELA (Groupe d'Étude des Lymphomes de l'Adulte) LNH03-2B study.

Although R-CHOP has changed the prognosis of DLBCL for the better, many patients are refractory to initial therapy or may relapse after achieving a complete response, he said. One recent study suggests that patients who experience relapse or have refractory disease after R-CHOP have poor outcomes, with a 3-year event-free survival rate of 21% (J. Clin. Oncol. 2010;28;4184-90).

Critical questions in the care of these patients include the optimal rituximab dosage and schedule, and the optimal chemotherapy to match it with, Dr. Recher said.

The randomized, open-label trial compared R-CHOP with R-ACVBP in 380 patients aged 18-59 years (median age, 47 in the R-ACVBP arm and 48 in the R-CHOP arm), with an age-adjusted IPI (International Prognostic Index) score of 1.

Patients who were randomized to R-ACVBP received induction with four cycles delivered every 2 weeks, plus intrathecal methotrexate on day 2, with granulocyte colony-stimulating factor (G-CSF) support from day 6 to day 13 of each cycle. These patients then received sequential consolidation therapy consisting of two courses of methotrexate plus leucovorin rescue, followed by four courses of rituximab, etoposide, and ifosfamide on day 1 and two courses of cytosine-arabinoside for 4 days, with consolidation courses administered at 14-day intervals.

Patients who were randomized to R-CHOP received eight cycles for 21 days each, along with intrathecal methotrexate on day 1 of the first four cycles.

The primary end point was event-free survival. Secondary end points were response rate (evaluated according to the Cheson criteria of 1999), progression-free survival, disease-free survival for complete responders, overall survival, neuromeningeal relapse rate, and toxicities. Both the safety and efficacy analyses were by intention to treat. Of the 380 patients enrolled, 161 in the R-ACVBP group and 165 in the R-CHOP group completed treatment.

There were no significant differences in the overall response rates at the end of treatment, with 84% of patients who received R-ACVBP having a complete response (CR) or complete response unconfirmed (CRu), and 8% having a partial response (overall response rate, 92%). In the R-CHOP arm, 80% of patients had a CR or CRu, and 8% had a partial response (ORR, 88%).

Grade 3 or 4 hematologic toxicities were more frequent among patients who received R-ACVBP vs. R-CHOP, with neutropenia occurring in 78% vs. 64% and febrile neutropenia in 38% and 9%, respectively; anemia in 35% vs. 5%, and thrombocytopenia in 30% vs. 3%. In addition, 51% of patients in the R-ACVBP arm required red blood cell transfusions, compared with 7% of R-CHOP patients, and 13% required platelet transfusions, compared with 1%.

The only grade 3 or greater general toxicity that occurred in more than 10% of patients was mucositis, which affected 18% of those on R-ACVBP but no patients on R-CHOP. Vomiting, infections, and neurologic toxicities were also more frequent among patients on R-ACVBP, but liver and lung toxicities were identical in the two groups. Cardiotoxicity was seen in 1% of R-CHOP patients, but not among R-ACVBP patients.

In all, 2.6% of patients on R-ACVBP died from toxicities that were attributable to treatment, as did 1.6% of those on R-CHOP.

The study was sponsored by GELA. Dr. Recher had no financial disclosures. Coauthors Dr. Bertrand Coiffier, Dr. Christian Gisselbrecht, and Dr. Andre Bosly disclosed receiving honoraria, research funding, and/or serving in an advisory role to Roche, maker of rituximab.

ORLANDO – Rituximab that was added to the ACVBP regimen was associated with significantly improved overall survival, compared with rituximab added to the CHOP regimen, in patients younger than age 60 with diffuse, large B-cell lymphoma, based on results of a study presented at the annual meeting of the American Society of Hematology.

The 3-year overall survival rate was 92% among patients younger than age 60 years who had diffuse, large B-cell lymphoma (DLBCL) and were assigned to receive R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone). The 3-year overall survival rate was 84% for patients who were assigned to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The difference in survival was significant (R-ACVBP hazard ratio, 0.439; P = .0071), reported Dr. Christian Recher of the Centre Hôpitalier Universitaire (CHU) Purpan in Toulouse, France.

In addition, R-ACVBP was associated with significantly better 3-year event-free survival (81% vs. 67%; HR, 0.559; P = .0035), progression-free survival (87% vs. 73%; HR, 0.482; P = .0015), and disease-free survival among complete responders (91% vs. 80%; HR, 0.393; P = .0019).

"R-ACVBP should be the standard of care for younger patients with this disease," said Dr. Recher on behalf of colleagues in the GELA (Groupe d'Étude des Lymphomes de l'Adulte) LNH03-2B study.

Although R-CHOP has changed the prognosis of DLBCL for the better, many patients are refractory to initial therapy or may relapse after achieving a complete response, he said. One recent study suggests that patients who experience relapse or have refractory disease after R-CHOP have poor outcomes, with a 3-year event-free survival rate of 21% (J. Clin. Oncol. 2010;28;4184-90).

Critical questions in the care of these patients include the optimal rituximab dosage and schedule, and the optimal chemotherapy to match it with, Dr. Recher said.

The randomized, open-label trial compared R-CHOP with R-ACVBP in 380 patients aged 18-59 years (median age, 47 in the R-ACVBP arm and 48 in the R-CHOP arm), with an age-adjusted IPI (International Prognostic Index) score of 1.

Patients who were randomized to R-ACVBP received induction with four cycles delivered every 2 weeks, plus intrathecal methotrexate on day 2, with granulocyte colony-stimulating factor (G-CSF) support from day 6 to day 13 of each cycle. These patients then received sequential consolidation therapy consisting of two courses of methotrexate plus leucovorin rescue, followed by four courses of rituximab, etoposide, and ifosfamide on day 1 and two courses of cytosine-arabinoside for 4 days, with consolidation courses administered at 14-day intervals.

Patients who were randomized to R-CHOP received eight cycles for 21 days each, along with intrathecal methotrexate on day 1 of the first four cycles.

The primary end point was event-free survival. Secondary end points were response rate (evaluated according to the Cheson criteria of 1999), progression-free survival, disease-free survival for complete responders, overall survival, neuromeningeal relapse rate, and toxicities. Both the safety and efficacy analyses were by intention to treat. Of the 380 patients enrolled, 161 in the R-ACVBP group and 165 in the R-CHOP group completed treatment.

There were no significant differences in the overall response rates at the end of treatment, with 84% of patients who received R-ACVBP having a complete response (CR) or complete response unconfirmed (CRu), and 8% having a partial response (overall response rate, 92%). In the R-CHOP arm, 80% of patients had a CR or CRu, and 8% had a partial response (ORR, 88%).

Grade 3 or 4 hematologic toxicities were more frequent among patients who received R-ACVBP vs. R-CHOP, with neutropenia occurring in 78% vs. 64% and febrile neutropenia in 38% and 9%, respectively; anemia in 35% vs. 5%, and thrombocytopenia in 30% vs. 3%. In addition, 51% of patients in the R-ACVBP arm required red blood cell transfusions, compared with 7% of R-CHOP patients, and 13% required platelet transfusions, compared with 1%.

The only grade 3 or greater general toxicity that occurred in more than 10% of patients was mucositis, which affected 18% of those on R-ACVBP but no patients on R-CHOP. Vomiting, infections, and neurologic toxicities were also more frequent among patients on R-ACVBP, but liver and lung toxicities were identical in the two groups. Cardiotoxicity was seen in 1% of R-CHOP patients, but not among R-ACVBP patients.

In all, 2.6% of patients on R-ACVBP died from toxicities that were attributable to treatment, as did 1.6% of those on R-CHOP.

The study was sponsored by GELA. Dr. Recher had no financial disclosures. Coauthors Dr. Bertrand Coiffier, Dr. Christian Gisselbrecht, and Dr. Andre Bosly disclosed receiving honoraria, research funding, and/or serving in an advisory role to Roche, maker of rituximab.

ORLANDO – For patients with newly diagnosed multiple myeloma, an intensive chemotherapy regimen with bortezomib, lenalidomide, and dexamethasone for induction followed by transplant and consolidation with the same regimen plus lenalidomide maintenance produced high rates of very good partial responses or better, with no major peripheral neuropathies, French investigators reported at the annual meeting of the American Society of Hematology.

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

Primary results of the phase II IFM 2008 study showed that 80% of patients had at least a very good partial response (VGPR), and nearly 50% of patients had either a stringent complete response (sCR) or complete response (CR) according to international uniform response criteria, said Dr. Murielle Roussel from Hôpital Purpan in Toulouse, France.

There were no cases of grade 3 or 4 peripheral neuropathy, suggesting that the regimen is relatively safe, said Dr. Roussel on behalf of colleagues in the Intergroupe Francophone du Myélome (IFM).

"This intensive program compares favorably to the results obtained with long-term treatment with novel combinations without high-dose therapy. It is, as you know, the framework for the high-dose therapy arm in the IFM/DFCI 2009 joint trial challenging the role of up-front autologous stem cell transplant," she said.

Evidence from recent clinical trials conducted by the IFM and others suggest that a combination of bortezomib, lenalidomide, and dexamethasone (VRD) is a promising three-drug induction regimen prior to autologous stem cell transplants (ASCT). Consolidation therapy can enhance the depth of response, and maintenance can prolong its duration, supporting the choice of VRD as the backbone for the trial, Dr. Roussel said.

The investigators enrolled 31 patients aged younger than 65 years with newly diagnosed multiple myeloma from eight IFM transplant centers. The patients underwent induction therapy with three cycles of VRD, each lasting 21 days. The regimen included bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11), lenalidomide (25 mg/day for days 1-14), and oral dexamethasone (40 mg on day 1, 8, and 14).

Patients were assessed for response after the third cycle, and peripheral stem cells were mobilized and harvested. They then underwent intensification with melphalan 200 mg/m2 and ASCT. After a 2-month hematologic recovery period, the patients could then receive two cycles of VRD consolidation, followed by a year of lenalidomide maintenance, with the drug given at 10 mg/day for 3 months, with dose escalation up to 15 mg if the lower dose was well tolerated.

The primary study outcome was best achieved response 1 month after consolidation. Secondary end points included response rates after three cycles of VRD, the safety and tolerability of the combination in the setting of high-dose therapy, the feasibility of stem cell harvest, progression-free survival, overall survival, time to progression, and duration of response.

The combined CR and sCR rate after induction was 23%, and 62% of patients had a VGPR or better. Following transplant, those rates rose to 36% and 68%, respectively; after consolidation, they were 48% and 84%.

Common toxicities of all grades included thrombocytopenia in 97% of patients, and anemia and neutropenia each in 87%. Sensory peripheral neuropathy occurred in 68% of patients, erythroderma or skin rash in 32%, pneumonia in 16%, and varicella zoster viral infections in 13%.

In all, 39% of patients experienced grade 3 or 4 neutropenia leading to lenalidomide dose reduction in eight patients (26% of the total cohort). In addition, 13% of patients had grade 3 thrombocytopenia, and 6% had grade 3 anemia. There were no grade 4 thrombocytopenia or anemia cases, and no grade 3 or 4 sensory peripheral neuropathy. Grade 1 or 2 neuropathy requiring reductions of bortezomib dose occurred in seven patients.

From one to five stem cell collections (median, two) were required to obtain a sufficient number for ASCT. Five patients needed a second-line mobilizing agent, and investigators were unable to obtain enough cells from one patient with stable disease; this patient did not undergo autologous transplant.

The IFM-2008 study is sponsored by University Hospital Toulouse, with support from Celgene and Janssen-Cilag. Dr. Roussel disclosed receiving research funding and serving on the speakers bureaus of the companies.

ORLANDO – For patients with newly diagnosed multiple myeloma, an intensive chemotherapy regimen with bortezomib, lenalidomide, and dexamethasone for induction followed by transplant and consolidation with the same regimen plus lenalidomide maintenance produced high rates of very good partial responses or better, with no major peripheral neuropathies, French investigators reported at the annual meeting of the American Society of Hematology.

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

Primary results of the phase II IFM 2008 study showed that 80% of patients had at least a very good partial response (VGPR), and nearly 50% of patients had either a stringent complete response (sCR) or complete response (CR) according to international uniform response criteria, said Dr. Murielle Roussel from Hôpital Purpan in Toulouse, France.

There were no cases of grade 3 or 4 peripheral neuropathy, suggesting that the regimen is relatively safe, said Dr. Roussel on behalf of colleagues in the Intergroupe Francophone du Myélome (IFM).

"This intensive program compares favorably to the results obtained with long-term treatment with novel combinations without high-dose therapy. It is, as you know, the framework for the high-dose therapy arm in the IFM/DFCI 2009 joint trial challenging the role of up-front autologous stem cell transplant," she said.

Evidence from recent clinical trials conducted by the IFM and others suggest that a combination of bortezomib, lenalidomide, and dexamethasone (VRD) is a promising three-drug induction regimen prior to autologous stem cell transplants (ASCT). Consolidation therapy can enhance the depth of response, and maintenance can prolong its duration, supporting the choice of VRD as the backbone for the trial, Dr. Roussel said.

The investigators enrolled 31 patients aged younger than 65 years with newly diagnosed multiple myeloma from eight IFM transplant centers. The patients underwent induction therapy with three cycles of VRD, each lasting 21 days. The regimen included bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11), lenalidomide (25 mg/day for days 1-14), and oral dexamethasone (40 mg on day 1, 8, and 14).

Patients were assessed for response after the third cycle, and peripheral stem cells were mobilized and harvested. They then underwent intensification with melphalan 200 mg/m2 and ASCT. After a 2-month hematologic recovery period, the patients could then receive two cycles of VRD consolidation, followed by a year of lenalidomide maintenance, with the drug given at 10 mg/day for 3 months, with dose escalation up to 15 mg if the lower dose was well tolerated.

The primary study outcome was best achieved response 1 month after consolidation. Secondary end points included response rates after three cycles of VRD, the safety and tolerability of the combination in the setting of high-dose therapy, the feasibility of stem cell harvest, progression-free survival, overall survival, time to progression, and duration of response.

The combined CR and sCR rate after induction was 23%, and 62% of patients had a VGPR or better. Following transplant, those rates rose to 36% and 68%, respectively; after consolidation, they were 48% and 84%.

Common toxicities of all grades included thrombocytopenia in 97% of patients, and anemia and neutropenia each in 87%. Sensory peripheral neuropathy occurred in 68% of patients, erythroderma or skin rash in 32%, pneumonia in 16%, and varicella zoster viral infections in 13%.

In all, 39% of patients experienced grade 3 or 4 neutropenia leading to lenalidomide dose reduction in eight patients (26% of the total cohort). In addition, 13% of patients had grade 3 thrombocytopenia, and 6% had grade 3 anemia. There were no grade 4 thrombocytopenia or anemia cases, and no grade 3 or 4 sensory peripheral neuropathy. Grade 1 or 2 neuropathy requiring reductions of bortezomib dose occurred in seven patients.

From one to five stem cell collections (median, two) were required to obtain a sufficient number for ASCT. Five patients needed a second-line mobilizing agent, and investigators were unable to obtain enough cells from one patient with stable disease; this patient did not undergo autologous transplant.

The IFM-2008 study is sponsored by University Hospital Toulouse, with support from Celgene and Janssen-Cilag. Dr. Roussel disclosed receiving research funding and serving on the speakers bureaus of the companies.

ORLANDO – For patients with newly diagnosed multiple myeloma, an intensive chemotherapy regimen with bortezomib, lenalidomide, and dexamethasone for induction followed by transplant and consolidation with the same regimen plus lenalidomide maintenance produced high rates of very good partial responses or better, with no major peripheral neuropathies, French investigators reported at the annual meeting of the American Society of Hematology.

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

Primary results of the phase II IFM 2008 study showed that 80% of patients had at least a very good partial response (VGPR), and nearly 50% of patients had either a stringent complete response (sCR) or complete response (CR) according to international uniform response criteria, said Dr. Murielle Roussel from Hôpital Purpan in Toulouse, France.

There were no cases of grade 3 or 4 peripheral neuropathy, suggesting that the regimen is relatively safe, said Dr. Roussel on behalf of colleagues in the Intergroupe Francophone du Myélome (IFM).

"This intensive program compares favorably to the results obtained with long-term treatment with novel combinations without high-dose therapy. It is, as you know, the framework for the high-dose therapy arm in the IFM/DFCI 2009 joint trial challenging the role of up-front autologous stem cell transplant," she said.

Evidence from recent clinical trials conducted by the IFM and others suggest that a combination of bortezomib, lenalidomide, and dexamethasone (VRD) is a promising three-drug induction regimen prior to autologous stem cell transplants (ASCT). Consolidation therapy can enhance the depth of response, and maintenance can prolong its duration, supporting the choice of VRD as the backbone for the trial, Dr. Roussel said.

The investigators enrolled 31 patients aged younger than 65 years with newly diagnosed multiple myeloma from eight IFM transplant centers. The patients underwent induction therapy with three cycles of VRD, each lasting 21 days. The regimen included bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11), lenalidomide (25 mg/day for days 1-14), and oral dexamethasone (40 mg on day 1, 8, and 14).

Patients were assessed for response after the third cycle, and peripheral stem cells were mobilized and harvested. They then underwent intensification with melphalan 200 mg/m2 and ASCT. After a 2-month hematologic recovery period, the patients could then receive two cycles of VRD consolidation, followed by a year of lenalidomide maintenance, with the drug given at 10 mg/day for 3 months, with dose escalation up to 15 mg if the lower dose was well tolerated.

The primary study outcome was best achieved response 1 month after consolidation. Secondary end points included response rates after three cycles of VRD, the safety and tolerability of the combination in the setting of high-dose therapy, the feasibility of stem cell harvest, progression-free survival, overall survival, time to progression, and duration of response.

The combined CR and sCR rate after induction was 23%, and 62% of patients had a VGPR or better. Following transplant, those rates rose to 36% and 68%, respectively; after consolidation, they were 48% and 84%.

Common toxicities of all grades included thrombocytopenia in 97% of patients, and anemia and neutropenia each in 87%. Sensory peripheral neuropathy occurred in 68% of patients, erythroderma or skin rash in 32%, pneumonia in 16%, and varicella zoster viral infections in 13%.

In all, 39% of patients experienced grade 3 or 4 neutropenia leading to lenalidomide dose reduction in eight patients (26% of the total cohort). In addition, 13% of patients had grade 3 thrombocytopenia, and 6% had grade 3 anemia. There were no grade 4 thrombocytopenia or anemia cases, and no grade 3 or 4 sensory peripheral neuropathy. Grade 1 or 2 neuropathy requiring reductions of bortezomib dose occurred in seven patients.

From one to five stem cell collections (median, two) were required to obtain a sufficient number for ASCT. Five patients needed a second-line mobilizing agent, and investigators were unable to obtain enough cells from one patient with stable disease; this patient did not undergo autologous transplant.

The IFM-2008 study is sponsored by University Hospital Toulouse, with support from Celgene and Janssen-Cilag. Dr. Roussel disclosed receiving research funding and serving on the speakers bureaus of the companies.

ORLANDO – A subcutaneous form of bortezomib appears to be a therapeutic chip off the old intravenous bortezomib block, but with better safety than the parent compound, investigators reported at the annual meeting of the American Society of Hematology.

In a randomized phase III study link in patients with relapsed multiple myeloma, the overall response rates (ORR) after four cycles in patients treated with either IV bortezomib (Velcade) or subcutaneous (SC) bortezomib were identical, at 42%. Complete responses occurred in 8% of patients treated with the IV drug and 6% with the SC drug; partial responses occurred in 34% and 36%, respectively, said Dr. Philippe Moreau from University Hospital in Nantes, France.

[Bortezomib-Based Regimens Help Older Patients With Multiple Myeloma]

"So we do have now similar efficacy with sub-Q, a more convenient route of administration for patients, especially those with poor venous access, we don’t require IV lines or central lines, and we do have, most importantly, a reduction of toxicity. In my opinion, these findings are really important for our patients," Dr. Moreau said.

Although patient exposure to the drug (as measured by area-under-the curve mean plasma concentrations) were virtually identical between the two routes of administration, the time to maximum plasma concentration (Tmax) was shorter with the IV formulation, at a median 0.03 hours, than with the SC version, at a median 0.50 hours.

In addition, maximum plasma concentrations (Cmax) of bortezomib were considerably higher with the IV formulation, at a mean 223 ng/mL, than with 20.4 ng/mL for SC. These differences may account for the lower toxicity with the SC formulation, Dr. Moreau said.

The investigators compared the ORR after four cycles of SC or IV bortezomib in previously treated patients with multiple myeloma. Secondary outcomes were complete response, near–complete response, and very good partial response rates after four cycles, ORR after eight cycles with or without dexamethasone, time-to-progression, progression-free survival, 1-year survival, time to response, and duration of response, as well as pharmacokinetics and pharmacodynamics and safety.

Patients with 1 to 3 previous lines of therapy for multiple myeloma were randomly assigned to receive IV bortezomib 1 mg/mL as a 3-5 second IV push (74 patients) or SC injections 2.5 mg/mL in the thigh or abdomen with rotation of injections within each cycle (148 patients). All of the study participants received a median of eight treatment cycles and remained on study for a median of 22.57 weeks.

The median cumulative dose was 31.46 mg/m2 in patients on the IV drug, and 33.76 mg/m2 in patients on the SC form. Slightly more than half of the patients in each group received dexamethasone (53% and 56%, respectively), at a median dose intensity in each group of 160 mg per cycle.

As with the primary end point, the ORR after 8 cycles of bortezomib with or without dexamethasone were identical in the two groups, at 52%. Of these responses, 12% were complete and 40% were partial in the IV group, compared with 10% and 42%, respectively, in the SC group.

The time to first response was also identical, at a median of 1.4 months in each group. Time to best response was a median 1.5 months in the IV group and 1.6 months in the SC group; the median duration of response was 8.8 months and 9.7 months, respectively. Median time to disease progression was 9.4 and 10.4 months, respectively, a difference that was not statistically significant.

The 1-year survival rates were 76.7% for patients who received IV bortezomib, and 72.6% of patients who received the drug subcutaneously.

An analysis of proteasome inhibition measured as the area under the effect-time curve showed that the subcutaneous formulation was comparable to IV push.

Grade 3 or 4 adverse events occurred in 70% of patients in the IV group and 57% of those in the SC group. Bortezomib dose reductions or discontinuations due to adverse events were higher among patients who received the IV form, at 43% and 27%, compared with 31% and 22% for those who received SC injections. Grade 3 or greater hematologic abnormalities were similar between groups, except for white blood cells counts, which were abnormally low in 18% of patients on IV, vs. 8% of those in the SC group.

Peripheral neuropathy of any grade was seen in 53% of IV patients, compared with 38% of SC patients (P =. 04). Also higher in the IV group were grade 2 or greater peripheral neuropathy events (41% vs 24%, P = .01) and grade 3 or greater events (16% vs. 6%, P = .03). Risk factors for peripheral neuropathy, including grade 1 neuropathy or diabetes at baseline or prior exposure to neurotoxic drugs, were similar between groups, however.

In the SC group, 6% of patients had at least 1 injection-site reaction reported as an adverse event. Redness at the injection site was reported by 57% of patients, but only 1% had a severe injection-site reaction. All of the reactions resolved, with a median time to resolution of 6 days.

In the question-and-answer session following the presentation, an audience member pointed out that neurotoxicity with bortezomib may not, as Dr. Moreau speculated, be related to the peak dose, because bortezomib given at a higher dose on a once-weekly schedule is associated with lower neuropathy than with lower doses given twice weekly.

The study was supported by Janssen-Cilag. Dr. Moreau disclosed that he has received honoraria from the company and from Celgene and Millennium Pharmaceuticals and has served on Millennium’s speakers bureau or scientific advisory board.

ORLANDO – A subcutaneous form of bortezomib appears to be a therapeutic chip off the old intravenous bortezomib block, but with better safety than the parent compound, investigators reported at the annual meeting of the American Society of Hematology.

In a randomized phase III study link in patients with relapsed multiple myeloma, the overall response rates (ORR) after four cycles in patients treated with either IV bortezomib (Velcade) or subcutaneous (SC) bortezomib were identical, at 42%. Complete responses occurred in 8% of patients treated with the IV drug and 6% with the SC drug; partial responses occurred in 34% and 36%, respectively, said Dr. Philippe Moreau from University Hospital in Nantes, France.

[Bortezomib-Based Regimens Help Older Patients With Multiple Myeloma]

"So we do have now similar efficacy with sub-Q, a more convenient route of administration for patients, especially those with poor venous access, we don’t require IV lines or central lines, and we do have, most importantly, a reduction of toxicity. In my opinion, these findings are really important for our patients," Dr. Moreau said.

Although patient exposure to the drug (as measured by area-under-the curve mean plasma concentrations) were virtually identical between the two routes of administration, the time to maximum plasma concentration (Tmax) was shorter with the IV formulation, at a median 0.03 hours, than with the SC version, at a median 0.50 hours.

In addition, maximum plasma concentrations (Cmax) of bortezomib were considerably higher with the IV formulation, at a mean 223 ng/mL, than with 20.4 ng/mL for SC. These differences may account for the lower toxicity with the SC formulation, Dr. Moreau said.

The investigators compared the ORR after four cycles of SC or IV bortezomib in previously treated patients with multiple myeloma. Secondary outcomes were complete response, near–complete response, and very good partial response rates after four cycles, ORR after eight cycles with or without dexamethasone, time-to-progression, progression-free survival, 1-year survival, time to response, and duration of response, as well as pharmacokinetics and pharmacodynamics and safety.

Patients with 1 to 3 previous lines of therapy for multiple myeloma were randomly assigned to receive IV bortezomib 1 mg/mL as a 3-5 second IV push (74 patients) or SC injections 2.5 mg/mL in the thigh or abdomen with rotation of injections within each cycle (148 patients). All of the study participants received a median of eight treatment cycles and remained on study for a median of 22.57 weeks.

The median cumulative dose was 31.46 mg/m2 in patients on the IV drug, and 33.76 mg/m2 in patients on the SC form. Slightly more than half of the patients in each group received dexamethasone (53% and 56%, respectively), at a median dose intensity in each group of 160 mg per cycle.

As with the primary end point, the ORR after 8 cycles of bortezomib with or without dexamethasone were identical in the two groups, at 52%. Of these responses, 12% were complete and 40% were partial in the IV group, compared with 10% and 42%, respectively, in the SC group.

The time to first response was also identical, at a median of 1.4 months in each group. Time to best response was a median 1.5 months in the IV group and 1.6 months in the SC group; the median duration of response was 8.8 months and 9.7 months, respectively. Median time to disease progression was 9.4 and 10.4 months, respectively, a difference that was not statistically significant.

The 1-year survival rates were 76.7% for patients who received IV bortezomib, and 72.6% of patients who received the drug subcutaneously.

An analysis of proteasome inhibition measured as the area under the effect-time curve showed that the subcutaneous formulation was comparable to IV push.

Grade 3 or 4 adverse events occurred in 70% of patients in the IV group and 57% of those in the SC group. Bortezomib dose reductions or discontinuations due to adverse events were higher among patients who received the IV form, at 43% and 27%, compared with 31% and 22% for those who received SC injections. Grade 3 or greater hematologic abnormalities were similar between groups, except for white blood cells counts, which were abnormally low in 18% of patients on IV, vs. 8% of those in the SC group.

Peripheral neuropathy of any grade was seen in 53% of IV patients, compared with 38% of SC patients (P =. 04). Also higher in the IV group were grade 2 or greater peripheral neuropathy events (41% vs 24%, P = .01) and grade 3 or greater events (16% vs. 6%, P = .03). Risk factors for peripheral neuropathy, including grade 1 neuropathy or diabetes at baseline or prior exposure to neurotoxic drugs, were similar between groups, however.

In the SC group, 6% of patients had at least 1 injection-site reaction reported as an adverse event. Redness at the injection site was reported by 57% of patients, but only 1% had a severe injection-site reaction. All of the reactions resolved, with a median time to resolution of 6 days.

In the question-and-answer session following the presentation, an audience member pointed out that neurotoxicity with bortezomib may not, as Dr. Moreau speculated, be related to the peak dose, because bortezomib given at a higher dose on a once-weekly schedule is associated with lower neuropathy than with lower doses given twice weekly.

The study was supported by Janssen-Cilag. Dr. Moreau disclosed that he has received honoraria from the company and from Celgene and Millennium Pharmaceuticals and has served on Millennium’s speakers bureau or scientific advisory board.

ORLANDO – A subcutaneous form of bortezomib appears to be a therapeutic chip off the old intravenous bortezomib block, but with better safety than the parent compound, investigators reported at the annual meeting of the American Society of Hematology.

In a randomized phase III study link in patients with relapsed multiple myeloma, the overall response rates (ORR) after four cycles in patients treated with either IV bortezomib (Velcade) or subcutaneous (SC) bortezomib were identical, at 42%. Complete responses occurred in 8% of patients treated with the IV drug and 6% with the SC drug; partial responses occurred in 34% and 36%, respectively, said Dr. Philippe Moreau from University Hospital in Nantes, France.

[Bortezomib-Based Regimens Help Older Patients With Multiple Myeloma]

"So we do have now similar efficacy with sub-Q, a more convenient route of administration for patients, especially those with poor venous access, we don’t require IV lines or central lines, and we do have, most importantly, a reduction of toxicity. In my opinion, these findings are really important for our patients," Dr. Moreau said.

Although patient exposure to the drug (as measured by area-under-the curve mean plasma concentrations) were virtually identical between the two routes of administration, the time to maximum plasma concentration (Tmax) was shorter with the IV formulation, at a median 0.03 hours, than with the SC version, at a median 0.50 hours.

In addition, maximum plasma concentrations (Cmax) of bortezomib were considerably higher with the IV formulation, at a mean 223 ng/mL, than with 20.4 ng/mL for SC. These differences may account for the lower toxicity with the SC formulation, Dr. Moreau said.

The investigators compared the ORR after four cycles of SC or IV bortezomib in previously treated patients with multiple myeloma. Secondary outcomes were complete response, near–complete response, and very good partial response rates after four cycles, ORR after eight cycles with or without dexamethasone, time-to-progression, progression-free survival, 1-year survival, time to response, and duration of response, as well as pharmacokinetics and pharmacodynamics and safety.

Patients with 1 to 3 previous lines of therapy for multiple myeloma were randomly assigned to receive IV bortezomib 1 mg/mL as a 3-5 second IV push (74 patients) or SC injections 2.5 mg/mL in the thigh or abdomen with rotation of injections within each cycle (148 patients). All of the study participants received a median of eight treatment cycles and remained on study for a median of 22.57 weeks.

The median cumulative dose was 31.46 mg/m2 in patients on the IV drug, and 33.76 mg/m2 in patients on the SC form. Slightly more than half of the patients in each group received dexamethasone (53% and 56%, respectively), at a median dose intensity in each group of 160 mg per cycle.

As with the primary end point, the ORR after 8 cycles of bortezomib with or without dexamethasone were identical in the two groups, at 52%. Of these responses, 12% were complete and 40% were partial in the IV group, compared with 10% and 42%, respectively, in the SC group.

The time to first response was also identical, at a median of 1.4 months in each group. Time to best response was a median 1.5 months in the IV group and 1.6 months in the SC group; the median duration of response was 8.8 months and 9.7 months, respectively. Median time to disease progression was 9.4 and 10.4 months, respectively, a difference that was not statistically significant.

The 1-year survival rates were 76.7% for patients who received IV bortezomib, and 72.6% of patients who received the drug subcutaneously.

An analysis of proteasome inhibition measured as the area under the effect-time curve showed that the subcutaneous formulation was comparable to IV push.

Grade 3 or 4 adverse events occurred in 70% of patients in the IV group and 57% of those in the SC group. Bortezomib dose reductions or discontinuations due to adverse events were higher among patients who received the IV form, at 43% and 27%, compared with 31% and 22% for those who received SC injections. Grade 3 or greater hematologic abnormalities were similar between groups, except for white blood cells counts, which were abnormally low in 18% of patients on IV, vs. 8% of those in the SC group.

Peripheral neuropathy of any grade was seen in 53% of IV patients, compared with 38% of SC patients (P =. 04). Also higher in the IV group were grade 2 or greater peripheral neuropathy events (41% vs 24%, P = .01) and grade 3 or greater events (16% vs. 6%, P = .03). Risk factors for peripheral neuropathy, including grade 1 neuropathy or diabetes at baseline or prior exposure to neurotoxic drugs, were similar between groups, however.

In the SC group, 6% of patients had at least 1 injection-site reaction reported as an adverse event. Redness at the injection site was reported by 57% of patients, but only 1% had a severe injection-site reaction. All of the reactions resolved, with a median time to resolution of 6 days.

In the question-and-answer session following the presentation, an audience member pointed out that neurotoxicity with bortezomib may not, as Dr. Moreau speculated, be related to the peak dose, because bortezomib given at a higher dose on a once-weekly schedule is associated with lower neuropathy than with lower doses given twice weekly.

The study was supported by Janssen-Cilag. Dr. Moreau disclosed that he has received honoraria from the company and from Celgene and Millennium Pharmaceuticals and has served on Millennium’s speakers bureau or scientific advisory board.

ORLANDO — Rituximab prophylaxis can help to reduce the incidence of chronic, steroid-requiring graft-vs.-host disease in patients who undergo allogeneic stem cell transplants, investigators suggested at the annual meeting of the American Society of Hematology.

The 1-year cumulative incidence of chronic graft-vs.-host disease (GVHD) among 64 allogeneic stem cell recipients who received prophylactic rituximab (Rituxan) was about 40%, compared with about 65% for historical controls, reported Dr. Joseph Antin, chief of the stem cell transplantation program at the Dana-Farber Cancer Institute in Boston.

[Outcomes After Allogeneic Hematopoietic-Cell Transplant Dramatically Better]

In addition, only about one-third of rituximab-treated patients required steroids to control chronic GVHD when it developed, compared with nearly 100% of historical controls, Dr. Antin said at a media briefing.

Results of the ongoing study suggest that the strategy of B-cell depletion with rituximab may be effective at preventing or controlling GVHD, a condition once believed to be principally T-cell mediated. "B cells actually have substantial overlapping activities with T cells. In addition to their ability to produce antibodies, they can function as antigen-presenting cells, they can produce cytokines, and they have immunoregulatory characteristics," Dr. Antin said.

The investigators had previously studied the use of rituximab in patients with active chronic GVHD, and found that patients had a "reasonable" but unsustained response rate, he noted.

They presented data on 58 evaluable patients out of 64 enrolled to date. Patients who were at least 3 months out from an allogeneic stem cell transplant and had either recovered from any degree of acute GVHD or had never developed it were given a prophylactic dose of rituximab 375 mg/m2 (the standard dosage used in lymphoma therapy) at study entry and at months 6, 9, and 12. The patients underwent immunologic assessments at the time of each dose, and at 18 and 24 months. The patients were also assessed for clinical signs of GVHD at 6, 9, 12, and 24 months.

Overall, 25 patients (median age, 55 years) underwent transplants for acute myeloid leukemia, 18 for Hodgkin’s or non-Hodgkin’s lymphoma, 10 for myelodysplasia or myeloproliferative disorders, 3 for acute lymphoblastic leukemia, and 2 for chronic lymphocytic leukemia or promylocytic leukemia.

In 33 cases, the donors were HLA matched but unrelated to the recipient; in the remaining 25 the donors were related matches.

"We were concerned about the potential toxicity of giving a B-cell antibody at the time of [immunologic] recovery. Much of the morbidity of transplantation involves opportunistic infections that are intrinsic to the immunoincompetence of patients as they have gone through this procedure. In addition to that, rituximab used after autologous transplantation can result in cytopenia, which we were concerned about," Dr. Antin said.

There were 11 severe adverse events: 4 infectious (sepsis, febrile neutropenia, and pneumonia), 5 respiratory (pneumonitis, dyspnea, and hypoxia), 1 thrombotic microangiopathy, and 1 prolonged pancytopenia.

The 1-year cumulative incidence of steroid-requiring GVHD was 28.1%, compared with close to 100% of historical controls, he noted. Most of the cases of GVHD that did occur were not serious, manifesting primarily as oral and ocular symptoms that were amenable to topical therapy.

The 2-year overall survival rate is currently greater than 70%, and there is little evidence to suggest that chronic GVHD might be contributing to mortality, Dr. Antin said.

"The one concern we have is that chronic GVHD is associated with a graft-vs.-leukemia effect, and anything that abrogates graft-vs.-host disease has the potential of increasing the relapse rate, and that’s something that we need to continue to follow," he said.

Lead author Dr. Corey Cutler of Harvard Medical School in Boston presented the data in session. The study is supported by Genentech, Gateway for Cancer Research, and the Stem Cell Cyclists of the Pan-Mass Challenge. None of the authors had relevant conflict of interest disclosures.

ORLANDO — Rituximab prophylaxis can help to reduce the incidence of chronic, steroid-requiring graft-vs.-host disease in patients who undergo allogeneic stem cell transplants, investigators suggested at the annual meeting of the American Society of Hematology.

The 1-year cumulative incidence of chronic graft-vs.-host disease (GVHD) among 64 allogeneic stem cell recipients who received prophylactic rituximab (Rituxan) was about 40%, compared with about 65% for historical controls, reported Dr. Joseph Antin, chief of the stem cell transplantation program at the Dana-Farber Cancer Institute in Boston.

[Outcomes After Allogeneic Hematopoietic-Cell Transplant Dramatically Better]

In addition, only about one-third of rituximab-treated patients required steroids to control chronic GVHD when it developed, compared with nearly 100% of historical controls, Dr. Antin said at a media briefing.

Results of the ongoing study suggest that the strategy of B-cell depletion with rituximab may be effective at preventing or controlling GVHD, a condition once believed to be principally T-cell mediated. "B cells actually have substantial overlapping activities with T cells. In addition to their ability to produce antibodies, they can function as antigen-presenting cells, they can produce cytokines, and they have immunoregulatory characteristics," Dr. Antin said.

The investigators had previously studied the use of rituximab in patients with active chronic GVHD, and found that patients had a "reasonable" but unsustained response rate, he noted.

They presented data on 58 evaluable patients out of 64 enrolled to date. Patients who were at least 3 months out from an allogeneic stem cell transplant and had either recovered from any degree of acute GVHD or had never developed it were given a prophylactic dose of rituximab 375 mg/m2 (the standard dosage used in lymphoma therapy) at study entry and at months 6, 9, and 12. The patients underwent immunologic assessments at the time of each dose, and at 18 and 24 months. The patients were also assessed for clinical signs of GVHD at 6, 9, 12, and 24 months.

Overall, 25 patients (median age, 55 years) underwent transplants for acute myeloid leukemia, 18 for Hodgkin’s or non-Hodgkin’s lymphoma, 10 for myelodysplasia or myeloproliferative disorders, 3 for acute lymphoblastic leukemia, and 2 for chronic lymphocytic leukemia or promylocytic leukemia.

In 33 cases, the donors were HLA matched but unrelated to the recipient; in the remaining 25 the donors were related matches.

"We were concerned about the potential toxicity of giving a B-cell antibody at the time of [immunologic] recovery. Much of the morbidity of transplantation involves opportunistic infections that are intrinsic to the immunoincompetence of patients as they have gone through this procedure. In addition to that, rituximab used after autologous transplantation can result in cytopenia, which we were concerned about," Dr. Antin said.

There were 11 severe adverse events: 4 infectious (sepsis, febrile neutropenia, and pneumonia), 5 respiratory (pneumonitis, dyspnea, and hypoxia), 1 thrombotic microangiopathy, and 1 prolonged pancytopenia.

The 1-year cumulative incidence of steroid-requiring GVHD was 28.1%, compared with close to 100% of historical controls, he noted. Most of the cases of GVHD that did occur were not serious, manifesting primarily as oral and ocular symptoms that were amenable to topical therapy.

The 2-year overall survival rate is currently greater than 70%, and there is little evidence to suggest that chronic GVHD might be contributing to mortality, Dr. Antin said.

"The one concern we have is that chronic GVHD is associated with a graft-vs.-leukemia effect, and anything that abrogates graft-vs.-host disease has the potential of increasing the relapse rate, and that’s something that we need to continue to follow," he said.

Lead author Dr. Corey Cutler of Harvard Medical School in Boston presented the data in session. The study is supported by Genentech, Gateway for Cancer Research, and the Stem Cell Cyclists of the Pan-Mass Challenge. None of the authors had relevant conflict of interest disclosures.

ORLANDO — Rituximab prophylaxis can help to reduce the incidence of chronic, steroid-requiring graft-vs.-host disease in patients who undergo allogeneic stem cell transplants, investigators suggested at the annual meeting of the American Society of Hematology.

The 1-year cumulative incidence of chronic graft-vs.-host disease (GVHD) among 64 allogeneic stem cell recipients who received prophylactic rituximab (Rituxan) was about 40%, compared with about 65% for historical controls, reported Dr. Joseph Antin, chief of the stem cell transplantation program at the Dana-Farber Cancer Institute in Boston.

[Outcomes After Allogeneic Hematopoietic-Cell Transplant Dramatically Better]

In addition, only about one-third of rituximab-treated patients required steroids to control chronic GVHD when it developed, compared with nearly 100% of historical controls, Dr. Antin said at a media briefing.

Results of the ongoing study suggest that the strategy of B-cell depletion with rituximab may be effective at preventing or controlling GVHD, a condition once believed to be principally T-cell mediated. "B cells actually have substantial overlapping activities with T cells. In addition to their ability to produce antibodies, they can function as antigen-presenting cells, they can produce cytokines, and they have immunoregulatory characteristics," Dr. Antin said.

The investigators had previously studied the use of rituximab in patients with active chronic GVHD, and found that patients had a "reasonable" but unsustained response rate, he noted.

They presented data on 58 evaluable patients out of 64 enrolled to date. Patients who were at least 3 months out from an allogeneic stem cell transplant and had either recovered from any degree of acute GVHD or had never developed it were given a prophylactic dose of rituximab 375 mg/m2 (the standard dosage used in lymphoma therapy) at study entry and at months 6, 9, and 12. The patients underwent immunologic assessments at the time of each dose, and at 18 and 24 months. The patients were also assessed for clinical signs of GVHD at 6, 9, 12, and 24 months.

Overall, 25 patients (median age, 55 years) underwent transplants for acute myeloid leukemia, 18 for Hodgkin’s or non-Hodgkin’s lymphoma, 10 for myelodysplasia or myeloproliferative disorders, 3 for acute lymphoblastic leukemia, and 2 for chronic lymphocytic leukemia or promylocytic leukemia.

In 33 cases, the donors were HLA matched but unrelated to the recipient; in the remaining 25 the donors were related matches.

"We were concerned about the potential toxicity of giving a B-cell antibody at the time of [immunologic] recovery. Much of the morbidity of transplantation involves opportunistic infections that are intrinsic to the immunoincompetence of patients as they have gone through this procedure. In addition to that, rituximab used after autologous transplantation can result in cytopenia, which we were concerned about," Dr. Antin said.

There were 11 severe adverse events: 4 infectious (sepsis, febrile neutropenia, and pneumonia), 5 respiratory (pneumonitis, dyspnea, and hypoxia), 1 thrombotic microangiopathy, and 1 prolonged pancytopenia.

The 1-year cumulative incidence of steroid-requiring GVHD was 28.1%, compared with close to 100% of historical controls, he noted. Most of the cases of GVHD that did occur were not serious, manifesting primarily as oral and ocular symptoms that were amenable to topical therapy.

The 2-year overall survival rate is currently greater than 70%, and there is little evidence to suggest that chronic GVHD might be contributing to mortality, Dr. Antin said.

"The one concern we have is that chronic GVHD is associated with a graft-vs.-leukemia effect, and anything that abrogates graft-vs.-host disease has the potential of increasing the relapse rate, and that’s something that we need to continue to follow," he said.

Lead author Dr. Corey Cutler of Harvard Medical School in Boston presented the data in session. The study is supported by Genentech, Gateway for Cancer Research, and the Stem Cell Cyclists of the Pan-Mass Challenge. None of the authors had relevant conflict of interest disclosures.

ORLANDO – Each of three bortezomib-based regimens was active as first-line therapy in elderly patients with multiple myeloma, and subsequent maintenance with bortezomib resulted in increases of very good partial responses or better in each trial arm, reported investigators from the phase IIIb UPFRONT study at the annual meeting of the American Society of Hematology.

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

In the randomized community-based study, investigator-confirmed overall response rates after induction and maintenance were 71% with a bortezomib (Velcade)–dexamethasone combination (VD), 79% with bortezomib-thalidomide-dexamethasone (VTD), and 73% with bortezomib-melphalan-prednisone (VMP), reported Dr. Ruben Niesvizky of the New York Weill Cornell Medical Center in New York.

Progression-free survival did not differ significantly after a median 13.4 months’ follow-up. There appeared to be a trend favoring VTD, even though grade 3 or greater adverse events, peripheral neuropathies, and study discontinuations because of adverse events were highest with this regimen, the authors found.

"It is well understood that patients who are not candidates for stem cell transplant are indeed a challenge. ... At the time that this trial was designed, we had three major bortezomib-containing regimens, which were the best performing combinations," Dr. Niesvizky said.

The investigators enrolled patients with newly diagnosed multiple myeloma who were ineligible for high-dose therapy and stem cell transplant. Participants had to have a Karnofsky performance score of 50% or greater, as well as measurable disease requiring systemic therapy.

The trial randomly assigned them to eight cycles of induction therapy with VD, VTD, or VMP (100 patients in each group) followed by five additional cycles of bortezomib maintenance. Maintenance cycles were 35 days long, with bortezomib 1.6 mg/m2 given on days 1, 8, 15, and 22. The median age range was 72-73.5 years in the three arms.

The primary end point was progression-free survival. Secondary end points were efficacy of the various regimens, as well as their respective safety and tolerability.

During induction, patients in the VD group received 76% of planned doses of bortezomib, compared with 63% of patients in the VTD group and 69% of those in the VMP group. During maintenance, 73% in the VD group received the intended dose, compared with 77% of patients on VTD and 85% of those on VMP.

Investigator-assessed, best-confirmed rates in the response-evaluable population were very good partial response (VGPR) or better in 36% of those on VD induction and 39% after bortezomib maintenance; 44% of those on VTD induction and 47% after maintenance; and 40% on VMP induction, and 44% after maintenance.

At a median 13.4 months’ follow-up, median progression-free survival reached 13.8 months with VD, 18.4 months with VTD, and 17.3 months with VMP. There were no significant differences in any of the pairwise comparisons, although patients on VMP appeared to plateau beginning around 22 months and continuing out to 33 months, the longest follow-up thus far.

Grade 3 or greater adverse events occurred during induction in 69% of those on VD and in 78% each of patients on VTD and VMP. Grade 3 or greater peripheral neuropathy was reported in 15%, 24%, and 20% of patients, respectively, and neutropenia in 1%, 3%, and 21%.

Peripheral neuropathy was more common in the VTD arm, compared with either of the other arms, both before and after bortezomib maintenance.

Millennium Pharmaceuticals, maker of bortezomib, funded the study. Dr. Niesvizky disclosed serving as a consultant and receiving research funding from the company. Several coauthors also disclosed consulting, research support, or speakers bureau relationships with Millennium, and two were employees.

ORLANDO – Each of three bortezomib-based regimens was active as first-line therapy in elderly patients with multiple myeloma, and subsequent maintenance with bortezomib resulted in increases of very good partial responses or better in each trial arm, reported investigators from the phase IIIb UPFRONT study at the annual meeting of the American Society of Hematology.

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

In the randomized community-based study, investigator-confirmed overall response rates after induction and maintenance were 71% with a bortezomib (Velcade)–dexamethasone combination (VD), 79% with bortezomib-thalidomide-dexamethasone (VTD), and 73% with bortezomib-melphalan-prednisone (VMP), reported Dr. Ruben Niesvizky of the New York Weill Cornell Medical Center in New York.

Progression-free survival did not differ significantly after a median 13.4 months’ follow-up. There appeared to be a trend favoring VTD, even though grade 3 or greater adverse events, peripheral neuropathies, and study discontinuations because of adverse events were highest with this regimen, the authors found.

"It is well understood that patients who are not candidates for stem cell transplant are indeed a challenge. ... At the time that this trial was designed, we had three major bortezomib-containing regimens, which were the best performing combinations," Dr. Niesvizky said.

The investigators enrolled patients with newly diagnosed multiple myeloma who were ineligible for high-dose therapy and stem cell transplant. Participants had to have a Karnofsky performance score of 50% or greater, as well as measurable disease requiring systemic therapy.

The trial randomly assigned them to eight cycles of induction therapy with VD, VTD, or VMP (100 patients in each group) followed by five additional cycles of bortezomib maintenance. Maintenance cycles were 35 days long, with bortezomib 1.6 mg/m2 given on days 1, 8, 15, and 22. The median age range was 72-73.5 years in the three arms.

The primary end point was progression-free survival. Secondary end points were efficacy of the various regimens, as well as their respective safety and tolerability.

During induction, patients in the VD group received 76% of planned doses of bortezomib, compared with 63% of patients in the VTD group and 69% of those in the VMP group. During maintenance, 73% in the VD group received the intended dose, compared with 77% of patients on VTD and 85% of those on VMP.

Investigator-assessed, best-confirmed rates in the response-evaluable population were very good partial response (VGPR) or better in 36% of those on VD induction and 39% after bortezomib maintenance; 44% of those on VTD induction and 47% after maintenance; and 40% on VMP induction, and 44% after maintenance.

At a median 13.4 months’ follow-up, median progression-free survival reached 13.8 months with VD, 18.4 months with VTD, and 17.3 months with VMP. There were no significant differences in any of the pairwise comparisons, although patients on VMP appeared to plateau beginning around 22 months and continuing out to 33 months, the longest follow-up thus far.

Grade 3 or greater adverse events occurred during induction in 69% of those on VD and in 78% each of patients on VTD and VMP. Grade 3 or greater peripheral neuropathy was reported in 15%, 24%, and 20% of patients, respectively, and neutropenia in 1%, 3%, and 21%.

Peripheral neuropathy was more common in the VTD arm, compared with either of the other arms, both before and after bortezomib maintenance.

Millennium Pharmaceuticals, maker of bortezomib, funded the study. Dr. Niesvizky disclosed serving as a consultant and receiving research funding from the company. Several coauthors also disclosed consulting, research support, or speakers bureau relationships with Millennium, and two were employees.

ORLANDO – Each of three bortezomib-based regimens was active as first-line therapy in elderly patients with multiple myeloma, and subsequent maintenance with bortezomib resulted in increases of very good partial responses or better in each trial arm, reported investigators from the phase IIIb UPFRONT study at the annual meeting of the American Society of Hematology.

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

In the randomized community-based study, investigator-confirmed overall response rates after induction and maintenance were 71% with a bortezomib (Velcade)–dexamethasone combination (VD), 79% with bortezomib-thalidomide-dexamethasone (VTD), and 73% with bortezomib-melphalan-prednisone (VMP), reported Dr. Ruben Niesvizky of the New York Weill Cornell Medical Center in New York.

Progression-free survival did not differ significantly after a median 13.4 months’ follow-up. There appeared to be a trend favoring VTD, even though grade 3 or greater adverse events, peripheral neuropathies, and study discontinuations because of adverse events were highest with this regimen, the authors found.

"It is well understood that patients who are not candidates for stem cell transplant are indeed a challenge. ... At the time that this trial was designed, we had three major bortezomib-containing regimens, which were the best performing combinations," Dr. Niesvizky said.

The investigators enrolled patients with newly diagnosed multiple myeloma who were ineligible for high-dose therapy and stem cell transplant. Participants had to have a Karnofsky performance score of 50% or greater, as well as measurable disease requiring systemic therapy.

The trial randomly assigned them to eight cycles of induction therapy with VD, VTD, or VMP (100 patients in each group) followed by five additional cycles of bortezomib maintenance. Maintenance cycles were 35 days long, with bortezomib 1.6 mg/m2 given on days 1, 8, 15, and 22. The median age range was 72-73.5 years in the three arms.

The primary end point was progression-free survival. Secondary end points were efficacy of the various regimens, as well as their respective safety and tolerability.

During induction, patients in the VD group received 76% of planned doses of bortezomib, compared with 63% of patients in the VTD group and 69% of those in the VMP group. During maintenance, 73% in the VD group received the intended dose, compared with 77% of patients on VTD and 85% of those on VMP.

Investigator-assessed, best-confirmed rates in the response-evaluable population were very good partial response (VGPR) or better in 36% of those on VD induction and 39% after bortezomib maintenance; 44% of those on VTD induction and 47% after maintenance; and 40% on VMP induction, and 44% after maintenance.

At a median 13.4 months’ follow-up, median progression-free survival reached 13.8 months with VD, 18.4 months with VTD, and 17.3 months with VMP. There were no significant differences in any of the pairwise comparisons, although patients on VMP appeared to plateau beginning around 22 months and continuing out to 33 months, the longest follow-up thus far.

Grade 3 or greater adverse events occurred during induction in 69% of those on VD and in 78% each of patients on VTD and VMP. Grade 3 or greater peripheral neuropathy was reported in 15%, 24%, and 20% of patients, respectively, and neutropenia in 1%, 3%, and 21%.

Peripheral neuropathy was more common in the VTD arm, compared with either of the other arms, both before and after bortezomib maintenance.

Millennium Pharmaceuticals, maker of bortezomib, funded the study. Dr. Niesvizky disclosed serving as a consultant and receiving research funding from the company. Several coauthors also disclosed consulting, research support, or speakers bureau relationships with Millennium, and two were employees.

ORLANDO – Younger patients with mantle cell lymphoma had significantly higher complete response rates after induction and better time to treatment failure after transplant with an experimental regimen adding high-dose cytarabine and R-DHAP to their treatment.

"Now we believe that the current gold standard for mantle cell lymphoma in young patients is the addition of high-dose Ara-C [cytarabine]," Dr. Olivier Hermine said on behalf of the European Mantle Cell Lymphoma Network during a press briefing at the American Society of Hematology annual meeting.

Dr. Hermine, head of the hematological department at Hôpital Necker in Paris, reported results of a randomized trial that compared outcomes in patients treated with alternating courses of the R-CHOP and R-DHAP regimens followed by myeloablative therapy containing high-dose cytarabine and autologous transplant with outcomes in a control arm in which patients were treated with six courses of R-CHOP plus myeloablation but without cytarabine or R-DHAP before transplant.

Among 420 patients with mantle cell lymphoma who were 65 years old or younger at the time of therapy, the combination of R-CHOP, R-DHAP, and high-dose cytarabine was associated with a 32% improvement in time to treatment failure (P = .0382).

In addition, 55% of those in the experimental arm had complete responses that were either confirmed or unconfirmed after induction, compared with 40% of those in the control group (P = .0028).

Overall response rates were similar between the groups, at 94% for R-CHOP/D-HAP and 90% for R-CHOP alone.

Longer follow-up will be needed to assess the effect on survival and on potential cure of mantle cell lymphoma. The goal of the next study will be to induce complete remissions, determined by minimal residual disease, before autologous stem-cell transplantation (ASCT), Dr. Hermine said.

Although long-term prognosis with mantle cell lymphoma historically has been poor, on the order of 3-4 years, a previous phase II study showed that a regimen of sequential R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) followed by ASCT was associated with an overall response rate of 95% and a complete response rate of 61%. This translated into a median event-free survival of 83 months and an overall survival rate of 75% at 5 years (Delarue R. et al. ASH 2008 annual meeting. Abstract 581).

In the current study, the investigators compared six courses of R-CHOP followed by myeloablative radiochemotherapy consisting of 12 Gy total body irradiation (TBI) and two cycles of cyclophosphamide 60 mg/kg followed by ASCT with six alternating courses of R-CHOP (three times) and R-DHAP (three times) followed by a myeloablative regimen consisting of 10 Gy TBI, and four cycles of cytarabine 1.5 g/m2 and melphalan 140 mg/m2 followed by ASCT.

Previously untreated patients aged 65 years or younger with stage II-IV mantle cell lymphoma and an ECOG performance status of 0 or 1 were randomly assigned to receive one of the two regimens. The randomization was stopped in May 2010 after the experimental (R-CHOP/R-DHAP) arm met the prespecified efficacy stopping criteria. The primary end point was time to treatment failure. Secondary end points were response rates, overall survival, and safety.

A total of 497 patients in Germany, France, Poland, and Belgium were enrolled. Dr. Hermine presented data on 420 patients with documented responses. In both arms, the overall response was 97% among patients who went on to ASCT. But in a per-protocol analysis, patients in the experimental arm had significantly better time to treatment failure (hazard ratio favoring R-CHOP/R-DHAP 0.68, P = .0382).

A total of 77 disease-related events were recorded among the 212 evaluable patients in the standard therapy arm, vs. 44 in the experimental arm. There were eight deaths during remission in the R-CHOP group; six were transplant related, and two were from a second malignancy. In the R-CHOP/R-DHAP group 11 deaths occurred: 8 patients died from ASCT-related causes, and 3 from second cancers.

The relapse rates after achieving a complete response, unconfirmed complete response, or partial response were 49 in the control arm and 22 in the experimental arm. Durations of remission after transplant were significantly longer among patients in the experimental arm, with the median not yet reached, compared with 48 months for R-CHOP (P = .0059).

The experimental arm was associated with increased rates of grade 3 or 4 hematologic toxicities, renal toxicities, and grade 1 or 2 nausea and vomiting during induction, compared with the standard therapy arm.

For the pre-ASCT conditioning regimen, the R-CHOP/R-DHAP regimen induced more grade 3 or 4 mucositis, while the R-CHOP-alone arm was associated with higher grade 1or 2 liver toxicity and constipation.

During the question-and-answer session following the presentation, Dr. Andrew D. Zelenetz from Memorial Sloan-Kettering Cancer Center in New York challenged Dr. Hermine to explain why the group broadly recommended the adoption of R-CHOP/R-DHAP plus high-dose cytarabine for all younger patients with MCL, given the strict inclusion criteria of the study.

Dr. Hermine agreed that the regimen might best be reserved for higher risk patients (International Prognostic Index score higher than 1), while lower-risk patients could benefit from the standard R-CHOP regimen.

Dr. Hermine and coauthors said they had no relevant conflicts of interest.

ORLANDO – Younger patients with mantle cell lymphoma had significantly higher complete response rates after induction and better time to treatment failure after transplant with an experimental regimen adding high-dose cytarabine and R-DHAP to their treatment.

"Now we believe that the current gold standard for mantle cell lymphoma in young patients is the addition of high-dose Ara-C [cytarabine]," Dr. Olivier Hermine said on behalf of the European Mantle Cell Lymphoma Network during a press briefing at the American Society of Hematology annual meeting.

Dr. Hermine, head of the hematological department at Hôpital Necker in Paris, reported results of a randomized trial that compared outcomes in patients treated with alternating courses of the R-CHOP and R-DHAP regimens followed by myeloablative therapy containing high-dose cytarabine and autologous transplant with outcomes in a control arm in which patients were treated with six courses of R-CHOP plus myeloablation but without cytarabine or R-DHAP before transplant.

Among 420 patients with mantle cell lymphoma who were 65 years old or younger at the time of therapy, the combination of R-CHOP, R-DHAP, and high-dose cytarabine was associated with a 32% improvement in time to treatment failure (P = .0382).

In addition, 55% of those in the experimental arm had complete responses that were either confirmed or unconfirmed after induction, compared with 40% of those in the control group (P = .0028).

Overall response rates were similar between the groups, at 94% for R-CHOP/D-HAP and 90% for R-CHOP alone.

Longer follow-up will be needed to assess the effect on survival and on potential cure of mantle cell lymphoma. The goal of the next study will be to induce complete remissions, determined by minimal residual disease, before autologous stem-cell transplantation (ASCT), Dr. Hermine said.

Although long-term prognosis with mantle cell lymphoma historically has been poor, on the order of 3-4 years, a previous phase II study showed that a regimen of sequential R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) followed by ASCT was associated with an overall response rate of 95% and a complete response rate of 61%. This translated into a median event-free survival of 83 months and an overall survival rate of 75% at 5 years (Delarue R. et al. ASH 2008 annual meeting. Abstract 581).

In the current study, the investigators compared six courses of R-CHOP followed by myeloablative radiochemotherapy consisting of 12 Gy total body irradiation (TBI) and two cycles of cyclophosphamide 60 mg/kg followed by ASCT with six alternating courses of R-CHOP (three times) and R-DHAP (three times) followed by a myeloablative regimen consisting of 10 Gy TBI, and four cycles of cytarabine 1.5 g/m2 and melphalan 140 mg/m2 followed by ASCT.

Previously untreated patients aged 65 years or younger with stage II-IV mantle cell lymphoma and an ECOG performance status of 0 or 1 were randomly assigned to receive one of the two regimens. The randomization was stopped in May 2010 after the experimental (R-CHOP/R-DHAP) arm met the prespecified efficacy stopping criteria. The primary end point was time to treatment failure. Secondary end points were response rates, overall survival, and safety.

A total of 497 patients in Germany, France, Poland, and Belgium were enrolled. Dr. Hermine presented data on 420 patients with documented responses. In both arms, the overall response was 97% among patients who went on to ASCT. But in a per-protocol analysis, patients in the experimental arm had significantly better time to treatment failure (hazard ratio favoring R-CHOP/R-DHAP 0.68, P = .0382).

A total of 77 disease-related events were recorded among the 212 evaluable patients in the standard therapy arm, vs. 44 in the experimental arm. There were eight deaths during remission in the R-CHOP group; six were transplant related, and two were from a second malignancy. In the R-CHOP/R-DHAP group 11 deaths occurred: 8 patients died from ASCT-related causes, and 3 from second cancers.

The relapse rates after achieving a complete response, unconfirmed complete response, or partial response were 49 in the control arm and 22 in the experimental arm. Durations of remission after transplant were significantly longer among patients in the experimental arm, with the median not yet reached, compared with 48 months for R-CHOP (P = .0059).

The experimental arm was associated with increased rates of grade 3 or 4 hematologic toxicities, renal toxicities, and grade 1 or 2 nausea and vomiting during induction, compared with the standard therapy arm.

For the pre-ASCT conditioning regimen, the R-CHOP/R-DHAP regimen induced more grade 3 or 4 mucositis, while the R-CHOP-alone arm was associated with higher grade 1or 2 liver toxicity and constipation.

During the question-and-answer session following the presentation, Dr. Andrew D. Zelenetz from Memorial Sloan-Kettering Cancer Center in New York challenged Dr. Hermine to explain why the group broadly recommended the adoption of R-CHOP/R-DHAP plus high-dose cytarabine for all younger patients with MCL, given the strict inclusion criteria of the study.

Dr. Hermine agreed that the regimen might best be reserved for higher risk patients (International Prognostic Index score higher than 1), while lower-risk patients could benefit from the standard R-CHOP regimen.

Dr. Hermine and coauthors said they had no relevant conflicts of interest.

ORLANDO – Younger patients with mantle cell lymphoma had significantly higher complete response rates after induction and better time to treatment failure after transplant with an experimental regimen adding high-dose cytarabine and R-DHAP to their treatment.

"Now we believe that the current gold standard for mantle cell lymphoma in young patients is the addition of high-dose Ara-C [cytarabine]," Dr. Olivier Hermine said on behalf of the European Mantle Cell Lymphoma Network during a press briefing at the American Society of Hematology annual meeting.

Dr. Hermine, head of the hematological department at Hôpital Necker in Paris, reported results of a randomized trial that compared outcomes in patients treated with alternating courses of the R-CHOP and R-DHAP regimens followed by myeloablative therapy containing high-dose cytarabine and autologous transplant with outcomes in a control arm in which patients were treated with six courses of R-CHOP plus myeloablation but without cytarabine or R-DHAP before transplant.

Among 420 patients with mantle cell lymphoma who were 65 years old or younger at the time of therapy, the combination of R-CHOP, R-DHAP, and high-dose cytarabine was associated with a 32% improvement in time to treatment failure (P = .0382).

In addition, 55% of those in the experimental arm had complete responses that were either confirmed or unconfirmed after induction, compared with 40% of those in the control group (P = .0028).

Overall response rates were similar between the groups, at 94% for R-CHOP/D-HAP and 90% for R-CHOP alone.

Longer follow-up will be needed to assess the effect on survival and on potential cure of mantle cell lymphoma. The goal of the next study will be to induce complete remissions, determined by minimal residual disease, before autologous stem-cell transplantation (ASCT), Dr. Hermine said.

Although long-term prognosis with mantle cell lymphoma historically has been poor, on the order of 3-4 years, a previous phase II study showed that a regimen of sequential R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) followed by ASCT was associated with an overall response rate of 95% and a complete response rate of 61%. This translated into a median event-free survival of 83 months and an overall survival rate of 75% at 5 years (Delarue R. et al. ASH 2008 annual meeting. Abstract 581).

In the current study, the investigators compared six courses of R-CHOP followed by myeloablative radiochemotherapy consisting of 12 Gy total body irradiation (TBI) and two cycles of cyclophosphamide 60 mg/kg followed by ASCT with six alternating courses of R-CHOP (three times) and R-DHAP (three times) followed by a myeloablative regimen consisting of 10 Gy TBI, and four cycles of cytarabine 1.5 g/m2 and melphalan 140 mg/m2 followed by ASCT.

Previously untreated patients aged 65 years or younger with stage II-IV mantle cell lymphoma and an ECOG performance status of 0 or 1 were randomly assigned to receive one of the two regimens. The randomization was stopped in May 2010 after the experimental (R-CHOP/R-DHAP) arm met the prespecified efficacy stopping criteria. The primary end point was time to treatment failure. Secondary end points were response rates, overall survival, and safety.

A total of 497 patients in Germany, France, Poland, and Belgium were enrolled. Dr. Hermine presented data on 420 patients with documented responses. In both arms, the overall response was 97% among patients who went on to ASCT. But in a per-protocol analysis, patients in the experimental arm had significantly better time to treatment failure (hazard ratio favoring R-CHOP/R-DHAP 0.68, P = .0382).

A total of 77 disease-related events were recorded among the 212 evaluable patients in the standard therapy arm, vs. 44 in the experimental arm. There were eight deaths during remission in the R-CHOP group; six were transplant related, and two were from a second malignancy. In the R-CHOP/R-DHAP group 11 deaths occurred: 8 patients died from ASCT-related causes, and 3 from second cancers.

The relapse rates after achieving a complete response, unconfirmed complete response, or partial response were 49 in the control arm and 22 in the experimental arm. Durations of remission after transplant were significantly longer among patients in the experimental arm, with the median not yet reached, compared with 48 months for R-CHOP (P = .0059).

The experimental arm was associated with increased rates of grade 3 or 4 hematologic toxicities, renal toxicities, and grade 1 or 2 nausea and vomiting during induction, compared with the standard therapy arm.

For the pre-ASCT conditioning regimen, the R-CHOP/R-DHAP regimen induced more grade 3 or 4 mucositis, while the R-CHOP-alone arm was associated with higher grade 1or 2 liver toxicity and constipation.

During the question-and-answer session following the presentation, Dr. Andrew D. Zelenetz from Memorial Sloan-Kettering Cancer Center in New York challenged Dr. Hermine to explain why the group broadly recommended the adoption of R-CHOP/R-DHAP plus high-dose cytarabine for all younger patients with MCL, given the strict inclusion criteria of the study.

Dr. Hermine agreed that the regimen might best be reserved for higher risk patients (International Prognostic Index score higher than 1), while lower-risk patients could benefit from the standard R-CHOP regimen.

Dr. Hermine and coauthors said they had no relevant conflicts of interest.

ORLANDO – An aggressive approach to treating early unfavorable Hodgkin’s lymphoma that combines the BEACOPP regimen at an escalated dose with the ABVD regimen and involved-field radiotherapy results in better tumor control than did ABVD and radiation alone, investigators have reported.

In the final analysis of the German Hodgkin Study Group (GHSG) HD14 trial, the estimated 5-year freedom-from-treatment-failure rate among patients treated with escalated-dose BEACOPP and ABVD plus radiotherapy (RT) was 94.3%, compared with 87.6% for those treated with ABVD/RT alone. The hazard ratio for BEACOPP/ABVD/RT was 0.49 (P =.0001), Dr. Peter Borchmann said at the annual meeting of the American Society of Hematology.

"We have this new treatment as the new standard of care at least in our studies. It will be challenged here in the U.S., because many doctors in the U.S., I guess, will still say ‘ABVD is the standard of care, and we don’t care about some 7% better tumor control at 5 years; we want to see overall survival differences.’ With this short follow-up we have now, there is no difference in overall survival," lead author Dr. Andreas Engert from University Hospital Cologne, Germany, said in a media briefing.

Although BEACOPP is associated with an increased risk for infertility, 18% of women up to age 40 years who were treated with the regimen reported having a pregnancy or giving birth more than 1 year after the end of therapy, compared with 11% treated with ABVD. Dr. Borchmann, also of University Hospital Cologne, said that all the women were able to conceive using their own eggs.

The GHSG HD14 trial compared four cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) with two cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by two cycles of ABVD. In both treatment groups, chemotherapy was followed by involved field radiotherapy (IF-RT) at a dose of 30 Gy.

The patients had stage I or II disease with early unfavorable risk factors, including at least three involved lymph node areas, elevated erythrocyte sedimentation rate, large mediastinal mass, or extranodal disease. They were randomly assigned to either ABVD plus IF-RT in the control arm (818 patients) or BEACOPP/ABVD plus IF-RT in the experimental arm (805 patients). Patients were recruited from cancer centers and smaller oncology practices in Germany, Austria, Switzerland, the Czech Republic, and the Netherlands.

In July of 2008, the control arm was closed following an interim analysis that showed that the experimental arm had met the prespecified criteria for superiority.

An intention-to-treat analysis showed that both regimens had excellent tumor control, with 93.8% of patients in the control arm having complete responses (CR) or complete responses unconfirmed (CRu), compared with 94.5% of patients in the BEACOPP/ABVD arm. A total of 1.2% of patients in the control arm had partial responses, compared with 0.5% in the BEACOPP/ABVD arm. Relapses occurred in 8.1% and 2.6% of patients in the two arms, respectively.

Acute toxicities of either grade III or IV according to World Health Organization criteria occurred in 51% of patients on ABVD alone, and 87% of patients in the combination arm. Hematologic toxicities occurred in 24% and 80% and leukopenia with infections occurred in 1.2% and 9.8%, respectively.

In addition, there were no cases of acute myeloid leukemia or myelodysplasia among control patients, compared with three (0.4%) patients treated with BEACOPP/ABVD. Conversely, there were 10 cases of non-Hodgkin’s lymphoma (1.2%) among patients on ABVD alone, vs. 5 (0.6%) in those on BEACOPP/ABVD. Solid tumors occurred in nine (1.1%) and eight (1.0%) patients, respectively.

There were 20 deaths in each treatment arm. In the control arm, there were no deaths attributed to the study regimen and six deaths related to toxicity of the salvage regimen, compared with four and one, respectively, in the BEACOPP/ABVD arm. Secondary neoplasms were the cause of death in seven patients on ABVD alone, and three on BEACOPP/ABVD.

"I think it’s very reasonable to say that this regimen [BEACOPP/ABVD] regimen will become the new standard treatment for early unfavorable Hodgkin lymphoma patients. And I think this is a very strong chemotherapy background for the much more important question we are asking all over the world right now: Do we need combined modality treatment for these patients, or can we restrict radiotherapy to a subset of patients [with PET-positive residual disease]," Dr. Borchmann concluded.

The trial was supported by the German Cancer Aid fund. Dr. Borchmann and Dr. Engert had no conflict of interest disclosures.

ORLANDO – An aggressive approach to treating early unfavorable Hodgkin’s lymphoma that combines the BEACOPP regimen at an escalated dose with the ABVD regimen and involved-field radiotherapy results in better tumor control than did ABVD and radiation alone, investigators have reported.

In the final analysis of the German Hodgkin Study Group (GHSG) HD14 trial, the estimated 5-year freedom-from-treatment-failure rate among patients treated with escalated-dose BEACOPP and ABVD plus radiotherapy (RT) was 94.3%, compared with 87.6% for those treated with ABVD/RT alone. The hazard ratio for BEACOPP/ABVD/RT was 0.49 (P =.0001), Dr. Peter Borchmann said at the annual meeting of the American Society of Hematology.

"We have this new treatment as the new standard of care at least in our studies. It will be challenged here in the U.S., because many doctors in the U.S., I guess, will still say ‘ABVD is the standard of care, and we don’t care about some 7% better tumor control at 5 years; we want to see overall survival differences.’ With this short follow-up we have now, there is no difference in overall survival," lead author Dr. Andreas Engert from University Hospital Cologne, Germany, said in a media briefing.

Although BEACOPP is associated with an increased risk for infertility, 18% of women up to age 40 years who were treated with the regimen reported having a pregnancy or giving birth more than 1 year after the end of therapy, compared with 11% treated with ABVD. Dr. Borchmann, also of University Hospital Cologne, said that all the women were able to conceive using their own eggs.

The GHSG HD14 trial compared four cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) with two cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by two cycles of ABVD. In both treatment groups, chemotherapy was followed by involved field radiotherapy (IF-RT) at a dose of 30 Gy.

The patients had stage I or II disease with early unfavorable risk factors, including at least three involved lymph node areas, elevated erythrocyte sedimentation rate, large mediastinal mass, or extranodal disease. They were randomly assigned to either ABVD plus IF-RT in the control arm (818 patients) or BEACOPP/ABVD plus IF-RT in the experimental arm (805 patients). Patients were recruited from cancer centers and smaller oncology practices in Germany, Austria, Switzerland, the Czech Republic, and the Netherlands.

In July of 2008, the control arm was closed following an interim analysis that showed that the experimental arm had met the prespecified criteria for superiority.

An intention-to-treat analysis showed that both regimens had excellent tumor control, with 93.8% of patients in the control arm having complete responses (CR) or complete responses unconfirmed (CRu), compared with 94.5% of patients in the BEACOPP/ABVD arm. A total of 1.2% of patients in the control arm had partial responses, compared with 0.5% in the BEACOPP/ABVD arm. Relapses occurred in 8.1% and 2.6% of patients in the two arms, respectively.

Acute toxicities of either grade III or IV according to World Health Organization criteria occurred in 51% of patients on ABVD alone, and 87% of patients in the combination arm. Hematologic toxicities occurred in 24% and 80% and leukopenia with infections occurred in 1.2% and 9.8%, respectively.

In addition, there were no cases of acute myeloid leukemia or myelodysplasia among control patients, compared with three (0.4%) patients treated with BEACOPP/ABVD. Conversely, there were 10 cases of non-Hodgkin’s lymphoma (1.2%) among patients on ABVD alone, vs. 5 (0.6%) in those on BEACOPP/ABVD. Solid tumors occurred in nine (1.1%) and eight (1.0%) patients, respectively.

There were 20 deaths in each treatment arm. In the control arm, there were no deaths attributed to the study regimen and six deaths related to toxicity of the salvage regimen, compared with four and one, respectively, in the BEACOPP/ABVD arm. Secondary neoplasms were the cause of death in seven patients on ABVD alone, and three on BEACOPP/ABVD.

"I think it’s very reasonable to say that this regimen [BEACOPP/ABVD] regimen will become the new standard treatment for early unfavorable Hodgkin lymphoma patients. And I think this is a very strong chemotherapy background for the much more important question we are asking all over the world right now: Do we need combined modality treatment for these patients, or can we restrict radiotherapy to a subset of patients [with PET-positive residual disease]," Dr. Borchmann concluded.

The trial was supported by the German Cancer Aid fund. Dr. Borchmann and Dr. Engert had no conflict of interest disclosures.

ORLANDO – An aggressive approach to treating early unfavorable Hodgkin’s lymphoma that combines the BEACOPP regimen at an escalated dose with the ABVD regimen and involved-field radiotherapy results in better tumor control than did ABVD and radiation alone, investigators have reported.

In the final analysis of the German Hodgkin Study Group (GHSG) HD14 trial, the estimated 5-year freedom-from-treatment-failure rate among patients treated with escalated-dose BEACOPP and ABVD plus radiotherapy (RT) was 94.3%, compared with 87.6% for those treated with ABVD/RT alone. The hazard ratio for BEACOPP/ABVD/RT was 0.49 (P =.0001), Dr. Peter Borchmann said at the annual meeting of the American Society of Hematology.

"We have this new treatment as the new standard of care at least in our studies. It will be challenged here in the U.S., because many doctors in the U.S., I guess, will still say ‘ABVD is the standard of care, and we don’t care about some 7% better tumor control at 5 years; we want to see overall survival differences.’ With this short follow-up we have now, there is no difference in overall survival," lead author Dr. Andreas Engert from University Hospital Cologne, Germany, said in a media briefing.

Although BEACOPP is associated with an increased risk for infertility, 18% of women up to age 40 years who were treated with the regimen reported having a pregnancy or giving birth more than 1 year after the end of therapy, compared with 11% treated with ABVD. Dr. Borchmann, also of University Hospital Cologne, said that all the women were able to conceive using their own eggs.

The GHSG HD14 trial compared four cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) with two cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by two cycles of ABVD. In both treatment groups, chemotherapy was followed by involved field radiotherapy (IF-RT) at a dose of 30 Gy.

The patients had stage I or II disease with early unfavorable risk factors, including at least three involved lymph node areas, elevated erythrocyte sedimentation rate, large mediastinal mass, or extranodal disease. They were randomly assigned to either ABVD plus IF-RT in the control arm (818 patients) or BEACOPP/ABVD plus IF-RT in the experimental arm (805 patients). Patients were recruited from cancer centers and smaller oncology practices in Germany, Austria, Switzerland, the Czech Republic, and the Netherlands.

In July of 2008, the control arm was closed following an interim analysis that showed that the experimental arm had met the prespecified criteria for superiority.

An intention-to-treat analysis showed that both regimens had excellent tumor control, with 93.8% of patients in the control arm having complete responses (CR) or complete responses unconfirmed (CRu), compared with 94.5% of patients in the BEACOPP/ABVD arm. A total of 1.2% of patients in the control arm had partial responses, compared with 0.5% in the BEACOPP/ABVD arm. Relapses occurred in 8.1% and 2.6% of patients in the two arms, respectively.

Acute toxicities of either grade III or IV according to World Health Organization criteria occurred in 51% of patients on ABVD alone, and 87% of patients in the combination arm. Hematologic toxicities occurred in 24% and 80% and leukopenia with infections occurred in 1.2% and 9.8%, respectively.

In addition, there were no cases of acute myeloid leukemia or myelodysplasia among control patients, compared with three (0.4%) patients treated with BEACOPP/ABVD. Conversely, there were 10 cases of non-Hodgkin’s lymphoma (1.2%) among patients on ABVD alone, vs. 5 (0.6%) in those on BEACOPP/ABVD. Solid tumors occurred in nine (1.1%) and eight (1.0%) patients, respectively.

There were 20 deaths in each treatment arm. In the control arm, there were no deaths attributed to the study regimen and six deaths related to toxicity of the salvage regimen, compared with four and one, respectively, in the BEACOPP/ABVD arm. Secondary neoplasms were the cause of death in seven patients on ABVD alone, and three on BEACOPP/ABVD.

"I think it’s very reasonable to say that this regimen [BEACOPP/ABVD] regimen will become the new standard treatment for early unfavorable Hodgkin lymphoma patients. And I think this is a very strong chemotherapy background for the much more important question we are asking all over the world right now: Do we need combined modality treatment for these patients, or can we restrict radiotherapy to a subset of patients [with PET-positive residual disease]," Dr. Borchmann concluded.

The trial was supported by the German Cancer Aid fund. Dr. Borchmann and Dr. Engert had no conflict of interest disclosures.

ORLANDO – Adding imatinib to standard therapy for Philadelphia chromosome–positive acute lymphoblastic leukemia significantly improves overall, event-free, and relapse-free survival, investigators reported at the annual meeting of the American Society of Hematology.

A comparison of outcomes in the pre- and post-imatinib (Gleevec) eras for patients treated under the same standard therapy protocol (induction therapy followed by allogeneic hematopoietic stem cell transplant [alloHSCT]) showed that 3-year overall survival improved from 25% before imatinib was introduced to 43% after its introduction (P = .0001).

Similarly, 3-year event-free survival rates nearly doubled, from 19% to 37% (P less than .0001), and relapse-free survival went from 36% to 53% (P = .0001), said Dr. Adele Fielding of University College London.

The addition of imatinib increased the complete remission rate by 10% with no increase in transplant-related mortality, and allowed for a near doubling in the rate of alloHSCT.

"Although there are a number of studies which have now been published detailing the value of imatinib in this disease, this is the largest such study, and because of the very large number of patients treated on the same study without imatinib, it allows us to make certain and very sensible conclusions," Dr. Fielding said.

The trial, designated UKALL12/ECOG2993, initially enrolled 266 patients from 1993 to 2003. These patients (the pre-imatinib cohort) received two phases of induction therapy over 2 months, followed by matched sibling or unrelated donor myeloablative allogeneic hematopoietic stem cell transplant, unless the patient was medically unfit or had no suitable donor.

In March 2003, an additional 86 patients had consolidation with imatinib 600 mg daily after the second induction chemotherapy (late-imatinib cohort). Beginning in late 2005, an additional 89 patients received imatinib concurrently with the second phase of induction chemotherapy (early-imatinib cohort).

All patients who received imatinib resumed the drug, if they were able to tolerate it, for an additional 2 years following the alloHSCT.

Patients who did not undergo transplantation could be put on 2 years of imatinib maintenance at the discretion of the treating institution.

In the pre-imatinib cohort, 82% of patients had a complete response following induction. The addition of imatinib significantly improved responses, with 92% of patients in each of the imatinib cohorts having a complete response (P = .004).

The 3-year follow-up data from the trial show that in addition to the gains in overall, event-free, and relapse-free survival mentioned earlier, patients who received imatinib and who also underwent a per-protocol bone marrow transplant had a 59% 3-year overall survival, compared with 28% for those who received imatinib but not a transplant. Patients who underwent a transplant that differed from the specified protocol had a 49% 3-year overall survival. Rates of event-free survival were similar to those in the overall survival analysis.

Risk of relapse over 3 years among patients who received imatinib and a per-protocol transplant was 25%, compared with 49% for imatinib/non-protocol transplant, and 73% for imatinib but no transplant.

The investigators also found that the early imatinib dosing strategy was associated with better outcomes than the late strategy, with 3-year overall survival rates of 48% vs. 34%, respectively (P = .05), event-free survival of 45% vs. 29% (P = .04), and relapse-free survival of 62% vs. 45% (P = .02).

In a comparison of all patients who achieved a complete response to induction but did not undergo bone marrow transplant, imatinib was associated with an improvement in overall survival (24% vs. 18% for patients treated pre imatinib; P = .02 in multivariate model controlling for age and white blood cell count). But when patients who relapsed or died within the median time to bone marrow transplant were excluded from this analysis, the investigators found no significant difference between the groups, with overall survival of 24% for imatinib and 22% pre imatinib.

"It appears that the improved outcome relates principally to a higher rate of allogeneic transplantation, with a very modest or possibly no long-term benefit to imatinib if transplant is not achieved," Dr. Fielding concluded in her data presentation.

Dr. Fielding had no disclosures. A coauthor, Dr. Anthony H. Goldstone, disclosed receiving honoraria from Roche.

ORLANDO – Adding imatinib to standard therapy for Philadelphia chromosome–positive acute lymphoblastic leukemia significantly improves overall, event-free, and relapse-free survival, investigators reported at the annual meeting of the American Society of Hematology.

A comparison of outcomes in the pre- and post-imatinib (Gleevec) eras for patients treated under the same standard therapy protocol (induction therapy followed by allogeneic hematopoietic stem cell transplant [alloHSCT]) showed that 3-year overall survival improved from 25% before imatinib was introduced to 43% after its introduction (P = .0001).

Similarly, 3-year event-free survival rates nearly doubled, from 19% to 37% (P less than .0001), and relapse-free survival went from 36% to 53% (P = .0001), said Dr. Adele Fielding of University College London.

The addition of imatinib increased the complete remission rate by 10% with no increase in transplant-related mortality, and allowed for a near doubling in the rate of alloHSCT.

"Although there are a number of studies which have now been published detailing the value of imatinib in this disease, this is the largest such study, and because of the very large number of patients treated on the same study without imatinib, it allows us to make certain and very sensible conclusions," Dr. Fielding said.

The trial, designated UKALL12/ECOG2993, initially enrolled 266 patients from 1993 to 2003. These patients (the pre-imatinib cohort) received two phases of induction therapy over 2 months, followed by matched sibling or unrelated donor myeloablative allogeneic hematopoietic stem cell transplant, unless the patient was medically unfit or had no suitable donor.

In March 2003, an additional 86 patients had consolidation with imatinib 600 mg daily after the second induction chemotherapy (late-imatinib cohort). Beginning in late 2005, an additional 89 patients received imatinib concurrently with the second phase of induction chemotherapy (early-imatinib cohort).

All patients who received imatinib resumed the drug, if they were able to tolerate it, for an additional 2 years following the alloHSCT.

Patients who did not undergo transplantation could be put on 2 years of imatinib maintenance at the discretion of the treating institution.

In the pre-imatinib cohort, 82% of patients had a complete response following induction. The addition of imatinib significantly improved responses, with 92% of patients in each of the imatinib cohorts having a complete response (P = .004).

The 3-year follow-up data from the trial show that in addition to the gains in overall, event-free, and relapse-free survival mentioned earlier, patients who received imatinib and who also underwent a per-protocol bone marrow transplant had a 59% 3-year overall survival, compared with 28% for those who received imatinib but not a transplant. Patients who underwent a transplant that differed from the specified protocol had a 49% 3-year overall survival. Rates of event-free survival were similar to those in the overall survival analysis.

Risk of relapse over 3 years among patients who received imatinib and a per-protocol transplant was 25%, compared with 49% for imatinib/non-protocol transplant, and 73% for imatinib but no transplant.

The investigators also found that the early imatinib dosing strategy was associated with better outcomes than the late strategy, with 3-year overall survival rates of 48% vs. 34%, respectively (P = .05), event-free survival of 45% vs. 29% (P = .04), and relapse-free survival of 62% vs. 45% (P = .02).

In a comparison of all patients who achieved a complete response to induction but did not undergo bone marrow transplant, imatinib was associated with an improvement in overall survival (24% vs. 18% for patients treated pre imatinib; P = .02 in multivariate model controlling for age and white blood cell count). But when patients who relapsed or died within the median time to bone marrow transplant were excluded from this analysis, the investigators found no significant difference between the groups, with overall survival of 24% for imatinib and 22% pre imatinib.

"It appears that the improved outcome relates principally to a higher rate of allogeneic transplantation, with a very modest or possibly no long-term benefit to imatinib if transplant is not achieved," Dr. Fielding concluded in her data presentation.

Dr. Fielding had no disclosures. A coauthor, Dr. Anthony H. Goldstone, disclosed receiving honoraria from Roche.

ORLANDO – Adding imatinib to standard therapy for Philadelphia chromosome–positive acute lymphoblastic leukemia significantly improves overall, event-free, and relapse-free survival, investigators reported at the annual meeting of the American Society of Hematology.

A comparison of outcomes in the pre- and post-imatinib (Gleevec) eras for patients treated under the same standard therapy protocol (induction therapy followed by allogeneic hematopoietic stem cell transplant [alloHSCT]) showed that 3-year overall survival improved from 25% before imatinib was introduced to 43% after its introduction (P = .0001).

Similarly, 3-year event-free survival rates nearly doubled, from 19% to 37% (P less than .0001), and relapse-free survival went from 36% to 53% (P = .0001), said Dr. Adele Fielding of University College London.

The addition of imatinib increased the complete remission rate by 10% with no increase in transplant-related mortality, and allowed for a near doubling in the rate of alloHSCT.

"Although there are a number of studies which have now been published detailing the value of imatinib in this disease, this is the largest such study, and because of the very large number of patients treated on the same study without imatinib, it allows us to make certain and very sensible conclusions," Dr. Fielding said.

The trial, designated UKALL12/ECOG2993, initially enrolled 266 patients from 1993 to 2003. These patients (the pre-imatinib cohort) received two phases of induction therapy over 2 months, followed by matched sibling or unrelated donor myeloablative allogeneic hematopoietic stem cell transplant, unless the patient was medically unfit or had no suitable donor.

In March 2003, an additional 86 patients had consolidation with imatinib 600 mg daily after the second induction chemotherapy (late-imatinib cohort). Beginning in late 2005, an additional 89 patients received imatinib concurrently with the second phase of induction chemotherapy (early-imatinib cohort).

All patients who received imatinib resumed the drug, if they were able to tolerate it, for an additional 2 years following the alloHSCT.

Patients who did not undergo transplantation could be put on 2 years of imatinib maintenance at the discretion of the treating institution.

In the pre-imatinib cohort, 82% of patients had a complete response following induction. The addition of imatinib significantly improved responses, with 92% of patients in each of the imatinib cohorts having a complete response (P = .004).

The 3-year follow-up data from the trial show that in addition to the gains in overall, event-free, and relapse-free survival mentioned earlier, patients who received imatinib and who also underwent a per-protocol bone marrow transplant had a 59% 3-year overall survival, compared with 28% for those who received imatinib but not a transplant. Patients who underwent a transplant that differed from the specified protocol had a 49% 3-year overall survival. Rates of event-free survival were similar to those in the overall survival analysis.

Risk of relapse over 3 years among patients who received imatinib and a per-protocol transplant was 25%, compared with 49% for imatinib/non-protocol transplant, and 73% for imatinib but no transplant.

The investigators also found that the early imatinib dosing strategy was associated with better outcomes than the late strategy, with 3-year overall survival rates of 48% vs. 34%, respectively (P = .05), event-free survival of 45% vs. 29% (P = .04), and relapse-free survival of 62% vs. 45% (P = .02).

In a comparison of all patients who achieved a complete response to induction but did not undergo bone marrow transplant, imatinib was associated with an improvement in overall survival (24% vs. 18% for patients treated pre imatinib; P = .02 in multivariate model controlling for age and white blood cell count). But when patients who relapsed or died within the median time to bone marrow transplant were excluded from this analysis, the investigators found no significant difference between the groups, with overall survival of 24% for imatinib and 22% pre imatinib.

"It appears that the improved outcome relates principally to a higher rate of allogeneic transplantation, with a very modest or possibly no long-term benefit to imatinib if transplant is not achieved," Dr. Fielding concluded in her data presentation.

Dr. Fielding had no disclosures. A coauthor, Dr. Anthony H. Goldstone, disclosed receiving honoraria from Roche.

ORLANDO – Among patients with cancer-associated thrombosis, women and those with lung cancer or a history of at least one venous thromboembolic event are at significantly increased risk for recurrent emboli and may require prophylaxis with low-molecular-weight heparin or more aggressive anticoagulation, investigators have reported.

In contrast, patients with stage I malignancies or breast cancer are at relatively low risk for venous thromboembolism (VTE) recurrence and may need only a vitamin K antagonist such as warfarin to prevent a second event, Dr. Martha L. Louzada said at a press briefing in advance of a Dec. 6 presentation at the annual meeting of the American Society of Hematology.

The investigators used the data from a retrospective chart study to develop a risk score for determining the clinical probability of VTE recurrence. Each independent risk predictor variable received a point score relative to the magnitude of risk it imposes. Patients with a score from –3 to 0 are deemed to be at low risk (4.5% chance of recurrence), whereas those with scores from 1 to 3 are considered to be at high risk (19.7% chance of recurrence). They were able to reproduce the rule by applying it to data from two randomized controlled trials that compared a low-molecular-weight heparin with a vitamin K antagonist.

"Our future goal is to prospectively validate this clinical prediction rule to assess further reproducibility and generalizability," Dr. Louzada of the University of Western Ontario in London said at the briefing.

To determine whether VTE prophylaxis strategies should be tailored to meet individual patient characteristics or cancer types, the investigators took a retrospective look at the charts of 543 patients with cancer and VTE who were followed at the thrombosis unit of the Ottawa Hospital from 2002 through 2004 and from 2007 through 2008. The investigators restricted their analysis to those patients who had recurrent VTE within 6 months of beginning anticoagulation therapy. They conducted a univariate analysis to gauge the strength of the association between each potential risk factor and VTE recurrence, and evaluated all likely risk-predictor candidates in a logistic regression model.

In all, 55 patients (10.1%) had a recurrent VTE, but the rates of recurrence were similar between the groups, suggesting that treatment type did not have an effect (recurrence rate 9.5% for vitamin K antagonists, 10.5% for low-molecular-weight heparin).

In the multivariate analysis, the authors identified as significant predictors of increased risk, lung cancer (odds ratio, 2.55); a history of prior VTE (OR, 2.42); and female gender (OR, 1.82). Predictors for decreased risk were stage I malignancies (OR, 0.75) and breast cancer (OR, 0.46).

"The patient even with breast cancer can have a high risk, because the majority of patients are females and being female is a high-risk predictor, whereas breast cancer is a low risk, so it’s going to depend on the stage of malignancy of the patient and also whether the patient has a previous history of venous thrombosis," she said.

The study was internally funded. Dr. Louzada said she had no relevant financial disclosures.

ORLANDO – Among patients with cancer-associated thrombosis, women and those with lung cancer or a history of at least one venous thromboembolic event are at significantly increased risk for recurrent emboli and may require prophylaxis with low-molecular-weight heparin or more aggressive anticoagulation, investigators have reported.

In contrast, patients with stage I malignancies or breast cancer are at relatively low risk for venous thromboembolism (VTE) recurrence and may need only a vitamin K antagonist such as warfarin to prevent a second event, Dr. Martha L. Louzada said at a press briefing in advance of a Dec. 6 presentation at the annual meeting of the American Society of Hematology.

The investigators used the data from a retrospective chart study to develop a risk score for determining the clinical probability of VTE recurrence. Each independent risk predictor variable received a point score relative to the magnitude of risk it imposes. Patients with a score from –3 to 0 are deemed to be at low risk (4.5% chance of recurrence), whereas those with scores from 1 to 3 are considered to be at high risk (19.7% chance of recurrence). They were able to reproduce the rule by applying it to data from two randomized controlled trials that compared a low-molecular-weight heparin with a vitamin K antagonist.

"Our future goal is to prospectively validate this clinical prediction rule to assess further reproducibility and generalizability," Dr. Louzada of the University of Western Ontario in London said at the briefing.

To determine whether VTE prophylaxis strategies should be tailored to meet individual patient characteristics or cancer types, the investigators took a retrospective look at the charts of 543 patients with cancer and VTE who were followed at the thrombosis unit of the Ottawa Hospital from 2002 through 2004 and from 2007 through 2008. The investigators restricted their analysis to those patients who had recurrent VTE within 6 months of beginning anticoagulation therapy. They conducted a univariate analysis to gauge the strength of the association between each potential risk factor and VTE recurrence, and evaluated all likely risk-predictor candidates in a logistic regression model.

In all, 55 patients (10.1%) had a recurrent VTE, but the rates of recurrence were similar between the groups, suggesting that treatment type did not have an effect (recurrence rate 9.5% for vitamin K antagonists, 10.5% for low-molecular-weight heparin).

In the multivariate analysis, the authors identified as significant predictors of increased risk, lung cancer (odds ratio, 2.55); a history of prior VTE (OR, 2.42); and female gender (OR, 1.82). Predictors for decreased risk were stage I malignancies (OR, 0.75) and breast cancer (OR, 0.46).

"The patient even with breast cancer can have a high risk, because the majority of patients are females and being female is a high-risk predictor, whereas breast cancer is a low risk, so it’s going to depend on the stage of malignancy of the patient and also whether the patient has a previous history of venous thrombosis," she said.

The study was internally funded. Dr. Louzada said she had no relevant financial disclosures.

ORLANDO – Among patients with cancer-associated thrombosis, women and those with lung cancer or a history of at least one venous thromboembolic event are at significantly increased risk for recurrent emboli and may require prophylaxis with low-molecular-weight heparin or more aggressive anticoagulation, investigators have reported.

In contrast, patients with stage I malignancies or breast cancer are at relatively low risk for venous thromboembolism (VTE) recurrence and may need only a vitamin K antagonist such as warfarin to prevent a second event, Dr. Martha L. Louzada said at a press briefing in advance of a Dec. 6 presentation at the annual meeting of the American Society of Hematology.

The investigators used the data from a retrospective chart study to develop a risk score for determining the clinical probability of VTE recurrence. Each independent risk predictor variable received a point score relative to the magnitude of risk it imposes. Patients with a score from –3 to 0 are deemed to be at low risk (4.5% chance of recurrence), whereas those with scores from 1 to 3 are considered to be at high risk (19.7% chance of recurrence). They were able to reproduce the rule by applying it to data from two randomized controlled trials that compared a low-molecular-weight heparin with a vitamin K antagonist.

"Our future goal is to prospectively validate this clinical prediction rule to assess further reproducibility and generalizability," Dr. Louzada of the University of Western Ontario in London said at the briefing.

To determine whether VTE prophylaxis strategies should be tailored to meet individual patient characteristics or cancer types, the investigators took a retrospective look at the charts of 543 patients with cancer and VTE who were followed at the thrombosis unit of the Ottawa Hospital from 2002 through 2004 and from 2007 through 2008. The investigators restricted their analysis to those patients who had recurrent VTE within 6 months of beginning anticoagulation therapy. They conducted a univariate analysis to gauge the strength of the association between each potential risk factor and VTE recurrence, and evaluated all likely risk-predictor candidates in a logistic regression model.

In all, 55 patients (10.1%) had a recurrent VTE, but the rates of recurrence were similar between the groups, suggesting that treatment type did not have an effect (recurrence rate 9.5% for vitamin K antagonists, 10.5% for low-molecular-weight heparin).

In the multivariate analysis, the authors identified as significant predictors of increased risk, lung cancer (odds ratio, 2.55); a history of prior VTE (OR, 2.42); and female gender (OR, 1.82). Predictors for decreased risk were stage I malignancies (OR, 0.75) and breast cancer (OR, 0.46).

"The patient even with breast cancer can have a high risk, because the majority of patients are females and being female is a high-risk predictor, whereas breast cancer is a low risk, so it’s going to depend on the stage of malignancy of the patient and also whether the patient has a previous history of venous thrombosis," she said.

The study was internally funded. Dr. Louzada said she had no relevant financial disclosures.