Busulfan-Melphalan Superior as Myeloablative Tx for High-Risk Neuroblastoma

CHICAGO – The combination of busulfan and melphalan is superior to the combination of carboplatin, etoposide, and melphalan when used as myeloablative therapy in children with high-risk neuroblastoma, new data show.

In a randomized trial conducted by the SIOPEN (International Society of Pediatric Oncology European Neuroblastoma) Group among 563 such patients, busulfan plus melphalan yielded higher 3-year rates of event-free survival (49% vs. 33%; P less than .001) and overall survival (60% vs. 48%; P = .003), investigators reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

It had a better toxicity profile overall as well. The main adverse effect of busulfan plus melphalan (BUMEL), as expected, was veno-occlusive disease, but only 5% of patients experienced a grade 3 occlusive event.

"This is the first time that in pediatric oncology that we can clearly demonstrate that the choice of the myeloablative therapy really matters," said principal investigator Dr. Ruth Ladenstein of the St. Anna Children’s Hospital and Research Institute in Vienna.

"Summing up all the results, we feel that current practice should now be in favor of busulfan-melphalan in high-risk neuroblastoma," she said.

Discussant Dr. Julie R. Park called the SIOPEN trial "a great achievement in pediatric clinical research," noting, for example, its collaborative nature and completion despite the use of two toxic myeloablative regimens.

Yet, she cautioned, the event-free survival rate of 33% for the CEM (carboplatin, etoposide, and melphalan) regimen was much lower than that observed in the previous COG (Children’s Oncology Group) A3973 trial of this regimen (46%), possibly because of different treatment strategies and patient populations, and dose-reductions of CEM for renal toxicity in the new trial.

"The SIOPEN trial does demonstrate that the busulfan-melphalan regimen is superior to carboplatin, etoposide, and melphalan in the context of receiving rapid COJEC [cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide] induction and in a cohort of patients with good response to induction therapy," said Dr. Park, chair of COG’s Neuroblastoma Scientific Committee and a pediatric oncologist at the University of Washington in Seattle. "The COG data indicate that these results may not be applicable to those children who have received the N6 Memorial Sloan-Kettering induction" regimen.

"The toxicities of busulfan-melphalan, primarily veno-occlusive disease, will need to be taken into account as we consider whether further modifications of consolidation therapy can occur," she added.

Perhaps of greater importance, the majority of the SIOPEN trial’s initially eligible patients were unable to undergo randomization because of an inadequate response to induction therapy, as has been seen on other trials.

"Future high-risk neuroblastoma trials must address the need for improved induction response, as poor induction remains a major barrier to our cure of these children," Dr. Park asserted. "And continued improvement of postconsolidation [therapy] needs to be studied, as that has shown our maximal success in treating these children."

The trial was the first high-risk neuroblastoma trial (HR-NBL1) undertaken by SIOPEN. The design called for rapid COJEC induction followed by peripheral stem cell harvest, a first round of local control (attempted complete surgery of the primary tumor), randomized myeloablative therapy with stem cell rescue, a second round of local control (radiation therapy to the primary tumor), and finally maintenance therapy.

Patients could proceed to randomized myeloablative therapy only if they had an adequate response of metastases to the rapid induction regimen and had an adequate number of stem cells harvested.

They were randomized to BUMEL or CEM. The busulfan was given orally until 2006, after which an intravenous form became available.

A preplanned interim analysis showed efficacy in favor of BUMEL, Dr. Ladenstein reported. The trial was therefore stopped early, after a median observation period of 3.5 years. The 563 randomized patients (just 43% of those initially enrolled) had a median age of 3 years. In all, 83% had stage IV disease.

Presenting the main efficacy results, she said "we find [them] quite extraordinary and above our expectations."

"Most interestingly, this really was related to a decreased relapse rate under the busulfan-melphalan regimen and was not related to [decreased] transplant-related mortality," she noted.

Stratified analyses suggested that BUMEL had the greatest benefit in patients who had residual disease after induction. "We believe that this is related to the potency of the drugs to work on the resting tumor cells," Dr. Ladenstein commented.

In a multivariate analysis that included age, disease stage, and treatment group, patients still had a significantly reduced risk of events if they were assigned to BUMEL instead of CEM (hazard ratio, 0.64; P less than .001).

CEM was associated with higher rates of grade 3/4 infectious, gastrointestinal, and renal adverse effects, and ototoxicity. BUMEL was associated with a higher rate of grade 3/4 veno-occlusive disease; patients in the trial did not receive prophylactic anticoagulation with defibrotide, she noted.

Dr. Ladenstein and Dr. Park said they had no disclosures. The intravenous form of busulfan was provided by Pierre Fabre Médicament Oncology.

CHICAGO – The combination of busulfan and melphalan is superior to the combination of carboplatin, etoposide, and melphalan when used as myeloablative therapy in children with high-risk neuroblastoma, new data show.

In a randomized trial conducted by the SIOPEN (International Society of Pediatric Oncology European Neuroblastoma) Group among 563 such patients, busulfan plus melphalan yielded higher 3-year rates of event-free survival (49% vs. 33%; P less than .001) and overall survival (60% vs. 48%; P = .003), investigators reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

It had a better toxicity profile overall as well. The main adverse effect of busulfan plus melphalan (BUMEL), as expected, was veno-occlusive disease, but only 5% of patients experienced a grade 3 occlusive event.

"This is the first time that in pediatric oncology that we can clearly demonstrate that the choice of the myeloablative therapy really matters," said principal investigator Dr. Ruth Ladenstein of the St. Anna Children’s Hospital and Research Institute in Vienna.

"Summing up all the results, we feel that current practice should now be in favor of busulfan-melphalan in high-risk neuroblastoma," she said.

Discussant Dr. Julie R. Park called the SIOPEN trial "a great achievement in pediatric clinical research," noting, for example, its collaborative nature and completion despite the use of two toxic myeloablative regimens.

Yet, she cautioned, the event-free survival rate of 33% for the CEM (carboplatin, etoposide, and melphalan) regimen was much lower than that observed in the previous COG (Children’s Oncology Group) A3973 trial of this regimen (46%), possibly because of different treatment strategies and patient populations, and dose-reductions of CEM for renal toxicity in the new trial.

"The SIOPEN trial does demonstrate that the busulfan-melphalan regimen is superior to carboplatin, etoposide, and melphalan in the context of receiving rapid COJEC [cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide] induction and in a cohort of patients with good response to induction therapy," said Dr. Park, chair of COG’s Neuroblastoma Scientific Committee and a pediatric oncologist at the University of Washington in Seattle. "The COG data indicate that these results may not be applicable to those children who have received the N6 Memorial Sloan-Kettering induction" regimen.

"The toxicities of busulfan-melphalan, primarily veno-occlusive disease, will need to be taken into account as we consider whether further modifications of consolidation therapy can occur," she added.

Perhaps of greater importance, the majority of the SIOPEN trial’s initially eligible patients were unable to undergo randomization because of an inadequate response to induction therapy, as has been seen on other trials.

"Future high-risk neuroblastoma trials must address the need for improved induction response, as poor induction remains a major barrier to our cure of these children," Dr. Park asserted. "And continued improvement of postconsolidation [therapy] needs to be studied, as that has shown our maximal success in treating these children."

The trial was the first high-risk neuroblastoma trial (HR-NBL1) undertaken by SIOPEN. The design called for rapid COJEC induction followed by peripheral stem cell harvest, a first round of local control (attempted complete surgery of the primary tumor), randomized myeloablative therapy with stem cell rescue, a second round of local control (radiation therapy to the primary tumor), and finally maintenance therapy.

Patients could proceed to randomized myeloablative therapy only if they had an adequate response of metastases to the rapid induction regimen and had an adequate number of stem cells harvested.

They were randomized to BUMEL or CEM. The busulfan was given orally until 2006, after which an intravenous form became available.

A preplanned interim analysis showed efficacy in favor of BUMEL, Dr. Ladenstein reported. The trial was therefore stopped early, after a median observation period of 3.5 years. The 563 randomized patients (just 43% of those initially enrolled) had a median age of 3 years. In all, 83% had stage IV disease.

Presenting the main efficacy results, she said "we find [them] quite extraordinary and above our expectations."

"Most interestingly, this really was related to a decreased relapse rate under the busulfan-melphalan regimen and was not related to [decreased] transplant-related mortality," she noted.

Stratified analyses suggested that BUMEL had the greatest benefit in patients who had residual disease after induction. "We believe that this is related to the potency of the drugs to work on the resting tumor cells," Dr. Ladenstein commented.

In a multivariate analysis that included age, disease stage, and treatment group, patients still had a significantly reduced risk of events if they were assigned to BUMEL instead of CEM (hazard ratio, 0.64; P less than .001).

CEM was associated with higher rates of grade 3/4 infectious, gastrointestinal, and renal adverse effects, and ototoxicity. BUMEL was associated with a higher rate of grade 3/4 veno-occlusive disease; patients in the trial did not receive prophylactic anticoagulation with defibrotide, she noted.

Dr. Ladenstein and Dr. Park said they had no disclosures. The intravenous form of busulfan was provided by Pierre Fabre Médicament Oncology.

CHICAGO – The combination of busulfan and melphalan is superior to the combination of carboplatin, etoposide, and melphalan when used as myeloablative therapy in children with high-risk neuroblastoma, new data show.

In a randomized trial conducted by the SIOPEN (International Society of Pediatric Oncology European Neuroblastoma) Group among 563 such patients, busulfan plus melphalan yielded higher 3-year rates of event-free survival (49% vs. 33%; P less than .001) and overall survival (60% vs. 48%; P = .003), investigators reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

It had a better toxicity profile overall as well. The main adverse effect of busulfan plus melphalan (BUMEL), as expected, was veno-occlusive disease, but only 5% of patients experienced a grade 3 occlusive event.

"This is the first time that in pediatric oncology that we can clearly demonstrate that the choice of the myeloablative therapy really matters," said principal investigator Dr. Ruth Ladenstein of the St. Anna Children’s Hospital and Research Institute in Vienna.

"Summing up all the results, we feel that current practice should now be in favor of busulfan-melphalan in high-risk neuroblastoma," she said.

Discussant Dr. Julie R. Park called the SIOPEN trial "a great achievement in pediatric clinical research," noting, for example, its collaborative nature and completion despite the use of two toxic myeloablative regimens.

Yet, she cautioned, the event-free survival rate of 33% for the CEM (carboplatin, etoposide, and melphalan) regimen was much lower than that observed in the previous COG (Children’s Oncology Group) A3973 trial of this regimen (46%), possibly because of different treatment strategies and patient populations, and dose-reductions of CEM for renal toxicity in the new trial.

"The SIOPEN trial does demonstrate that the busulfan-melphalan regimen is superior to carboplatin, etoposide, and melphalan in the context of receiving rapid COJEC [cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide] induction and in a cohort of patients with good response to induction therapy," said Dr. Park, chair of COG’s Neuroblastoma Scientific Committee and a pediatric oncologist at the University of Washington in Seattle. "The COG data indicate that these results may not be applicable to those children who have received the N6 Memorial Sloan-Kettering induction" regimen.

"The toxicities of busulfan-melphalan, primarily veno-occlusive disease, will need to be taken into account as we consider whether further modifications of consolidation therapy can occur," she added.

Perhaps of greater importance, the majority of the SIOPEN trial’s initially eligible patients were unable to undergo randomization because of an inadequate response to induction therapy, as has been seen on other trials.

"Future high-risk neuroblastoma trials must address the need for improved induction response, as poor induction remains a major barrier to our cure of these children," Dr. Park asserted. "And continued improvement of postconsolidation [therapy] needs to be studied, as that has shown our maximal success in treating these children."

The trial was the first high-risk neuroblastoma trial (HR-NBL1) undertaken by SIOPEN. The design called for rapid COJEC induction followed by peripheral stem cell harvest, a first round of local control (attempted complete surgery of the primary tumor), randomized myeloablative therapy with stem cell rescue, a second round of local control (radiation therapy to the primary tumor), and finally maintenance therapy.

Patients could proceed to randomized myeloablative therapy only if they had an adequate response of metastases to the rapid induction regimen and had an adequate number of stem cells harvested.

They were randomized to BUMEL or CEM. The busulfan was given orally until 2006, after which an intravenous form became available.

A preplanned interim analysis showed efficacy in favor of BUMEL, Dr. Ladenstein reported. The trial was therefore stopped early, after a median observation period of 3.5 years. The 563 randomized patients (just 43% of those initially enrolled) had a median age of 3 years. In all, 83% had stage IV disease.

Presenting the main efficacy results, she said "we find [them] quite extraordinary and above our expectations."

"Most interestingly, this really was related to a decreased relapse rate under the busulfan-melphalan regimen and was not related to [decreased] transplant-related mortality," she noted.

Stratified analyses suggested that BUMEL had the greatest benefit in patients who had residual disease after induction. "We believe that this is related to the potency of the drugs to work on the resting tumor cells," Dr. Ladenstein commented.

In a multivariate analysis that included age, disease stage, and treatment group, patients still had a significantly reduced risk of events if they were assigned to BUMEL instead of CEM (hazard ratio, 0.64; P less than .001).

CEM was associated with higher rates of grade 3/4 infectious, gastrointestinal, and renal adverse effects, and ototoxicity. BUMEL was associated with a higher rate of grade 3/4 veno-occlusive disease; patients in the trial did not receive prophylactic anticoagulation with defibrotide, she noted.

Dr. Ladenstein and Dr. Park said they had no disclosures. The intravenous form of busulfan was provided by Pierre Fabre Médicament Oncology.