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Lenalidomide maintenance improves MCL survival after ASCT
SAN DIEGO – For patients 65 years or younger with mantle cell lymphoma (MCL) who have undergone autologous stem cell transplantation (ASCT), maintenance therapy with lenalidomide (Revlimid) can significantly improve progression-free survival (PFS), suggest results of the phase, 3 randomized MCL0208 trial.
After a median follow-up of 39 months, the 3-year PFS in an intention-to-treat analysis was 80% for patients treated with ASCT and lenalidomide maintenance, compared with 64% for patients treated with ASCT alone, reported Marco Ladetto, MD, of Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo in Alessandria, Italy.
“Lenalidomide maintenance after autologous stem cell transplant has substantial clinical activity in mantle cell lymphoma in terms of progression-free survival,” he said at the annual meeting of the American Society of Hematology. “Follow-up is still too short for meaningful overall survival considerations.”
Dr. Ladetto and his colleagues at centers in Italy and Portugal enrolled patients aged 18-65 years with previously untreated MCL stage III or IV, or stage II with bulky disease (5 cm or greater), and good performance status.
The patients first underwent induction with three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, and prednisone), which was followed by treatment with rituximab plus high-dose cyclophosphamide and two cycles of rituximab with high-dose cytarabine. Stem cells were collected after the first course of the latter regimen.
The patients then underwent conditioning with BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT.
Following ASCT, patients with complete or partial remissions were randomized either to maintenance therapy with lenalidomide 15 mg for 21 of 28 days for each cycle or to observation.
Of the 303 patients initially enrolled, 248 went on to ASCT, and 205 went on to randomization – 104 assigned to maintenance and 101 assigned to observation.
A total of 52 patients completed 2 years of maintenance: Of the rest, 2 patients died from toxicities (thrombotic thrombocytopenic purpura and pneumonia), 7 had disease progression, 41 dropped out for nonprogression reasons, and 2 patients were still in maintenance at the time of the data cutoff. In this arm, 6 of 8 patients with partial responses converted to complete responses by the end of maintenance. More than a quarter of patients (28%) received less than 25% of the planned lenalidomide dose.
In the observation arm, 1 patient died from pneumonia, 20 had disease progression, 3 were lost to follow-up, 6 were still under observation, and 71 completed observation. In this arm, 1 of 4 patients with a partial response converted to a complete response at the end of the observation period.
Despite suboptimal dosing in a large proportion of patients, the PFS primary endpoint showed significant benefit for lenalidomide, with an unstratified hazard ratio of 0.52 (P = .015) and a stratified HR of 0.51 (P = .013).
At a median follow-up of 39 months from randomization, 3-year overall survival (OS) rates were 93% with lenalidomide and 86% with observation, a difference that was not statistically significant.
Grade 3 or 4 hematologic toxicities occurred in 63% of patients in the lenalidomide arm, compared with 11% in the observation arm. The respective rates of granulocytopenia were 59% vs. 10%. Nonhematological grade 3 toxicity was comparable in the two arms except for grade 3 or 4 infections, which were more common with lenalidomide. Seven patients in the lenalidomide arm and three patients in the observation arm developed second cancers.
Dr. Ladetto noted that difficulties in delivering the planned dose of lenalidomide may have been caused by an already-stressed hematopoietic compartment; he commented that the question of the relative benefit of a fixed lenalidomide schedule or an until-progression approach still needs to be answered.
Additionally, the induction schedule used in the trial, while feasible, is not superior to “less cumbersome and possibly less toxic regimens,” he said.
The study was supported by the Italian Lymphoma Foundation (Fondazione Italiana Linfomi) with the European Mantle Cell Lymphoma Network. Dr. Ladetto reported honoraria from Roche, Celgene, Acerta, Janssen, AbbVie, and Sandoz, as well as off-label use of lenalidomide.
SOURCE: Ladetto M et al. ASH 2018, Abstract 401.
SAN DIEGO – For patients 65 years or younger with mantle cell lymphoma (MCL) who have undergone autologous stem cell transplantation (ASCT), maintenance therapy with lenalidomide (Revlimid) can significantly improve progression-free survival (PFS), suggest results of the phase, 3 randomized MCL0208 trial.
After a median follow-up of 39 months, the 3-year PFS in an intention-to-treat analysis was 80% for patients treated with ASCT and lenalidomide maintenance, compared with 64% for patients treated with ASCT alone, reported Marco Ladetto, MD, of Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo in Alessandria, Italy.
“Lenalidomide maintenance after autologous stem cell transplant has substantial clinical activity in mantle cell lymphoma in terms of progression-free survival,” he said at the annual meeting of the American Society of Hematology. “Follow-up is still too short for meaningful overall survival considerations.”
Dr. Ladetto and his colleagues at centers in Italy and Portugal enrolled patients aged 18-65 years with previously untreated MCL stage III or IV, or stage II with bulky disease (5 cm or greater), and good performance status.
The patients first underwent induction with three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, and prednisone), which was followed by treatment with rituximab plus high-dose cyclophosphamide and two cycles of rituximab with high-dose cytarabine. Stem cells were collected after the first course of the latter regimen.
The patients then underwent conditioning with BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT.
Following ASCT, patients with complete or partial remissions were randomized either to maintenance therapy with lenalidomide 15 mg for 21 of 28 days for each cycle or to observation.
Of the 303 patients initially enrolled, 248 went on to ASCT, and 205 went on to randomization – 104 assigned to maintenance and 101 assigned to observation.
A total of 52 patients completed 2 years of maintenance: Of the rest, 2 patients died from toxicities (thrombotic thrombocytopenic purpura and pneumonia), 7 had disease progression, 41 dropped out for nonprogression reasons, and 2 patients were still in maintenance at the time of the data cutoff. In this arm, 6 of 8 patients with partial responses converted to complete responses by the end of maintenance. More than a quarter of patients (28%) received less than 25% of the planned lenalidomide dose.
In the observation arm, 1 patient died from pneumonia, 20 had disease progression, 3 were lost to follow-up, 6 were still under observation, and 71 completed observation. In this arm, 1 of 4 patients with a partial response converted to a complete response at the end of the observation period.
Despite suboptimal dosing in a large proportion of patients, the PFS primary endpoint showed significant benefit for lenalidomide, with an unstratified hazard ratio of 0.52 (P = .015) and a stratified HR of 0.51 (P = .013).
At a median follow-up of 39 months from randomization, 3-year overall survival (OS) rates were 93% with lenalidomide and 86% with observation, a difference that was not statistically significant.
Grade 3 or 4 hematologic toxicities occurred in 63% of patients in the lenalidomide arm, compared with 11% in the observation arm. The respective rates of granulocytopenia were 59% vs. 10%. Nonhematological grade 3 toxicity was comparable in the two arms except for grade 3 or 4 infections, which were more common with lenalidomide. Seven patients in the lenalidomide arm and three patients in the observation arm developed second cancers.
Dr. Ladetto noted that difficulties in delivering the planned dose of lenalidomide may have been caused by an already-stressed hematopoietic compartment; he commented that the question of the relative benefit of a fixed lenalidomide schedule or an until-progression approach still needs to be answered.
Additionally, the induction schedule used in the trial, while feasible, is not superior to “less cumbersome and possibly less toxic regimens,” he said.
The study was supported by the Italian Lymphoma Foundation (Fondazione Italiana Linfomi) with the European Mantle Cell Lymphoma Network. Dr. Ladetto reported honoraria from Roche, Celgene, Acerta, Janssen, AbbVie, and Sandoz, as well as off-label use of lenalidomide.
SOURCE: Ladetto M et al. ASH 2018, Abstract 401.
SAN DIEGO – For patients 65 years or younger with mantle cell lymphoma (MCL) who have undergone autologous stem cell transplantation (ASCT), maintenance therapy with lenalidomide (Revlimid) can significantly improve progression-free survival (PFS), suggest results of the phase, 3 randomized MCL0208 trial.
After a median follow-up of 39 months, the 3-year PFS in an intention-to-treat analysis was 80% for patients treated with ASCT and lenalidomide maintenance, compared with 64% for patients treated with ASCT alone, reported Marco Ladetto, MD, of Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo in Alessandria, Italy.
“Lenalidomide maintenance after autologous stem cell transplant has substantial clinical activity in mantle cell lymphoma in terms of progression-free survival,” he said at the annual meeting of the American Society of Hematology. “Follow-up is still too short for meaningful overall survival considerations.”
Dr. Ladetto and his colleagues at centers in Italy and Portugal enrolled patients aged 18-65 years with previously untreated MCL stage III or IV, or stage II with bulky disease (5 cm or greater), and good performance status.
The patients first underwent induction with three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, and prednisone), which was followed by treatment with rituximab plus high-dose cyclophosphamide and two cycles of rituximab with high-dose cytarabine. Stem cells were collected after the first course of the latter regimen.
The patients then underwent conditioning with BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT.
Following ASCT, patients with complete or partial remissions were randomized either to maintenance therapy with lenalidomide 15 mg for 21 of 28 days for each cycle or to observation.
Of the 303 patients initially enrolled, 248 went on to ASCT, and 205 went on to randomization – 104 assigned to maintenance and 101 assigned to observation.
A total of 52 patients completed 2 years of maintenance: Of the rest, 2 patients died from toxicities (thrombotic thrombocytopenic purpura and pneumonia), 7 had disease progression, 41 dropped out for nonprogression reasons, and 2 patients were still in maintenance at the time of the data cutoff. In this arm, 6 of 8 patients with partial responses converted to complete responses by the end of maintenance. More than a quarter of patients (28%) received less than 25% of the planned lenalidomide dose.
In the observation arm, 1 patient died from pneumonia, 20 had disease progression, 3 were lost to follow-up, 6 were still under observation, and 71 completed observation. In this arm, 1 of 4 patients with a partial response converted to a complete response at the end of the observation period.
Despite suboptimal dosing in a large proportion of patients, the PFS primary endpoint showed significant benefit for lenalidomide, with an unstratified hazard ratio of 0.52 (P = .015) and a stratified HR of 0.51 (P = .013).
At a median follow-up of 39 months from randomization, 3-year overall survival (OS) rates were 93% with lenalidomide and 86% with observation, a difference that was not statistically significant.
Grade 3 or 4 hematologic toxicities occurred in 63% of patients in the lenalidomide arm, compared with 11% in the observation arm. The respective rates of granulocytopenia were 59% vs. 10%. Nonhematological grade 3 toxicity was comparable in the two arms except for grade 3 or 4 infections, which were more common with lenalidomide. Seven patients in the lenalidomide arm and three patients in the observation arm developed second cancers.
Dr. Ladetto noted that difficulties in delivering the planned dose of lenalidomide may have been caused by an already-stressed hematopoietic compartment; he commented that the question of the relative benefit of a fixed lenalidomide schedule or an until-progression approach still needs to be answered.
Additionally, the induction schedule used in the trial, while feasible, is not superior to “less cumbersome and possibly less toxic regimens,” he said.
The study was supported by the Italian Lymphoma Foundation (Fondazione Italiana Linfomi) with the European Mantle Cell Lymphoma Network. Dr. Ladetto reported honoraria from Roche, Celgene, Acerta, Janssen, AbbVie, and Sandoz, as well as off-label use of lenalidomide.
SOURCE: Ladetto M et al. ASH 2018, Abstract 401.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: The 3-year PFS rate was 80% for patients on lenalidomide maintenance, compared with 64% for patients on observation alone.
Study details: An open-label, randomized, phase 3 trial with 205 patients randomized to lenalidomide or observation.
Disclosures: The study was supported by the Italian Lymphoma Foundation (Fondazione Italiana Linfomi) with the European Mantle Cell Lymphoma Network. Dr. Ladetto reported honoraria from Roche, Celgene, Acerta, Janssen, AbbVie, and Sandoz, as well as off-label use of lenalidomide.
Source: Ladetto M et al. ASH 2018, Abstract 401.
Quizartinib improves survival of FLT3-mutated AML
Single-agent therapy with quizartinib slightly but significantly prolonged survival – compared with salvage chemotherapy – for patients with relapsed/refractory acute myeloid leukemia (AML) bearing the FLT3-ITD mutation, results of the phase 3 randomized QuANTUM-R trial showed.
Median overall survival (OS), the trial’s primary endpoint, was 6.2 months for 245 patients randomized to quizartinib, compared with 4.7 months for 122 patients assigned to salvage chemotherapy, a difference that translated into a hazard ratio (HR) for death of 0.76 (P = .0177), reported Jorge E. Cortes, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“This study is the first study that demonstrates in a randomized fashion an overall survival benefit in the salvage setting for patients with FLT-3 mutated refractory or relapsed AML,” he said at the annual meeting of the American Society of Hematology. “I will also add that these results you saw here are very consistent with all the trials previously with quizartinib with more than 1,000 patients treated.”
Quizartinib, a tyrosine kinase inhibitor (TKI), has previously been shown to be associated with higher response rates among patients with AML bearing the FLT3-ITD mutation than in patients with AML without the deleterious mutation.
Investigators in the QuANTUM-R trial enrolled 367 adults with FTL3-ITD mutated AML that was refractory to the most recent line of therapy or had relapsed within 6 months of first remission, with or without hematopoietic stem cell transplant (HSCT).
The patients had all received at least one cycle of standard-dose induction therapy containing an anthracycline or mitoxantrone, and had a 3% or greater FLT3-ITD allelic ratio in their AML cells.
The patients were randomly assigned on a 2:1 basis to receive either quizartinib or salvage chemotherapy. Quizartinib was dosed 30 mg per day for 15 days, which could be titrated upward to 60 mg daily if the corrected QT interval by Fredericia (QTcF) was 450 ms or less on day 16.
Chemotherapy was the investigator’s choice of one of three specified regimens: either low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to two cycles of MEC or FLAG-IDA were permitted; quizartinib and LoDAC were given until lack of benefit, unacceptable toxicity, or until the patient went on to HSCT.
The analysis was by intention-to-treat. In the quizartinib arm, 241 of the 245 randomized patients (98.4%) received treatment. In the chemotherapy arm, 94 of 122 randomized patients (77%) received chemotherapy. Of this group, 22 received LoDAC, 25 received MEC, and 47 received FLAG-IDA.
The median treatment duration was 97 days in the quizartinib arm versus 28 days (one cycle) in the chemotherapy arm.
The 1-year overall survival rate was 27% for patients assigned to quizartinib, compared with 20% for patients assigned to chemotherapy.
An analysis of OS by subgroup indicated a trend or significant benefit for quizartinib in all categories, including age over or under 65 years, sex, low or high-intensity chemotherapy, response to prior therapy, FLT3 variant allele frequency, prior allogenic HSCT, and AML risk score.
For the secondary endpoint of event-free survival in the ITT population, there was no significant difference between the study arms. In a per-protocol analysis, however, median event-free survival was better with quizartinib, at 1.4 months versus 0.0 months (P = .006).
In all, 32% of patients assigned to quizartinib went on to HSCT, compared with 12% of patients randomized to chemotherapy.
Rates of treatment-emergent adverse events (TEAEs) were similar between the study arms, despite higher total drug exposure in patients randomized to quizartinib. The most frequent grade 3 or greater TEAEs in each arm were infections and cytopenia-related events.
Two patients discontinued quizartinib due to QTcF prolongation. Grade 3 QTcF (greater than 500 ms) occurred in 3% of patients treated with quizartinib, but no grade 4 cases were seen.
The adverse event profile for patients who resumed quizartinib following HSCT was similar to that of patients who received the drug pretransplant.
The combination of standard chemotherapy, with or without quizartinib, is currently being explored in the phase 3 QuANTUM-First trial, Dr. Cortes said.
Daiichi Sankyo sponsored the trial. Dr. Cortes reported financial relationships with Daiichi Sankyo, Pfizer, Arog, Astellas Pharma, and Novartis.
SOURCE: Cortes JE et al. ASH 2018, Abstract 563.
Single-agent therapy with quizartinib slightly but significantly prolonged survival – compared with salvage chemotherapy – for patients with relapsed/refractory acute myeloid leukemia (AML) bearing the FLT3-ITD mutation, results of the phase 3 randomized QuANTUM-R trial showed.
Median overall survival (OS), the trial’s primary endpoint, was 6.2 months for 245 patients randomized to quizartinib, compared with 4.7 months for 122 patients assigned to salvage chemotherapy, a difference that translated into a hazard ratio (HR) for death of 0.76 (P = .0177), reported Jorge E. Cortes, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“This study is the first study that demonstrates in a randomized fashion an overall survival benefit in the salvage setting for patients with FLT-3 mutated refractory or relapsed AML,” he said at the annual meeting of the American Society of Hematology. “I will also add that these results you saw here are very consistent with all the trials previously with quizartinib with more than 1,000 patients treated.”
Quizartinib, a tyrosine kinase inhibitor (TKI), has previously been shown to be associated with higher response rates among patients with AML bearing the FLT3-ITD mutation than in patients with AML without the deleterious mutation.
Investigators in the QuANTUM-R trial enrolled 367 adults with FTL3-ITD mutated AML that was refractory to the most recent line of therapy or had relapsed within 6 months of first remission, with or without hematopoietic stem cell transplant (HSCT).
The patients had all received at least one cycle of standard-dose induction therapy containing an anthracycline or mitoxantrone, and had a 3% or greater FLT3-ITD allelic ratio in their AML cells.
The patients were randomly assigned on a 2:1 basis to receive either quizartinib or salvage chemotherapy. Quizartinib was dosed 30 mg per day for 15 days, which could be titrated upward to 60 mg daily if the corrected QT interval by Fredericia (QTcF) was 450 ms or less on day 16.
Chemotherapy was the investigator’s choice of one of three specified regimens: either low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to two cycles of MEC or FLAG-IDA were permitted; quizartinib and LoDAC were given until lack of benefit, unacceptable toxicity, or until the patient went on to HSCT.
The analysis was by intention-to-treat. In the quizartinib arm, 241 of the 245 randomized patients (98.4%) received treatment. In the chemotherapy arm, 94 of 122 randomized patients (77%) received chemotherapy. Of this group, 22 received LoDAC, 25 received MEC, and 47 received FLAG-IDA.
The median treatment duration was 97 days in the quizartinib arm versus 28 days (one cycle) in the chemotherapy arm.
The 1-year overall survival rate was 27% for patients assigned to quizartinib, compared with 20% for patients assigned to chemotherapy.
An analysis of OS by subgroup indicated a trend or significant benefit for quizartinib in all categories, including age over or under 65 years, sex, low or high-intensity chemotherapy, response to prior therapy, FLT3 variant allele frequency, prior allogenic HSCT, and AML risk score.
For the secondary endpoint of event-free survival in the ITT population, there was no significant difference between the study arms. In a per-protocol analysis, however, median event-free survival was better with quizartinib, at 1.4 months versus 0.0 months (P = .006).
In all, 32% of patients assigned to quizartinib went on to HSCT, compared with 12% of patients randomized to chemotherapy.
Rates of treatment-emergent adverse events (TEAEs) were similar between the study arms, despite higher total drug exposure in patients randomized to quizartinib. The most frequent grade 3 or greater TEAEs in each arm were infections and cytopenia-related events.
Two patients discontinued quizartinib due to QTcF prolongation. Grade 3 QTcF (greater than 500 ms) occurred in 3% of patients treated with quizartinib, but no grade 4 cases were seen.
The adverse event profile for patients who resumed quizartinib following HSCT was similar to that of patients who received the drug pretransplant.
The combination of standard chemotherapy, with or without quizartinib, is currently being explored in the phase 3 QuANTUM-First trial, Dr. Cortes said.
Daiichi Sankyo sponsored the trial. Dr. Cortes reported financial relationships with Daiichi Sankyo, Pfizer, Arog, Astellas Pharma, and Novartis.
SOURCE: Cortes JE et al. ASH 2018, Abstract 563.
Single-agent therapy with quizartinib slightly but significantly prolonged survival – compared with salvage chemotherapy – for patients with relapsed/refractory acute myeloid leukemia (AML) bearing the FLT3-ITD mutation, results of the phase 3 randomized QuANTUM-R trial showed.
Median overall survival (OS), the trial’s primary endpoint, was 6.2 months for 245 patients randomized to quizartinib, compared with 4.7 months for 122 patients assigned to salvage chemotherapy, a difference that translated into a hazard ratio (HR) for death of 0.76 (P = .0177), reported Jorge E. Cortes, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“This study is the first study that demonstrates in a randomized fashion an overall survival benefit in the salvage setting for patients with FLT-3 mutated refractory or relapsed AML,” he said at the annual meeting of the American Society of Hematology. “I will also add that these results you saw here are very consistent with all the trials previously with quizartinib with more than 1,000 patients treated.”
Quizartinib, a tyrosine kinase inhibitor (TKI), has previously been shown to be associated with higher response rates among patients with AML bearing the FLT3-ITD mutation than in patients with AML without the deleterious mutation.
Investigators in the QuANTUM-R trial enrolled 367 adults with FTL3-ITD mutated AML that was refractory to the most recent line of therapy or had relapsed within 6 months of first remission, with or without hematopoietic stem cell transplant (HSCT).
The patients had all received at least one cycle of standard-dose induction therapy containing an anthracycline or mitoxantrone, and had a 3% or greater FLT3-ITD allelic ratio in their AML cells.
The patients were randomly assigned on a 2:1 basis to receive either quizartinib or salvage chemotherapy. Quizartinib was dosed 30 mg per day for 15 days, which could be titrated upward to 60 mg daily if the corrected QT interval by Fredericia (QTcF) was 450 ms or less on day 16.
Chemotherapy was the investigator’s choice of one of three specified regimens: either low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to two cycles of MEC or FLAG-IDA were permitted; quizartinib and LoDAC were given until lack of benefit, unacceptable toxicity, or until the patient went on to HSCT.
The analysis was by intention-to-treat. In the quizartinib arm, 241 of the 245 randomized patients (98.4%) received treatment. In the chemotherapy arm, 94 of 122 randomized patients (77%) received chemotherapy. Of this group, 22 received LoDAC, 25 received MEC, and 47 received FLAG-IDA.
The median treatment duration was 97 days in the quizartinib arm versus 28 days (one cycle) in the chemotherapy arm.
The 1-year overall survival rate was 27% for patients assigned to quizartinib, compared with 20% for patients assigned to chemotherapy.
An analysis of OS by subgroup indicated a trend or significant benefit for quizartinib in all categories, including age over or under 65 years, sex, low or high-intensity chemotherapy, response to prior therapy, FLT3 variant allele frequency, prior allogenic HSCT, and AML risk score.
For the secondary endpoint of event-free survival in the ITT population, there was no significant difference between the study arms. In a per-protocol analysis, however, median event-free survival was better with quizartinib, at 1.4 months versus 0.0 months (P = .006).
In all, 32% of patients assigned to quizartinib went on to HSCT, compared with 12% of patients randomized to chemotherapy.
Rates of treatment-emergent adverse events (TEAEs) were similar between the study arms, despite higher total drug exposure in patients randomized to quizartinib. The most frequent grade 3 or greater TEAEs in each arm were infections and cytopenia-related events.
Two patients discontinued quizartinib due to QTcF prolongation. Grade 3 QTcF (greater than 500 ms) occurred in 3% of patients treated with quizartinib, but no grade 4 cases were seen.
The adverse event profile for patients who resumed quizartinib following HSCT was similar to that of patients who received the drug pretransplant.
The combination of standard chemotherapy, with or without quizartinib, is currently being explored in the phase 3 QuANTUM-First trial, Dr. Cortes said.
Daiichi Sankyo sponsored the trial. Dr. Cortes reported financial relationships with Daiichi Sankyo, Pfizer, Arog, Astellas Pharma, and Novartis.
SOURCE: Cortes JE et al. ASH 2018, Abstract 563.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: The hazard ratio for death with quizartinib was 0.76 (P = .0177).
Study details: A randomized phase 3 trial comparing quizartinib to salvage chemotherapy on a 2:1 basis in 367 adults with FLT3-ITD mutated AML.
Disclosures: Daiichi Sankyo sponsored the trial. Dr. Cortes reported financial relationships with Daiichi Sankyo, Pfizer, Arog, Astellas Pharma, and Novartis.
Source: Cortes JE et al. ASH 2018, Abstract 563.
DRd improves PFS in transplant-ineligible MM
SAN DIEGO—An interim analysis from the MAIA trial showed that adding daratumumab to lenalidomide and dexamethasone could significantly improve progression-free survival (PFS) in older patients with multiple myeloma (MM) who were ineligible for transplant.
The 30-month PFS rate was 71% in patients who received daratumumab plus lenalidomide and dexamethasone (DRd) and 56% in patients who received only lenalidomide and dexamethasone (Rd).
“These results support DRd as a new standard of care for elderly patients with myeloma who are ineligible for transplant,” said Thierry Facon, MD, of Hôpital Claude Huriez and the University of Lille in France.
Dr. Facon presented results from MAIA during the late-breaking abstracts session at the 2018 ASH Annual Meeting (abstract LBA-2).
The phase 3 trial (NCT02252172) enrolled 737 transplant-ineligible patients with newly diagnosed MM.
The patients were randomly assigned to DRd or Rd. Daratumumab was given at 16 mg/kg weekly for cycles 1 and 2, every other week for cycles 3 through 6, and every 4 weeks from cycle 7 until disease progression.
Lenalidomide was given at 25 mg orally per day on days 1-21 until disease progression, and dexamethasone was given at 40 mg orally or intravenously weekly until disease progression.
The median patient age was 73 years, and 99% of all patients were 65 or older. Demographic and clinical characteristics were well balanced between the treatment arms.
Results
The primary endpoint of PFS was superior with DRd.
At a median follow-up of 28 months, the median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm.
The 30-month PFS rate was 71% in the DRd arm and 56% in the Rd arm (hazard ratio [HR]=0.56; P<0.0001).
DRd was associated with a significantly higher overall response rate than Rd—93% and 81%, respectively (P<0.0001).
The complete response rates were 48% and 25%, respectively (P<0.0001). The rates of very good partial response or better were 79% and 53%, respectively (P<0.0001). And the rates of minimal residual disease negativity were 24% and 7%, respectively (P<0.0001).
DRd was associated with infusion-related reactions in 41% of patients, and 3% were grade 3 or 4 in severity.
Hematologic treatment-emergent adverse events of grade 3 or higher that were more common with DRd than Rd included neutropenia (50% vs. 35%) and lymphopenia (15% vs. 11%).
Conversely, grade 3/4 thrombocytopenia (7% vs. 9%) and anemia (12% vs. 20%) were more frequent with Rd.
Nonhematologic treatment-emergent adverse events that were more frequent with DRd included diarrhea, constipation, fatigue, peripheral edema, and pneumonia.
Rates of asthenia, back pain, nausea, and deep vein thrombosis/pulmonary embolism were similar between the treatment arms.
Janssen funded this study. Dr. Facon reported relationships with Celgene, Janssen, Takeda, Sanofi, Amgen, Karyopharm, and Oncopeptides.
SAN DIEGO—An interim analysis from the MAIA trial showed that adding daratumumab to lenalidomide and dexamethasone could significantly improve progression-free survival (PFS) in older patients with multiple myeloma (MM) who were ineligible for transplant.
The 30-month PFS rate was 71% in patients who received daratumumab plus lenalidomide and dexamethasone (DRd) and 56% in patients who received only lenalidomide and dexamethasone (Rd).
“These results support DRd as a new standard of care for elderly patients with myeloma who are ineligible for transplant,” said Thierry Facon, MD, of Hôpital Claude Huriez and the University of Lille in France.
Dr. Facon presented results from MAIA during the late-breaking abstracts session at the 2018 ASH Annual Meeting (abstract LBA-2).
The phase 3 trial (NCT02252172) enrolled 737 transplant-ineligible patients with newly diagnosed MM.
The patients were randomly assigned to DRd or Rd. Daratumumab was given at 16 mg/kg weekly for cycles 1 and 2, every other week for cycles 3 through 6, and every 4 weeks from cycle 7 until disease progression.
Lenalidomide was given at 25 mg orally per day on days 1-21 until disease progression, and dexamethasone was given at 40 mg orally or intravenously weekly until disease progression.
The median patient age was 73 years, and 99% of all patients were 65 or older. Demographic and clinical characteristics were well balanced between the treatment arms.
Results
The primary endpoint of PFS was superior with DRd.
At a median follow-up of 28 months, the median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm.
The 30-month PFS rate was 71% in the DRd arm and 56% in the Rd arm (hazard ratio [HR]=0.56; P<0.0001).
DRd was associated with a significantly higher overall response rate than Rd—93% and 81%, respectively (P<0.0001).
The complete response rates were 48% and 25%, respectively (P<0.0001). The rates of very good partial response or better were 79% and 53%, respectively (P<0.0001). And the rates of minimal residual disease negativity were 24% and 7%, respectively (P<0.0001).
DRd was associated with infusion-related reactions in 41% of patients, and 3% were grade 3 or 4 in severity.
Hematologic treatment-emergent adverse events of grade 3 or higher that were more common with DRd than Rd included neutropenia (50% vs. 35%) and lymphopenia (15% vs. 11%).
Conversely, grade 3/4 thrombocytopenia (7% vs. 9%) and anemia (12% vs. 20%) were more frequent with Rd.
Nonhematologic treatment-emergent adverse events that were more frequent with DRd included diarrhea, constipation, fatigue, peripheral edema, and pneumonia.
Rates of asthenia, back pain, nausea, and deep vein thrombosis/pulmonary embolism were similar between the treatment arms.
Janssen funded this study. Dr. Facon reported relationships with Celgene, Janssen, Takeda, Sanofi, Amgen, Karyopharm, and Oncopeptides.
SAN DIEGO—An interim analysis from the MAIA trial showed that adding daratumumab to lenalidomide and dexamethasone could significantly improve progression-free survival (PFS) in older patients with multiple myeloma (MM) who were ineligible for transplant.
The 30-month PFS rate was 71% in patients who received daratumumab plus lenalidomide and dexamethasone (DRd) and 56% in patients who received only lenalidomide and dexamethasone (Rd).
“These results support DRd as a new standard of care for elderly patients with myeloma who are ineligible for transplant,” said Thierry Facon, MD, of Hôpital Claude Huriez and the University of Lille in France.
Dr. Facon presented results from MAIA during the late-breaking abstracts session at the 2018 ASH Annual Meeting (abstract LBA-2).
The phase 3 trial (NCT02252172) enrolled 737 transplant-ineligible patients with newly diagnosed MM.
The patients were randomly assigned to DRd or Rd. Daratumumab was given at 16 mg/kg weekly for cycles 1 and 2, every other week for cycles 3 through 6, and every 4 weeks from cycle 7 until disease progression.
Lenalidomide was given at 25 mg orally per day on days 1-21 until disease progression, and dexamethasone was given at 40 mg orally or intravenously weekly until disease progression.
The median patient age was 73 years, and 99% of all patients were 65 or older. Demographic and clinical characteristics were well balanced between the treatment arms.
Results
The primary endpoint of PFS was superior with DRd.
At a median follow-up of 28 months, the median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm.
The 30-month PFS rate was 71% in the DRd arm and 56% in the Rd arm (hazard ratio [HR]=0.56; P<0.0001).
DRd was associated with a significantly higher overall response rate than Rd—93% and 81%, respectively (P<0.0001).
The complete response rates were 48% and 25%, respectively (P<0.0001). The rates of very good partial response or better were 79% and 53%, respectively (P<0.0001). And the rates of minimal residual disease negativity were 24% and 7%, respectively (P<0.0001).
DRd was associated with infusion-related reactions in 41% of patients, and 3% were grade 3 or 4 in severity.
Hematologic treatment-emergent adverse events of grade 3 or higher that were more common with DRd than Rd included neutropenia (50% vs. 35%) and lymphopenia (15% vs. 11%).
Conversely, grade 3/4 thrombocytopenia (7% vs. 9%) and anemia (12% vs. 20%) were more frequent with Rd.
Nonhematologic treatment-emergent adverse events that were more frequent with DRd included diarrhea, constipation, fatigue, peripheral edema, and pneumonia.
Rates of asthenia, back pain, nausea, and deep vein thrombosis/pulmonary embolism were similar between the treatment arms.
Janssen funded this study. Dr. Facon reported relationships with Celgene, Janssen, Takeda, Sanofi, Amgen, Karyopharm, and Oncopeptides.
Risk of second cancers in Hodgkin lymphoma survivors
Survivors of childhood Hodgkin lymphoma (HL) have a 14-fold higher risk of second cancers compared to the general population, according to new research.
The subsequent malignant neoplasms (SMNs) observed in HL survivors tended to follow specific patterns depending on the patient’s age at treatment, sex, treatment modality, and region of the body treated.
And although the risk of SMNs appears to be somewhat lower for HL patients treated in more recent decades, it is still significantly higher than the risk in the general population, according to investigators.
Anna S. Holmqvist, MD, PhD, of the University of Lund in Sweden, and her colleagues conducted this research and reported the results in Cancer.
The investigators looked at data from the Late Effects Study Group, a multinational cohort of patients age 16 or younger who were treated for HL and other cancers from 1955 through 1986.
The current report is the third update from an expanded cohort including data on 1,136 patients with a median follow-up of 26.6 years. The median patient age at diagnosis was 11 years (range, birth to 16 years), and the patients were followed for 23,212 person-years after HL diagnosis.
In all, 162 patients developed 196 SMNs, including breast cancer (n=54), basal cell carcinoma (n=34), thyroid cancer (n=30), colorectal cancer (n=15), lung cancer (n=11), and other malignancies (n=40). The disease site was not available in 12 cases.
The cumulative incidence of any SMN 40 years after HL diagnosis was 26.4%. By age 50, the cumulative incidence of any SMN was 27.2%.
The standardized incidence ratio for the entire cohort was 14.0, compared with the general population as derived from the Surveillance, Epidemiology and End Results database.
Risk factors by cancer type
Females treated with chest radiotherapy between the ages of 10 and 16 who did not receive alkylating agents or received low doses of alkylating agents had the highest risk of developing breast cancer. The cumulative incidence of breast cancer by age 50 was 45.3% in these patients.
The patients with the highest risk for subsequent lung cancer were males treated with chest radiotherapy before age 10. The cumulative incidence of lung cancer by age 50 was 4.2% in these patients.
Patients with the highest risk for colorectal cancer had received abdominal/pelvic radiotherapy and high-dose alkylating agents. The cumulative incidence of colorectal cancer by age 50 was 9.5% in these patients.
Patients with the highest risk for thyroid cancers were females who had been treated with radiotherapy to the neck before the age of 10. The cumulative incidence of thyroid cancer by age 50 was 17.3% in these patients.
The investigators noted that HL patients treated more recently are likely to have received lower doses and volumes of radiotherapy compared to patients treated in the 1950s, ’60s and ’70s.
“However, for the cohort of patients treated between 1955 and 1986, it is clear that continued surveillance for SMNs is essential because their risk continues to increase as these survivors enter their fourth and subsequent decades of life,” the investigators wrote.
They did not report a funding source for this research or make any conflict-of-interest disclosures.
Survivors of childhood Hodgkin lymphoma (HL) have a 14-fold higher risk of second cancers compared to the general population, according to new research.
The subsequent malignant neoplasms (SMNs) observed in HL survivors tended to follow specific patterns depending on the patient’s age at treatment, sex, treatment modality, and region of the body treated.
And although the risk of SMNs appears to be somewhat lower for HL patients treated in more recent decades, it is still significantly higher than the risk in the general population, according to investigators.
Anna S. Holmqvist, MD, PhD, of the University of Lund in Sweden, and her colleagues conducted this research and reported the results in Cancer.
The investigators looked at data from the Late Effects Study Group, a multinational cohort of patients age 16 or younger who were treated for HL and other cancers from 1955 through 1986.
The current report is the third update from an expanded cohort including data on 1,136 patients with a median follow-up of 26.6 years. The median patient age at diagnosis was 11 years (range, birth to 16 years), and the patients were followed for 23,212 person-years after HL diagnosis.
In all, 162 patients developed 196 SMNs, including breast cancer (n=54), basal cell carcinoma (n=34), thyroid cancer (n=30), colorectal cancer (n=15), lung cancer (n=11), and other malignancies (n=40). The disease site was not available in 12 cases.
The cumulative incidence of any SMN 40 years after HL diagnosis was 26.4%. By age 50, the cumulative incidence of any SMN was 27.2%.
The standardized incidence ratio for the entire cohort was 14.0, compared with the general population as derived from the Surveillance, Epidemiology and End Results database.
Risk factors by cancer type
Females treated with chest radiotherapy between the ages of 10 and 16 who did not receive alkylating agents or received low doses of alkylating agents had the highest risk of developing breast cancer. The cumulative incidence of breast cancer by age 50 was 45.3% in these patients.
The patients with the highest risk for subsequent lung cancer were males treated with chest radiotherapy before age 10. The cumulative incidence of lung cancer by age 50 was 4.2% in these patients.
Patients with the highest risk for colorectal cancer had received abdominal/pelvic radiotherapy and high-dose alkylating agents. The cumulative incidence of colorectal cancer by age 50 was 9.5% in these patients.
Patients with the highest risk for thyroid cancers were females who had been treated with radiotherapy to the neck before the age of 10. The cumulative incidence of thyroid cancer by age 50 was 17.3% in these patients.
The investigators noted that HL patients treated more recently are likely to have received lower doses and volumes of radiotherapy compared to patients treated in the 1950s, ’60s and ’70s.
“However, for the cohort of patients treated between 1955 and 1986, it is clear that continued surveillance for SMNs is essential because their risk continues to increase as these survivors enter their fourth and subsequent decades of life,” the investigators wrote.
They did not report a funding source for this research or make any conflict-of-interest disclosures.
Survivors of childhood Hodgkin lymphoma (HL) have a 14-fold higher risk of second cancers compared to the general population, according to new research.
The subsequent malignant neoplasms (SMNs) observed in HL survivors tended to follow specific patterns depending on the patient’s age at treatment, sex, treatment modality, and region of the body treated.
And although the risk of SMNs appears to be somewhat lower for HL patients treated in more recent decades, it is still significantly higher than the risk in the general population, according to investigators.
Anna S. Holmqvist, MD, PhD, of the University of Lund in Sweden, and her colleagues conducted this research and reported the results in Cancer.
The investigators looked at data from the Late Effects Study Group, a multinational cohort of patients age 16 or younger who were treated for HL and other cancers from 1955 through 1986.
The current report is the third update from an expanded cohort including data on 1,136 patients with a median follow-up of 26.6 years. The median patient age at diagnosis was 11 years (range, birth to 16 years), and the patients were followed for 23,212 person-years after HL diagnosis.
In all, 162 patients developed 196 SMNs, including breast cancer (n=54), basal cell carcinoma (n=34), thyroid cancer (n=30), colorectal cancer (n=15), lung cancer (n=11), and other malignancies (n=40). The disease site was not available in 12 cases.
The cumulative incidence of any SMN 40 years after HL diagnosis was 26.4%. By age 50, the cumulative incidence of any SMN was 27.2%.
The standardized incidence ratio for the entire cohort was 14.0, compared with the general population as derived from the Surveillance, Epidemiology and End Results database.
Risk factors by cancer type
Females treated with chest radiotherapy between the ages of 10 and 16 who did not receive alkylating agents or received low doses of alkylating agents had the highest risk of developing breast cancer. The cumulative incidence of breast cancer by age 50 was 45.3% in these patients.
The patients with the highest risk for subsequent lung cancer were males treated with chest radiotherapy before age 10. The cumulative incidence of lung cancer by age 50 was 4.2% in these patients.
Patients with the highest risk for colorectal cancer had received abdominal/pelvic radiotherapy and high-dose alkylating agents. The cumulative incidence of colorectal cancer by age 50 was 9.5% in these patients.
Patients with the highest risk for thyroid cancers were females who had been treated with radiotherapy to the neck before the age of 10. The cumulative incidence of thyroid cancer by age 50 was 17.3% in these patients.
The investigators noted that HL patients treated more recently are likely to have received lower doses and volumes of radiotherapy compared to patients treated in the 1950s, ’60s and ’70s.
“However, for the cohort of patients treated between 1955 and 1986, it is clear that continued surveillance for SMNs is essential because their risk continues to increase as these survivors enter their fourth and subsequent decades of life,” the investigators wrote.
They did not report a funding source for this research or make any conflict-of-interest disclosures.
Lack of gut diversity hurts survival after HCT
SAN DIEGO – The success or failure of hematopoietic cell transplants may be related to the diversity of species in the gut microbiome, investigators contend.
A study of fecal samples from patients scheduled to undergo hematopoietic cell transplant (HCT) in the United States, Europe, and Japan showed that intestinal microbial diversity was significantly associated with overall survival, reported Jonathan U. Peled, MD, PhD, from the bone marrow transplantation service at Memorial Sloan Kettering Cancer Center in New York City.
“Patients with low diversity pretransplant have a poorer overall survival than patients with a higher diversity after transplantation,” he said at the annual meeting of the American Society of Hematology. “The implication is, if we could come up with a way to remediate microbiome injury, there might be time to implement it before the transplant.”
There are about 100 trillion symbiotic microbes in and on the human body, and 95% of them live in the gastrointestinal tract, which has a surface area that if stretched out would equal the size of two tennis courts, Dr. Peled said.
Previous studies by his group and others have shown that the composition of intestinal microbiota is associated with survival, relapses, graft-versus-host disease, and infections in patients in the early weeks after allogeneic HCT.
The international team previously reported that intestinal diversity measured around the time of neutrophil engraftment was predictive of overall survival, and they hypothesized that the same might be true of the pretransplant microbiota composition.
To test this idea, they collected 1,922 stools samples approximately once weekly for 3 weeks pretransplant from 991 adult patients scheduled for allo-HCT for various diagnoses in two U.S. cohorts and one cohort each in Europe and Japan.
They found that on average patients in all four cohorts had microbiota diversity values ranging from 70% to 150% lower than those of healthy volunteers whose samples were sequenced by the investigators, as well as those in a publicly available database.
The investigators also asked whether one or more bacterial species accounted for 30% or more of a microbiome, a phenomenon known as “monodomination.”
“A third, or in some cases 95+%, of bacteria in an individual’s intestine are all the exact same strain,” Dr. Peled said.
They found that the incidence and prevalence of the monodomination phenotype was “strikingly similar” at all four transplant sites.
The patterns of microbiota injury were similar despite differences in antibiotic strategies among the four centers and different dietary patterns of patients in the regions studied.
Studies in animal models suggest that T cells responsible for graft-versus-host disease migrate to the gut as early as 2 or 3 days post transplant, and by that time more than half of transplant patients have a monodomination event in their guts, Dr. Peled said.
Some strategies to remediate or prevent microbiome damage – and potentially improve HCT outcomes – may include the use of over-the-counter or custom-made probiotics, fecal transplants, a “prebiotic” approach in which the patient is asked to follow a specific diet that promotes the growth of beneficial bacteria, or a “postbiotic” approach in which patients receive metabolites of agents or foods thought to have a beneficial effect.
“Finally, we can think about different antibiotic strategies, to use or not use different types of antibiotics at different times in a rational way,” Dr. Peled said.
Dr. Peled reported current or prior financial relationships with Seres Therapeutics, the Parker Institute for Cancer Immunotherapy, and Merck/Society for Immunotherapy of Cancer.
SOURCE: Peled JU et al. ASH 2018, Abstract 811.
SAN DIEGO – The success or failure of hematopoietic cell transplants may be related to the diversity of species in the gut microbiome, investigators contend.
A study of fecal samples from patients scheduled to undergo hematopoietic cell transplant (HCT) in the United States, Europe, and Japan showed that intestinal microbial diversity was significantly associated with overall survival, reported Jonathan U. Peled, MD, PhD, from the bone marrow transplantation service at Memorial Sloan Kettering Cancer Center in New York City.
“Patients with low diversity pretransplant have a poorer overall survival than patients with a higher diversity after transplantation,” he said at the annual meeting of the American Society of Hematology. “The implication is, if we could come up with a way to remediate microbiome injury, there might be time to implement it before the transplant.”
There are about 100 trillion symbiotic microbes in and on the human body, and 95% of them live in the gastrointestinal tract, which has a surface area that if stretched out would equal the size of two tennis courts, Dr. Peled said.
Previous studies by his group and others have shown that the composition of intestinal microbiota is associated with survival, relapses, graft-versus-host disease, and infections in patients in the early weeks after allogeneic HCT.
The international team previously reported that intestinal diversity measured around the time of neutrophil engraftment was predictive of overall survival, and they hypothesized that the same might be true of the pretransplant microbiota composition.
To test this idea, they collected 1,922 stools samples approximately once weekly for 3 weeks pretransplant from 991 adult patients scheduled for allo-HCT for various diagnoses in two U.S. cohorts and one cohort each in Europe and Japan.
They found that on average patients in all four cohorts had microbiota diversity values ranging from 70% to 150% lower than those of healthy volunteers whose samples were sequenced by the investigators, as well as those in a publicly available database.
The investigators also asked whether one or more bacterial species accounted for 30% or more of a microbiome, a phenomenon known as “monodomination.”
“A third, or in some cases 95+%, of bacteria in an individual’s intestine are all the exact same strain,” Dr. Peled said.
They found that the incidence and prevalence of the monodomination phenotype was “strikingly similar” at all four transplant sites.
The patterns of microbiota injury were similar despite differences in antibiotic strategies among the four centers and different dietary patterns of patients in the regions studied.
Studies in animal models suggest that T cells responsible for graft-versus-host disease migrate to the gut as early as 2 or 3 days post transplant, and by that time more than half of transplant patients have a monodomination event in their guts, Dr. Peled said.
Some strategies to remediate or prevent microbiome damage – and potentially improve HCT outcomes – may include the use of over-the-counter or custom-made probiotics, fecal transplants, a “prebiotic” approach in which the patient is asked to follow a specific diet that promotes the growth of beneficial bacteria, or a “postbiotic” approach in which patients receive metabolites of agents or foods thought to have a beneficial effect.
“Finally, we can think about different antibiotic strategies, to use or not use different types of antibiotics at different times in a rational way,” Dr. Peled said.
Dr. Peled reported current or prior financial relationships with Seres Therapeutics, the Parker Institute for Cancer Immunotherapy, and Merck/Society for Immunotherapy of Cancer.
SOURCE: Peled JU et al. ASH 2018, Abstract 811.
SAN DIEGO – The success or failure of hematopoietic cell transplants may be related to the diversity of species in the gut microbiome, investigators contend.
A study of fecal samples from patients scheduled to undergo hematopoietic cell transplant (HCT) in the United States, Europe, and Japan showed that intestinal microbial diversity was significantly associated with overall survival, reported Jonathan U. Peled, MD, PhD, from the bone marrow transplantation service at Memorial Sloan Kettering Cancer Center in New York City.
“Patients with low diversity pretransplant have a poorer overall survival than patients with a higher diversity after transplantation,” he said at the annual meeting of the American Society of Hematology. “The implication is, if we could come up with a way to remediate microbiome injury, there might be time to implement it before the transplant.”
There are about 100 trillion symbiotic microbes in and on the human body, and 95% of them live in the gastrointestinal tract, which has a surface area that if stretched out would equal the size of two tennis courts, Dr. Peled said.
Previous studies by his group and others have shown that the composition of intestinal microbiota is associated with survival, relapses, graft-versus-host disease, and infections in patients in the early weeks after allogeneic HCT.
The international team previously reported that intestinal diversity measured around the time of neutrophil engraftment was predictive of overall survival, and they hypothesized that the same might be true of the pretransplant microbiota composition.
To test this idea, they collected 1,922 stools samples approximately once weekly for 3 weeks pretransplant from 991 adult patients scheduled for allo-HCT for various diagnoses in two U.S. cohorts and one cohort each in Europe and Japan.
They found that on average patients in all four cohorts had microbiota diversity values ranging from 70% to 150% lower than those of healthy volunteers whose samples were sequenced by the investigators, as well as those in a publicly available database.
The investigators also asked whether one or more bacterial species accounted for 30% or more of a microbiome, a phenomenon known as “monodomination.”
“A third, or in some cases 95+%, of bacteria in an individual’s intestine are all the exact same strain,” Dr. Peled said.
They found that the incidence and prevalence of the monodomination phenotype was “strikingly similar” at all four transplant sites.
The patterns of microbiota injury were similar despite differences in antibiotic strategies among the four centers and different dietary patterns of patients in the regions studied.
Studies in animal models suggest that T cells responsible for graft-versus-host disease migrate to the gut as early as 2 or 3 days post transplant, and by that time more than half of transplant patients have a monodomination event in their guts, Dr. Peled said.
Some strategies to remediate or prevent microbiome damage – and potentially improve HCT outcomes – may include the use of over-the-counter or custom-made probiotics, fecal transplants, a “prebiotic” approach in which the patient is asked to follow a specific diet that promotes the growth of beneficial bacteria, or a “postbiotic” approach in which patients receive metabolites of agents or foods thought to have a beneficial effect.
“Finally, we can think about different antibiotic strategies, to use or not use different types of antibiotics at different times in a rational way,” Dr. Peled said.
Dr. Peled reported current or prior financial relationships with Seres Therapeutics, the Parker Institute for Cancer Immunotherapy, and Merck/Society for Immunotherapy of Cancer.
SOURCE: Peled JU et al. ASH 2018, Abstract 811.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: Hematopoietic cell transplant candidates in the United States, Europe, and Japan all had similar patterns of low intestinal microbiota diversity and predomination of a single taxonomic species.
Study details: An analysis of stool samples from 991 adults scheduled for hematopoietic cell transplant at four transplant centers in the United States, Germany, and Japan.
Disclosures: Dr. Peled reported current or prior financial relationships with Seres Therapeutics, the Parker Institute for Cancer Immunotherapy, and Merck/Society for Immunotherapy of Cancer.
Source: Peled JU et al. ASH 2018, Abstract 811.
Survivors of childhood Hodgkin lymphoma face 14-fold risk of second cancers
Survivors of childhood Hodgkin lymphoma have a 14-fold greater risk for second cancers, compared with the general population, according to newly published data.
The subsequent malignant neoplasms (SMNs) tend to follow specific patterns depending on the patient’s age at treatment, sex, treatment modality, and body region treated.
And although the risk of SMNs appears to be somewhat lower for patients treated in more recent decades, it is still significantly elevated, compared with that of the general population, according to Anna S. Holmqvist, MD, PhD, from Lund University (Sweden), and her colleagues.
“A major goal of the current study was to develop evidence with which to guide the screening of survivors of HL for the development of [solid] SMNs,” the investigators wrote in Cancer.
They examined at data from the Late Effects Study Group, a multinational cohort of patients aged 16 years or younger who were treated for Hodgkin lymphoma and other cancers from 1955 to 1986.
The current report is the third update from an expanded cohort, including data on 1,136 patients with a median follow-up of 26.6 years. The median patient age at diagnosis was 11 years and the patients were followed for 23,212 person-years following the Hodgkin lymphoma diagnosis.
In all, 162 patients developed a total of 196 solid SMNs, including breast cancer in 54 patients, basal cell carcinoma in 34 patients, thyroid cancer in 30, colorectal cancer in 15, lung cancer in 11, other malignancies in 40, and disease site not available in 12 patients.
The cumulative incidence of any solid SMN 40 years after a diagnosis of Hodgkin lymphoma was 26.4%. The standardized incidence ratio for the entire cohort was 14.0, compared with the general population as derived from the Surveillance, Epidemiology and End Results database.
Predisposing factors for breast cancer in females included a Hodgkin lymphoma diagnosis from the ages of 10-16 years, and treatment with radiotherapy to the chest.
The patients at highest risk for subsequent development of lung cancer were males treated with chest radiotherapy before age 10 years. Those at highest risk for colorectal cancer were males and females who had received abdominal/pelvic radiotherapy and high-dose alkylating agents. Patients at highest risk for thyroid cancers were females who had been treated with radiotherapy to the neck before the age of 10.
The cumulative incidence for breast cancer by age 50 years for those at highest risk was 45.3%. The respective cumulative incidences for lung, colorectal, and thyroid cancers by age 50 were 4.2%, 9.5%, and 17.3%.
The investigators noted that patients treated more recently are likely to have received lower doses and volumes of radiotherapy, compared with patients treated in 1970s and earlier. “However, for the cohort of patients treated between 1955 and 1986, it is clear that continued surveillance for [solid] SMNs is essential because their risk continues to increase as these survivors enter their fourth and subsequent decades of life.”
No specific funding source for the study was reported. The authors made no financial disclosures.
SOURCE: Holmqvist AS et al. Cancer. 2018 Dec 17. doi: 10.1002/cncr.31807.
Survivors of childhood Hodgkin lymphoma have a 14-fold greater risk for second cancers, compared with the general population, according to newly published data.
The subsequent malignant neoplasms (SMNs) tend to follow specific patterns depending on the patient’s age at treatment, sex, treatment modality, and body region treated.
And although the risk of SMNs appears to be somewhat lower for patients treated in more recent decades, it is still significantly elevated, compared with that of the general population, according to Anna S. Holmqvist, MD, PhD, from Lund University (Sweden), and her colleagues.
“A major goal of the current study was to develop evidence with which to guide the screening of survivors of HL for the development of [solid] SMNs,” the investigators wrote in Cancer.
They examined at data from the Late Effects Study Group, a multinational cohort of patients aged 16 years or younger who were treated for Hodgkin lymphoma and other cancers from 1955 to 1986.
The current report is the third update from an expanded cohort, including data on 1,136 patients with a median follow-up of 26.6 years. The median patient age at diagnosis was 11 years and the patients were followed for 23,212 person-years following the Hodgkin lymphoma diagnosis.
In all, 162 patients developed a total of 196 solid SMNs, including breast cancer in 54 patients, basal cell carcinoma in 34 patients, thyroid cancer in 30, colorectal cancer in 15, lung cancer in 11, other malignancies in 40, and disease site not available in 12 patients.
The cumulative incidence of any solid SMN 40 years after a diagnosis of Hodgkin lymphoma was 26.4%. The standardized incidence ratio for the entire cohort was 14.0, compared with the general population as derived from the Surveillance, Epidemiology and End Results database.
Predisposing factors for breast cancer in females included a Hodgkin lymphoma diagnosis from the ages of 10-16 years, and treatment with radiotherapy to the chest.
The patients at highest risk for subsequent development of lung cancer were males treated with chest radiotherapy before age 10 years. Those at highest risk for colorectal cancer were males and females who had received abdominal/pelvic radiotherapy and high-dose alkylating agents. Patients at highest risk for thyroid cancers were females who had been treated with radiotherapy to the neck before the age of 10.
The cumulative incidence for breast cancer by age 50 years for those at highest risk was 45.3%. The respective cumulative incidences for lung, colorectal, and thyroid cancers by age 50 were 4.2%, 9.5%, and 17.3%.
The investigators noted that patients treated more recently are likely to have received lower doses and volumes of radiotherapy, compared with patients treated in 1970s and earlier. “However, for the cohort of patients treated between 1955 and 1986, it is clear that continued surveillance for [solid] SMNs is essential because their risk continues to increase as these survivors enter their fourth and subsequent decades of life.”
No specific funding source for the study was reported. The authors made no financial disclosures.
SOURCE: Holmqvist AS et al. Cancer. 2018 Dec 17. doi: 10.1002/cncr.31807.
Survivors of childhood Hodgkin lymphoma have a 14-fold greater risk for second cancers, compared with the general population, according to newly published data.
The subsequent malignant neoplasms (SMNs) tend to follow specific patterns depending on the patient’s age at treatment, sex, treatment modality, and body region treated.
And although the risk of SMNs appears to be somewhat lower for patients treated in more recent decades, it is still significantly elevated, compared with that of the general population, according to Anna S. Holmqvist, MD, PhD, from Lund University (Sweden), and her colleagues.
“A major goal of the current study was to develop evidence with which to guide the screening of survivors of HL for the development of [solid] SMNs,” the investigators wrote in Cancer.
They examined at data from the Late Effects Study Group, a multinational cohort of patients aged 16 years or younger who were treated for Hodgkin lymphoma and other cancers from 1955 to 1986.
The current report is the third update from an expanded cohort, including data on 1,136 patients with a median follow-up of 26.6 years. The median patient age at diagnosis was 11 years and the patients were followed for 23,212 person-years following the Hodgkin lymphoma diagnosis.
In all, 162 patients developed a total of 196 solid SMNs, including breast cancer in 54 patients, basal cell carcinoma in 34 patients, thyroid cancer in 30, colorectal cancer in 15, lung cancer in 11, other malignancies in 40, and disease site not available in 12 patients.
The cumulative incidence of any solid SMN 40 years after a diagnosis of Hodgkin lymphoma was 26.4%. The standardized incidence ratio for the entire cohort was 14.0, compared with the general population as derived from the Surveillance, Epidemiology and End Results database.
Predisposing factors for breast cancer in females included a Hodgkin lymphoma diagnosis from the ages of 10-16 years, and treatment with radiotherapy to the chest.
The patients at highest risk for subsequent development of lung cancer were males treated with chest radiotherapy before age 10 years. Those at highest risk for colorectal cancer were males and females who had received abdominal/pelvic radiotherapy and high-dose alkylating agents. Patients at highest risk for thyroid cancers were females who had been treated with radiotherapy to the neck before the age of 10.
The cumulative incidence for breast cancer by age 50 years for those at highest risk was 45.3%. The respective cumulative incidences for lung, colorectal, and thyroid cancers by age 50 were 4.2%, 9.5%, and 17.3%.
The investigators noted that patients treated more recently are likely to have received lower doses and volumes of radiotherapy, compared with patients treated in 1970s and earlier. “However, for the cohort of patients treated between 1955 and 1986, it is clear that continued surveillance for [solid] SMNs is essential because their risk continues to increase as these survivors enter their fourth and subsequent decades of life.”
No specific funding source for the study was reported. The authors made no financial disclosures.
SOURCE: Holmqvist AS et al. Cancer. 2018 Dec 17. doi: 10.1002/cncr.31807.
FROM CANCER
Key clinical point:
Major finding: The risk for a subsequent malignant neoplasm among survivors of childhood Hodgkin lymphoma was 14-fold higher than that of the general population.
Study details: The third update of data on a cohort of 1,136 childhood Hodgkin lymphoma survivors followed for a median of 26.6 years.
Disclosures: No specific funding source for the study was reported. The authors made no financial disclosures.
Source: Holmqvist AS et al. Cancer. 2018 Dec 17. doi: 10.1002/cncr.31807.
Adjuvant modified FOLFIRINOX improves survival of pancreatic cancer
For patients with completely or near-completely resected pancreatic ductal adenocarcinoma, adjuvant therapy with a modified FOLFIRINOX regimen was associated with significantly better 3-year disease-free survival and overall survival compared with gemcitabine, results of the phase 3 randomized PRODIGE 24 trial showed.
At a median follow-up of 33.6 months, median disease-free survival was 21.6 months for 247 patients assigned to receive adjuvant modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), compared with 12.8 months for 246 patients randomized to receive gemcitabine.
The median overall survival was 54.4 months for patients treated with FOLFIRINOX, vs. 35 months for patients treated with gemcitabine, a difference that translated into a hazard ratio (HR) of 0.65 (P = .003) for the combination regimen, reported Thierry Conroy, MD, of Institut de Cancérologie de Lorraine in Vandoeuvre-lès-Nancy, France, and colleagues in the Canadian Cancer Trials Group and Unicancer-GI-PRODIGE Group.
“The disease-free survival benefit with modified FOLFIRINOX was significant in the majority of subgroups, including subgroups of patients with adverse prognostic factors (i.e., T3 or T4 tumor status, positive lymph nodes, or R1 resection),” they wrote. The report is in The New England Journal of Medicine.
The survival advantage with FOLFIRINOX came at the cost of more frequent adverse events, however, although the only treatment-related death occurred in a patient treated with gemcitabine.
A previous randomized trial by the PRODIGE group showed a survival advantage of FOLFIRINOX over gemcitabine in patients with metastatic pancreatic cancer, prompting the investigators to look at the same two regimens as adjuvant therapy for patients with pancreatic cancer following R0 (clear surgical margins) or RI (minimal residual disease) resections. In the current trial, FOLFIRINOX was modified by the elimination of a bolus dose of fluorouracil to decrease hematologic toxicities and diarrhea without compromising efficacy.
In the intention-to-treat analysis, 493 patients were randomly assigned to receive either modified FOLFIRINOX, consisting of oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, which was reduced to 150 mg/m2 after a protocol-specified safety analysis, leucovorin 400 mg/m2, and fluorouracil 2,400 mg/m2 every 2 weeks, or gemcitabine 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks for 24 weeks.
The disease-free survival primary endpoint and overall survival secondary endpoints were as reported before.
The 3-year overall survival rates were 63.4% with modified FOLFIRINOX, compared with 48.6% with gemcitabine.
Additional secondary endpoints also favored FOLFIRINOX, including metastasis-free survival at a median 30.4 month vs. 17.7 months, respectively, translating into a stratified HR of 0.59 (P less than .001). The 3-year metastasis-free survival rates were 48.2% vs. 30.9% for gemcitabine.
The median cancer-specific survival was not reached in the combination therapy group compared with 36.4 months with gemcitabine monotherapy, a difference that translated into a stratified HR for death from the treated cancer or treatment-related complications of 0.63 (P = .003).
The safety analysis included data on 238 patients treated with FOLFIRINOX and 241 with gemcitabine.
Grade 3 or 4 adverse events occurred in 75.9% of patients treated with modified FOLFIRINOX and 52.9% of patients treated with gemcitabine. The single treatment-related death was from interstitial pneumonitis in a patient treated with gemcitabine.
Grade 3 or 4 diarrhea, increase in the gamma-glutamyltransferase level, paresthesia, fatigue, sensory peripheral neuropathy, nausea, vomiting, abdominal pain, and mucositis were all significantly more frequent with modified FOLFIRINOX.
Slightly more than half (56.8%) of patients in the FOLFIRINOX arm received granulocyte-colony stimulating factor support as either primary prophylaxis or therapy for uncomplicated neutropenia, with no delays in treatment.
The investigators acknowledged that although “disease-free survival is not validated as a surrogate endpoint for overall survival in trials of adjuvant therapy for pancreatic cancer, this criterion was robust and correlated with overall survival.”
The study was supported by R&D Unicancer, which received a grant from Chugai Pharmaceutical the French Ministry of Health and the Institut National du Cancer, and by the French National League against Cancer. The Canadian Cancer Trials Group Pancreatic Adenocarcinoma part of the trial was supported by a Program Grant from the Canadian Cancer Society and by grants from 7 Days in May. Dr. Conroy disclosed receiving travel grants form Roche.
SOURCE: Conroy T et al. N Engl J Med. 2018 Dec 19;379:2395-406.
Is surgery followed by 6 months of adjuvant chemotherapy the appropriate sequence in patients with a disease that may be systemic at diagnosis? Can we further improve outcomes by delivering modified FOLFIRINOX before surgery? The administration of preoperative chemotherapy has several theoretical advantages, including maximizing the potential for an R0 resection by downstaging tumor; treating micrometastatic disease early, thus selecting patients whose disease responds to therapy, while sparing from surgery those whose disease will inevitably progress; and administering chemotherapy when patients are more likely to have fewer or less serious side effects. Retrospective data suggest that neoadjuvant treatment may lead to results that are superior to those with a surgery-first approach, and prospective, randomized trials ought to evaluate this further.
Is there a role for radiation therapy in this context? Will it decrease the incidence of local recurrence among patients with a positive surgical margin who have systemic control with modified FOLFIRINOX therapy? Can preoperative radiotherapy increase the likelihood of an R0 resection? These, too, are questions for future randomized trials.
This trial represents the culmination of more than a decade of careful work that initially established FOLFIRINOX as a standard treatment for advanced pancreatic cancer. The remarkable results that have been achieved with adjuvant modified FOLFIRINOX therapy in the PRODIGE 24 trial have now changed the standard of care for many patients with resectable tumors. However, the majority of patients with pancreatic cancer present with far more advanced disease. For them, this remains a recalcitrant cancer.
Hedy L. Kindler, MD, is with the Section of Hematology/Oncology at the University of Chicago. Her remarks are adapted and condensed from an editorial accompanying the study. She disclosed consulting/advisory board activities for 14 companies, and institutional research funding from six companies.
Is surgery followed by 6 months of adjuvant chemotherapy the appropriate sequence in patients with a disease that may be systemic at diagnosis? Can we further improve outcomes by delivering modified FOLFIRINOX before surgery? The administration of preoperative chemotherapy has several theoretical advantages, including maximizing the potential for an R0 resection by downstaging tumor; treating micrometastatic disease early, thus selecting patients whose disease responds to therapy, while sparing from surgery those whose disease will inevitably progress; and administering chemotherapy when patients are more likely to have fewer or less serious side effects. Retrospective data suggest that neoadjuvant treatment may lead to results that are superior to those with a surgery-first approach, and prospective, randomized trials ought to evaluate this further.
Is there a role for radiation therapy in this context? Will it decrease the incidence of local recurrence among patients with a positive surgical margin who have systemic control with modified FOLFIRINOX therapy? Can preoperative radiotherapy increase the likelihood of an R0 resection? These, too, are questions for future randomized trials.
This trial represents the culmination of more than a decade of careful work that initially established FOLFIRINOX as a standard treatment for advanced pancreatic cancer. The remarkable results that have been achieved with adjuvant modified FOLFIRINOX therapy in the PRODIGE 24 trial have now changed the standard of care for many patients with resectable tumors. However, the majority of patients with pancreatic cancer present with far more advanced disease. For them, this remains a recalcitrant cancer.
Hedy L. Kindler, MD, is with the Section of Hematology/Oncology at the University of Chicago. Her remarks are adapted and condensed from an editorial accompanying the study. She disclosed consulting/advisory board activities for 14 companies, and institutional research funding from six companies.
Is surgery followed by 6 months of adjuvant chemotherapy the appropriate sequence in patients with a disease that may be systemic at diagnosis? Can we further improve outcomes by delivering modified FOLFIRINOX before surgery? The administration of preoperative chemotherapy has several theoretical advantages, including maximizing the potential for an R0 resection by downstaging tumor; treating micrometastatic disease early, thus selecting patients whose disease responds to therapy, while sparing from surgery those whose disease will inevitably progress; and administering chemotherapy when patients are more likely to have fewer or less serious side effects. Retrospective data suggest that neoadjuvant treatment may lead to results that are superior to those with a surgery-first approach, and prospective, randomized trials ought to evaluate this further.
Is there a role for radiation therapy in this context? Will it decrease the incidence of local recurrence among patients with a positive surgical margin who have systemic control with modified FOLFIRINOX therapy? Can preoperative radiotherapy increase the likelihood of an R0 resection? These, too, are questions for future randomized trials.
This trial represents the culmination of more than a decade of careful work that initially established FOLFIRINOX as a standard treatment for advanced pancreatic cancer. The remarkable results that have been achieved with adjuvant modified FOLFIRINOX therapy in the PRODIGE 24 trial have now changed the standard of care for many patients with resectable tumors. However, the majority of patients with pancreatic cancer present with far more advanced disease. For them, this remains a recalcitrant cancer.
Hedy L. Kindler, MD, is with the Section of Hematology/Oncology at the University of Chicago. Her remarks are adapted and condensed from an editorial accompanying the study. She disclosed consulting/advisory board activities for 14 companies, and institutional research funding from six companies.
For patients with completely or near-completely resected pancreatic ductal adenocarcinoma, adjuvant therapy with a modified FOLFIRINOX regimen was associated with significantly better 3-year disease-free survival and overall survival compared with gemcitabine, results of the phase 3 randomized PRODIGE 24 trial showed.
At a median follow-up of 33.6 months, median disease-free survival was 21.6 months for 247 patients assigned to receive adjuvant modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), compared with 12.8 months for 246 patients randomized to receive gemcitabine.
The median overall survival was 54.4 months for patients treated with FOLFIRINOX, vs. 35 months for patients treated with gemcitabine, a difference that translated into a hazard ratio (HR) of 0.65 (P = .003) for the combination regimen, reported Thierry Conroy, MD, of Institut de Cancérologie de Lorraine in Vandoeuvre-lès-Nancy, France, and colleagues in the Canadian Cancer Trials Group and Unicancer-GI-PRODIGE Group.
“The disease-free survival benefit with modified FOLFIRINOX was significant in the majority of subgroups, including subgroups of patients with adverse prognostic factors (i.e., T3 or T4 tumor status, positive lymph nodes, or R1 resection),” they wrote. The report is in The New England Journal of Medicine.
The survival advantage with FOLFIRINOX came at the cost of more frequent adverse events, however, although the only treatment-related death occurred in a patient treated with gemcitabine.
A previous randomized trial by the PRODIGE group showed a survival advantage of FOLFIRINOX over gemcitabine in patients with metastatic pancreatic cancer, prompting the investigators to look at the same two regimens as adjuvant therapy for patients with pancreatic cancer following R0 (clear surgical margins) or RI (minimal residual disease) resections. In the current trial, FOLFIRINOX was modified by the elimination of a bolus dose of fluorouracil to decrease hematologic toxicities and diarrhea without compromising efficacy.
In the intention-to-treat analysis, 493 patients were randomly assigned to receive either modified FOLFIRINOX, consisting of oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, which was reduced to 150 mg/m2 after a protocol-specified safety analysis, leucovorin 400 mg/m2, and fluorouracil 2,400 mg/m2 every 2 weeks, or gemcitabine 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks for 24 weeks.
The disease-free survival primary endpoint and overall survival secondary endpoints were as reported before.
The 3-year overall survival rates were 63.4% with modified FOLFIRINOX, compared with 48.6% with gemcitabine.
Additional secondary endpoints also favored FOLFIRINOX, including metastasis-free survival at a median 30.4 month vs. 17.7 months, respectively, translating into a stratified HR of 0.59 (P less than .001). The 3-year metastasis-free survival rates were 48.2% vs. 30.9% for gemcitabine.
The median cancer-specific survival was not reached in the combination therapy group compared with 36.4 months with gemcitabine monotherapy, a difference that translated into a stratified HR for death from the treated cancer or treatment-related complications of 0.63 (P = .003).
The safety analysis included data on 238 patients treated with FOLFIRINOX and 241 with gemcitabine.
Grade 3 or 4 adverse events occurred in 75.9% of patients treated with modified FOLFIRINOX and 52.9% of patients treated with gemcitabine. The single treatment-related death was from interstitial pneumonitis in a patient treated with gemcitabine.
Grade 3 or 4 diarrhea, increase in the gamma-glutamyltransferase level, paresthesia, fatigue, sensory peripheral neuropathy, nausea, vomiting, abdominal pain, and mucositis were all significantly more frequent with modified FOLFIRINOX.
Slightly more than half (56.8%) of patients in the FOLFIRINOX arm received granulocyte-colony stimulating factor support as either primary prophylaxis or therapy for uncomplicated neutropenia, with no delays in treatment.
The investigators acknowledged that although “disease-free survival is not validated as a surrogate endpoint for overall survival in trials of adjuvant therapy for pancreatic cancer, this criterion was robust and correlated with overall survival.”
The study was supported by R&D Unicancer, which received a grant from Chugai Pharmaceutical the French Ministry of Health and the Institut National du Cancer, and by the French National League against Cancer. The Canadian Cancer Trials Group Pancreatic Adenocarcinoma part of the trial was supported by a Program Grant from the Canadian Cancer Society and by grants from 7 Days in May. Dr. Conroy disclosed receiving travel grants form Roche.
SOURCE: Conroy T et al. N Engl J Med. 2018 Dec 19;379:2395-406.
For patients with completely or near-completely resected pancreatic ductal adenocarcinoma, adjuvant therapy with a modified FOLFIRINOX regimen was associated with significantly better 3-year disease-free survival and overall survival compared with gemcitabine, results of the phase 3 randomized PRODIGE 24 trial showed.
At a median follow-up of 33.6 months, median disease-free survival was 21.6 months for 247 patients assigned to receive adjuvant modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), compared with 12.8 months for 246 patients randomized to receive gemcitabine.
The median overall survival was 54.4 months for patients treated with FOLFIRINOX, vs. 35 months for patients treated with gemcitabine, a difference that translated into a hazard ratio (HR) of 0.65 (P = .003) for the combination regimen, reported Thierry Conroy, MD, of Institut de Cancérologie de Lorraine in Vandoeuvre-lès-Nancy, France, and colleagues in the Canadian Cancer Trials Group and Unicancer-GI-PRODIGE Group.
“The disease-free survival benefit with modified FOLFIRINOX was significant in the majority of subgroups, including subgroups of patients with adverse prognostic factors (i.e., T3 or T4 tumor status, positive lymph nodes, or R1 resection),” they wrote. The report is in The New England Journal of Medicine.
The survival advantage with FOLFIRINOX came at the cost of more frequent adverse events, however, although the only treatment-related death occurred in a patient treated with gemcitabine.
A previous randomized trial by the PRODIGE group showed a survival advantage of FOLFIRINOX over gemcitabine in patients with metastatic pancreatic cancer, prompting the investigators to look at the same two regimens as adjuvant therapy for patients with pancreatic cancer following R0 (clear surgical margins) or RI (minimal residual disease) resections. In the current trial, FOLFIRINOX was modified by the elimination of a bolus dose of fluorouracil to decrease hematologic toxicities and diarrhea without compromising efficacy.
In the intention-to-treat analysis, 493 patients were randomly assigned to receive either modified FOLFIRINOX, consisting of oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, which was reduced to 150 mg/m2 after a protocol-specified safety analysis, leucovorin 400 mg/m2, and fluorouracil 2,400 mg/m2 every 2 weeks, or gemcitabine 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks for 24 weeks.
The disease-free survival primary endpoint and overall survival secondary endpoints were as reported before.
The 3-year overall survival rates were 63.4% with modified FOLFIRINOX, compared with 48.6% with gemcitabine.
Additional secondary endpoints also favored FOLFIRINOX, including metastasis-free survival at a median 30.4 month vs. 17.7 months, respectively, translating into a stratified HR of 0.59 (P less than .001). The 3-year metastasis-free survival rates were 48.2% vs. 30.9% for gemcitabine.
The median cancer-specific survival was not reached in the combination therapy group compared with 36.4 months with gemcitabine monotherapy, a difference that translated into a stratified HR for death from the treated cancer or treatment-related complications of 0.63 (P = .003).
The safety analysis included data on 238 patients treated with FOLFIRINOX and 241 with gemcitabine.
Grade 3 or 4 adverse events occurred in 75.9% of patients treated with modified FOLFIRINOX and 52.9% of patients treated with gemcitabine. The single treatment-related death was from interstitial pneumonitis in a patient treated with gemcitabine.
Grade 3 or 4 diarrhea, increase in the gamma-glutamyltransferase level, paresthesia, fatigue, sensory peripheral neuropathy, nausea, vomiting, abdominal pain, and mucositis were all significantly more frequent with modified FOLFIRINOX.
Slightly more than half (56.8%) of patients in the FOLFIRINOX arm received granulocyte-colony stimulating factor support as either primary prophylaxis or therapy for uncomplicated neutropenia, with no delays in treatment.
The investigators acknowledged that although “disease-free survival is not validated as a surrogate endpoint for overall survival in trials of adjuvant therapy for pancreatic cancer, this criterion was robust and correlated with overall survival.”
The study was supported by R&D Unicancer, which received a grant from Chugai Pharmaceutical the French Ministry of Health and the Institut National du Cancer, and by the French National League against Cancer. The Canadian Cancer Trials Group Pancreatic Adenocarcinoma part of the trial was supported by a Program Grant from the Canadian Cancer Society and by grants from 7 Days in May. Dr. Conroy disclosed receiving travel grants form Roche.
SOURCE: Conroy T et al. N Engl J Med. 2018 Dec 19;379:2395-406.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Modified FOLFIRINOX resulted in significantly better disease-free and overall survival compared with gemcitabine as adjuvant therapy following complete/near complete resection of pancreatic ductal adenocarcinoma.
Major finding: Median disease-free survival was 21.6 months with modified FOLFIRINOX vs. 12.8 months with gemcitabine.
Study details: Randomized phase 3 trial of 493 patients with resected pancreatic cancer.
Disclosures: The study was supported by R&D Unicancer, which received a grant from Chugai Pharmaceutical the French Ministry of Health and the Institut National du Cancer, and by the French National League against Cancer. The Canadian Cancer Trials Group Pancreatic Adenocarcinoma part of the trial was supported by a Program Grant from the Canadian Cancer Society and by grants from 7 Days in May. Dr. Conroy disclosed receiving travel grants form Roche.
Source: Conroy T et al. N Engl J Med. 2018 Dec 19 379:2395-406.
Sorafenib extends PFS for refractory desmoid tumors
For patients with progressive, refractory, or symptomatic desmoid tumors – also known as aggressive fibromatosis – treatment with daily sorafenib (Nexavar) was associated with durable responses and a significant improvement in progression-free survival.
After a median follow-up of 27.2 months, the 2-year progression-free survival (PFS) rate for patients randomly assigned to receive 400 mg sorafenib daily was 81%, compared with 36% for patients assigned to placebo (P less than .001), reported Mrinal M. Gounder, MD, from Memorial Sloan Kettering Cancer Center in New York City, and his colleagues.
“Other agents that are used to treat these tumors include anthracyclines [e.g., pegylated liposomal doxorubicin], vinca alkaloids, and pazopanib. On the basis of the predictable toxic-effects profile and substantial progression-free survival advantage conferred by sorafenib, the drug has antitumor activity as first-line therapy or as subsequent therapy for desmoid tumors,” they wrote in the New England Journal of Medicine.
There is no accepted standard of care for the systemic treatment for desmoid tumors, with options ranging from hormonal blockade, cytotoxic chemotherapy, and targeted agents such as tyrosine kinase inhibitors (TKIs).
Based on a retrospective study showing that the multitargeting oral TKI sorafenib was associated with a 25% response rate and acceptable safety in patients with desmoid tumors, the investigators initiated a phase 3, randomized trial to evaluate the efficacy and safety of sorafenib in this population.
They enrolled 87 patients aged 18 years or older with a histologically documented desmoid tumor that showed clinical and radiographic progression of at least 10% in maximum unidimensional measurement within the last 6 months, symptomatic disease, or recurrent or primary disease that was either inoperable or deemed to require extensive surgery.
The patients were randomized in double-blinded fashion on a 2:1 basis to receive either sorafenib 400 mg daily or placebo until progression. Crossover to sorafenib was allowed for patients assigned to placebo who experienced disease progressions.
As noted before, investigator-assessed PFS, the primary endpoint, clearly favored sorafenib.
Objective response rates before crossover were 33% in the sorafenib arm, consisting of 1 complete and 15 partial responses, and 20% in the placebo arm, consisting of 7 partial responses. The respective median times to objective response were 9.6 months versus 13.3 months. The earliest response, defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, occurred at 2.2 months in the sorafenib arm versus 8.8 months in the placebo arm.
The authors also performed an exploratory analysis looking at MRI as a measure of response evaluation and found that “changes in T2-weighted signal intensity and volumetric measurements may be better measures of treatment effect than RECIST. This is particularly evident when the best response according to RECIST is stable disease.”
The most frequently reported adverse events among patients treated with sorafenib were grade 1 or 2 rash in 73%, fatigue in 67%, hypertension in 55%, and diarrhea in 51%. The most frequent treatment-emergent adverse events in the placebo group were rash of any kind in 42% and palmar-plantar erythrodysesthesia syndrome in 22%.
The investigators acknowledged that the mechanism of action of sorafenib in desmoid tumors is unknown, but noted that they are looking for clues in 25 sets of paired biopsy samples.
The study was supported by grants from the National Cancer Institute, Bayer, Memorial Sloan Kettering Cancer Center, the American Society of Clinical Oncology, Desmoid Tumor Research Foundation, and an Orphan Products Clinical Trials Grant from the Food and Drug Administration. Dr. Gounder reported fees for advisory board activities/consulting for Bayer, Epizyme, Karyopharm Therapeutics, Daiichi Sankyo, TRACON Pharmaceuticals, and Amgen, and travel expenses from Epizyme.
SOURCE: Gounder MM et al. N Engl J Med. 2018 Dec 19. doi: 10.1056/NEJMoa1805052.
For patients with progressive, refractory, or symptomatic desmoid tumors – also known as aggressive fibromatosis – treatment with daily sorafenib (Nexavar) was associated with durable responses and a significant improvement in progression-free survival.
After a median follow-up of 27.2 months, the 2-year progression-free survival (PFS) rate for patients randomly assigned to receive 400 mg sorafenib daily was 81%, compared with 36% for patients assigned to placebo (P less than .001), reported Mrinal M. Gounder, MD, from Memorial Sloan Kettering Cancer Center in New York City, and his colleagues.
“Other agents that are used to treat these tumors include anthracyclines [e.g., pegylated liposomal doxorubicin], vinca alkaloids, and pazopanib. On the basis of the predictable toxic-effects profile and substantial progression-free survival advantage conferred by sorafenib, the drug has antitumor activity as first-line therapy or as subsequent therapy for desmoid tumors,” they wrote in the New England Journal of Medicine.
There is no accepted standard of care for the systemic treatment for desmoid tumors, with options ranging from hormonal blockade, cytotoxic chemotherapy, and targeted agents such as tyrosine kinase inhibitors (TKIs).
Based on a retrospective study showing that the multitargeting oral TKI sorafenib was associated with a 25% response rate and acceptable safety in patients with desmoid tumors, the investigators initiated a phase 3, randomized trial to evaluate the efficacy and safety of sorafenib in this population.
They enrolled 87 patients aged 18 years or older with a histologically documented desmoid tumor that showed clinical and radiographic progression of at least 10% in maximum unidimensional measurement within the last 6 months, symptomatic disease, or recurrent or primary disease that was either inoperable or deemed to require extensive surgery.
The patients were randomized in double-blinded fashion on a 2:1 basis to receive either sorafenib 400 mg daily or placebo until progression. Crossover to sorafenib was allowed for patients assigned to placebo who experienced disease progressions.
As noted before, investigator-assessed PFS, the primary endpoint, clearly favored sorafenib.
Objective response rates before crossover were 33% in the sorafenib arm, consisting of 1 complete and 15 partial responses, and 20% in the placebo arm, consisting of 7 partial responses. The respective median times to objective response were 9.6 months versus 13.3 months. The earliest response, defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, occurred at 2.2 months in the sorafenib arm versus 8.8 months in the placebo arm.
The authors also performed an exploratory analysis looking at MRI as a measure of response evaluation and found that “changes in T2-weighted signal intensity and volumetric measurements may be better measures of treatment effect than RECIST. This is particularly evident when the best response according to RECIST is stable disease.”
The most frequently reported adverse events among patients treated with sorafenib were grade 1 or 2 rash in 73%, fatigue in 67%, hypertension in 55%, and diarrhea in 51%. The most frequent treatment-emergent adverse events in the placebo group were rash of any kind in 42% and palmar-plantar erythrodysesthesia syndrome in 22%.
The investigators acknowledged that the mechanism of action of sorafenib in desmoid tumors is unknown, but noted that they are looking for clues in 25 sets of paired biopsy samples.
The study was supported by grants from the National Cancer Institute, Bayer, Memorial Sloan Kettering Cancer Center, the American Society of Clinical Oncology, Desmoid Tumor Research Foundation, and an Orphan Products Clinical Trials Grant from the Food and Drug Administration. Dr. Gounder reported fees for advisory board activities/consulting for Bayer, Epizyme, Karyopharm Therapeutics, Daiichi Sankyo, TRACON Pharmaceuticals, and Amgen, and travel expenses from Epizyme.
SOURCE: Gounder MM et al. N Engl J Med. 2018 Dec 19. doi: 10.1056/NEJMoa1805052.
For patients with progressive, refractory, or symptomatic desmoid tumors – also known as aggressive fibromatosis – treatment with daily sorafenib (Nexavar) was associated with durable responses and a significant improvement in progression-free survival.
After a median follow-up of 27.2 months, the 2-year progression-free survival (PFS) rate for patients randomly assigned to receive 400 mg sorafenib daily was 81%, compared with 36% for patients assigned to placebo (P less than .001), reported Mrinal M. Gounder, MD, from Memorial Sloan Kettering Cancer Center in New York City, and his colleagues.
“Other agents that are used to treat these tumors include anthracyclines [e.g., pegylated liposomal doxorubicin], vinca alkaloids, and pazopanib. On the basis of the predictable toxic-effects profile and substantial progression-free survival advantage conferred by sorafenib, the drug has antitumor activity as first-line therapy or as subsequent therapy for desmoid tumors,” they wrote in the New England Journal of Medicine.
There is no accepted standard of care for the systemic treatment for desmoid tumors, with options ranging from hormonal blockade, cytotoxic chemotherapy, and targeted agents such as tyrosine kinase inhibitors (TKIs).
Based on a retrospective study showing that the multitargeting oral TKI sorafenib was associated with a 25% response rate and acceptable safety in patients with desmoid tumors, the investigators initiated a phase 3, randomized trial to evaluate the efficacy and safety of sorafenib in this population.
They enrolled 87 patients aged 18 years or older with a histologically documented desmoid tumor that showed clinical and radiographic progression of at least 10% in maximum unidimensional measurement within the last 6 months, symptomatic disease, or recurrent or primary disease that was either inoperable or deemed to require extensive surgery.
The patients were randomized in double-blinded fashion on a 2:1 basis to receive either sorafenib 400 mg daily or placebo until progression. Crossover to sorafenib was allowed for patients assigned to placebo who experienced disease progressions.
As noted before, investigator-assessed PFS, the primary endpoint, clearly favored sorafenib.
Objective response rates before crossover were 33% in the sorafenib arm, consisting of 1 complete and 15 partial responses, and 20% in the placebo arm, consisting of 7 partial responses. The respective median times to objective response were 9.6 months versus 13.3 months. The earliest response, defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, occurred at 2.2 months in the sorafenib arm versus 8.8 months in the placebo arm.
The authors also performed an exploratory analysis looking at MRI as a measure of response evaluation and found that “changes in T2-weighted signal intensity and volumetric measurements may be better measures of treatment effect than RECIST. This is particularly evident when the best response according to RECIST is stable disease.”
The most frequently reported adverse events among patients treated with sorafenib were grade 1 or 2 rash in 73%, fatigue in 67%, hypertension in 55%, and diarrhea in 51%. The most frequent treatment-emergent adverse events in the placebo group were rash of any kind in 42% and palmar-plantar erythrodysesthesia syndrome in 22%.
The investigators acknowledged that the mechanism of action of sorafenib in desmoid tumors is unknown, but noted that they are looking for clues in 25 sets of paired biopsy samples.
The study was supported by grants from the National Cancer Institute, Bayer, Memorial Sloan Kettering Cancer Center, the American Society of Clinical Oncology, Desmoid Tumor Research Foundation, and an Orphan Products Clinical Trials Grant from the Food and Drug Administration. Dr. Gounder reported fees for advisory board activities/consulting for Bayer, Epizyme, Karyopharm Therapeutics, Daiichi Sankyo, TRACON Pharmaceuticals, and Amgen, and travel expenses from Epizyme.
SOURCE: Gounder MM et al. N Engl J Med. 2018 Dec 19. doi: 10.1056/NEJMoa1805052.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: There is no accepted standard of systemic therapy for recurrent, refractory, or symptomatic desmoid tumors.
Major finding: Median progression-free survival with sorafenib after a median follow-up of 27.2 months was 81% versus 36% for placebo.
Study details: A double-blind, phase 3 trial with 2:1 randomization of sorafenib to placebo in 87 patients.
Disclosures: The study was supported by grants from the National Cancer Institute, Bayer, Memorial Sloan Kettering Cancer Center, the American Society of Clinical Oncology, Desmoid Tumor Research Foundation, and an Orphan Products Clinical Trials Grant from the Food and Drug Administration. Dr. Gounder reported fees for advisory board activities/consulting for Bayer, Epizyme, Karyopharm Therapeutics, Daiichi Sankyo, TRACON Pharmaceuticals, and Amgen, and travel expenses from Epizyme.
Source: Gounder MM et al. N Engl J Med. 2018 Dec 19. doi: 10.1056/NEJMoa1805052.
Frontline veliparib/cisplatin/etoposide shows efficacy in advanced SCLC
For patients with extensive-stage small-cell lung cancer (ES-SCLC), the addition of the poly (ADP ribose) polymerase (PARP) inhibitor veliparib to frontline chemotherapy with cisplatin and etoposide resulted in a slight but significant improvement in progression-free survival but not overall survival, compared with cisplatin/etoposide alone, investigators reported in the Journal of Clinical Oncology.
Among 128 patients with newly diagnosed ES-SCLC, the median progression-free survival (PFS; the primary endpoint) for those randomized to veliparib/cisplatin/etoposide was 6.1 months, compared with 5.5 months for patients randomized to cisplatin/etoposide alone.
This translated into an unstratified hazard ratio for PFS with veliparib of 0.75 (one-sided P = .06) and a stratified HR of 0.63 (one-sided P = .01), reported Taofeek K. Owonikoko, MD, PhD, and his colleagues at Emory University in Atlanta.
“Although the initial result of our study is promising, additional confirmation in a larger definitive study is warranted, given the mixed results reported by other studies of PARP inhibitors in this patient population,” they wrote.
Median overall survival (OS) with cisplatin/etoposide in ES-SCLC is approximately 9-11 months, and fewer than 5% of patients survive out to 5 years. To see whether the addition of a PARP inhibitor to the standard of care could improve outcomes, the investigators first demonstrated in a phase 1 trial that the combination of veliparib with a platinum doublet of cisplatin and etoposide was safe (Lung Cancer. 2015 Jul;89[1]:66-70), and in the current study, they evaluated efficacy.
A total of 128 eligible patients (median age, 66 years; 52% men) with ES-SCLC were included in the analysis. Extensive-stage disease was defined as the presence of extrathoracic metastatic disease, malignant pleural effusion, and bilateral or contralateral supraclavicular adenopathy.
The patients were stratified by sex and serum lactate dehydrogenase (LDH) levels and then randomized to receive a maximum of four 3-week cycles of of cisplatin 75 mg/m2 intravenously on day 1 and etoposide 100 mg/m2 on days 1 through 3, plus either oral veliparib 100 mg twice daily on days 1 through 7 or placebo.
The primary endpoint of PFS was as noted before. Median overall survival was 10.3 months in the veliparib arm versus 8.9 months in the cisplatin/etoposide alone arm, a difference that was not statistically significant. The respective overall response rates were 71.9% vs. 65.6%, but this difference was also not significant.
Looking at the treatment effect by strata, the investigators found that men with high serum LDH levels had a significant PFS benefit with veliparib (HR, 0.34; one-sided P less than .001), but no significant benefit was seen in men with normal LDH or in women regardless of LDH status.
Grade 3 or greater hematologic toxicities that occurred more frequently in the veliparib arm included CD4 lymphopenia in 8% vs. 0% and neutropenia in 49% vs. 32%.
The investigators noted that the discrepancy between the magnitude of the risk reduction as measured by the hazard ratio and the actual, modest difference in median PFS between the study arms may be explained by the fact that men with elevated LDH represented the largest patient strata.
“Therefore, we hypothesize that this cohort probably contained a sufficient proportion of patients with SCLC who harbored some biologic vulnerability to this therapeutic strategy,” they wrote.
They acknowledged that although toxicities were higher with veliparib combination, the ability to deliver chemotherapy was equal between the arms.
Further exploration of the combination of veliparib/cisplatin/etoposide may be justified if results of another ongoing phase 2 study (NCT02289690) of a carboplatin-based chemotherapy doublet plus veliparib has similar efficacy results, Dr. Owonikoko and his associates concluded.
The study was coordinated by the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group and supported by the National Cancer Institute. Dr. Owonikoko disclosed a consulting or advisory role with AbbVie, developer of veliparib, and other companies, as well as institutional research funding from AbbVie and others.
SOURCE: Owonikoko TK et al. J Clin Oncol. 2018 Dec 5. doi: 10.1200/JCO.18.00264.
For patients with extensive-stage small-cell lung cancer (ES-SCLC), the addition of the poly (ADP ribose) polymerase (PARP) inhibitor veliparib to frontline chemotherapy with cisplatin and etoposide resulted in a slight but significant improvement in progression-free survival but not overall survival, compared with cisplatin/etoposide alone, investigators reported in the Journal of Clinical Oncology.
Among 128 patients with newly diagnosed ES-SCLC, the median progression-free survival (PFS; the primary endpoint) for those randomized to veliparib/cisplatin/etoposide was 6.1 months, compared with 5.5 months for patients randomized to cisplatin/etoposide alone.
This translated into an unstratified hazard ratio for PFS with veliparib of 0.75 (one-sided P = .06) and a stratified HR of 0.63 (one-sided P = .01), reported Taofeek K. Owonikoko, MD, PhD, and his colleagues at Emory University in Atlanta.
“Although the initial result of our study is promising, additional confirmation in a larger definitive study is warranted, given the mixed results reported by other studies of PARP inhibitors in this patient population,” they wrote.
Median overall survival (OS) with cisplatin/etoposide in ES-SCLC is approximately 9-11 months, and fewer than 5% of patients survive out to 5 years. To see whether the addition of a PARP inhibitor to the standard of care could improve outcomes, the investigators first demonstrated in a phase 1 trial that the combination of veliparib with a platinum doublet of cisplatin and etoposide was safe (Lung Cancer. 2015 Jul;89[1]:66-70), and in the current study, they evaluated efficacy.
A total of 128 eligible patients (median age, 66 years; 52% men) with ES-SCLC were included in the analysis. Extensive-stage disease was defined as the presence of extrathoracic metastatic disease, malignant pleural effusion, and bilateral or contralateral supraclavicular adenopathy.
The patients were stratified by sex and serum lactate dehydrogenase (LDH) levels and then randomized to receive a maximum of four 3-week cycles of of cisplatin 75 mg/m2 intravenously on day 1 and etoposide 100 mg/m2 on days 1 through 3, plus either oral veliparib 100 mg twice daily on days 1 through 7 or placebo.
The primary endpoint of PFS was as noted before. Median overall survival was 10.3 months in the veliparib arm versus 8.9 months in the cisplatin/etoposide alone arm, a difference that was not statistically significant. The respective overall response rates were 71.9% vs. 65.6%, but this difference was also not significant.
Looking at the treatment effect by strata, the investigators found that men with high serum LDH levels had a significant PFS benefit with veliparib (HR, 0.34; one-sided P less than .001), but no significant benefit was seen in men with normal LDH or in women regardless of LDH status.
Grade 3 or greater hematologic toxicities that occurred more frequently in the veliparib arm included CD4 lymphopenia in 8% vs. 0% and neutropenia in 49% vs. 32%.
The investigators noted that the discrepancy between the magnitude of the risk reduction as measured by the hazard ratio and the actual, modest difference in median PFS between the study arms may be explained by the fact that men with elevated LDH represented the largest patient strata.
“Therefore, we hypothesize that this cohort probably contained a sufficient proportion of patients with SCLC who harbored some biologic vulnerability to this therapeutic strategy,” they wrote.
They acknowledged that although toxicities were higher with veliparib combination, the ability to deliver chemotherapy was equal between the arms.
Further exploration of the combination of veliparib/cisplatin/etoposide may be justified if results of another ongoing phase 2 study (NCT02289690) of a carboplatin-based chemotherapy doublet plus veliparib has similar efficacy results, Dr. Owonikoko and his associates concluded.
The study was coordinated by the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group and supported by the National Cancer Institute. Dr. Owonikoko disclosed a consulting or advisory role with AbbVie, developer of veliparib, and other companies, as well as institutional research funding from AbbVie and others.
SOURCE: Owonikoko TK et al. J Clin Oncol. 2018 Dec 5. doi: 10.1200/JCO.18.00264.
For patients with extensive-stage small-cell lung cancer (ES-SCLC), the addition of the poly (ADP ribose) polymerase (PARP) inhibitor veliparib to frontline chemotherapy with cisplatin and etoposide resulted in a slight but significant improvement in progression-free survival but not overall survival, compared with cisplatin/etoposide alone, investigators reported in the Journal of Clinical Oncology.
Among 128 patients with newly diagnosed ES-SCLC, the median progression-free survival (PFS; the primary endpoint) for those randomized to veliparib/cisplatin/etoposide was 6.1 months, compared with 5.5 months for patients randomized to cisplatin/etoposide alone.
This translated into an unstratified hazard ratio for PFS with veliparib of 0.75 (one-sided P = .06) and a stratified HR of 0.63 (one-sided P = .01), reported Taofeek K. Owonikoko, MD, PhD, and his colleagues at Emory University in Atlanta.
“Although the initial result of our study is promising, additional confirmation in a larger definitive study is warranted, given the mixed results reported by other studies of PARP inhibitors in this patient population,” they wrote.
Median overall survival (OS) with cisplatin/etoposide in ES-SCLC is approximately 9-11 months, and fewer than 5% of patients survive out to 5 years. To see whether the addition of a PARP inhibitor to the standard of care could improve outcomes, the investigators first demonstrated in a phase 1 trial that the combination of veliparib with a platinum doublet of cisplatin and etoposide was safe (Lung Cancer. 2015 Jul;89[1]:66-70), and in the current study, they evaluated efficacy.
A total of 128 eligible patients (median age, 66 years; 52% men) with ES-SCLC were included in the analysis. Extensive-stage disease was defined as the presence of extrathoracic metastatic disease, malignant pleural effusion, and bilateral or contralateral supraclavicular adenopathy.
The patients were stratified by sex and serum lactate dehydrogenase (LDH) levels and then randomized to receive a maximum of four 3-week cycles of of cisplatin 75 mg/m2 intravenously on day 1 and etoposide 100 mg/m2 on days 1 through 3, plus either oral veliparib 100 mg twice daily on days 1 through 7 or placebo.
The primary endpoint of PFS was as noted before. Median overall survival was 10.3 months in the veliparib arm versus 8.9 months in the cisplatin/etoposide alone arm, a difference that was not statistically significant. The respective overall response rates were 71.9% vs. 65.6%, but this difference was also not significant.
Looking at the treatment effect by strata, the investigators found that men with high serum LDH levels had a significant PFS benefit with veliparib (HR, 0.34; one-sided P less than .001), but no significant benefit was seen in men with normal LDH or in women regardless of LDH status.
Grade 3 or greater hematologic toxicities that occurred more frequently in the veliparib arm included CD4 lymphopenia in 8% vs. 0% and neutropenia in 49% vs. 32%.
The investigators noted that the discrepancy between the magnitude of the risk reduction as measured by the hazard ratio and the actual, modest difference in median PFS between the study arms may be explained by the fact that men with elevated LDH represented the largest patient strata.
“Therefore, we hypothesize that this cohort probably contained a sufficient proportion of patients with SCLC who harbored some biologic vulnerability to this therapeutic strategy,” they wrote.
They acknowledged that although toxicities were higher with veliparib combination, the ability to deliver chemotherapy was equal between the arms.
Further exploration of the combination of veliparib/cisplatin/etoposide may be justified if results of another ongoing phase 2 study (NCT02289690) of a carboplatin-based chemotherapy doublet plus veliparib has similar efficacy results, Dr. Owonikoko and his associates concluded.
The study was coordinated by the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group and supported by the National Cancer Institute. Dr. Owonikoko disclosed a consulting or advisory role with AbbVie, developer of veliparib, and other companies, as well as institutional research funding from AbbVie and others.
SOURCE: Owonikoko TK et al. J Clin Oncol. 2018 Dec 5. doi: 10.1200/JCO.18.00264.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Adding a PARP inhibitor to standard chemotherapy may improve progression-free survival in patients with extensive-stage small-cell lung cancer (ES-SCLC).
Major finding: The stratified hazard ratio for PFS with veliparib/cisplatin/etoposide was 0.63 (one-sided P = .01).
Study details: Randomized phase 2 trial in 128 patients with newly diagnosed ES-SCLC.
Disclosures: The study was coordinated by the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group and supported by the National Cancer Institute. Dr. Owonikoko disclosed a consulting or advisory role with AbbVie, the developer of veliparib, and other companies, as well as institutional research funding from AbbVie and others.
Source: Owonikoko TK et al. J Clin Oncol. 2018 Dec 5. doi: 10.1200/JCO.18.00264.
Low BMP-10 levels correlate with poor ovarian cancer survival
Loss of expression of bone morphogenetic protein-10 (BMP-10) in ovarian cancer cells appears to be a marker for poor prognosis, investigators claim.
Low expression of BMP-10 in ovarian cancer tissues and cell lines significantly correlated with higher-stage disease, high-risk features, and poor prognosis. Conversely, over-expression of BMP-10 was significantly associated with inhibition of ovarian cancer cell proliferation, migration, and invasion, reported Yufeng Jin, PhD, and colleagues from Nantong (China) University.
“Loss of BMP-10 expression might represent a poor prognosis in ovarian cancer patients. Meanwhile, loss of BMP-10 could promote malignant behaviors in ovarian cell lines, suggesting it might be a promising tumor suppressor,” they wrote in Pathology – Research and Practice.
Other members of the BMP family of cytokines and metabolites have recently been implicated in development of esophageal squamous cell cancer, breast cancer, and colorectal cancer, and BMP-10 has been linked to ovarian tumor progression, the investigators noted.
To get a better sense of BMP-10’s potential role as an ovarian cancer suppressor, the investigators first examined eight paired samples of ovarian cancers and adjacent normal tissues, and observed that in most pairs expression of the protein was significantly lower in the cancerous tissues (P less than .01).
Next, they looked at BMP-10 expression in ovarian tissues with varying histological grades; they found that it was overexpressed in normal tissues, but underexpressed in ovarian cancer tissues, especially those from patients with advanced grade disease.
The investigators then looked at the association between BMP-10 expression and clinicopathologic features, using a cutoff of 30% as a mean value for BMP-10 expression in tissues. They found the expression of the protein trended toward correlation with FIGO (International Federation of Gynecology and Obstetrics) stage (P = .08) and correlated significantly with histologic grade (P = .018), lymph node metastasis (P = .004), and peritoneal fluid (P = .032). There were no significant correlations with patient age, histologic subtype, residual tumor size or tumor cells in peritoneal fluid, however.
The authors also found that patients whose tissues had low levels of BMP-10 expression had significantly shorter overall survival (P less than .01), and in multivariate analysis, they saw that expression of the protein was an independent prognostic factor (hazard ratio, 4.834; P = .002).
Turning to in vitro studies, they observed that overexpression of the protein inhibited proliferation of an ovarian cancer cell line (Ovca3), while introduction of an antibody that neutralized BMP-10 allowed proliferation to occur unimpeded.
Finally, they showed that BMP-10 overexpression impaired the wound-healing and invasive properties of Ovca3 cells, while knockdown of the protein’s expression promoted migration and invasion of a different ovarian carcinoma cell line (Skov3).
The investigators acknowledged that their study was limited by small sample sizes, and they noted that they did not investigate potential mechanisms for BMP-10’s effect on ovarian cells.
Nonetheless, they concluded that “BMP-10 should be considered as a promising prognostic marker and a crucial regulator for progression of ovarian cancer.”
The study was supported by the Nantong Health and Family Planning Commission. All authors declared having no conflicts of interest.
SOURCE: Jin Y et al. Pathol Res Pract. 2019 Oct 28. doi: 10.1016/j.prp.2018.10.025.
Loss of expression of bone morphogenetic protein-10 (BMP-10) in ovarian cancer cells appears to be a marker for poor prognosis, investigators claim.
Low expression of BMP-10 in ovarian cancer tissues and cell lines significantly correlated with higher-stage disease, high-risk features, and poor prognosis. Conversely, over-expression of BMP-10 was significantly associated with inhibition of ovarian cancer cell proliferation, migration, and invasion, reported Yufeng Jin, PhD, and colleagues from Nantong (China) University.
“Loss of BMP-10 expression might represent a poor prognosis in ovarian cancer patients. Meanwhile, loss of BMP-10 could promote malignant behaviors in ovarian cell lines, suggesting it might be a promising tumor suppressor,” they wrote in Pathology – Research and Practice.
Other members of the BMP family of cytokines and metabolites have recently been implicated in development of esophageal squamous cell cancer, breast cancer, and colorectal cancer, and BMP-10 has been linked to ovarian tumor progression, the investigators noted.
To get a better sense of BMP-10’s potential role as an ovarian cancer suppressor, the investigators first examined eight paired samples of ovarian cancers and adjacent normal tissues, and observed that in most pairs expression of the protein was significantly lower in the cancerous tissues (P less than .01).
Next, they looked at BMP-10 expression in ovarian tissues with varying histological grades; they found that it was overexpressed in normal tissues, but underexpressed in ovarian cancer tissues, especially those from patients with advanced grade disease.
The investigators then looked at the association between BMP-10 expression and clinicopathologic features, using a cutoff of 30% as a mean value for BMP-10 expression in tissues. They found the expression of the protein trended toward correlation with FIGO (International Federation of Gynecology and Obstetrics) stage (P = .08) and correlated significantly with histologic grade (P = .018), lymph node metastasis (P = .004), and peritoneal fluid (P = .032). There were no significant correlations with patient age, histologic subtype, residual tumor size or tumor cells in peritoneal fluid, however.
The authors also found that patients whose tissues had low levels of BMP-10 expression had significantly shorter overall survival (P less than .01), and in multivariate analysis, they saw that expression of the protein was an independent prognostic factor (hazard ratio, 4.834; P = .002).
Turning to in vitro studies, they observed that overexpression of the protein inhibited proliferation of an ovarian cancer cell line (Ovca3), while introduction of an antibody that neutralized BMP-10 allowed proliferation to occur unimpeded.
Finally, they showed that BMP-10 overexpression impaired the wound-healing and invasive properties of Ovca3 cells, while knockdown of the protein’s expression promoted migration and invasion of a different ovarian carcinoma cell line (Skov3).
The investigators acknowledged that their study was limited by small sample sizes, and they noted that they did not investigate potential mechanisms for BMP-10’s effect on ovarian cells.
Nonetheless, they concluded that “BMP-10 should be considered as a promising prognostic marker and a crucial regulator for progression of ovarian cancer.”
The study was supported by the Nantong Health and Family Planning Commission. All authors declared having no conflicts of interest.
SOURCE: Jin Y et al. Pathol Res Pract. 2019 Oct 28. doi: 10.1016/j.prp.2018.10.025.
Loss of expression of bone morphogenetic protein-10 (BMP-10) in ovarian cancer cells appears to be a marker for poor prognosis, investigators claim.
Low expression of BMP-10 in ovarian cancer tissues and cell lines significantly correlated with higher-stage disease, high-risk features, and poor prognosis. Conversely, over-expression of BMP-10 was significantly associated with inhibition of ovarian cancer cell proliferation, migration, and invasion, reported Yufeng Jin, PhD, and colleagues from Nantong (China) University.
“Loss of BMP-10 expression might represent a poor prognosis in ovarian cancer patients. Meanwhile, loss of BMP-10 could promote malignant behaviors in ovarian cell lines, suggesting it might be a promising tumor suppressor,” they wrote in Pathology – Research and Practice.
Other members of the BMP family of cytokines and metabolites have recently been implicated in development of esophageal squamous cell cancer, breast cancer, and colorectal cancer, and BMP-10 has been linked to ovarian tumor progression, the investigators noted.
To get a better sense of BMP-10’s potential role as an ovarian cancer suppressor, the investigators first examined eight paired samples of ovarian cancers and adjacent normal tissues, and observed that in most pairs expression of the protein was significantly lower in the cancerous tissues (P less than .01).
Next, they looked at BMP-10 expression in ovarian tissues with varying histological grades; they found that it was overexpressed in normal tissues, but underexpressed in ovarian cancer tissues, especially those from patients with advanced grade disease.
The investigators then looked at the association between BMP-10 expression and clinicopathologic features, using a cutoff of 30% as a mean value for BMP-10 expression in tissues. They found the expression of the protein trended toward correlation with FIGO (International Federation of Gynecology and Obstetrics) stage (P = .08) and correlated significantly with histologic grade (P = .018), lymph node metastasis (P = .004), and peritoneal fluid (P = .032). There were no significant correlations with patient age, histologic subtype, residual tumor size or tumor cells in peritoneal fluid, however.
The authors also found that patients whose tissues had low levels of BMP-10 expression had significantly shorter overall survival (P less than .01), and in multivariate analysis, they saw that expression of the protein was an independent prognostic factor (hazard ratio, 4.834; P = .002).
Turning to in vitro studies, they observed that overexpression of the protein inhibited proliferation of an ovarian cancer cell line (Ovca3), while introduction of an antibody that neutralized BMP-10 allowed proliferation to occur unimpeded.
Finally, they showed that BMP-10 overexpression impaired the wound-healing and invasive properties of Ovca3 cells, while knockdown of the protein’s expression promoted migration and invasion of a different ovarian carcinoma cell line (Skov3).
The investigators acknowledged that their study was limited by small sample sizes, and they noted that they did not investigate potential mechanisms for BMP-10’s effect on ovarian cells.
Nonetheless, they concluded that “BMP-10 should be considered as a promising prognostic marker and a crucial regulator for progression of ovarian cancer.”
The study was supported by the Nantong Health and Family Planning Commission. All authors declared having no conflicts of interest.
SOURCE: Jin Y et al. Pathol Res Pract. 2019 Oct 28. doi: 10.1016/j.prp.2018.10.025.
Key clinical point: Expression levels of BMP-10 significantly correlated with ovarian cancer features and patient prognosis.
Major finding: Patients whose tissues had low levels of BMP-10 expression had significantly shorter overall survival (P less than .01),
Study details: Analysis of BMP-10 expression in ovarian cancers, normal tissues, and ovarian cancer cell lines.
Disclosures: The study was supported by the Nantong Health and Family Planning Commission. All authors declared having no conflicts of interest.
Source: Jin Y et al. Pathol Res Pract. 2018 Oct 28. doi: 10.1016/j.prp.2018.10.025.